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Credentials

Education ?

Medical School
Ross University
Foreign school

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Associations
American Board of Internal Medicine

Affiliations ?

Dr. Smith is affiliated with 3 hospitals.

Hospital Affiliations

Score

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  • Alaska Regional Hospital
    2801 Debarr Rd, Anchorage, AK 99508
    •  
  • Providence Extended Care Center
    4900 Eagle St, Anchorage, AK 99503
  • Alaska Hospitalist Group, LLC
  • Publications & Research

    Dr. Smith has contributed to 420 publications.
    Title Alcohol Misuse and Abuse in Assisted Living.
    Date May 2012
    Journal Journal of the American Medical Directors Association
    Title Molecular Characterization of Vegetative Incompatibility Genes That Restrict Hypovirus Transmission in the Chestnut Blight Fungus Cryphonectria Parasitica.
    Date May 2012
    Journal Genetics
    Excerpt

    Genetic nonself recognition systems such as vegetative incompatibility operate in many filamentous fungi to regulate hyphal fusion between genetically dissimilar individuals and to restrict the spread of virulence-attenuating mycoviruses that have potential for biological control of pathogenic fungi. We report here the use of a comparative genomics approach to identify seven candidate polymorphic genes associated with four vegetative incompatibility (vic) loci of the chestnut blight fungus Cryphonectria parasitica. Disruption of candidate alleles in one of two strains that were heteroallelic at vic2, vic6, or vic7 resulted in enhanced virus transmission, but did not prevent barrage formation associated with mycelial incompatibility. Detailed characterization of the vic6 locus revealed the involvement of nonallelic interactions between two tightly linked genes in barrage formation, heterokaryon formation, and asymmetric, gene-specific influences on virus transmission. The combined results establish molecular identities of genes associated with four C. parasitica vic loci and provide insights into how these recognition factors interact to trigger incompatibility and restrict virus transmission.

    Title Correlates of Family Health History Discussions Between College Students and Physicians: Does Family Cancer History Make a Difference?
    Date April 2012
    Journal The Journal of Primary Prevention
    Excerpt

    Effective communication between young adults and their healthcare providers can contribute to early detection of risk for developing cancer and establishment of lifelong habits for engagement in healthcare and health promotion behaviors. Our objectives were to examine factors influencing family health history discussions between college students and physicians and factors associated with perceptions about who is responsible for initiating such discussions. Data from an internet-based study of 632 college students were analyzed. Approximately 60% of college student participants reported they had discussed their family health history with a physician. The perception that physicians are responsible for initiating family health history discussions was associated with being non-White and less than completely knowledgeable about cancer. Having a discussion with a physician was associated with being female, having a regular physician, perceiving genetics as a risk for developing cancer, and having a family member diagnosed with cancer. Understanding variation among college students' perceptions about their role in initiating health-history-related discussions and characteristics of those who have or have not discussed family health issues with physicians can inform healthcare practice to foster optimal healthcare interactions in early adulthood.

    Title Serial Changes in Plasma Total Cortisol, Plasma Free Cortisol, and Tissue Cortisol Activity in Patients with Septic Shock: an Observational Study.
    Date April 2012
    Journal Shock (augusta, Ga.)
    Excerpt

    Published data on adrenocortical function in septic shock have enrolled patients at various stages of critical illness and predominantly used plasma total cortisol, with minimal information on serial changes. Moreover, plasma free cortisol and tissue corticosteroid activity may not be strongly associated; however, few published data exist. The aim of this prospective observational study was to investigate serial changes in plasma total and free cortisol and tissue cortisol activity in septic shock. Twenty-nine adult patients admitted with septic shock to a tertiary-level intensive care unit were enrolled. A low-dose corticotropin test was performed on day 1. Plasma total and free cortisol, cortisone, transcortin, and urinary free cortisol and cortisone were analyzed on days 1 to 5, 7, and 10. Urinary and plasma cortisol-cortisone ratios (F:E ratio) were calculated as indices of 11-β hydroxysteroid dehydrogenase 2 and global 11-β hydroxysteroid dehydrogenase activity, respectively. Baseline total and free plasma cortisol values from 10 healthy control subjects were obtained for comparative analysis. Baseline plasma total and free cortisol levels were significantly higher than controls (457.8 ± 193 vs. 252 ± 66 nmol/L, P = 0.0002; and 50.83 ± 43.19 vs. 6.4 ± 3.2, P < 0.0001, respectively). Plasma free cortisol rose proportionately higher than total cortisol (124% ± 217.3% vs. 40% ± 33.2%, P = 0.007) following corticotropin. Baseline plasma and urinary F:E ratios were elevated over the reference ranges (13.13 ± 1.5, 1.69 ± 2.8) and were not correlated with plasma free cortisol values (r = 0.2, 0.3 respectively). Over the study period, total cortisol levels and plasma F:E ratios remained elevated, whereas plasma free cortisol levels and urinary F:E ratio declined. At baseline, plasma free cortisol levels were higher in patients who subsequently survived (23.7 ± 10.5 vs. 57.9 ± 45.8 nmol/L, P = 0.04). In septic shock, there is a differential response of plasma total and free cortisol over time and in response to corticotropin. Changes in plasma and urinary F:E ratios suggest tissue modulation of 11-β hydroxysteroid dehydrogenase activity. Total plasma cortisol measurements may not reflect the global adrenal response in septic shock.

    Title A Micropatterning and Image Processing Approach to Simplify Measurement of Cellular Traction Forces.
    Date March 2012
    Journal Acta Biomaterialia
    Excerpt

    Quantification of the traction forces that cells apply to their surroundings has been critical to the advancement of our understanding of cancer, development and basic cell biology. This field was made possible through the development of engineered cell culture systems that permit optical measurement of cell-mediated displacements and computational algorithms that allow conversion of these displacements into stresses and forces. Here, we present a novel advancement of traction force microscopy on polyacrylamide (PAA) gels that addresses limitations of existing technologies. Through an indirect patterning technique, we generated PAA gels with fluorescent 1 μm dot markers in a regularized array. This improves existing traction measurements since (i) multiple fields of view can be measured in one experiment without the need for cell removal; (ii) traction vectors are modeled as discrete point forces, and not as a continuous field, using an extremely simple computational algorithm that we have made available online; and (iii) the pattern transfer technique is amenable to any of the published techniques for producing patterns on glass. In the future, this technique will be used for measuring traction forces on complex patterns with multiple, spatially distinct ligands in systems for applying strain to the substrate, and in sandwich cultures that generate quasi-three-dimensional environments for cells.

    Title [18f]fluorothymidine Pet Imaging in the Diagnosis of Leptomeningeal Involvement with Diffuse Large B-cell Lymphoma.
    Date February 2012
    Journal Cancer Imaging : the Official Publication of the International Cancer Imaging Society
    Excerpt

    The diagnosis of leptomeningeal carcinomatosis remains difficult despite improvement in central nervous system (CNS) imaging and cytologic examination of the cerebral spinal fluid. False-negative results are common, providing obstacles in assessing both prophylactic and therapeutic efforts. As a result of increased survival of patients with a variety of systemic neoplasms it is likely that central nervous involvement will need to be addressed more often. This article presents a patient with a diffuse large B-cell lymphoma with polymorphic features. Imaging using 18F-labeled fluorodeoxythymidine (FLT) proved useful in demonstrating both parenchymal and leptomeningeal CNS involvement. The potential for FLT to identify proliferative tissue may make it uniquely suitable for detection of CNS malignant disease.

    Title Characterizing the Normal Developmental Trajectory of Expressive Language Lateralization Using Magnetoencephalography.
    Date January 2012
    Journal Journal of the International Neuropsychological Society : Jins
    Excerpt

    To characterize the developmental trajectory for expressive language representation and to test competing explanations for the relative neuroplasticity of language in childhood, we studied 28 healthy children and adolescents (aged 5-19 years) participating in a covert verb generation task in magnetoencephalography. Lateralization of neuromagnetic responses in the frontal lobe was quantified using a bootstrap statistical thresholding procedure for differential beamformer analyses. We observed a significant positive correlation between left hemisphere lateralization and age. Findings suggest that adult-typical left hemisphere lateralization emerges from an early bilateral language network, which may explain the pediatric advantage for interhemispheric plasticity of language.

    Title Contribution of Unfolding and Intermolecular Architecture to Fibronectin Fiber Extensibility.
    Date January 2012
    Journal Biophysical Journal
    Excerpt

    The extracellular matrix contains components with remarkable mechanical properties, including fibronectin (Fn) fibers with extensibilities of >700% strain. We utilized what we consider a novel technique to quantify the extent of molecular unfolding that contributes to Fn fiber extension, and we compared this behavior with stochastic models of Fn fibers with different molecular arrangements. In vitro unfolding as a function of strain was measured by fluorescently labeling cysteines in modules FnIII7 and III15 in artificial Fn fibers. A calibration technique we also consider novel made it possible to demonstrate that 44% of cysteines in these modules were exposed in Fn fibers strained to 421% extension, up from 8% exposure without strain. In silico unfolding was measured by applying a constant strain rate to a fiber represented by a network of wormlike chain springs, each representing an individual Fn molecule. Unfolding rates were calculated with a tension-dependent stochastic model applied to FnIII modules in each molecule. A comparison of these approaches revealed that only a molecular arrangement permitting unequal mechanical loading of Fn molecules recapitulates in vitro unfolding. These data have implications for Fn-dependent mechanotransduction and give insight into how the molecular architecture of natural materials permits such remarkable extensibility.

    Title Evaluation of the Effects of Hospital Visit Stress on Physiologic Parameters in the Cat.
    Date January 2012
    Journal Journal of Feline Medicine and Surgery
    Excerpt

    Physiologic parameters such as blood pressure, rectal temperature, heart rate, and respiratory rate are an important part of the medical assessment of a patient. However, these factors can potentially be affected by stress. The purpose of this study was to compare physiologic parameter data gathered from cats in the home environment with those gathered in a veterinary hospital. Thirty healthy cats were evaluated both at home and at Colorado State University's Veterinary Medical Center. Doppler systolic blood pressure, temperature, heart rate, and respiratory rate were recorded, and the differences between the values obtained in the home and veterinary clinic environments were evaluated using the Wilcoxon sign rank test. A significant difference was found in blood pressure, heart rate, and respiratory rate between the home and veterinary hospital environments. This information may help practitioners recognize that physiologic abnormalities can sometimes be due to transportation or environmental stress rather than medical illness.

    Title Oscillatory Vagal Maneuvers Produce Ventricular Entrainment in Patients with Atrial Fibrillation.
    Date January 2012
    Journal Clinical Autonomic Research : Official Journal of the Clinical Autonomic Research Society
    Excerpt

    Atrial fibrillation (AF) is the most common sustained dysrhythmia and appears to be an independent predictor of sudden cardiac death. The irregular ventricular rhythm contains both linear and non-linear patterns; however, it remains unclear whether vagally mediated effects are present within these patterns.

    Title One Declarative Memory System or Two? The Relationship Between Episodic and Semantic Memory in Children with Temporal Lobe Epilepsy.
    Date January 2012
    Journal Neuropsychology
    Excerpt

    This study explored verbal semantic and episodic memory in children with unilateral temporal lobe epilepsy to determine whether they had impairments in both or only 1 aspect of memory, and to examine relations between performance in the 2 domains.

    Title Eszopiclone Facilitation of the Antidepressant Efficacy of Fluoxetine Using a Social Defeat Stress Model.
    Date December 2011
    Journal Pharmacology, Biochemistry, and Behavior
    Excerpt

    This study analyzed the interaction of the sleep aid eszopiclone (ESZ) and antidepressant fluoxetine (FLX) on social defeat stress (SDS) in the mouse. Beta adrenoreceptors, brain-derived neurotrophic factor (BDNF) and cAMP response element binding protein (CREB) expression in the hippocampus and frontal cortex were also analyzed. Subjects were adult male 'intruder' C57/B6 mice that were exposed to a retired 'resident' male breeder ICR mouse in this animal's home cage for a 5 min period for each of 10 consecutive days, and the resident established physical dominance. The following day, all animals were assigned to one of four drug treatment groups, and treatment was given for up to 18 days: vehicle, ESZ only (3mg/kg), FLX (10mg/kg) only, or ESZ+FLX. A social interaction test was given on days 1, 5, 10, and 15 of drug treatment to assess SDS. Results showed that the ESZ+FLX group spent less time in avoidance zones during the interaction test at days 1 and 5, and more time in the interaction zone at day 5 compared to defeated mice given vehicle. All drug treatment groups spent more time in the interaction zone compared to defeated mice given vehicle on day 1 as well as day 10. SDS completely dissipated by the fourth interaction test according to both behavioral measures. Neurochemically, SDS did not produce changes in any marker analyzed. This study shows the combination of ESZ and FLX alleviated SDS, but a neurochemical correlate remains elusive.

    Title Single Cell 3-d Platform to Study Ligand Mobility in Cell-cell Contact.
    Date November 2011
    Journal Lab on a Chip
    Excerpt

    Lateral mobility and dimensionality have both been shown to influence cellular behavior, but have yet to be combined and applied in a single in vitro platform to address, e.g., cell adhesion in a setting mimicking the three-dimensional environment of neighboring cells in a reductionist way. To study the effect of the lateral mobility of cell adhesive ligands in three dimensions we present and characterize a platform, which enables patterning of single cells into microwells presenting a cell membrane mimetic interface pre-patterned to its walls. Soluble E-cadherin extracellular domains coupled through an optimized streptavidin-antibody linkage to lipids in a supported lipid bilayer (SPB) were presented on the microwell walls as either laterally mobile or immobile ligands. The fluidity was controlled through a small change in temperature by choosing phospholipids for the SPB with a lipid phase transition temperature around 30 °C. The platform thus enabled the investigation of cell adhesion to either laterally immobile or mobile E-cadherin ligands presented on the same cell membrane mimetic surface. Chinese hamster ovary (CHO) cells engineered to express E-cadherin that were cultured on the platform demonstrated that enhanced cadherin lateral mobility significantly decreased the formation of actin bundles and resulted in more diffuse actin organization, while constraining the cell shape to that of the microwell. This example highlights the potential to use in vitro cell culture platforms to mimic direct cell-cell interaction in a controlled environment that nevertheless captures the dynamic nature of the native cell environment.

    Title Invasive Breast Cancer.
    Date November 2011
    Journal Journal of the National Comprehensive Cancer Network : Jnccn
    Title Amphetamine Locomotor Sensitization and Conditioned Place Preference in Adolescent Male and Female Rats Neonatally Treated with Quinpirole.
    Date November 2011
    Journal Behavioural Pharmacology
    Excerpt

    Neonatal quinpirole treatment has been shown to produce an increase in dopamine D2-like receptor sensitivity that persists throughout the subject's lifetime. The objective was to analyze the effects of neonatal quinpirole treatment on effects of amphetamine in adolescent rats using locomotor sensitization and conditioned place preference procedures. Sprague-Dawley rats were treated with quinpirole (1 mg/kg) or saline from postnatal days (P)1 to P11 and raised to adolescence. For locomotor sensitization, subjects were given amphetamine (1 mg/kg) or saline every second day from P35 to P47 and were placed into a locomotor arena. In female rats, neonatal quinpirole treatment enhanced amphetamine locomotor sensitization compared with quinpirole-free controls sensitized to amphetamine. Male rats demonstrated sensitization to amphetamine, although this was muted compared with female rats, and were unaffected by neonatal quinpirole. For conditioned place preference, subjects were conditioned for 8 consecutive days (P32-39) with amphetamine (1 mg/kg) or saline and a drug-free preference test was conducted at P40. Rats treated with neonatal quinpirole enhanced time spent in the amphetamine-paired context compared with quinpirole-free controls conditioned with amphetamine, but only female controls conditioned with amphetamine spent more time in the drug-paired context compared with saline-treated controls. Increased D₂-like receptor sensitivity appears to have enhanced the behavioral effects of amphetamine, but these effects were more prevalent in adolescent female rats compared with male rats.

    Title Widespread Cortical Thinning in Children with Frontal Lobe Epilepsy.
    Date October 2011
    Journal Epilepsia
    Excerpt

    Spread of seizure activity outside the frontal lobe due to cortico-cortical connections can result in alteration in the cortex beyond the frontal lobe in children with intractable frontal lobe epilepsy (FLE). The aim of this study was to identify regions of reduced cortical thickness in children with intractable FLE.

    Title Sub-patterns of Language Network Reorganization in Pediatric Localization Related Epilepsy: a Multisite Study.
    Date August 2011
    Journal Human Brain Mapping
    Excerpt

    To study the neural networks reorganization in pediatric epilepsy, a consortium of imaging centers was established to collect functional imaging data. Common paradigms and similar acquisition parameters were used. We studied 122 children (64 control and 58 LRE patients) across five sites using EPI BOLD fMRI and an auditory description decision task. After normalization to the MNI atlas, activation maps generated by FSL were separated into three sub-groups using a distance method in the principal component analysis (PCA)-based decisional space. Three activation patterns were identified: (1) the typical distributed network expected for task in left inferior frontal gyrus (Broca's) and along left superior temporal gyrus (Wernicke's) (60 controls, 35 patients); (2) a variant left dominant pattern with greater activation in IFG, mesial left frontal lobe, and right cerebellum (three controls, 15 patients); and (3) activation in the right counterparts of the first pattern in Broca's area (one control, eight patients). Patients were over represented in Groups 2 and 3 (P < 0.0004). There were no scanner (P = 0.4) or site effects (P = 0.6). Our data-driven method for fMRI activation pattern separation is independent of a priori notions and bias inherent in region of interest and visual analyses. In addition to the anticipated atypical right dominant activation pattern, a sub-pattern was identified that involved intensity and extent differences of activation within the distributed left hemisphere language processing network. These findings suggest a different, perhaps less efficient, cognitive strategy for LRE group to perform the task.

    Title Quinazoline Sulfonamides As Dual Binders of the Proteins B-cell Lymphoma 2 and B-cell Lymphoma Extra Long with Potent Proapoptotic Cell-based Activity.
    Date June 2011
    Journal Journal of Medicinal Chemistry
    Excerpt

    ABT-737 and ABT-263 are potent inhibitors of the BH3 antiapoptotic proteins, Bcl-x(L) and Bcl-2. This class of putative anticancer agents invariantly contains an acylsulfonamide core. We have designed and synthesized a series of novel quinazoline-based inhibitors of Bcl-2 and Bcl-x(L) that contain a heterocyclic alternative to the acylsulfonamide. These compounds exhibit submicromolar, mechanism-based activity in human small-cell lung carcinoma cell lines in the presence of 10% human serum. This comprises the first successful demonstration of a quinazoline sulfonamide core serving as an effective benzoylsulfonamide bioisostere. Additionally, these novel quinazolines comprise only the second known class of Bcl-2 family protein inhibitors to induce mechanism-based cell death.

    Title Bayespeak--an R Package for Analysing Chip-seq Data.
    Date May 2011
    Journal Bioinformatics (oxford, England)
    Excerpt

    Identification of genomic regions of interest in ChIP-seq data, commonly referred to as peak-calling, aims to find the locations of transcription factor binding sites, modified histones or nucleosomes. The BayesPeak algorithm was developed to model the data structure using Bayesian statistical techniques and was shown to be a reliable method, but did not have a full-genome implementation.

    Title Disruption of Fungal Cell Wall by Antifungal Echinacea Extracts.
    Date March 2011
    Journal Medical Mycology : Official Publication of the International Society for Human and Animal Mycology
    Excerpt

    In addition to widespread use in reducing the symptoms of colds and flu, Echinacea is traditionally employed to treat fungal and bacterial infections. However, to date the mechanism of antimicrobial activity of Echinacea extracts remains unclear. We utilized a set of &#x223C;4,600 viable gene deletion mutants of Saccharomyces cerevisiae to identify mutations that increase sensitivity to Echinacea. Thus, a set of chemical-genetic profiles for 16 different Echinacea treatments was generated, from which a consensus set of 23 Echinacea-sensitive mutants was identified. Of the 23 mutants, only 16 have a reported function. Ten of these 16 are involved in cell wall integrity/structure suggesting that a target for Echinacea is the fungal cell wall. Follow-up analyses revealed an increase in sonication-associated cell death in the yeasts S. cerevisiae and Cryptococcus neoformans after Echinacea extract treatments. Furthermore, fluorescence microscopy showed that Echinacea-treated S. cerevisiae was significantly more prone to cell wall damage than non-treated cells. This study further demonstrates the potential of gene deletion arrays to understand natural product antifungal mode of action and provides compelling evidence that the fungal cell wall is a target of Echinacea extracts and may thus explain the utility of this phytomedicine in treating mycoses.

    Title Isolation of Streptomyces Species from Soil.
    Date February 2011
    Journal Current Protocols in Microbiology
    Excerpt

    This unit describes a general protocol for the isolation of Streptomyces species from soil and fresh water, using a procedure for the selective growth of Streptomyces species. Preparation of the necessary growth medium, recognition of the morphology of the bacteria, and safety considerations are also covered.

    Title The Positive Predictive Value of a Hyperkalemia Diagnosis in Automated Health Care Data.
    Date February 2011
    Journal Pharmacoepidemiology and Drug Safety
    Excerpt

    Our objectives were to determine performance of coded hyperkalemia diagnosis at identifying (1) clinically evident hyperkalemia and (2) serum potassium>6 mmol/L.

    Title Breast Cancer: Noninvasive and Special Situations.
    Date January 2011
    Journal Journal of the National Comprehensive Cancer Network : Jnccn
    Title Dimensionality Controls Cytoskeleton Assembly and Metabolism of Fibroblast Cells in Response to Rigidity and Shape.
    Date January 2011
    Journal Plos One
    Excerpt

    Various physical parameters, including substrate rigidity, size of adhesive islands and micro-and nano-topographies, have been shown to differentially regulate cell fate in two-dimensional (2-D) cell cultures. Cells anchored in a three-dimensional (3-D) microenvironment show significantly altered phenotypes, from altered cell adhesions, to cell migration and differentiation. Yet, no systematic analysis has been performed that studied how the integrated cellular responses to the physical characteristics of the environment are regulated by dimensionality (2-D versus 3-D).

    Title Older Women in a State-wide, Evidence-based Falls Prevention Program: Who Enrolls and What Benefits Are Obtained?
    Date January 2011
    Journal Women's Health Issues : Official Publication of the Jacobs Institute of Women's Health
    Excerpt

    Older women who are vulnerable to falls and their negative consequences have been shown, in controlled randomized clinical trials, to benefit from fall prevention programs. The purpose of this study was to identify personal characteristics of female participants enrolled in a falls prevention program, the effectiveness of the program for female participants, and whether personal characteristics indicate which women might benefit most from programs delivered in real-world settings.

    Title Patient-reported Outcome of Pediatric Epilepsy Surgery: Social Inclusion or Exclusion As Young Adults?
    Date December 2010
    Journal Epilepsia
    Excerpt

    The purpose of this study was to examine the social relationships and participation in educational, vocational, and community life in young adults who had undergone epilepsy surgery during childhood or adolescence.

    Title Remediating Office Environments of Spore-forming Bacteria.
    Date December 2010
    Journal Journal of Occupational and Environmental Hygiene
    Excerpt

    This study examines decontamination processes that were developed on an emergency basis to eliminate Bacillus anthracis spores from deliberately contaminated buildings. The recommended steps include a survey with sampling, the removal of sensitive items, and HEPA vacuuming of all readily available surfaces, followed by biocide treatment and subsequent analyses for viable cells. There are several analytical challenges posed by this approach. These include the ability to discriminate the added strain from naturally occurring resident microbes, determining detection limits for anthrax spores in settled dusts, and detecting viable but nonculturable spores. There are also logistical issues relating to the various skill sets required from investigation to reconstruction. In the present study, a model office was constructed, and a strain of Bacillus pumilus was isolated from the carpet and reintroduced to the office in excess. The abundance of the B. pumilus strain was monitored in settled dust using a strain-specific, quantitative polymerase chain reaction (QPCR)-based detection method following repeated HEPA vacuum cleanings. The QPCR method had a limit of detection corresponding to < or = 10(2) colony forming units per gram of settled dust. QPCR results were compared with measures of dust recoveries and fungal glucan and endotoxin levels in the dust samples. The largest fraction (ca. 81%) of added spores was recovered during the first HEPA cleaning. Subsequent cleanings resulted in incrementally lower recoveries, with removal of 93% of the initial inoculum by the third HEPA vacuuming. HEPA vacuuming prior to removal of items such as office contents and furnishings would result in much less resuspension of dust and limiting the extent of contamination. This approach also ensures that residual contaminants are as low as can be reasonably achieved.

    Title "just Because You've Got Lung Cancer Doesn't Mean I Will": Lung Cancer, Smoking, and Family Dynamics.
    Date November 2010
    Journal Journal of Family Nursing
    Excerpt

    Although individuals who are diagnosed with smoking-related disorders are offered smoking cessation programs, little attention has been directed toward reducing tobacco use among healthy relatives who smoke. The purpose of this article is to report smoking relatives' responses to a family member's diagnosis of lung disease, their constructions of smoking in this context, and their interaction patterns with the patient. Interviews with 11 family members where there was a diagnosis of lung cancer and 3 family members where there was another serious smoking-related diagnosis were analyzed. Family members used two strategies to support their continued smoking: distancing themselves from the diagnosis and taking the position that smoking cessation needed to be internally motivated by the "right reason" and initiated at the "right time" to anticipate success. The few participants who chose to quit, did so in support of their ill family member. The findings provide direction for intervening with family members who smoke.

    Title Both Calcitonin and Calcitonin Gene-related Peptides' Thresholds of Hypophagia Are Considerably Lower in Chicks Selected for High Rather Than Low Juvenile Body Weight.
    Date November 2010
    Journal Physiology & Behavior
    Excerpt

    Effects of intracerebroventricular (ICV) injection of calcitonin (CT) and calcitonin gene-related peptide (CGRP) on food and water intake were measured in two lines of White Plymouth Rock chickens from a common base population that have undergone long-term divergent selection for either low (LWS) or high (HWS) juvenile body weight. These lines contain anorexic and obese individuals and serve as models for hypo- and hyperphagia. For both ICV injection of CT and CGRP, line HWS responded to a lower dose with decreased food intake than did line LWS. Both peptides were also associated with reduced water intake in both lines. Although plasma glucose concentrations were inherently different between lines, neither CT nor CGRP affected these levels. Comprehensive behavior analyses were conducted and only the number of food pecks was differentially suppressed between lines after both CT and CGRP injection. Thus, the selection program may have caused alterations in the endogenous CT and CGRP systems that synergistically, with other neurotransmitter systems, contribute to the role of food intake on the differential body weights between these lines.

    Title Prdm16 Promotes Stem Cell Maintenance in Multiple Tissues, Partly by Regulating Oxidative Stress.
    Date November 2010
    Journal Nature Cell Biology
    Excerpt

    To better understand the mechanisms that regulate stem cell identity and function, we sought to identify genes that are preferentially expressed by stem cells and critical for their function in multiple tissues. Prdm16 is a transcription factor that regulates leukaemogenesis, palatogenesis and brown-fat development, but which was not known to be required for stem cell function. We demonstrate that Prdm16 is preferentially expressed by stem cells throughout the nervous and haematopoietic systems and is required for their maintenance. In the haematopoietic and nervous systems, Prdm16 deficiency led to changes in the levels of reactive oxygen species (ROS), depletion of stem cells, increased cell death and altered cell-cycle distribution. In neural stem/progenitor cells, Prdm16 binds to the Hgf promoter, and Hgf expression declined in the absence of Prdm16. Addition of recombinant HGF to Prdm16-deficient neural stem cells in cell culture reduced the depletion of these cells and partially rescued the increase in ROS levels. Administration of the anti-oxidant, N-acetyl-cysteine, to Prdm16-deficient mice partially rescued defects in neural stem/progenitor cell function and neural development. Prdm16 therefore promotes stem cell maintenance in multiple tissues, partly by modulating oxidative stress.

    Title Identification and Correction of Previously Unreported Spatial Phenomena Using Raw Illumina Beadarray Data.
    Date October 2010
    Journal Bmc Bioinformatics
    Excerpt

    A key stage for all microarray analyses is the extraction of feature-intensities from an image. If this step goes wrong, then subsequent preprocessing and processing stages will stand little chance of rectifying the matter. Illumina employ random construction of their BeadArrays, making feature-intensity extraction even more important for the Illumina platform than for other technologies. In this paper we show that using raw Illumina data it is possible to identify, control, and perhaps correct for a range of spatial-related phenomena that affect feature-intensity extraction.

    Title Longitudinal Brain Volumes in Children with Intractable Partial Seizures.
    Date October 2010
    Journal Pediatric Neurology
    Excerpt

    Cross sectional studies in children with epilepsy have reported variable changes in brain volume. The study hypothesis was that seizures result in injury to the developing brain, which is manifested as a reduction in brain volume. The aim was to evaluate the gray and white matter volumes longitudinally in children with partial epilepsy. All patients had two magnetic resonance scans, 1-7 years apart. The total, cerebral, and hemispheric gray and white matter volumes of 20 children with intractable partial epilepsy were measured. The correlation between change in volume and age at epilepsy onset and duration of epilepsy were assessed. There were no significant differences in total, cerebral, or hemispheric gray and white matter volumes with time. Up to six patients exhibited greater than 10% volume loss in total, cerebral, or hemispheric gray or white matter. There were no significant correlations between change in volume and age or duration of epilepsy. The findings suggest that volume loss does not occur in the shorter-term monitoring of children with partial seizures. It is possible that volume loss could become evident with long-term monitoring of children with epilepsy. Alternatively, brain volume may be an insensitive measure of alteration in brain structure secondary to epilepsy, and that other imaging techniques, such as diffusion tensor imaging, may be more sensitive for detecting microstructural changes induced by recurrent seizures.

    Title The Contribution of Neuropsychology to Diagnostic Assessment in Epilepsy.
    Date October 2010
    Journal Epilepsy & Behavior : E&b
    Excerpt

    Neuropsychology plays a vital role in the treatment of epilepsy, providing information on the effects of seizures on higher cortical functions through the measurement of behavioral abilities and disabilities. This is accomplished through the design, administration and interpretation of neuropsychological tests, including those used in functional neuroimaging or cortical mapping and in intracarotid anesthetic procedures. The objective of this paper is to define and summarize in some detail the role and methods of neuropsychologists in specialized epilepsy centers. Included are information and recommendations regarding basic ingredients of a thorough neuropsychological assessment in the epilepsy setting, as well as suggestions for an abbreviated alternative exam when needed, with emphasis on functions associated with specific brain regions. The paper is intended for novice and experienced neuropsychologists to enable them to develop or evaluate their current practices, and also for other clinicians, who seek a better understanding of the methodology underlying the neuropsychological input to their work.

    Title Vagal Modulation of Heart Rate Variability During Atrial Fibrillation in Pigs.
    Date October 2010
    Journal Experimental Biology and Medicine (maywood, N.j.)
    Excerpt

    Atrial fibrillation (AF) is the most common sustained cardiac dysrhythmia and is associated with an increased risk for sudden cardiac death. The ventricular rhythm is irregular and displays both non-linear and linear patterns; however, it has not been determined whether vagally derived patterns are manifest within the irregular rhythm. Moreover, indices of increased vagal control are associated with reduced risk of sudden cardiac death. In this study, we sought to determine whether the ventricular rhythm pattern during AF is, in part, modulated by vagal activity. Vagal oscillations were forced at 0.15 Hz by neck suction in 12 pigs with sustained AF with and without glycopyrrolate (0.15 microg/kg, intravenously) vagal blockade. Vagal activity was evaluated using time- and frequency-domain heart rate variability measures. The standard deviation of RR intervals (SDRRI) was significantly increased during vagal activation compared with baseline (P = 0.006). Moreover, SDRRI correlated significantly with spectral power at 0.15 Hz during baseline (r = 0.90, P < .001) and vagal activation (r = 0.86, P < 0.05). Glycopyrrolate blocked the increase in SDRRI (P < 0.001) and blunted spectral power at 0.15 Hz (P < 0.05). These results indicate that: (1) power spectral analysis may be used to assess parasympathetic regulation during AF, and (2) vagal oscillations produce an entrainment of the ventricular rhythm during AF in pigs.

    Title A Qualitative Case Study Examining Intervention Tailoring for Minorities.
    Date October 2010
    Journal American Journal of Health Behavior
    Excerpt

    To explore issues of intervention tailoring for ethnic minorities based on information and experiences shared by researchers affiliated with the Health Maintenance Consortium (HMC).

    Title Neuropsychological Decline/improvement in Opsoclonus Myoclonus Ataxia.
    Date October 2010
    Journal Neurocase
    Excerpt

    Opsoclonus myoclonus ataxia (OMA) is a rare neurological disorder (incidence = approximately 1/5 million) primarily associated with involuntary conjugate saccadic eye movements, involuntary muscle jerks, cerebellar ataxia, and neuropsychological impairments. Unfortunately, there is limited published data regarding the nature and course of neuropsychological impairments following OMA diagnosis and treatment. This study presents neuropsychological data obtained at 1, 4, and 18 months post-diagnosis of a 52-year-old male with OMA. The patient initially demonstrated significant global neurocognitive, psychomotor, and psychological difficulties with substantial improvement over time. Treatment included medication management, physical rehabilitation, and psychological intervention.

    Title Urinary Excretion of Ecgonine and Five Other Cocaine Metabolites Following Controlled Oral, Intravenous, Intranasal, and Smoked Administration of Cocaine.
    Date September 2010
    Journal Journal of Analytical Toxicology
    Excerpt

    Urinary excretion of ecgonine (EC) was compared to that of cocaine, benzoylecgonine, ecgonine methyl ester and minor metabolites, meta-hydroxybenzoylecgonine, para-hydroxybenzoylecgonine, and norbenzoylecgonine, following controlled administration of oral, intravenous, intranasal, and smoked cocaine. Urine EC concentrations peaked later than all other analytes and had longer detection times than the other minor metabolites. With a 50 ng/mL cutoff concentration and following low doses of 10 to 45 mg cocaine by multiple routes, detection times extended up to 98 h. Maximum concentrations (Cmax) were 6-14 mole % of those for benzoylecgonine, Cmax increased with dose, time to maximum concentration (Tmax) was independent of dose, and route of administration did not have a significant impact on Cmax or Tmax for metabolites. EC is an analyte to consider for identifying cocaine use due to its stability in urine and long detection times.

    Title Evaluation of the Aldose Reductase Inhibitor Fidarestat on Ischemia-reperfusion Injury in Rat Retina.
    Date September 2010
    Journal International Journal of Molecular Medicine
    Excerpt

    This study evaluated the effects of retinal ischemia-reperfusion (IR) injury and pre-treatment with the potent and specific aldose reductase inhibitor fidarestat on apoptosis, aldose reductase and sorbitol dehydrogenase expression, sorbitol pathway intermediate concentrations, and oxidative-nitrosative stress. Female Wistar rats were pre-treated with either vehicle (N-methyl-D-glucamine) or fidarestat, 32 mg kg(-1) d(-1) for both, in the right jugular vein, for 3 consecutive days. A group of vehicle- and fidarestat-treated rats were subjected to 45-min retinal ischemia followed by 24-h reperfusion. Ischemia was induced 30 min after the last vehicle or fidarestat administration. Retinal IR resulted in a remarkable increase in retinal cell death. The number of TUNEL-positive nuclei increased 48-fold in the IR group compared with non-ischemic controls (p<0.01), and this increase was partially prevented by fidarestat. AR expression (Western blot analysis) increased by 19% in the IR group (p<0.05), and this increase was prevented by fidarestat. Sorbitol dehydrogenase and nitrated protein expressions were similar among all experimental groups. Retinal sorbitol concentrations tended to increase in the IR group but the difference with non-ischemic controls did not achieve statistical significance (p=0.08). Retinal fructose concentrations were 2.2-fold greater in the IR group than in the non-ischemic controls (p<0.05). Fidarestat pre-treatment of rats subjected to IR reduced retinal sorbitol concentration to the levels in non-ischemic controls. Retinal fructose concentrations were reduced by 41% in fidarestat-pre-treated IR group vs. untreated ischemic controls (p=0.0517), but remained 30% higher than in the non-ischemic control group. In conclusion, IR injury to rat retina is associated with a dramatic increase in cell death, elevated AR expression and sorbitol pathway intermediate accumulation. These changes were prevented or alleviated by the AR inhibitor fidarestat. The results identify AR as an important therapeutic target for diseases involving IR injury, and provide the rationale for development of fidarestat and other AR inhibitors.

    Title Rb Stabilizes Xpc and Promotes Cellular Ner.
    Date August 2010
    Journal Anticancer Research
    Excerpt

    It has long been thought that the G(1)/S cell cycle checkpoint allows time for DNA repair by delaying S-phase entry. The p53 tumor suppressor pathway regulates the G(1)/S checkpoint by regulating the cyclin-dependent kinase inhibitor p21(Waf1/Cip1), but p53 also regulates the nucleotide excision DNA repair protein XPC. Here, using p53-null cell lines we show that additional mechanisms stabilize XPC protein and promote nucleotide excision repair (NER) in concert with the G(1)/S checkpoint. At least one mechanism to stabilize and destabilize XPC involves ubiquitin-mediated degradation of XPC, as the ubiquitin ligase inhibitor MG-132 blocked XPC degradation. The retinoblastoma protein RB, in its unphosphorylated form actually stabilized XPC and promoted NER as measured by host cell reactivation experiments. The data suggest that XPC protein and XPC-mediated NER are tightly linked to the G(1)/S checkpoint, even in cells lacking functional p53.

    Title Medical Inappropriateness Review: Appropriately Performed by a Medical Committee.
    Date June 2010
    Journal Health Matrix (cleveland, Ohio : 1991)
    Title High-frequency Ventricular Ectopy Can Increase Sympathetic Neural Activity in Humans.
    Date June 2010
    Journal Heart Rhythm : the Official Journal of the Heart Rhythm Society
    Excerpt

    Sudden cardiac death is usually caused by ventricular arrhythmias and in many cases, is preceded by frequent ventricular ectopy. It is known that ectopic beats cause transient increases in sympathetic nerve activity (SNA).

    Title Self-perceptions of Social Function 2 Years After Pediatric Epilepsy Surgery.
    Date June 2010
    Journal Epilepsy & Behavior : E&b
    Excerpt

    The present qualitative study explored how participants perceive their quality of life within the social domain 2 years following epilepsy surgery. Semistructured, open-ended interviews were conducted with 27 participants (11-21 years old), 2 years following epilepsy surgery. Thirteen of the 27 participants were seizure free. Data were transcribed and coded inductively to allow for the identification of salient themes. Many of the seizure-free participants reported greater independence following surgery. However, most participants, irrespective of seizure status, continued to report some problems with peer relations and isolation. These findings suggest that self-perceived improvements in social function among seizure-free participants may require longer than 2 years to develop.

    Title Toward Competency-based Certification of Clinical Ethics Consultants: a Four-step Process.
    Date June 2010
    Journal The Journal of Clinical Ethics
    Excerpt

    While consensus exists among many practitioners of ethics consultation about the need for and identification of core competencies and standards, there has been virtually no attempt to determine how these competencies and standards are best taught and assessed. We believe that clinical ethics consultation has reached a state of sufficient maturity that expert practitioners can evaluate those who are new to the field. We will outline several steps that can facilitate the creation of a certification process for clinical ethics consultants, assuring the competency and quality of consultation for the patients, families, and healthcare professionals who utilize ECSs.

    Title Bilobed Flap for Axillary Reconstruction.
    Date June 2010
    Journal Plastic and Reconstructive Surgery
    Title The Threshold of Amylin-induced Anorexia is Lower in Chicks Selected for Low Compared to High Juvenile Body Weight.
    Date May 2010
    Journal Behavioural Brain Research
    Excerpt

    Chicks that have undergone long-term selection for low body weight responded to intracerebroventricular amylin injection with reduced food intake at a dose considerably lower and with a greater magnitude suppression than those selected for high body weight. Behaviors unrelated to ingestion were not affected. These data support the thesis of correlated amylin system responses to selection for low or high body weight, with possible implications to other species.

    Title Weight-based Heparin Protocol Using Antifactor Xa Monitoring.
    Date May 2010
    Journal American Journal of Health-system Pharmacy : Ajhp : Official Journal of the American Society of Health-system Pharmacists
    Excerpt

    The performance of a weight-based dosing protocol for unfractionated heparin (UFH) infusions using antifactor Xa monitoring was evaluated.

    Title Neuropsychology in Epilepsy: Children Are Not Small Adults.
    Date May 2010
    Journal Epilepsia
    Title Unattended Emotional Faces Elicit Early Lateralized Amygdala-frontal and Fusiform Activations.
    Date May 2010
    Journal Neuroimage
    Excerpt

    Human adaptive behaviour to potential threats involves specialized brain responses allowing rapid and reflexive processing of the sensory input and a more directed processing for later evaluation of the nature of the threat. The amygdalae are known to play a key role in emotion processing. It is suggested that the amygdalae process threat-related information through a fast subcortical route and slower cortical feedback. Evidence from human data supporting this hypothesis is lacking. The present study investigated event-related neural responses during processing of facial emotions in the unattended hemifield using magnetoencephalography (MEG) and found activations of the amygdala and anterior cingulate cortex to fear as early as 100 ms. The right amygdala exhibited temporally dissociated activations to input from different visual fields, suggesting early subcortical versus later cortical processing of fear. We also observed asymmetrical fusiform activity related to lateralized feed-forward processing of the faces in the visual-ventral stream. Results demonstrate fast, automatic, and parallel processing of unattended emotional faces, providing important insights into the specific and dissociated neural pathways in emotion and face perception.

    Title Selenomethionine or Methylseleninic Acid Inhibits Mutagenesis of a Reporter Gene in Mouse Bone Marrow.
    Date May 2010
    Journal Anticancer Research
    Excerpt

    Recent laboratory and clinical studies have utilized selenium in the form of pure seleno-L-methionine (SeMet) in combination with DNA-damaging cancer chemotherapy drugs. In mice, the selenium protected bone marrow and other tissues from dose-limiting toxicity. In fact, because of the protection from dose-limiting toxicity, a doubling or even tripling of the maximum tolerated dose (MTD) was enabled. Previously we showed that SeMet protects bone marrow by a DNA repair mechanism that requires the XPC DNA repair protein. XPC is rate-limiting and is required for repair of cisplatin or carboplatin adducts. Herein we used a mouse strain that carries a lambda phage reporter gene in the genome that serves as a mutagenesis target. SeMet protects from carboplatin mutagenesis in mouse bone marrow. Methylseleninic acid (MSA), a metabolite of SeMet, also protected against mutagenesis in mouse bone marrow.

    Title Microfabricated Three-dimensional Environments for Single Cell Studies.
    Date April 2010
    Journal Biointerphases
    Title Identification and Application of Aflp-derived Genetic Markers for Quantitative Pcr-based Tracking of Bacillus and Paenibacillus Spp. Released in Soil.
    Date April 2010
    Journal Canadian Journal of Microbiology
    Excerpt

    In this study, we show that noncoding sequences from amplified fragment length polymorphisms (AFLPs) can provide robust and sensitive genetic markers suitable for PCR-based discrimination of closely related strains of Bacillus and Paenibacillus, and quantitative PCR (qPCR)-based tracking of the strains in complex natural systems like soil. Quantitative PCR was accurate in the approximately 1 x 10(9) to approximately 1 x 10(4) colony forming units (CFU)/g soil range. The detection limit was improved to approximately 1 x 10(2) CFU/g when amplicons were analyzed by gel electrophoresis. Studies with laboratory-contained intact soil-core microcosms indicated that environmental persistence trends vary among different strains. For example, Bacillus circulans ATCC 9500, Bacillus amyloliquefaciens DSL 13563-0, Bacillus licheniformis ATCC 12713, Paenibacillus polymyxa NRRL B-4317, and 3 Bacillus subtilisstrains (ATCC 6051A, ATCC 55405, and NRRL B-941) died down to below the 1 x 10(2) CFU/g detection limit by days 28-105. In contrast, over a 105-day period, B. licheniformis ATCC 55406, Bacillus megaterium NRRL B-14308, and P. polymyxa strains ATCC 55407 and DSL 13540-4 died down but persisted at levels just above the detection limit, whereas Bacillus thuringiensis ATCC 13367 experienced a less than 10-fold decrease in cell numbers.

    Title Central Institutional Review Board-facilitated Review Metrics Omit Critical Components.
    Date March 2010
    Journal Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
    Title Crosslinking of Cell-derived 3d Scaffolds Up-regulates the Stretching and Unfolding of New Extracellular Matrix Assembled by Reseeded Cells.
    Date March 2010
    Journal Integrative Biology : Quantitative Biosciences from Nano to Macro
    Excerpt

    Elevated levels of tissue crosslinking are associated with numerous diseases (cancer stroma, organ fibrosis), and also eliminate the otherwise remarkable clinical successes of tissue-derived scaffolds, instead eliciting a foreign body reaction. Nevertheless, it is not well understood how the initial physical and biochemical properties of cellular microenvironments, stem cell niches, or of 3D tissue scaffolds guide the assembly and remodeling of new extracellular matrix (ECM) that is ultimately sensed by cells. Here, we incorporated FRET-based mechanical strain sensors, either into cell-derived ECM scaffolds or into the fibronectin (Fn) matrix assembled by reseeded fibroblasts, and demonstrated the following. Cell-generated tensile forces change the conformation of Fn in both 3D scaffolds and new matrix over time. The time course by which new matrix fibers are stretched by reseeded cells is accelerated by scaffold crosslinking. Importantly, stretching Fn fibers increases their elastic modulus (rigidity) and alters their biochemical display. Regulated by Fn fiber unfolding, more soluble Fn binds to the native than to the crosslinked scaffolds. Additionally, matrix assembly of fibroblasts is decreased by scaffold crosslinking. Taken together, scaffold crosslinking has a multifactorial impact on the microenvironment that reseeded cells assemble and respond to, with far-reaching implications for tissue engineering and disease physiology.

    Title Nccn Clinical Practice Guidelines in Oncology: Breast Cancer Screening and Diagnosis.
    Date March 2010
    Journal Journal of the National Comprehensive Cancer Network : Jnccn
    Title Attention and Material-specific Memory in Children with Lateralized Epilepsy.
    Date February 2010
    Journal Neuropsychologia
    Excerpt

    Epilepsy is frequently associated with attention and memory problems. In adults, lateralization of seizure focus impacts the type of memory affected (left-sided lesions primarily impact verbal memory, while right-sided lesions primarily impact visual memory), but the relationship between seizure focus and the nature of the memory impairment is less clear in children. The current study examines the correlation between parent-reported attention problems and material-specific memory (verbal or visual-spatial) in 65 children (ages 6-16) with medically intractable lateralized epilepsy. There were no significant differences in attention and memory between those with left-lateralized epilepsy (n=25) and those with right-lateralized epilepsy (n=40). However, in the left-lateralized group attention problems were significantly negatively correlated only with delayed visual memory (r=-.450, p<.05), while the right-lateralized group demonstrated the opposite pattern (attention problems significantly negatively correlated with delayed verbal memory; r=-.331, p<.05). These findings suggest that lateralization of seizure focus may in fact impact children's memory in a material-specific manner, while problems with attention may impact memory more globally. Therefore, interventions designed to improve attention in children with epilepsy may have utility in improving certain aspects of memory, but further suggest that in children with lateralized epilepsy, material-specific memory deficits may not resolve with such interventions.

    Title Factor Structure and Psychometrics of the Adolescent Health Risk Behavior Survey Instrument.
    Date February 2010
    Journal American Journal of Health Behavior
    Excerpt

    To explore the factor structure and psychometric properties of data collected with the Adolescent Health Risk Behavior Survey (AHRBS) instrument.

    Title The Restraint Spiral: Emergent Themes in the Perceptions of the Physical Restraint of Juveniles.
    Date February 2010
    Journal Child Welfare
    Excerpt

    This qualitative investigation explores the experiences of both children who were physically restrained in a juvenile facility and that of the adult professionals who restrained them. Among the major themes identified were the rationalizations of safety and noncompliance for restraint use by the adults. Children associated fear, anger, and retraumatization with the experience of being restrained. Both the children who were restrained and the adults who restrained them identified lingering emotional and behavioral postrestraint effects. Restraint incidents were found to follow a predictable 10-layered behavioral spiral. Implications for practice and further research are explored.

    Title Stretched Extracellular Matrix Proteins Turn Fouling and Are Functionally Rescued by the Chaperones Albumin and Casein.
    Date February 2010
    Journal Nano Letters
    Excerpt

    While evidence is mounting that cells exploit protein unfolding for mechanochemical signal conversion (mechanotransduction), what mechanisms are in place to deal with the unwanted consequences of exposing hydrophobic residues upon force-induced protein unfolding? Here, we show that mechanical chaperones exist that can transiently bind to hydrophobic residues that are freshly exposed by mechanical force. The stretch-upregulated binding of albumin or casein to fibronectin fibers is reversible and does not inhibit fiber contraction once the tension is released.

    Title The Aldose Reductase Inhibitor Fidarestat Suppresses Ischemia-reperfusion-induced Inflammatory Response in Rat Retina.
    Date February 2010
    Journal Pharmacology
    Excerpt

    Recent studies suggest that increased aldose reductase (AR) activity plays an important role in ischemia-reperfusion injury in the retina. The mechanisms are not completely understood, but may be linked to inflammation. In the present study, we investigated whether the AR inhibitor fidarestat suppressed the retinal inflammatory response induced by ischemia-reperfusion in a rat model. The inflammatory response was manifested by increased gene expression of tumor necrosis factor-alpha and intercellular adhesion molecule-1 (ICAM-1) as well as elevated protein levels of soluble ICAM-1. This response was partially suppressed by the AR inhibitor fidarestat. The findings may reveal beneficial effects of AR inhibition on retinal inflammation associated with ischemia-reperfusion and are in agreement with recent developments in pharmacological research suggesting that pathological conditions other than diabetes may benefit from AR inhibitors.

    Title Nuclear Factor of Activated T Cells Regulates Osteopontin Expression in Arterial Smooth Muscle in Response to Diabetes-induced Hyperglycemia.
    Date February 2010
    Journal Arteriosclerosis, Thrombosis, and Vascular Biology
    Excerpt

    Hyperglycemia is a recognized risk factor for cardiovascular disease in diabetes. Recently, we reported that high glucose activates the Ca(2+)/calcineurin-dependent transcription factor nuclear factor of activated T cells (NFAT) in arteries ex vivo. Here, we sought to determine whether hyperglycemia activates NFAT in vivo and whether this leads to vascular complications.

    Title Morphology Hypothesized to Influence Aerosol Particle Deliquescence.
    Date January 2010
    Journal Physical Chemistry Chemical Physics : Pccp
    Excerpt

    The deliquescence phase transitions of populations of internally mixed particles of solid ammonium bisulfate and letovicite, having overall extents of neutralization between 0.60 and 0.75 and diameters between 15 and 60 nm, were studied using a hygroscopic tandem nano-differential mobility analyzer (HTnDMA). Populations having particles sufficiently small or large, as well as particles sufficiently acidic or neutralized, behaved as expected, with prompt transitions of all particles at a single relative humidity. Populations having particles of simultaneously intermediate diameter and acidity, however, behaved differently and unexpectedly. Subpopulations of individual particles did exhibit prompt deliquescence but did so over a broad range of relative humidity (RH) for the entire population. For example, some particles of 20-nm diameter and an extent of neutralization of 0.65 deliquesced promptly at as low as 38% RH, whereas some particles in the same experiment deliquesced promptly at as high as 59% RH. Across this 21% RH span, prompt deliquescence of particle subpopulations was observed, which resulted in the continuous deliquescence of the population as the aerosol progressed from dominantly solid to dominantly aqueous particles for increasing RH. Morphological differences among particles in different subpopulations that drive variable rates of water uptake, such as coatings of letovicite of varying thickness, porosity, and hence water permeability on cores of ammonium bisulfate, are hypothesized to explain these observations.

    Title A Possible Solution, but Not the Last Word.
    Date January 2010
    Journal The Hastings Center Report
    Title The Relations Between White Matter and Declarative Memory in Older Children and Adolescents.
    Date January 2010
    Journal Brain Research
    Excerpt

    Neural communication between the temporal and frontal cortex underlies mature declarative memory skills. The integrity of white matter pathways connecting these regions is likely critical in supporting this communication. Little is known about the relationship between white matter and declarative memory in older children and adolescents, an age period when advanced function in this domain is established. We acquired diffusion tensor imaging (DTI) data for 22 participants (9-15 years). Multiple DTI indices were calculated for the uncinate fasciculus - the major white matter tract connecting temporal and prefrontal regions. Indices were also calculated for compartments of lobar and posterior fossa white matter. Measures of visual-perceptual and auditory-verbal memory were administered. Correlation analyses were used to examine the relations between age, DTI indices, and memory. Voxel-wise analyses were also conducted. Age-related increases in FA were evident for frontal, parietal, and temporal hemispheric white matter. Proficiency in auditory-verbal memory was related to white matter integrity in the left uncinate fasciculus as well as parietal and cerebellar white matter. Proficiency in recall of a complex design was related to integrity within parietal and temporal regions. Our findings support the role of white matter in facilitating connectivity between cerebral regions important for declarative memory.

    Title Gamma(2)-melanocyte Stimulating Hormone Decreases Food Intake in Chicks.
    Date January 2010
    Journal Neuroscience Letters
    Excerpt

    The role of gamma melanocyte stimulating hormone (gamma-MSH) in appetite regulation is controversial in mammals and to our knowledge unreported within the avian class. Thus, the present study was designed to determine the effects of intracerebroventricularly (i.c.v.) administered gamma2-MSH on food intake using Cobb-500 chicks as models. In Experiment 1, chicks that received i.c.v. gamma2-MSH decreased their food intake throughout the 180 min observation period and plasma glucose concentration was not affected. Water intake was also decreased in i.c.v. gamma2-MSH-treated chicks, but only from 30 to 90 min post-injection. In Experiment 2, food pecking efficiency was decreased in i.c.v. gamma2-MSH-treated chicks and the amount of time spent sitting was increased. Other behaviors were not significantly affected by i.c.v. gamma2-MSH including distance traveled, the number of jumps, escape attempts, defecations, food pecks, exploratory pecks, and the amount of time spent standing, preening, perching, or in deep rest. These data suggest that gamma2-MSH is associated with anorexigenic effects and because of gamma-MSH's selectivity, implicates the melanocortin 3 receptor in appetite regulation.

    Title Mistrust and Self-isolation: Barriers to Social Support for Older Adult Methadone Clients.
    Date January 2010
    Journal Journal of Gerontological Social Work
    Excerpt

    The purpose of this study is to explore barriers to the use, maintenance, and expansion of social supports in older adult methadone clients.

    Title Inverse Mapping the Neuronal Substrates of Face Categorizations.
    Date December 2009
    Journal Cerebral Cortex (new York, N.y. : 1991)
    Excerpt

    Face perception is a complex process involving a network of brain structures, dynamically processing information to enable judgments about a face to be made (e.g., familiarity, identity, and expression). Here we introduce an analysis methodology that makes it possible to directly study this information processing in the brain from spatially and temporally resolved magnetoencephalographic signals. We apply our methodology to the study of 2 face categorization tasks, gender and expressiveness, and track the processing of 3 key visual features that underlie behavioral performance, over time and throughout the cortex. We find information processing correlates beginning from 90 ms following stimulus onset, where features are processed in isolation in occipital extrastriate regions. Over time, processing of successively more features and feature combinations takes place in occipitotemporal regions, with maximal information processing of visual information coinciding with the well-established face-selective M170 component at 170 ms. Later still, around 250-400 ms, cortical activity responds significantly more to task-specific features and their complex combinations. These results indicate a complex process of visual information processing during face perception with face parts processed in isolation at very early stages, and task-specific processing of combinations of features taking place within 300 ms. Crucially, our approach specifically establishes which information in the visual stimulus the brain signal is responding to and how this varies with time, cortical location, and task demands to establish a more precise tracking of information processing mechanisms in the cortex during face perception.

    Title Fibronectin Forms the Most Extensible Biological Fibers Displaying Switchable Force-exposed Cryptic Binding Sites.
    Date November 2009
    Journal Proceedings of the National Academy of Sciences of the United States of America
    Excerpt

    Rather than maximizing toughness, as needed for silk and muscle titin fibers to withstand external impact, the much softer extracellular matrix fibers made from fibronectin (Fn) can be stretched by cell generated forces and display extraordinary extensibility. We show that Fn fibers can be extended more than 8-fold (>700% strain) before 50% of the fibers break. The Young's modulus of single fibers, given by the highly nonlinear slope of the stress-strain curve, changes orders of magnitude, up to MPa. Although many other materials plastically deform before they rupture, evidence is provided that the reversible breakage of force-bearing backbone hydrogen bonds enables the large strain. When tension is released, the nano-sized Fn domains first contract in the crowded environment of fibers within seconds into random coil conformations (molten globule states), before the force-bearing hydrogen bond networks that stabilize the domain's secondary structures are reestablished within minutes (double exponential). The exposure of cryptic binding sites on Fn type III modules increases steeply upon stretching. Thus fiber extension steadily up-regulates fiber rigidity and cryptic epitope exposure, both of which are known to differentially alter cell behavior. Finally, since stress-strain relationships cannot directly be measured in native extracellular matrix (ECM), the stress-strain curves were correlated with stretch-induced alterations of intramolecular fluorescence resonance energy transfer (FRET) obtained from trace amounts of Fn probes (mechanical strain sensors) that can be incorporated into native ECM. Physiological implications of the extraordinary extensibility of Fn fibers and contraction kinetics are discussed.

    Title Eight-month Follow-up of Physical Activity and Central Adiposity: Results from an Internet-delivered Randomized Control Trial Intervention.
    Date November 2009
    Journal Journal of Physical Activity & Health
    Excerpt

    Less than half of U.S. adults engage in the recommended amount of physical activity (PA). Internet-delivered PA programs increase short-term PA but long-term adherence is largely equivocal.

    Title "i Can't Remember": Memory Deficits in Children with Epilepsy.
    Date November 2009
    Journal The Canadian Journal of Neurological Sciences. Le Journal Canadien Des Sciences Neurologiques
    Excerpt

    Compared with the literature on epilepsy in adults, there is relatively little written about memory in children. This paucity of findings exists despite the fact that childhood is a critical time for laying down memories that contribute to adult attainments. This paper reviews the evidence for memory deficits in children with intractable epilepsy. The nature of these deficits and their impact on the child's daily function are described. The evidence of neural, seizure-related and treatment factors that contribute to these impairments is presented.

    Title Neurosurgical Management of Intractable Rolandic Epilepsy in Children: Role of Resection in Eloquent Cortex. Clinical Article.
    Date October 2009
    Journal Journal of Neurosurgery. Pediatrics
    Excerpt

    The authors undertook this study to review their experience with cortical resections in the rolandic region in children with intractable epilepsy.

    Title Using Computed Tomography to Assist with Diagnosis of Avascular Necrosis Complicating Chronic Scaphoid Nonunion.
    Date October 2009
    Journal The Journal of Hand Surgery
    Excerpt

    The primary aim of our study was to investigate use of long axis computed tomography (CT) in predicting avascular necrosis of the proximal pole of the scaphoid and subsequent fracture nonunion after internal fixation. In addition, we describe a new technique of measuring the position of a scaphoid fracture and provide data on its reproducibility.

    Title Tumor Necrosis Factor-alpha Does Not Mediate Diabetes-induced Vascular Inflammation in Mice.
    Date September 2009
    Journal Arteriosclerosis, Thrombosis, and Vascular Biology
    Excerpt

    Vascular inflammation is a key feature of both micro- and macrovascular complications in diabetes. Several lines of evidence have implicated the cytokine tumor necrosis factor (TNF) alpha as an important mediator of inflammation in diabetes. In the present study we evaluated the role of TNF alpha in streptozotocin (STZ)-induced diabetes on vascular inflammation in C57BL/6 wild-type and apoE-/- mice.

    Title Cognitive Simulators for Medical Education and Training.
    Date September 2009
    Journal Journal of Biomedical Informatics
    Excerpt

    Simulators for honing procedural skills (such as surgical skills and central venous catheter placement) have proven to be valuable tools for medical educators and students. While such simulations represent an effective paradigm in surgical education, there is an opportunity to add a layer of cognitive exercises to these basic simulations that can facilitate robust skill learning in residents. This paper describes a controlled methodology, inspired by neuropsychological assessment tasks and embodied cognition, to develop cognitive simulators for laparoscopic surgery. These simulators provide psychomotor skill training and offer the additional challenge of accomplishing cognitive tasks in realistic environments. A generic framework for design, development and evaluation of such simulators is described. The presented framework is generalizable and can be applied to different task domains. It is independent of the types of sensors, simulation environment and feedback mechanisms that the simulators use. A proof of concept of the framework is provided through developing a simulator that includes cognitive variations to a basic psychomotor task. The results of two pilot studies are presented that show the validity of the methodology in providing an effective evaluation and learning environments for surgeons.

    Title The Xpc Gene Markedly Affects Cell Survival in Mouse Bone Marrow.
    Date September 2009
    Journal Mutagenesis
    Excerpt

    The XPC protein (encoded by the xeroderma pigmentosum Xpc gene) is a key DNA damage recognition factor that is required for global genomic nucleotide excision repair (G-NER). In contrast to transcription-coupled nucleotide excision repair (TC-NER), XPC and G-NER have been reported to contribute only modestly to cell survival after DNA damage. Previous studies were conducted using fibroblasts of human or mouse origin. Since the advent of Xpc-/- mice, no study has focused on the bone marrow of these mice. We used carboplatin to induce DNA damage in Xpc-/- and strain-matched wild-type mice. Using several independent methods, Xpc-/- bone marrow was approximately 10-fold more sensitive to carboplatin than the wild type. Importantly, 12/20 Xpc-/- mice died while 0/20 wild-type mice died. We conclude that G-NER, and XPC specifically, can contribute substantially to cell survival. The data are important in the context of cancer chemotherapy, where Xpc gene status and G-NER may be determinants of response to DNA-damaging agents including carboplatin. Additionally, altered cell cycles and altered DNA damage signalling may contribute to the cell survival end point.

    Title The Anorectic Effect of Neuropeptide Af is Associated with Satiety-related Hypothalamic Nuclei.
    Date August 2009
    Journal Journal of Neuroendocrinology
    Excerpt

    Neuropeptide AF (NPAF), a member of the RFamide family, is encoded by the same gene as neuropeptide FF (NPFF), which causes short-term anorexia. However, reports on the role of NPAF on appetite-related process are lacking. Thus, i.c.v. injections of 4.0, 8.0 and 16.0 nmol NPAF were administered to chicks to observe its effect on food and water intake. Chicks treated with 8.0 and 16.0 nmol i.c.v. NPAF decreased both their food and water intake. Additionally, all doses of NPAF injected caused a similar reduction in whole blood glucose concentration 180 min after injection. In a second experiment, chicks that received i.c.v. NPAF had an increased number of c-Fos immunoreactive cells in the dorsomedial, paraventricular (magnocellular and parvicellular parts) and ventromedial nuclei. The arcuate nucleus and lateral hypothalamic area were not affected. In a third experiment, NPAF-treated chicks exhibited fewer feeding pecks and spent less time perching, whereas they spent an increased time in deep rest. Other behaviours, including exploratory pecking, escape attempts, defecations, distance moved, and time spent standing, sitting and preening, were not affected by NPAF injection. We conclude that NPAF causes anorectic effects that are associated with the hypothalamus.

    Title Pathology Type Does Not Predict Language Lateralization in Children with Medically Intractable Epilepsy.
    Date August 2009
    Journal Epilepsia
    Excerpt

    We examined potential differences in the effects of pathology type on language lateralization in pediatric epilepsy.

    Title Hyperspectral Remote Detection of Niche Partitioning Among Canopy Trees Driven by Blowdown Gap Disturbances in the Central Amazon.
    Date August 2009
    Journal Oecologia
    Excerpt

    Advanced recruitment and neutral processes play important roles in determining tree species composition in tropical forest canopy gaps, with few gaps experiencing clear secondary successional processes. However, most studies are limited to the relatively limited spatial scales provided by forest inventory plots, and investigations over the entire range of gap size are needed to better understand how ecological processes vary with tree mortality events. This study employed a landscape approach to test the hypothesis that tree species composition and forest structural attributes differ between large blowdown gaps and relatively undisturbed primary forest. Spectral mixture analysis on hyperspectral satellite imagery was employed to direct field sampling to widely distributed sites, and blowdown plots were compared with undisturbed primary forest plots. Tree species composition and forest structural attributes differed markedly between gap and non-gap sites, providing evidence of niche partitioning in response to disturbance across the region. Large gaps were dominated by classic Neotropical pioneer genera such as Cecropia and Vismia, and average tree size was significantly smaller. Mean wood density of trees recovering in large gaps (0.55 g cm(-3)) was significantly lower than in primary forest plots (0.71 g cm(-3)), a difference similar to that found when comparing less dynamic (i.e., tree recruitment, growth, and mortality) Central Amazon forests with more dynamic Western Amazon forests. Based on results, we hypothesize that the importance of neutral processes weaken, and niche processes strengthen, in determining community assembly along a gradient in gap size and tree mortality intensity. Over evolutionary time scales, pervasive dispersal among colonizers could result in the loss of tree diversity in the pioneer guild through competitive exclusion. Results also underscore the importance of considering disturbance processes across the landscape when addressing forest carbon balance.

    Title Display of Peptides on the Surface of Tobacco Mosaic Virus Particles.
    Date July 2009
    Journal Current Topics in Microbiology and Immunology
    Excerpt

    In this review, we focus on the potential that tobacco mosaic virus (TMV) has as a carrier for immunogenic epitopes, and the factors that must be considered in order to bring products based on this platform to the market. Large Scale Biology Corporation developed facile and scaleable methods for manufacture of candidate peptide display vaccines based on TMV. We describe how rational design of peptide vaccines can improve the manufacturability of particular TMV products. We also discuss downstream processing and purification of the vaccine products, with particular attention to the metrics that a product must attain in order to meet criteria for regulatory approval as injectable biologics.

    Title Generation and Analysis of Transcriptomic Resources for a Model System on the Rise: the Sea Anemone Aiptasia Pallida and Its Dinoflagellate Endosymbiont.
    Date July 2009
    Journal Bmc Genomics
    Excerpt

    The most diverse marine ecosystems, coral reefs, depend upon a functional symbiosis between cnidarian hosts and unicellular dinoflagellate algae. The molecular mechanisms underlying the establishment, maintenance, and breakdown of the symbiotic partnership are, however, not well understood. Efforts to dissect these questions have been slow, as corals are notoriously difficult to work with. In order to expedite this field of research, we generated and analyzed a collection of expressed sequence tags (ESTs) from the sea anemone Aiptasia pallida and its dinoflagellate symbiont (Symbiodinium sp.), a system that is gaining popularity as a model to study cellular, molecular, and genomic questions related to cnidarian-dinoflagellate symbioses.

    Title Continued Family Smoking After Lung Cancer Diagnosis: the Patient's Perspective.
    Date July 2009
    Journal Oncology Nursing Forum
    Excerpt

    To explore the influence of lung cancer diagnosis on interpersonal dynamics in families in which one or more members continue to smoke following diagnosis.

    Title Transmission of Facial Expressions of Emotion Co-evolved with Their Efficient Decoding in the Brain: Behavioral and Brain Evidence.
    Date July 2009
    Journal Plos One
    Excerpt

    Competent social organisms will read the social signals of their peers. In primates, the face has evolved to transmit the organism's internal emotional state. Adaptive action suggests that the brain of the receiver has co-evolved to efficiently decode expression signals. Here, we review and integrate the evidence for this hypothesis. With a computational approach, we co-examined facial expressions as signals for data transmission and the brain as receiver and decoder of these signals. First, we show in a model observer that facial expressions form a lowly correlated signal set. Second, using time-resolved EEG data, we show how the brain uses spatial frequency information impinging on the retina to decorrelate expression categories. Between 140 to 200 ms following stimulus onset, independently in the left and right hemispheres, an information processing mechanism starts locally with encoding the eye, irrespective of expression, followed by a zooming out to processing the entire face, followed by a zooming back in to diagnostic features (e.g. the opened eyes in "fear", the mouth in "happy"). A model categorizer demonstrates that at 200 ms, the left and right brain have represented enough information to predict behavioral categorization performance.

    Title Identifying New Cannabis Use with Urine Creatinine-normalized Thccooh Concentrations and Time Intervals Between Specimen Collections.
    Date July 2009
    Journal Journal of Analytical Toxicology
    Excerpt

    A previously recommended method for detecting new cannabis use with creatinine-normalized 11-nor-9-carboxy-Delta(9)-tetrahydrocannabinol (THCCOOH) urine concentrations in periodically collected specimens for treatment, workplace and judicial drug testing applications is refined by considering the time interval between urine collections. All urine specimens were collected from six less-than-daily cannabis users who smoked placebo, 1.75%, and 3.55% THC cigarettes in randomized order, each separated by one week. Ratios (n = 24,322) were calculated by dividing each creatinine-normalized THCCOOH concentration (U2) by that of a previously collected specimen (U1). Maximum, 95% limit, and median U2/U1 ratios with 15 and 6 ng THCCOOH/mL cutoff concentrations, with and without new use between specimens, were calculated for each 24-h interval after smoking up to 168 h and are included in tables. These ratios decreased with increasing interval between collections providing improved decision values for determining new cannabis use. For example, with a 15 ng THCCOOH/mL cutoff concentration and no new use between specimens, the maximum, 95% limit, and median U2/U1 ratios were 3.05, 1.59, and 0.686, respectively, when the collection interval was <or = 24 h and 0.215, 0.135, and 0.085 when it was 96-119.9 h.

    Title Advance Care Planning: Beyond the Living Will.
    Date June 2009
    Journal Cleveland Clinic Journal of Medicine
    Excerpt

    For a variety of reasons, the most commonly used advance directive documents (eg, the living will) may not be very useful in many situations that older adults encounter. The durable power of attorney for health care is a more versatile document. We advocate focusing less on "signing away" certain interventions and more on clarifying the goals of care in the ambulatory setting.

    Title Optimization Strategies for Electrospun Silk Fibroin Tissue Engineering Scaffolds.
    Date June 2009
    Journal Biomaterials
    Excerpt

    As a contribution to the functionality of scaffolds in tissue engineering, here we report on advanced scaffold design through introduction and evaluation of topographical, mechanical and chemical cues. For scaffolding, we used silk fibroin (SF), a well-established biomaterial. Biomimetic alignment of fibers was achieved as a function of the rotational speed of the cylindrical target during electrospinning of a SF solution blended with polyethylene oxide. Seeding fibrous SF scaffolds with human mesenchymal stem cells (hMSCs) demonstrated that fiber alignment could guide hMSC morphology and orientation demonstrating the impact of scaffold topography on the engineering of oriented tissues. Beyond currently established methodologies to measure bulk properties, we assessed the mechanical properties of the fibers by conducting extension at breakage experiments on the level of single fibers. Chemical modification of the scaffolds was tested using donor/acceptor fluorophore labeled fibronectin. Fluorescence resonance energy transfer imaging allowed to assess the conformation of fibronectin when adsorbed on the SF scaffolds, and demonstrated an intermediate extension level of its subunits. Biological assays based on hMSCs showed enhanced cellular adhesion and spreading as a result of fibronectin adsorbed on the scaffolds. Our studies demonstrate the versatility of SF as a biomaterial to engineer modified fibrous scaffolds and underscore the use of biofunctionally relevant analytical assays to optimize fibrous biomaterial scaffolds.

    Title Wide Variation in Content of Inpatient Do-not-resuscitate Order Forms Used at National Cancer Institute-designated Cancer Centers in the United States.
    Date May 2009
    Journal Supportive Care in Cancer : Official Journal of the Multinational Association of Supportive Care in Cancer
    Excerpt

    Determining resuscitation status (RS) for inpatients with advanced cancer is emotionally charged and often conflictual. Available data suggest that clinicians have inconsistent practices when establishing and documenting do-not-resuscitate (DNR) orders. Lack of standardization may contribute to ineffective and unclear discussions regarding RS. To inform revisions of DNR order forms used at one comprehensive cancer center, we surveyed National Cancer Institute-designated cancer centers (NCICCs) to determine if a standardized approach to documenting inpatient DNR orders exists.

    Title Determination of Sulfadimethoxine and 4n-acetylsulfadimethoxine in Bovine Plasma, Urine, Oral Fluid, and Kidney and Liver Biopsy Samples Obtained Surgically from Standing Animals by Lc/ms/ms.
    Date April 2009
    Journal Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences
    Excerpt

    A quantitative method was developed and validated to measure the concentration of sulfadimethoxine (SDM) and its major metabolite, (4)N-acetylsulfadimethoxine (AcSDM), in bovine tissues and body fluids. Liquid chromatography/tandem mass spectrometry (LC/MS/MS) gave quantitative results for these two analytes in extracts from bovine plasma, urine, oral fluid, kidney, and liver, using SDM-d(4) as internal standard (I.S.). The lower limit of quantitation (LLOQ) for both analytes in these matrices was validated at 2, 100, and 5 ng/mL in plasma, urine, and oral fluid respectively, and 10 ng/g in both kidney (cortex) and liver. The overall accuracy (average of 4 levels) is, for plasma, 104% (SDM) and 95% (AcSDM), with standard deviation of 9% (SDM) and 15% (AcSDM); for urine, 100% (SDM) and 106% (AcSDM), with standard deviation of 5% (SDM) and 6% (AcSDM); for oral fluid, 103% (SDM) and 103% (AcSDM), with standard deviation of 4% (SDM) and 4% (AcSDM); for kidney, 101% (SDM) and 111% (AcSDM), with standard deviation of 7% (SDM) and 6% (AcSDM); and for liver, 99% (SDM) and 115% (AcSDM), with standard deviation of 11% (SDM) and 9% (AcSDM). C18 SPE cartridges were used to clean-up these matrices, except for urine which was diluted directly with buffer before analysis by LC/MS/MS.

    Title Broadband Criticality of Human Brain Network Synchronization.
    Date April 2009
    Journal Plos Computational Biology
    Excerpt

    Self-organized criticality is an attractive model for human brain dynamics, but there has been little direct evidence for its existence in large-scale systems measured by neuroimaging. In general, critical systems are associated with fractal or power law scaling, long-range correlations in space and time, and rapid reconfiguration in response to external inputs. Here, we consider two measures of phase synchronization: the phase-lock interval, or duration of coupling between a pair of (neurophysiological) processes, and the lability of global synchronization of a (brain functional) network. Using computational simulations of two mechanistically distinct systems displaying complex dynamics, the Ising model and the Kuramoto model, we show that both synchronization metrics have power law probability distributions specifically when these systems are in a critical state. We then demonstrate power law scaling of both pairwise and global synchronization metrics in functional MRI and magnetoencephalographic data recorded from normal volunteers under resting conditions. These results strongly suggest that human brain functional systems exist in an endogenous state of dynamical criticality, characterized by a greater than random probability of both prolonged periods of phase-locking and occurrence of large rapid changes in the state of global synchronization, analogous to the neuronal "avalanches" previously described in cellular systems. Moreover, evidence for critical dynamics was identified consistently in neurophysiological systems operating at frequency intervals ranging from 0.05-0.11 to 62.5-125 Hz, confirming that criticality is a property of human brain functional network organization at all frequency intervals in the brain's physiological bandwidth.

    Title Sex Differences in Episodic Memory Among Children with Intractable Epilepsy.
    Date April 2009
    Journal Epilepsy & Behavior : E&b
    Excerpt

    This study investigated whether children with epilepsy exhibit sex differences in episodic memory. Fifty-one children and adolescents (26 boys and 25 girls) with intractable epilepsy were administered two verbal-auditory tasks (learning and recall of a word list and story recall) and two visual tasks (design recall and face recognition). Girls exhibited an advantage on the delayed recall of stories and on the learning phase of the word list task. No significant differences were observed on the delayed recall of words or the visual tasks. These results identify a particular risk for cognitive impairment in boys that could have an important impact on their academic performance.

    Title Information Processing Algorithms in the Brain.
    Date April 2009
    Journal Trends in Cognitive Sciences
    Excerpt

    If the brain is a machine that processes information, then its cognitive activity can be interpreted as a set of information processing states linking stimulus to response (i.e. as a mechanism or an algorithm). The cornerstone of this research agenda is the existence of a method to translate the measurable states of brain activity into the information processing states of a cognitive theory. Here, we contend that reverse correlation methods can provide this translation and we frame the transitions between information processing states in the context of automata theory. We illustrate, using examples from visual cognition, how this novel framework can be applied to understand the information processing algorithms of the brain in cognitive neuroscience.

    Title Protostadienol Biosynthesis and Metabolism in the Pathogenic Fungus Aspergillus Fumigatus.
    Date April 2009
    Journal Organic Letters
    Excerpt

    Details of the fungal biosynthetic pathway to helvolic acid and other fusidane antibiotics remain obscure. During product characterization of oxidosqualene cyclases in Aspergillus fumigatus, we found the long-sought cyclase that makes (17Z)-protosta-17(20),24-dien-3beta-ol, the precursor of helvolic acid. We then identified a gene cluster encoding the pathway to helvolic acid, which is controlled by a transcription regulator (LaeA) associated with fungal virulence. Evidence regarding the evolutionary origin and taxonomic distribution of fusidane biosynthesis is also presented.

    Title Case Study. Chaplains and Confidentiality. Commentary.
    Date March 2009
    Journal The Hastings Center Report
    Title Grunting for Worms: Seismic Vibrations Cause Diplocardia Earthworms to Emerge from the Soil.
    Date March 2009
    Journal Biology Letters
    Excerpt

    Harvesting earthworms by a practice called 'worm grunting' is a widespread and profitable business in the southeastern USA. Although a variety of techniques are used, most involve rhythmically scraping a wooden stake driven into the ground, with a flat metal object. A common assumption is that vibrations cause the worms to surface, but this phenomenon has not been studied experimentally. We demonstrate that Diplocardia earthworms emerge from the soil within minutes following the onset of grunting. Broadband low frequency (below 500 Hz) pulsed vibrations were present in the soil throughout the area where worms were harvested, and the number of worms emerging decreased as the seismic signal decayed over distance. The findings are discussed in relation to two hypotheses: that worms are escaping vibrations caused by digging foragers and that worms are surfacing in response to vibrations caused by falling rain.

    Title Breast Cancer. Clinical Practice Guidelines in Oncology.
    Date March 2009
    Journal Journal of the National Comprehensive Cancer Network : Jnccn
    Title Effect of Short-term Pretrial Practice on Surgical Proficiency in Simulated Environments: a Randomized Trial of the "preoperative Warm-up" Effect.
    Date March 2009
    Journal Journal of the American College of Surgeons
    Excerpt

    Surgery is a skill-driven discipline. While other high-stake professions with comparable cognitive and psychomotor skill requirements often use warm-up exercises for achieving better proficiency, the effects of such practice have not been investigated sufficiently in surgical tasks.

    Title Chaplaincy and Clinical Ethics: a Common Set of Questions.
    Date March 2009
    Journal The Hastings Center Report
    Title Hiv-associated Nephropathy in Caucasians: Case Report and Review of Literature.
    Date March 2009
    Journal International Journal of Std & Aids
    Excerpt

    HIV-associated nephropathy (HIVAN) is almost exclusively seen in African-Americans (AA) and is rare in Caucasians. The mechanisms responsible for the predilection of HIVAN in AA are not well understood. In transgenic mouse studies, genetic background plays a vital role in the development of the HIVAN phenotype. Larger studies in humans have been initiated to study genetic polymorphisms responsible for HIVAN. As our case illustrates, HIVAN should be considered in Caucasian patients with HIV infection complicated by nephrotic syndrome and renal failure.

    Title Canopy Nitrogen, Carbon Assimilation, and Albedo in Temperate and Boreal Forests: Functional Relations and Potential Climate Feedbacks.
    Date January 2009
    Journal Proceedings of the National Academy of Sciences of the United States of America
    Excerpt

    The availability of nitrogen represents a key constraint on carbon cycling in terrestrial ecosystems, and it is largely in this capacity that the role of N in the Earth's climate system has been considered. Despite this, few studies have included continuous variation in plant N status as a driver of broad-scale carbon cycle analyses. This is partly because of uncertainties in how leaf-level physiological relationships scale to whole ecosystems and because methods for regional to continental detection of plant N concentrations have yet to be developed. Here, we show that ecosystem CO(2) uptake capacity in temperate and boreal forests scales directly with whole-canopy N concentrations, mirroring a leaf-level trend that has been observed for woody plants worldwide. We further show that both CO(2) uptake capacity and canopy N concentration are strongly and positively correlated with shortwave surface albedo. These results suggest that N plays an additional, and overlooked, role in the climate system via its influence on vegetation reflectivity and shortwave surface energy exchange. We also demonstrate that much of the spatial variation in canopy N can be detected by using broad-band satellite sensors, offering a means through which these findings can be applied toward improved application of coupled carbon cycle-climate models.

    Title Differential Feed Intake Responses to Central Corticotrophin Releasing Factor in Lines of Chickens Divergently Selected for Low or High Body Weight.
    Date January 2009
    Journal Comparative Biochemistry and Physiology. Part A, Molecular & Integrative Physiology
    Excerpt

    Effects of intracerebroventricular (ICV) injection of corticotrophin releasing factor (CRF) on feed intake were evaluated in two lines of White Plymouth Rock chickens that have been selected from a common base population for high (HWS) or low (LWS) juvenile body weight. Both lines responded with reduced feed intake after ICV CRF; however, the threshold of response was lower in line LWS than HWS. Additionally, the effects of two receptor antagonists, astressin and alpha-helical CRF (9-41; alpha-CRF), and the effect of CRF fragment 6-33, (which displaces CRF from its binding protein), were evaluated in these lines. Although all three antagonists increased feed intake in line LWS but not line HWS, they attenuated the appetite-reducing effects of CRF only in line HWS. Peripheral plasma corticosterone concentrations after an acute stressor were higher in line LWS than in line HWS. These data support the thesis of correlated responses in the CRF system to selection for high or low juvenile body weight. These differences may contribute to differential feed intake, and hence altered body weights.

    Title The Acute Effect of Atrioventricular Pacing on Sympathetic Nerve Activity in Patients with Normal and Depressed Left Ventricular Function.
    Date October 2008
    Journal American Journal of Physiology. Heart and Circulatory Physiology
    Excerpt

    Although modest elevations in pacing rate improve cardiac output and induce reflex sympathoinhibition, the threshold rate above which hemodynamic perturbations induce reflex sympathoexcitation remains unknown. Systolic blood pressure (SBP), diastolic blood pressure (DBP), and mean arterial pressures (MAP) and sympathetic nerve activity (SNA) were measured during normal sinus rhythm (NSR) and atrioventricular (AV) sequential pacing in 25 patients. Pacing was performed at 100, 120, and 140 beats/min with an AV interval of 100 ms. Patients were divided into two groups based on normal or abnormal left ventricular ejection fraction (LVEF): group 1 (n = 11; mean LVEF, 55%) and group 2 (n = 14; mean LVEF, 31%). In group 1, relative to NSR, SBP decreased an average of 2%, 3%, and 8% at 100, 120, and 140 beats/min (P < 0.001), respectively. DBP and MAP increased 9%, 15%, and 15% (P = 0.001) and 3%, 6%, and 5% [P = not significant (NS)], respectively. In group 2, SBP reductions were even greater, with an average decrease of 4%, 8%, and 16% (P < 0.001). Whereas DBP increased 9%, 9%, and 8% at 100, 120, and 140 beats/min (P = NS), MAP increased 3% and 2% at 100 and 120 beats/min but decreased 3% at 140 beats/min (P = 0.001). SNA recordings were obtained in 11 patients (6 in group 1 and 5 in group 2). In group 1, SNA decreased during all rates, with a mean 21% reduction. In group 2, however, SNA decreased at 100 and 120 beats/min (49% and 38%) but increased 24% at 140 beats/min. Patients with depressed LVEF exhibited altered hemodynamic and sympathetic responses to rapid sequential pacing. The implications of these findings in device programming and arrhythmia rate control await future studies.

    Title Assay to Mechanically Tune and Optically Probe Fibrillar Fibronectin Conformations from Fully Relaxed to Breakage.
    Date October 2008
    Journal Matrix Biology : Journal of the International Society for Matrix Biology
    Excerpt

    In response to growing needs for quantitative biochemical and cellular assays that address whether the extracellular matrix (ECM) acts as a mechanochemical signal converter to co-regulate cellular mechanotransduction processes, a new assay is presented where plasma fibronectin fibers are manually deposited onto elastic sheets, while force-induced changes in protein conformation are monitored by fluorescence resonance energy transfer (FRET). Fully relaxed assay fibers can be stretched at least 5-6 fold, which involves Fn domain unfolding, before the fibers break. In native fibroblast ECM, this full range of stretch-regulated conformations coexists in every field of view confirming that the assay fibers are physiologically relevant model systems. Since alterations of protein function will directly correlate with their extension in response to force, the FRET vs. strain curves presented herein enable the mapping of fibronectin strain distributions in 2D and 3D cell cultures with high spatial resolution. Finally, cryptic sites for fibronectin's N-terminal 70-kD fragment were found to be exposed at relatively low strain, demonstrating the assay's potential to analyze stretch-regulated protein-protein interactions.

    Title Internet-delivered Behavior Change Program Increases Physical Activity and Improves Cardiometabolic Disease Risk Factors in Sedentary Adults: Results of a Randomized Controlled Trial.
    Date September 2008
    Journal Preventive Medicine
    Excerpt

    OBJECTIVES: To determine whether the Active Living Every Day (ALED-I) internet-delivered theory-based physical activity (PA) behavior change program increases PA and improves cardiometabolic disease risk factors (CDRF) in sedentary overweight adults. METHODS: The study was a randomized control trial that took place in southern Wyoming and northern Colorado from 2005-2007. Thirty-two men and women (21-65 years) were randomized to a 16-week ALED-I intervention (n=14; age=41.4+/-3.7 years; BMI=32.3+/-1.3 kg/m(2)) or a delayed intent-to-treat control condition (n=18; age=49.4+/-1.7 years; BMI=30.6+/-0.8 kg/m(2)). At baseline and post-intervention, PA by pedometer and CDRFs were measured. RESULTS: Both groups had similar baseline PA levels. ALED-I increased PA by an average of 1384 steps/day (p=0.03) compared to 816 steps/day (p=0.14) for the control group. Waist circumference (100.6+/-2.4 vs. 96.6+/-2.7 cm) and Coronary Risk Ratio (5.1+/-0.3 vs. 4.7+/-0.3) decreased in the ALED-I group and did not change in the control group (99.2+/-2.2 vs.99.8+/-2.1 cm) and (3.7+/-0.1 vs. 3.7+/-0.1), respectively. CONCLUSIONS: The internet-delivered ALED program increased PA and improved some CDRFs in sedentary overweight/obese adults. To our knowledge, this is the first efficacy trial of the internet-delivered ALED program. Further studies are warranted due to the reach and cost-effectiveness of internet-delivered PA programs.

    Title Astrocytic Inclusions in Epilepsy: Expanding the Spectrum of Filaminopathies.
    Date September 2008
    Journal Journal of Neuropathology and Experimental Neurology
    Excerpt

    We report the finding of unique astrocytic inclusions in a series of pediatric epilepsy patients, all of whom presented with seizures in their first year of life and had mild-to-moderate developmental delay. All eventually underwent surgical treatment for refractory epilepsy and, on pathological examination, were found to have distinctive, eosinophilic, globular cytoplasmic inclusions confined to cortical astrocytes. These inclusions were almost exclusively juxtanuclear, highly refractile, spared distal subpial, or perivascular astrocytic processes and were strongly and exclusively immunopositive for filamin A, an actin binding protein involved in neuronal migration. Identical inclusions have been identified and characterized in cases of Aicardi syndrome, a rare neurodevelopmental disease. The presence of the same inclusions in the cortex of epilepsy patients, some of whom had concomitant brain anomalies related to migrational problems, prompted us to consider that these patients may lie within a spectrum of disease involving dysfunction of filamin or filamin-interacting proteins. The term "filaminopathy" is tentatively proposed as a distinct pathological entity for this condition in which clinical manifestations range from epilepsy in mildly neurologically impaired patients to severe mental and physical handicap in the Aicardi syndrome. Future studies will be necessary to unravel the exact nature of the filamin A protein or gene aberrations in these patients.

    Title Concentration Distribution of the Marijuana Metabolite Delta9-tetrahydrocannabinol-9-carboxylic Acid and the Cocaine Metabolite Benzoylecgonine in the Department of Defense Urine Drug-testing Program.
    Date September 2008
    Journal Journal of Analytical Toxicology
    Excerpt

    Urine drug testing has been employed for punitive purposes by the Department of Defense since December 1981 (Memorandum 62884, Deputy Secretary of Defense Frank C. Carlucci). Federal Workplace Drug Testing Programs were initiated in response to Executive Order 12564 issued on September 15, 1986, that required Drug-Free Federal Workplaces be established. In their respective programs, a positive urine drug test may be referred to a military court martial or to an administrative board. To address safety and insurance requirements, the testing of civilians has expanded beyond Federal Programs to include pre-employment and post-accident urine drug testing. During adjudication, an Expert Toxicologist may be asked to opine what can be discerned from the concentration of drug or drug metabolite found in the urine. Little can be opined with certainty from a positive urine drug test as to the amount of drug ingested, when the drug was ingested, and in most instances, whether the individual felt the effects of the drug, or was under the influence of the drug found in the urine. What may be useful to both the Expert and to the Trier-of-Facts is the frequency that a particular urine drug concentration is encountered in positive drug tests. The finding that 50% of all positive marijuana and cocaine urine metabolite concentrations in the military testing program over the three-year period of October 1, 2004 through September 30, 2007, are below a median value of 65 and 968 ng/mL, respectively, provide reference points. A median drug concentration combined with the percentile or frequency that a particular urine drug concentration occurs may provide evaluative information for a determination of the facts and the outcome of judicial or administrative proceedings. This may be especially useful to jurors when the concentration of marijuana or cocaine metabolite is perceptibly low. The information would also be applicable to medical review officers, medical examiners, drug treatment professionals, probation officers, and program analysts coordinating drug policy decisions.

    Title Assessing Severity of Epilepsy in Children: Preliminary Evidence of Validity and Reliability of a Single-item Scale.
    Date September 2008
    Journal Epilepsy & Behavior : E&b
    Excerpt

    The development and initial validity and reliability testing of a single-item, 7-point global rating scale designed for neurologists to assess the overall severity of epilepsy in children, the Global Assessment of Severity of Epilepsy (GASE) Scale, is described. The GASE Scale was quick and easy to use. Median epilepsy severity in the development sample was 3 (moderately severe), with a range from 1 ("not severe at all") in 36 patients (26.9%) to 7 ("extremely severe") in 7 patients (5.2%). Preliminary evidence of construct validity was found in support for our a priori predictions of associations between GASE scores and neurologists' ratings of seven individual clinical aspects of epilepsy and in a cumulative R(2) for the GASE score of 81% using ratings of the clinical aspects of epilepsy. Weighted kappa was 0.85 (95% CI: 0.79, 0.90) for inter-rater reliability and 0.90 (95% CI: 0.82, 0.98) and 0.95 (95% CI: 0.91, 0.98) for test-retest reliability for each of two raters. These promising initial results support continuation of the multistage process of testing the validity and reliability of the GASE Scale within various clinical contexts.

    Title Differential Appetite-related Responses to Central Neuropeptide S in Lines of Chickens Divergently Selected for Low or High Body Weight.
    Date September 2008
    Journal Journal of Neuroendocrinology
    Excerpt

    The anorexigenic 20 amino acid neuropeptide S (NPS) has not been studied in an animal model of hypo- or hyperphagia. The present study aimed to elucidate whether central NPS appetite-related effects are different in lines of chickens that had undergone long-term divergent selection for low (LWS) or high (HWS) body weight and that were hypo- and hyperphagic, respectively. It took a longer time for food intake to be reduced in LWS than HWS chicks administered the lowest dose of NPS tested (0.14 nmol) and, at the highest dose tested (0.56 nmol), they had a greater reduction in food intake than did HWS chicks. HWS chicks responded with a similar magnitude of food intake reduction that was independent of NPS dose. Although water intake was reduced concurrently with food intake after central NPS in both lines, blood glucose concentrations were not affected. Hypothalamic signalling was different between the lines. Although both lines respond to central NPS with decreased c-Fos immunoreactivity in the lateral hypothalamus, the periventricular nucleus had increased c-Fos immunoreactivity in LWS but not HWS chicks. After central NPS treatment, there was increased c-Fos immunoreactivity in the paraventricular nucleus in HWS but not LWS chicks. These data support the notion of differences in the central NPS system between the LWS and HWS lines and infer that central NPS may differentially affect appetite-related processes in other species that contain hypo- and hyperphagic individuals.

    Title Real-time Fluorescence-based Detection of Furanocoumarin Photoadducts of Dna.
    Date August 2008
    Journal Phytochemical Analysis : Pca
    Excerpt

    Real-time fluorescence detection systems were adapted to identify DNA adducts formed by photogenotoxic phytochemicals. Two assays were developed: the first was based on quantitative polymerase chain reaction (qPCR) while the second used thermal denaturation and renaturation (D-R). Both assays employed yeast DNA, the fluorescent dye SYBR Green and a real-time PCR thermocycler. The furanocoumarins 8-methoxypsoralen (8-MOP), 5-methoxypsoralen (5-MOP), psoralen, angelicin and imperatorin, and the furanochrome khellin, were tested for adduct forming ability with up to 2 h of UVA light exposure (lambda = 320-400 nm). The known bifunctional compounds, 8-MOP, 5-MOP and psoralen, were inferred to form biadducts here based on both D-R and qPCR assays, as expected from previous research. The known monofunctional compound angelicin was used as a negative control and did not form biadducts based on either assay. Two compounds of unknown functional specificity, imperatorin and khellin, were determined to be positive and negative for biadduct activity, respectively. Detection of biadducts with 8-MOP, 5-MOP, psoralen and imperatorin, but not angelicin or khellin, was further verified by temperature gradient gel electrophoresis. The fluorescence methods improve and expand upon existing assays to monitor DNA adducts.

    Title The Prevalence of Mental and Physical Health Disorders Among Older Methadone Patients.
    Date August 2008
    Journal The American Journal of Geriatric Psychiatry : Official Journal of the American Association for Geriatric Psychiatry
    Excerpt

    OBJECTIVES: The aging opioid-addicted cohort from the 1970s has begun to alter the demographic characteristics of individuals in need of services for heroin addiction. Yet, despite clear trends that indicate the population of older methadone patients is increasing, little is known about their well-being and service needs. The goal of this study was to assess the physical and mental health status of older methadone patients. DESIGN: Face-to-face interviews were conducted with study participants. SETTING: This study was conducted at a free-standing methadone clinic in a Midwestern industrial city. PARTICIPANTS: A clinic sample of 140 adult methadone patients over the age of 50 was recruited for face-to-face interviews. MEASURES: Mental health status was assessed by the Composite International Diagnostic Interview. The SF-12v2 was administered to measure a range of physical health issues. Participants were also asked about a variety of chronic conditions. In addition, respondents provided access to their drug screen results from monthly urine tests for illegal drug use for 1 year before and 1 year after the interview. RESULTS: Findings revealed that over half (57.1%) of respondents had at least one mental health disorder in the past year. In the year before the interview, the most prevalent mental health disorder experienced by older adult patients was major depressive episode (32.9%). The most prevalent anxiety disorders were posttraumatic stress disorder (27.8%) and generalized anxiety disorder (29.7%). Additionally, women experienced significantly higher levels of depression than males (43.8% versus 27.2%), and nearly twice the prevalence rate of agoraphobia and panic disorders. Regarding physical health, respondents reported high rates of health problems in the past year, including arthritis (54.3%) and hypertension (44.9%). The majority of respondents reported having fair to poor physical health (57.7%). When examining the entire 24-month period during which urine data were collected, three quarters (76.4%) of the respondents had at least 1 month where the urine screen detected illegal drug use. CONCLUSIONS: In the next decade, the growing and aging substance abusing population will require clinicians trained in both geriatrics and substance abuse. Health and mental health professionals have the opportunity to address the specialized needs of this population and prepare for the shifting service needs these older patients will require.

    Title Face Processing in Adolescents with and Without Epilepsy.
    Date July 2008
    Journal International Journal of Psychophysiology : Official Journal of the International Organization of Psychophysiology
    Excerpt

    Children with temporal lobe epilepsy frequently suffer memory deficits, often marked in face processing. To determine the neural correlates of this dysfunction, we investigated face processing in adolescents with intractable epilepsy compared to typically developing controls. The M170 and M220 MEG event-related fields (ERFs) were recorded while the adolescents completed an n-back task on blocks of upright and inverted faces. Source analyses of the ERF data were performed using an event-related beamforming technique that allowed the detection of multiple sources. The control adolescents showed the expected waveforms and inversion effects, although there were differences in source localization, compared to the adult literature. The participants with epilepsy had poor performance on the tasks. The adolescents with extra-temporal lobe epilepsy showed both the M170 and M220 but the source localizations were highly atypical. The patients with right temporal lobe epilepsy had an absent or highly atypical M220, a component related to face recognition processes. We hypothesize that the children with extra-temporal lobe epilepsy have difficulty with face encoding processes while the patients with right temporal lobe epilepsy have specific difficulty with face recognition.

    Title Isomerization of Delta-9-thc to Delta-8-thc when Tested As Trifluoroacetyl-, Pentafluoropropionyl-, or Heptafluorobutyryl- Derivatives.
    Date July 2008
    Journal Journal of Mass Spectrometry : Jms
    Excerpt

    For GC-MS analysis of delta-9-tetrahydrocannabinol (delta-9-THC), perfluoroacid anhydrides in combination with perfluoroalcohols are commonly used for derivatization. This reagent mixture is preferred because it allows simultaneous derivatization of delta-9-THC and its acid metabolite, 11-nor-delta-9-THC-9-carboxylic acid present in biological samples. When delta-9-THC was derivatized by trifluoroacetic anhydride/hexafluoroisopropanol (TFAA/HFIPOH) and analyzed by GC-MS using full scan mode (50-550 amu), two peaks (P1 and P2) with an identical molecular mass of 410 amu were observed. On the basis of the total ion chromatogram (TIC), P1 with a shorter retention time (RT) was the major peak (TIC 84%). To identify the peaks, delta-8-THC was also tested under the same conditions. The RT and spectra of the major peak (TIC 95%) were identical with that of P1 for delta-9-THC. A minor peak (5%) present also correlated well with the latter peak (P2) for the delta-9-THC derivative. The fragmentation pathway of P1 was primarily demethylation followed by retro Diels-Alder fragmentation (M - 15-68, base peak 100%) indicating P1 as a delta-8-THC-trifluoroacetyl compound. This indicated that delta-9-THC isomerized to delta-8-THC during derivatization with TFAA/HFIPOH. Similar results were also observed when delta-9-THC was derivatized with pentafluoropropionic anhydride/pentafluoropropanol or heptafluorobutyric anhydride/heptafluorobutanol. No isomerization was observed when chloroform was used in derivatization with TFAA. In this reaction, the peaks of delta-8-THC-TFA and delta-9-THC-TFA had retention times and mass spectra matching with P1 and P2, respectively. Because of isomerization, perfluoroacid anhydrides/perfluoroalcohols are not suitable derivatizing agents for analysis of delta-9-THC; whereas the TFAA in chloroform is suitable for the analysis.

    Title Antifungal and Antioxidant Activities of the Phytomedicine Pipsissewa, Chimaphila Umbellata.
    Date July 2008
    Journal Phytochemistry
    Excerpt

    Bioassay-guided fractionation of Chimaphila umbellata (L.) W. Bart (Pyrolaceae) ethanol extracts led to the identification of 2,7-dimethyl-1,4-naphthoquinone (chimaphilin) as the principal antifungal component. The structure of chimaphilin was confirmed by 1H and 13C NMR spectroscopy. The antifungal activity of chimaphilin was evaluated using the microdilution method with Saccharomyces cerevisiae (0.05mg/mL) and the dandruff-associated fungi Malassezia globosa (0.39mg/mL) and Malassezia restricta (0.55mg/mL). Pronounced antioxidant activity of C. umbellata crude extract was also identified using the DPPH (2,2-diphenyl-1-picrylhydrazyl) assay, suggesting this phytomedicine has an antioxidant function in wound healing. A chemical-genetic profile was completed with chimaphilin using approximately 4700 S. cerevisiae gene deletion mutants. Cellular roles of deleted genes in the most susceptible mutants and secondary assays indicate that the targets for chimaphilin include pathways involved in cell wall biogenesis and transcription.

    Title Intermittent Hypoxia: Cause of or Therapy for Systemic Hypertension?
    Date July 2008
    Journal Experimental Biology and Medicine (maywood, N.j.)
    Excerpt

    During acute episodes of hypoxia, chemoreceptor-mediated sympathetic activity increases heart rate, cardiac output, peripheral resistance and systemic arterial pressure. However, different intermittent hypoxia paradigms produce remarkably divergent effects on systemic arterial pressure in the post-hypoxic steady state. The hypertensive effects of obstructive sleep apnea (OSA) vs. the depressor effects of therapeutic hypoxia exemplify this divergence. OSA, a condition afflicting 15-25% of American men and 5-10% of women, has been implicated in the pathogenesis of systemic hypertension and is a major risk factor for heart disease and stroke. OSA imposes a series of brief, intense episodes of hypoxia and hypercapnia, leading to persistent, maladaptive chemoreflex-mediated activation of the sympathetic nervous system which culminates in hypertension. Conversely, extensive evidence in animals and humans has shown controlled intermittent hypoxia conditioning programs to be safe, efficacious modalities for prevention and treatment of hypertension. This article reviews the pertinent literature in an attempt to reconcile the divergent effects of intermittent hypoxia therapy and obstructive sleep apnea on hypertension. Special emphasis is placed on research conducted in the nations of the former Soviet Union, where intermittent hypoxia conditioning programs are being applied therapeutically to treat hypertension in patients. Also reviewed is evidence regarding mechanisms of the pro- and anti-hypertensive effects of intermittent hypoxia.

    Title Classification Images Reveal the Information Sensitivity of Brain Voxels in Fmri.
    Date June 2008
    Journal Neuroimage
    Excerpt

    Reverse correlation methods have been widely used in neuroscience for many years and have recently been applied to study the sensitivity of human brain signals (EEG, MEG) to complex visual stimuli. Here we employ one such method, Bubbles (Gosselin, F., Schyns, P.G., 2001. Bubbles: A technique to reveal the use of information in recognition tasks. Vis. Res. 41, 2261-2271), in conjunction with fMRI in the context of a 3AFC facial expression categorization task. We highlight the regions of the brain showing significant sensitivity with respect to the critical visual information required to perform the categorization judgments. Moreover, we reveal the actual subset of visual information which modulates BOLD sensitivity within each such brain region. Finally, we show the potential which lies within analyzing brain function in terms of the information states of different brain regions. Thus, we can now analyse human brain function in terms of the specific visual information different brain regions process.

    Title Phenotypic Evolution of Waldenstrom's Macroglobulinemia to Extramedullary Plasmacytoma.
    Date May 2008
    Journal Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
    Title Psychosocial Outcomes in Children Two Years After Epilepsy Surgery: Has Anything Changed?
    Date May 2008
    Journal Epilepsia
    Excerpt

    We prospectively explored psychosocial outcomes in children (7-18 years) 2 years after epilepsy surgery. This study built on our previous one that examined these children 1 year after surgery.

    Title Intensive Care Telemedicine: Evaluating a Model for Proactive Remote Monitoring and Intervention in the Critical Care Setting.
    Date May 2008
    Journal Studies in Health Technology and Informatics
    Excerpt

    Historically, telemedicine has focused on the application of traditional physician-to-patient (and physician-to-physician) interactions enhanced by two-way video and audio capability. This "one-on-one" interaction via a telemedicine link can dramatically extend a physician's or other caregiver's geographic range and availability. However, this same telemedicine model is most often implemented "on-demand" for a specified time-limited encounter. The remote Intensive Care Unit (ICU) model to be described similarly expands the geographic range of ICU physicians, but also allows a single specialist to simultaneously monitor multiple patients on a continuous basis by leveraging computerized "intelligent" algorithms and an electronic medical record interface. This new application of telemedicine wedded to computer technology facilitates maximum leveraging of specialists' cognitive skills but also mandates significant process changes in how ICU services are provided. In short, the remote ICU represents a "re-engineering" of how ICU care is delivered and establishes a new paradigm for the field of telemedicine, expanding the reach, scope and availability of intensivist specialty expertise.The re-engineering occurs through a number of ways. First, the telemedicine connection is continuously available in a pro-active fashion that can be provided 24 hours a day, 7 days a week (24/7). Secondly, the system utilizes computerized clinical intelligence algorithms with direct electronic links to physiologic, laboratory and lab/pharmacy data as well as patient diagnoses to focus attention on potential adverse outcomes or trends in individual patients and notify caregivers before trends manifest as adverse outcomes. Third, the traditional physician, nurse, and patient relationship is substantially augmented when there is an ICU physician immediately available to address issues in patient care, particularly at night when physicians are less likely to be present at the bedside. The current preliminary data suggest that this system can be quite effective in improving ICU quality of care, thus leading to reductions in the cost of ICU care, ICU patient mortality, ICU patient outliers, and ICU length of stay (LOS).Given the extensive data showing improved ICU outcomes with daily ICU physician participation in care of critically ill patients, and the national shortage of ICU physicians, nurses, and ancillary staff; the electronic ICU system is gaining popularity as an alternative paradigm for the expansion of an ICU team's expertise in the care of the severely ill. Interestingly, internal Quality Improvement (QI) data from several healthcare systems have shown that improved outcomes occur even when remote ICU telemedicine is applied to a pre-existing 24/7 in-house intensivist care model. The reasons for this remain speculative at this point, but pro-active and hourly remote "virtual rounds" on the most critically-ill patients, and use of computerized algorithms in triaging ICU physicians' attention may contribute to the success of this system. Also, we will show how the system supports key elements of error reduction theory even in well-staffed critical care units.Multiple challenges remain before remote ICU systems become more broadly accepted and applied. These include cost of implementation of the system, resistance to the system by ICU physicians and nurses, and integration of data systems and clinical information into the remote electronic ICU model. In this chapter, we will provide background information on error reduction theory and the role of the remote ICU model, review current data supporting use of the remote ICU system, address the current obstacles to effective implementation, and look to the future of the field for solutions to these challenges.

    Title Amylin Causes Anorexigenic Effects Via the Hypothalamus and Brain Stem in Chicks.
    Date May 2008
    Journal Regulatory Peptides
    Excerpt

    This study was conducted to determine the effects of amylin on appetite-related processes in chicks. Broiler chicks were centrally and peripherally injected with amylin, and feed and water intake were quantified. Feed intake was reduced after both central and peripheral amylin, but water intake was not affected. To determine if the hypothalamus and brainstem were involved in the anorexigenic effect, chicks were centrally and peripherally injected with amylin, and c-Fos immunoreactivity was quantified in the lateral hypothalamus (LH), ventromedial hypothalamus (VMH), area postrema (AP) and the nucleus of the solitary tract (NTS). Amylin decreased c-Fos immunoreactivity in the LH, did not affect the VMH, and increased c-Fos immunoreactivity in the AP and NTS. To determine if alimentary transit time was affected, chicks received central amylin and were gavaged with chicken feed slurry containing a visible marker. Amylin-treated chicks had increased alimentary canal transit time. Chicks also responded to central amylin with increased anxiety-related behaviors and increased plasma corticosterone concentration. These results demonstrate that amylin affects feeding, alimentary canal transit, and behavior through hypothalamic and brainstem mechanisms in chicks.

    Title Beta-melanocyte-stimulating Hormone Potently Reduces Appetite Via the Hypothalamus in Chicks.
    Date April 2008
    Journal Journal of Neuroendocrinology
    Excerpt

    The melanocortin system together with other appetite-related systems plays a significant role in appetite regulation. The appetite-related effects of one such melanocortin, beta-melanocyte-stimulating hormone (MSH), are well documented in rodents; however, its effects in the avian class are not thoroughly understood. Thus, we designed a study to determine the effects of i.c.v. beta-MSH injection on food and water intake, plasma corticosterone concentration, ingestive and non-ingestive behaviours, and hypothalamic neuronal activation using Cobb-500 chicks. Chicks responded to beta-MSH-treatment with a reduction in food and water intake; however when water intake was measured independently of food intake, it was not affected. beta-MSH-treated chicks also had increased plasma corticosterone concentrations and increased c-Fos reactivity in the periventricular, paraventricular and infundibular nuclei, and the ventromedial hypothalamus; however, the lateral hypothalamus was not affected. The effect on food intake is primary because behaviours that may be competitive with food intake were not increased in beta-MSH-treated chicks. Based on these results, we conclude that beta-MSH causes anorexigenic effects that are likely primarily mediated via stimulation of satiety-related hypothalamic nuclei in broiler-type chicks.

    Title Vaccination of Feral Pigs (sus Scrofa) Using Iophenoxic Acid As a Simulated Vaccine.
    Date April 2008
    Journal Australian Veterinary Journal
    Excerpt

    To develop an encapsulation method for delivery of vaccines to feral pigs, and quantify the effect of iophenoxic acid on captive feral pig blood iodine concentrations to assist in investigation of factors affecting vaccine uptake.

    Title Physically Active Lifestyle Enhances Vagal-cardiac Function but Not Central Autonomic Neural Interaction in Elderly Humans.
    Date March 2008
    Journal Experimental Biology and Medicine (maywood, N.j.)
    Excerpt

    The cause of the age-related impairment of arterial baroreflex function remains ill-defined; moreover, it is unknown whether this impairment results from aging per se or from an inactive lifestyle associated with aging. In this study, we sought to: 1) determine whether elderly individuals who maintained an active lifestyle had an enhanced carotid baroreflex function as compared with their sedentary counterparts; and 2) determine whether this difference was due in part to altered function of the arterial baroreceptor and/or altered central modulation. Eight healthy, sedentary (SED, 68+/-2 yr) and eight physically active (ACT, 68+/-1 yr) elderly men with peak O(2) consumption 25.5+/-1.2 vs 35.7+/-2.4 ml/min/kg (P<0.01), respectively, were assessed with carotid baroreceptor (CBR) function using 5s pulses of neck pressure or suction (ranging from +40 to -80 Torr) delivered to the carotid sinus region at rest and during lower body negative pressure (LBNP) of -15 and -40 Torr. Changes in heart rate (HR) and mean arterial pressure (MAP) were assessed for CBR-HR and CBR-MAP gains, respectively. Overall CBR-HR gains in a range of approximately 120 mmHg of carotid sinus pressure were greater (P<0.01) in ACT than SED at rest and during LBNP. The derived peak CBR-HR slopes between ACT and SED at rest were -0.32+/-0.07 vs -0.11+/-0.02 bpm/mmHg (P=0.007), respectively. However, there was no statistical difference (P=0.37) in CBR-MAP gains between the groups. Neither CBR-MAP (P=0.08) nor CBR-HR (P=0.41) gain was augmented by LBNP in the elderly. CONCLUSION: Active lifestyle enhances the CBR-HR reflex sensitivity as a result of the improved vagal-cardiac function in elderly people. Aging is associated with an absence of central autonomic interaction in the control of blood pressure regardless of physical fitness.

    Title Feasibility of Flap Reconstruction in Conjunction with Intraoperative Radiation Therapy for Advanced and Recurrent Head and Neck Cancer.
    Date February 2008
    Journal The Laryngoscope
    Excerpt

    BACKGROUND: Radiation is a known risk factor for poor wound healing. Patients undergoing intraoperative radiation therapy (IORT) typically receive higher cumulative doses to their wound beds than patients treated with conventional radiation therapy. We review our experience with IORT in patients undergoing resection of head and neck cancer and flap reconstruction. Logistics of delivery and outcomes are discussed. METHODS: A retrospective chart review was performed on all patients at Beth Israel Medical Center who underwent IORT for head and neck cancer between 2000 and 2007. Twenty-one patients receiving 22 treatments involving flap reconstruction were identified. The results of these reconstructions were evaluated for complications and functional outcome. RESULTS: All patients had complex surgical wounds of the face, upper aerodigestive tract, or neck who received IORT in conjunction with pedicled or free flap closure. Twenty-five flaps in 21 patients were performed in the setting of IORT. All patients received between 10 and 15 Gy of IORT administered directly to the wound bed. There were no perioperative mortalities. Wound breakdown occurred in three cases, all of which were treated successfully by operative revision. Functionally, most patients did well and performed similarly to historic controls for their type of reconstruction. CONCLUSIONS: Reconstruction using flaps in the context of IORT can be achieved with expectation of good wound healing in the majority of cases despite heavy cumulative doses of radiation to recipient wound beds.

    Title Brain Tissue Oxygen Tension in Clinical Brain Death: a Case Series.
    Date February 2008
    Journal Neurological Research
    Excerpt

    OBJECTIVES: Brain death is a clinical diagnosis often confirmed with supplementary tests. In this study, we examined the relationship between brain death and the partial pressure of brain tissue oxygen (PbtO(2)). We hypothesized that a sustained PbtO(2) of 0 is associated with brain death. METHODS: One hundred and twenty-six patients (Glasgow coma scale < or = 8, median age: 50 years) who underwent PbtO(2) monitoring were studied prospectively during a 2 year period in the neurointensive care unit at a university-based level I trauma center. PbtO(2), intracranial pressure (ICP), mean arterial pressure (MAP), cerebral perfusion pressure (CPP) and brain temperature (BT) were compared before and after the diagnosis of brain death. RESULTS: Six patients (median age: 52 years) experienced brain death. In these patients, PbtO(2) decreased toward 0 mmHg as ICP increased and CPP decreased. PbtO(2) reached 0 only when there was clinical evidence for brain death. During the subsequent 12 hours until the second brain death examination, PbtO(2) remained 0 mmHg and did not respond to oxygen challenge. In addition, TCD examination demonstrated a 'to and fro' pattern consistent with brain death and cerebral circulatory arrest. PbtO(2) of 0 mmHg was observed in five non-brain dead patients. These episodes were transient (>30 minutes) and responded to an oxygen challenge, directed treatment or catheter replacement. DISCUSSION: A sustained (>30 minutes) brain PbtO(2) of 0 is consistent with brain death. We suggest that a sustained 'zero' PbtO(2) may be used to determine when a brain death examination is appropriate in the pharmacologically suppressed patient.

    Title Research Issues Affecting Preoperative Systemic Therapy for Operable Breast Cancer.
    Date February 2008
    Journal Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
    Excerpt

    Preoperative systemic therapy (PST) in operable breast cancer allows a small increase in breast conservation rates and has significant potential as a research platform. PST offers the ability to discern treatment effect in vivo, and may allow smaller trials targeting specific breast cancer subtypes and making more efficient use of resources. Early observations of a specific outcome of interest in individual patient subgroups may improve the design of larger definitive randomized adjuvant trials using survival as a main outcome. PST offers the potential for therapeutic adjustments midcourse, which assumes the existence of validated intermediate end points and effective alternative therapies. This article reviews critical research issues affecting the design of PST trials, including the appropriate selection of trial end points and markers for long-term outcome, baseline marker expression as a predictor of response, and statistical considerations using novel trial designs. Key issues regarding optimal tumor subtype selection for individual trials, novel approaches using nontherapeutic window trial designs, and ethical and advocacy considerations are also discussed. PST requires an experienced and cohesive multidisciplinary team for it to fulfill its potential in both research and clinical care.

    Title Excretion of Methamphetamine and Amphetamine in Human Sweat Following Controlled Oral Methamphetamine Administration.
    Date February 2008
    Journal Clinical Chemistry
    Excerpt

    Understanding methamphetamine (MAMP) and amphetamine (AMP) excretion in sweat is important for interpreting sweat and hair testing results in judicial, workplace, and drug treatment settings.

    Title Excretion of Delta9-tetrahydrocannabinol in Sweat.
    Date February 2008
    Journal Forensic Science International
    Excerpt

    Sweat testing is a noninvasive technique for monitoring drug exposure over a 7-day period in treatment, criminal justice, and employment settings. We evaluated Delta(9)-tetrahydrocannabinol (THC) excretion in 11 daily cannabis users after cessation of drug use. PharmChek sweat patches worn for 7 days were analyzed for THC by gas chromatography-mass spectrometry (GC/MS). The limit of quantification (LOQ) for the method was 0.4 ng THC/patch. Sweat patches worn the first week of continuously monitored abstinence had THC above the United States Substance Abuse Mental Health Services Administration's proposed cutoff concentration for federal workplace testing of 1 ng THC/patch. Mean+/-S.E.M. THC concentrations were 3.85+/-0.86 ng THC/patch. Eight of 11 subjects had negative patches the second week and one produced THC positive patches for 4 weeks of monitored abstinence. We also tested daily and weekly sweat patches from seven subjects who were administered oral doses of up to 14.8 mg THC/day for five consecutive days. In this oral THC administration study, no daily or weekly patches had THC above the LOQ; concurrent plasma THC concentrations were all less than 6.1 microg/L. In conclusion, using proposed federal cutoff concentrations, most daily cannabis users will have a positive sweat patch in the first week after ceasing drug use and a negative patch after subsequent weeks, although patches may remain positive for 4 weeks or more. Oral ingestion of up to 14.8 mg THC daily does not produce a THC positive sweat patch test.

    Title Force-induced Unfolding of Fibronectin in the Extracellular Matrix of Living Cells.
    Date January 2008
    Journal Plos Biology
    Excerpt

    Whether mechanically unfolded fibronectin (Fn) is present within native extracellular matrix fibrils is controversial. Fn extensibility under the influence of cell traction forces has been proposed to originate either from the force-induced lengthening of an initially compact, folded quaternary structure as is found in solution (quaternary structure model, where the dimeric arms of Fn cross each other), or from the force-induced unfolding of type III modules (unfolding model). Clarification of this issue is central to our understanding of the structural arrangement of Fn within fibrils, the mechanism of fibrillogenesis, and whether cryptic sites, which are exposed by partial protein unfolding, can be exposed by cell-derived force. In order to differentiate between these two models, two fluorescence resonance energy transfer schemes to label plasma Fn were applied, with sensitivity to either compact-to-extended conformation (arm separation) without loss of secondary structure or compact-to-unfolded conformation. Fluorescence resonance energy transfer studies revealed that a significant fraction of fibrillar Fn within a three-dimensional human fibroblast matrix is partially unfolded. Complete relaxation of Fn fibrils led to a refolding of Fn. The compactly folded quaternary structure with crossed Fn arms, however, was never detected within extracellular matrix fibrils. We conclude that the resting state of Fn fibrils does not contain Fn molecules with crossed-over arms, and that the several-fold extensibility of Fn fibrils involves the unfolding of type III modules. This could imply that Fn might play a significant role in mechanotransduction processes.

    Title Base Excision Dna Repair Defect in Gadd45a-deficient Cells.
    Date January 2008
    Journal Oncogene
    Excerpt

    As one of a number of p53-regulated genes, Gadd45a (growth arrest and DNA damage inducible gene) has been shown to delay carcinogenesis and decrease mutation frequency. Gadd45a is known to regulate nucleotide excision DNA repair (NER) in response to UV radiation. Here, we report an emerging role for Gadd45a in base excision repair (BER). Gadd45a-null mouse embryo fibroblasts MEF and gadd45a-deficient human colon cancer cells exhibited slow BER after treatment with methyl methanesulfonate (MMS) a pure base-damaging agent. In addition, removal of AP sites by apurinic/apyrimidinic endonuclease 1/redox factor 1 (APE1/Ref1) was significantly delayed in gadd45a-null cells. Moreover, the localization of APE1/Ref1 within the nucleus was observed in gadd45a wild-type cells, whereas APE1 become mainly distributed in the cytoplasm, and there is a reduced interaction with proliferating cell nuclear antigen (PCNA) in Gadd45a-deficient cells. Inasmuch as p53 has been shown to regulate BER in addition to the NER pathway, our data suggest that p53-regulated gene Gadd45a contributes to the BER response by affecting the interaction of cellular APE1/Ref1 with PCNA. Gadd45a might be a key component gene of the p53 pathway involved in protection from carcinogenic base damage and maintenance of genomic stability, although the downstream mechanism including APE1/Ref1 will need further study.

    Title Dynamics of Visual Information Integration in the Brain for Categorizing Facial Expressions.
    Date December 2007
    Journal Current Biology : Cb
    Excerpt

    A key to understanding visual cognition is to determine when, how, and with what information the human brain distinguishes between visual categories. So far, the dynamics of information processing for categorization of visual stimuli has not been elucidated. By using an ecologically important categorization task (seven expressions of emotion), we demonstrate, in three human observers, that an early brain event (the N170 Event Related Potential, occurring 170 ms after stimulus onset) integrates visual information specific to each expression, according to a pattern. Specifically, starting 50 ms prior to the ERP peak, facial information tends to be integrated from the eyes downward in the face. This integration stops, and the ERP peaks, when the information diagnostic for judging a particular expression has been integrated (e.g., the eyes in fear, the corners of the nose in disgust, or the mouth in happiness). Consequently, the duration of information integration from the eyes down determines the latency of the N170 for each expression (e.g., with "fear" being faster than "disgust," itself faster than "happy"). For the first time in visual categorization, we relate the dynamics of an important brain event to the dynamics of a precise information-processing function.

    Title Laparoscopic Subtotal Cholecystectomy Without Cystic Duct Ligation.
    Date December 2007
    Journal The British Journal of Surgery
    Excerpt

    Cholecystectomy is made hazardous by distortion of the anatomy of Calot's triangle by acute or chronic inflammation. Laparoscopic subtotal cholecystectomy (LSTC) without cystic duct ligation is an alternative to conversion to open surgery in difficult cases.

    Title Acute Kidney Injury Complicating Minimal Change Disease: the Case for Careful Use of Diuretics and Angiotensin-converting Enzyme Inhibitors.
    Date December 2007
    Journal Nephrology (carlton, Vic.)
    Title Cocaine and Metabolites Urinary Excretion After Controlled Smoked Administration.
    Date December 2007
    Journal Journal of Analytical Toxicology
    Excerpt

    Understanding cocaine and metabolites urinary excretion following smoking is important for interpretation of urine test results in judicial, workplace and treatment settings. In National Institute on Drug Abuse approved studies on a secure research unit, six subjects smoked placebo, 10, 20, and 40 mg cocaine with a precise dose delivery device and six different subjects smoked 42 mg cocaine in a glass pipe. Urine specimens (n = 700) were collected for up to seven days and analyzed for cocaine (COC), benzoylecgonine (BE), ecgonine methylester (EME), m-hydroxybenzoylecgonine (mOHBE), p-hydroxybenzoylecgonine (pOHBE), norbenzoylecgonine (NBE), and ecgonine (EC) by gas chromatography-mass spectrometry. Results (mean +/- SE) for the 40-mg precise delivery doses are as follows: (Table can not be represented) Mean C(max) for all analytes linearly increased with increasing dose. T(max) was not dose-dependent. All metabolites were detected in some subjects within 2 h. EC concentrations were significantly higher after smoked cocaine in a precise delivery coil compared to a glass "crack" pipe.

    Title Central Alpha-melanocyte Stimulating Hormone Attenuates Behavioral Effects of Neuropeptide Y in Chicks.
    Date November 2007
    Journal Physiology & Behavior
    Excerpt

    This experiment was conducted to determine the effects of central alpha-melanocyte stimulating hormone (alpha-MSH) and its interaction with neuropeptide Y (NPY) on ingestive and non-ingestive behaviors in chicks. Chicks received intracerebroventricular injections of either 0, 0.12 nM alpha-MSH, 0.06 nM NPY, or 0.12 nM alpha-MSH+0.06 nM NPY. Immediately following injection, chicks were placed in an observation arena and the number of steps, jumps, feed pecks, drinks, exploratory pecks, escape attempts, the total distance traveled, and the amount of time spent standing, sitting, sleeping, and preening were monitored for 60 min. Chicks treated with NPY consumed 69% more feed than controls whereas alpha-MSH-treated chicks consumed 71% less. Feed intake of the NPY+alpha-MSH groups was similar to alpha-MSH-treated chicks at 66% less than aCSF-treated chicks. Differences in pecking were found and followed a similar pattern as feed intake. All treatments increased the amount of time chicks were in a sitting posture, and the alpha-MSH+NPY group spent more time sitting than alpha-MSH and NPY alone. The sitting response after alpha-MSH+NPY treatment was similar to the alpha-MSH group but not the NPY group. Other behaviors were not affected by treatment. Thus, we conclude that alpha-MSH, at a concentration that causes a similar magnitude decrease in feed intake as NPY increases feed intake, is a more potent appetite-related signal than NPY. alpha-MSH causes behavioral effects that may secondarily affect feed intake at a low magnitude and may modulate the behavioral effects of NPY in chicks, contributing to the overall effect on feed intake.

    Title Case Study. All for One, or One for All? Commentary.
    Date November 2007
    Journal The Hastings Center Report
    Title High Intake of Palatable Food Predicts Binge-eating Independent of Susceptibility to Obesity: an Animal Model of Lean Vs Obese Binge-eating and Obesity with and Without Binge-eating.
    Date November 2007
    Journal International Journal of Obesity (2005)
    Excerpt

    To determine the stability of individual differences in non-nutritive 'junk' palatable food (PF) intake in rats; assess the relationship of these differences to binge-eating characteristics and susceptibility to obesity; and evaluate the practicality of using these differences to model binge-eating and obesity.

    Title From a Face to Its Category Via a Few Information Processing States in the Brain.
    Date November 2007
    Journal Neuroimage
    Excerpt

    Cognitive neuroscience assumes a correspondence between specific spatio-temporal patterns of neural activity and the states of a mechanism that processes cognitive information. Mechanistic explanations of cognition should therefore translate patterns of neural activity into the components of a formal mechanism: a set of information processing states and their transitions. For the first time, we carried out this research programme with four naive observers instructed to categorise randomly presented face information. With classification image techniques, we revealed the diagnostic features that the brain requires to produce correct behaviour (i.e., two eyes for gender categorisation in one session; the mouth for expression in the other session). With the same techniques applied to brain signals, we revealed the features processing states associated with modulations of oscillatory EEG energy (measured on occipito-temporal face-sensitive electrodes). Here we show how transitions between distinct feature processing states in the theta/alpha [4-12 Hz] oscillatory bands implement two face categorisations. On the left and right occipito-temporal electrodes of each observer, processing of the contra-lateral eye precedes bilateral integration of the features required for behaviour. For the first time, we relate stimulus information to behaviour via sequences of categorisation-specific feature processing states in the brain.

    Title The Effects of Rate and Irregularity on Sympathetic Nerve Activity in Human Subjects.
    Date November 2007
    Journal Heart Rhythm : the Official Journal of the Heart Rhythm Society
    Excerpt

    BACKGROUND: We have recently shown that atrial fibrillation is associated with an increase in sympathetic nerve activity (SNA) compared with sinus rhythm. It remains unclear, however, whether these findings are true at various rates and whether the magnitude of sympathoexcitation is related to the degree of irregularity. OBJECTIVE: To determine the role of irregularity in mediating the SNA changes at various pacing rates. Univariate analysis showed that as the irregularity increased, SBP increased (r = 0.44, P < .001) but that MAP and DBP did not change significantly. METHODS: Using custom-made software, atrioventricular sequential pacing with predetermined rates (100, 120, and 140 bpm) and irregularities (standard deviation = 0%, 5%, 15%, and 25% of mean cycle length) was performed in 23 patients referred for electrophysiologic evaluation. Pacing at each rate/irregularity was performed for 2 minutes, with 2 minutes of recovery in between. Systolic, diastolic, and mean arterial blood pressure (SBP, DBP, and MAP), central venous pressure (CVP), and SNA were measured at baseline and during pacing. RESULTS: Univariate analysis showed that as the irregularity increased, SBP increased (r = 0.44, P < .001 but that MAP and DBP did not change significantly. A significant correlation was found between the pacing irregularity and SNA, with greater sympathoexcitation noted at greater degrees of irregularity (r = 0.2, P = .04). A five-variable linear model using DBP, MAP, CVP, and degree of pacing irregularity to predict SNA was highly statistically significant (r = 0.46, P < .001). After controlling for hemodynamic changes, for every 1% increase in irregularity, there was a 6.1% increase in SNA. CONCLUSION: We have shown that greater degrees of irregularity cause greater sympathoexcitation and that the effects of irregular pacing on SNA are independent of the hemodynamic changes.

    Title Beadarray: R Classes and Methods for Illumina Bead-based Data.
    Date October 2007
    Journal Bioinformatics (oxford, England)
    Excerpt

    The R/Bioconductor package beadarray allows raw data from Illumina experiments to be read and stored in convenient R classes. Users are free to choose between various methods of image processing, background correction and normalization in their analysis rather than using the defaults in Illumina's; proprietary software. The package also allows quality assessment to be carried out on the raw data. The data can then be summarized and stored in a format which can be used by other R/Bioconductor packages to perform downstream analyses. Summarized data processed by Illumina's; BeadStudio software can also be read and analysed in the same manner. Availability: The beadarray package is available from the Bioconductor web page at www.bioconductor.org. A user's guide and example data sets are provided with the package.

    Title Chemical Burn Induced by Cutaneous Exposure to a Concentrated Sodium Hypochlorite and Alkyl Sulfate Solution.
    Date October 2007
    Journal Cutaneous and Ocular Toxicology
    Excerpt

    BACKGROUND: Acute irritant contact dermatitis induced by cutaneous exposure to chemicals is a common dermatologic problem in the workplace. In severe cases, irritant contact responses can result in a caustic burn. Chemical burn induced by concentrated sodium hypochlorite (the active ingredient in bleach) has been reported infrequently in the literature, with no previously reported cases of chemical burn due to an alkyl sulfate (a common surfactant in cleaning fluids). Here we describe a chemical burn in a 16-year-old girl resulting from exposure to a solution of concentrated sodium hypochlorite and alkyl sulfate applied as a sanitizer to the interior of roller skates worn at work. OBSERVATIONS: The diagnosis was made on the basis of the patient's exposure history, clinical appearance, and laboratory results. On physical examination, the erythematous plaque, located at the site of chemical exposure, had intact skin lines, surrounding edema, and decreased sensitivity to touch. The peripheral white blood cell count was within normal limits and bacterial and fungal cultures from the lesion were negative. CONCLUSIONS: The irritant effect of exposure to chemicals, including those that usually are not major irritants, and the possible additive effect of simultaneous exposure to different chemicals, should be considered in the differential diagnosis of acute dermatitis of unknown etiology. Moreover, increased reporting of cases of chemical-induced acute irritant contact dermatitis will help lead to crucial early and appropriate treatment.

    Title Micro-well Arrays for 3d Shape Control and High Resolution Analysis of Single Cells.
    Date October 2007
    Journal Lab on a Chip
    Excerpt

    In addition to rigidity, matrix composition, and cell shape, dimensionality is now considered an important property of the cell microenvironment which directs cell behavior. However, available tools for cell culture in two-dimensional (2D) versus three-dimensional (3D) environments are difficult to compare, and no tools exist which provide 3D shape control of single cells. We developed polydimethylsiloxane (PDMS) substrates for the culture of single cells in 3D arrays which are compatible with high-resolution microscopy. Cell adhesion was limited to within microwells by passivation of the flat upper surface through 'wet-printing' of a non-fouling polymer and backfilling of the wells with specific adhesive proteins or lipid bilayers. Endothelial cells constrained within microwells were viable, and intracellular features could be imaged with high resolution objectives. Finally, phalloidin staining of actin stress fibers showed that the cytoskeleton of cells in microwells was 3D and not limited to the cell-substrate interface. Thus, microwells can be used to produce microenvironments for large numbers of single cells with 3D shape control and can be added to a repertoire of tools which are ever more sought after for both fundamental biological studies as well as high throughput cell screening assays.

    Title Just Whose Autonomy is It?
    Date September 2007
    Journal Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
    Title Zotarolimus, a Novel Sirolimus Analogue with Potent Anti-proliferative Activity on Coronary Smooth Muscle Cells and Reduced Potential for Systemic Immunosuppression.
    Date September 2007
    Journal Journal of Cardiovascular Pharmacology
    Excerpt

    Sirolimus (rapamycin) is an immunosuppressant used in preventing allograft rejection and in drug-eluting stents to prevent restenosis after angioplasty. Zotarolimus, an analogue of sirolimus, was designed to have a shorter in vivo half-life. Zotarolimus was found to be mechanistically similar to sirolimus in having high-affinity binding to the immunophilin FKBP12 and comparable potency for inhibiting in vitro proliferation of both human and rat T cells. Rat pharmacokinetic studies with intravenous dosing demonstrated terminal elimination half-lives of 9.4 hours and 14.0 hours for zotarolimus and sirolimus, respectively. Given orally, T1/2 values were 7.9 hours and 33.4 hours, respectively. Consistent with its shorter duration, zotarolimus showed a corresponding and statistically significant 4-fold reduction in potency for systemic immunosuppression in 3 rat disease models. Pharmacokinetic studies in cynomolgus monkey underpredicted the half-life difference between zotarolimus and sirolimus apparent from recent clinical data. In vitro inhibition of human coronary artery smooth muscle cell proliferation by zotarolimus was comparable to sirolimus. Drug-eluting stents for local delivery of zotarolimus to the vessel wall of coronary arteries are in clinical development. The pharmacological profile of zotarolimus suggests it may be advantageous for preventing restenosis with a reduced potential for causing systemic immunosuppression or other side effects.

    Title Use of Digital Webcam Images to Track Spring Green-up in a Deciduous Broadleaf Forest.
    Date August 2007
    Journal Oecologia
    Excerpt

    Understanding relationships between canopy structure and the seasonal dynamics of photosynthetic uptake of CO(2) by forest canopies requires improved knowledge of canopy phenology at eddy covariance flux tower sites. We investigated whether digital webcam images could be used to monitor the trajectory of spring green-up in a deciduous northern hardwood forest. A standard, commercially available webcam was mounted at the top of the eddy covariance tower at the Bartlett AmeriFlux site. Images were collected each day around midday. Red, green, and blue color channel brightness data for a 640 x 100-pixel region-of-interest were extracted from each image. We evaluated the green-up signal extracted from webcam images against changes in the fraction of incident photosynthetically active radiation that is absorbed by the canopy (f (APAR)), a broadband normalized difference vegetation index (NDVI), and the light-saturated rate of canopy photosynthesis (A(max)), inferred from eddy flux measurements. The relative brightness of the green channel (green %) was relatively stable through the winter months. A steady rising trend in green % began around day 120 and continued through day 160, at which point a stable plateau was reached. The relative brightness of the blue channel (blue %) also responded to spring green-up, although there was more day-to-day variation in the signal because blue % was more sensitive to changes in the quality (spectral distribution) of incident radiation. Seasonal changes in blue % were most similar to those in f (APAR) and broadband NDVI, whereas changes in green % proceeded more slowly, and were drawn out over a longer period of time. Changes in A(max) lagged green-up by at least a week. We conclude that webcams offer an inexpensive means by which phenological changes in the canopy state can be quantified. A network of cameras could offer a novel opportunity to implement a regional or national phenology monitoring program.

    Title Stereotactic Radiosurgery in the Management of Brain Metastasis.
    Date August 2007
    Journal Neurosurgical Focus
    Excerpt

    Metastatic disease to the brain occurs in a significant percentage of patients with cancer and can limit survival and worsen quality of life. Glucocorticoids and whole-brain radiation therapy (WBRT) have been the mainstay of intracranial treatments, while craniotomy for tumor resection has been the standard local therapy. In the last few years however, stereotactic radiosurgery (SRS) has emerged as an alternative form of local therapy. Studies completed over the past decade have helped to define the role of SRS. The authors review the evolution of the techniques used and the indications for SRS use to treat brain metastases. Stereotactic radiosurgery, compared with craniotomy, is a powerful local treatment modality especially useful for small, multiple, and deep metastases, and it is usually combined with WBRT for better regional control.

    Title A History of Caloric Restriction Induces Neurochemical and Behavioral Changes in Rats Consistent with Models of Depression.
    Date August 2007
    Journal Pharmacology, Biochemistry, and Behavior
    Excerpt

    A history of dieting is common in individuals suffering from eating disorders for which depression and mood disturbances are also comorbid. We investigated the effect of a history of caloric restriction (HCR) in rats that involved cyclic food restriction and refeeding with varying levels of access to palatable food (PF) on: 1) responses to the SSRI, fluoxetine; 2) monoamine levels in brain regions central to the control of feeding, reward, and mood regulation; and 3) behavioral tests of anxiety and depression. HCR coupled with intermittent but not daily access to PF exaggerated rats' anorectic response to fluoxetine (p<0.05); was associated with a significant 71% and 58% reduction of 5-HT and dopamine, respectively, in the medial prefrontal cortex; and induced behaviors consistent with models of depression. HCR, irrespective of access to PF, abolished the strong association between 5-HT and dopamine turnover in the nucleus accumbens in control rats (r=0.71 vs. -0.06, p<0.01). Access to PF, irrespective of HCR, reduced hypothalamic dopamine. Together, these findings suggest that a history of frequent food restriction-induced weight fluctuation imposes neurochemical changes that negatively impact feeding and mood regulation.

    Title Modern Instrumental Methods in Forensic Toxicology.
    Date July 2007
    Journal Journal of Analytical Toxicology
    Excerpt

    This article reviews modern analytical instrumentation in forensic toxicology for identification and quantification of drugs and toxins in biological fluids and tissues. A brief description of the theory and inherent strengths and limitations of each methodology is included. The focus is on new technologies that address current analytical limitations. A goal of this review is to encourage innovations to improve our technological capabilities and to encourage use of these analytical techniques in forensic toxicology practice.

    Title Cannabinoid Concentrations in Hair from Documented Cannabis Users.
    Date July 2007
    Journal Forensic Science International
    Excerpt

    Fifty-three head hair specimens were collected from 38 males with a history of cannabis use documented by questionnaire, urinalysis and controlled, double blind administration of delta9-tetrahydrocannabinol (THC) in an institutional review board approved protocol. The subjects completed a questionnaire indicating daily cannabis use (N=18) or non-daily use, i.e. one to five cannabis cigarettes per week (N=20). Drug use was also documented by a positive cannabinoid urinalysis, a hair specimen was collected from each subject and they were admitted to a closed research unit. Additional hair specimens were collected following smoking of two 2.7% THC cigarettes (N=13) or multiple oral doses totaling 116 mg THC (N=2). Cannabinoid concentrations in all hair specimens were determined by ELISA and GCMSMS. Pre- and post-dose detection rates did not differ statistically, therefore, all 53 specimens were considered as one group for further comparisons. Nineteen specimens (36%) had no detectable THC or 11-nor-9-carboxy-THC (THCCOOH) at the GCMSMS limits of quantification (LOQ) of 1.0 and 0.1 pg/mg hair, respectively. Two specimens (3.8%) had measurable THC only, 14 (26%) THCCOOH only, and 18 (34%) both cannabinoids. Detection rates were significantly different (p<0.05, Fishers' exact test) between daily cannabis users (85%) and non-daily users (52%). There was no difference in detection rates between African-American and Caucasian subjects (p>0.3, Fisher's exact test). For specimens with detectable cannabinoids, concentrations ranged from 3.4 to >100 pg THC/mg and 0.10 to 7.3 pg THCCOOH/mg hair. THC and THCCOOH concentrations were positively correlated (r=0.38, p<0.01, Pearson's product moment correlation). Using an immunoassay cutoff concentration of 5 pg THC equiv./mg hair, 83% of specimens that screened positive were confirmed by GCMSMS at a cutoff concentration of 0.1 pg THCCOOH/mg hair.

    Title Team of Teachers.
    Date July 2007
    Journal Journal for Nurses in Staff Development : Jnsd : Official Journal of the National Nursing Staff Development Organization
    Title Intrahemispheric Reorganization of Language in Children with Medically Intractable Epilepsy of the Left Hemisphere.
    Date June 2007
    Journal Journal of the International Neuropsychological Society : Jins
    Excerpt

    We investigated language representation in nine children (six male, three female; 5.6-17.7 years of age) who underwent surgical treatment of medically intractable epilepsy of the left hemisphere. Although interhemispheric reorganization has been previously documented in similar groups, this is the first study to systematically evaluate possible intrahemispheric effects of early insult. All cases had left hemisphere seizure foci and underwent extraoperative stimulation mapping (ESM) for language localization prior to receiving cortical resections. To compare ESM findings across subjects and to assess intrahemispheric reorganization, we developed a novel coregistration technique whereby independent raters plotted two-dimensional (2D) ESM findings in 3D standard space. Expressive language sites identified with ESM were compared with a structural probability map of pars opercularis, or Broca's area. The average difference between independent raters' estimates of 28 language sites was 3.9 mm (SD = 2.0), indicating excellent agreement; the coregistration procedure permitted assessment of 2D ESM findings in 3D standard space. We observed language sites in regions substantially anterior and superior to canonical Broca's area, possibly reflecting intrahemispheric reorganization. Findings suggest that left hemisphere insult in young children may result in anterior displacement of language within the frontal cortex.

    Title Texas Hospitals' Experience with the Texas Advance Directives Act.
    Date May 2007
    Journal Critical Care Medicine
    Excerpt

    The Texas Advance Directives Act (TADA) provides legal immunity for physicians who discontinue life-sustaining treatment judged to be medically inappropriate. The process includes review and affirmation of physicians' judgments by an ethics or medical committee. This study was undertaken to determine awareness of and experience with the medical appropriateness review process at Texas Hospital Association (THA) member hospitals from 1999 to 2004.

    Title Bcl-2 Family Proteins Are Essential for Platelet Survival.
    Date May 2007
    Journal Cell Death and Differentiation
    Excerpt

    Platelets are relatively short-lived, anucleated cells that are essential for proper hemostasis. The regulation of platelet survival in the circulation remains poorly understood. The process of platelet activation and senescence in vivo is associated with processes similar to those observed during apoptosis in nucleated cells, including loss of mitochondrial membrane potential, caspase activation, phosphatidylserine (PS) externalization, and cell shrinkage. ABT-737, a potent antagonist of Bcl-2, Bcl-X(L), and Bcl-w, induces apoptosis in nucleated cells dependent on these proteins for survival. In vivo, ABT-737 induces a reduction of circulating platelets that is maintained during drug therapy, followed by recovery to normal levels within several days after treatment cessation. Whole body scintography utilizing ([111])Indium-labeled platelets in dogs shows that ABT-737-induced platelet clearance is primarily mediated by the liver. In vitro, ABT-737 treatment leads to activation of key apoptotic processes including cytochrome c release, caspase-3 activation, and PS externalization in isolated platelets. Despite these changes, ABT-737 is ineffective in promoting platelet activation as measured by granule release markers and platelet aggregation. Taken together, these data suggest that ABT-737 induces an apoptosis-like response in platelets that is distinct from platelet activation and results in enhanced clearance in vivo by the reticuloendothelial system.

    Title Invasive Breast Cancer.
    Date May 2007
    Journal Journal of the National Comprehensive Cancer Network : Jnccn
    Title The Goals of Ethics Consultation: Rejecting the Role of "ethics Police".
    Date April 2007
    Journal The American Journal of Bioethics : Ajob
    Title Manipulation of Base Excision Repair to Sensitize Ovarian Cancer Cells to Alkylating Agent Temozolomide.
    Date April 2007
    Journal Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
    Excerpt

    To improve the treatment of women with ovarian cancer, we are investigating the modulation of a prominent DNA-damaging agent, temozolomide, by manipulating the DNA base excision repair (BER) pathway via BER inhibitor, methoxyamine, and overexpression of N-methylpurine DNA glycosylase (MPG).

    Title Assembly of Trans-encapsidated Recombinant Viral Vectors Engineered from Tobacco Mosaic Virus and Semliki Forest Virus and Their Evaluation As Immunogens.
    Date April 2007
    Journal Virology
    Excerpt

    RNA virus vectors are attractive vaccine delivery agents capable of directing high-level gene expression without integration into host cell DNA. However, delivery of non-encapsidated RNA viral vectors into animal cells is relatively inefficient. By introducing the tobacco mosaic virus (TMV) origin of assembly into the RNA genome of Semliki Forest virus (SFV), we generated an SFV expression vector that could be efficiently packaged (trans-encapsidated) in vitro by purified TMV coat protein (CP). Using cellular assays, pseudovirus disassembly, RNA replication and reporter gene expression were demonstrated. We also evaluated the immune response to trans-encapsidated recombinant SFV carrying a model antigen gene (beta-galactosidase) in C57/B6 mice. Relative to RNA alone, vector encapsidation significantly improved the humoral and cellular immune responses. Furthermore, reassembly with recombinant TMV CPs permitted the display of peptide epitopes on the capsid surface as either genetic fusions or through chemical conjugation, to complement the immunoreactivity of the encapsidated RNA genetic payload. The SFV vector/TMV CP system described provides an alternative nucleic acid delivery mechanism that is safe, easy to manufacture in vitro and that also facilitates the generation of unique nucleic acid/protein antigen compositions.

    Title Sleep Apnoea and Hypertension: Role of Chemoreflexes in Humans.
    Date March 2007
    Journal Experimental Physiology
    Excerpt

    The link between sleep apnoea and systemic hypertension in humans is well documented. However, a direct causal association between the two diseases independent of comorbidities has been difficult to establish. Comorbidities clearly play an important role in this strong relationship; however, new findings also suggest that sleep apnoea is an independent risk factor for hypertension. This relationship appears to be at least in part a result of chronically elevated sympathetic activity, and therefore manifests as a neurally mediated hypertension. Although the mechanism(s) for this causal relationship of sleep apnoea to hypertension remains ill defined, a growing body of literature suggests that autonomic dysfunction, mediated by abnormal chemoreflex control of sympathetic activity, is a potential mechanism. Abnormal chemoreflex responses to both acute and chronic apnoea or hypoxia have been demonstrated. Hypothesized mechanisms by which chemoreflex dysfunction may contribute to chronically elevated sympathetic tone and ultimately hypertension are explored in this review. Thus, this review focuses on the current evidence linking chemoreflex function to obstructive sleep apnoea and systemic hypertension in humans and provides an analysis of these data and their implications.

    Title Sleep Apnoea and Hypertension: Physiological Bases for a Causal Relation Themed Issue.
    Date March 2007
    Journal Experimental Physiology
    Title Chemotherapeutic Selectivity Conferred by Selenium: a Role for P53-dependent Dna Repair.
    Date March 2007
    Journal Molecular Cancer Therapeutics
    Excerpt

    Selenium in various chemical forms has been the subject of cancer chemoprevention trials, but, more recently, selenium has been used in combination with DNA-damaging chemotherapeutics. Specifically, selenium protected tissues from dose-limiting toxicity and, in fact, allowed delivery of higher chemotherapeutic doses. At the same time, selenium did not protect cancer cells. Therefore, we seek to define the genetic basis for the observed selectivity of selenium in combination chemotherapeutics. The tumor suppressor p53 is mutated in the vast majority of cancers, but is by definition wild-type in nontarget tissues such as bone marrow and gut epithelium, tissues that are often dose-limiting due to DNA damage. We used primary, low-passage mouse embryonic fibroblasts that are wild-type or null for p53 genes to test differential effects of selenium. Seleno-l-methionine, nontoxic by itself, was used to pretreat cell cultures before exposure to UV radiation or UV-mimetic cancer chemotherapy drugs. Seleno-l-methionine pretreatment caused a DNA repair response, which protected from subsequent challenge with DNA-damaging agents. The observed DNA repair response and subsequent DNA damage protection were p53 dependent as neither was observed in p53-null cells. The data suggest that (a) p53 may be an important genetic determinant that distinguishes normal cells from cancer cells, and (b) combinatorial chemotherapeutics that act by p53-dependent mechanisms may enhance chemotherapeutic efficacy by increasing the chemotherapeutic window distinguishing cancer cells from normal cells.

    Title Temporal Lobe Surgery for Intractable Epilepsy in Children: an Analysis of Outcomes in 126 Children.
    Date February 2007
    Journal Neurosurgery
    Excerpt

    OBJECTIVE: Temporal lobectomy is a well-established neurosurgical procedure for temporal lobe epilepsy. In this study, we conducted a retrospective review of children with drug-resistant temporal lobe epilepsy to evaluate seizure outcome after temporal lobe surgery. METHODS: We reviewed the medical records of 126 children who had surgery for temporal lobe epilepsy at The Hospital for Sick Children between 1983 and 2003. The records were examined for preoperative and intraoperative factors that could predict patient outcome after surgery. RESULTS: The mean age at seizure onset was 5.9 years. The mean seizure duration before surgery was 5.6 years. All patients had preoperative computed tomographic scans, magnetic resonance imaging scans, or both. The mean age at the time of surgery was 13.5 years. Sixty-two patients underwent left temporal resections and 64 patients underwent right temporal resections. The histopathology of the temporal resections revealed low-grade brain tumors in 65 children (52%) and cavernous malformations in four children. Ganglioglioma and astrocytoma were the most common tumors encountered. Mesial temporal sclerosis was found in 16 patients (13%), astrogliosis in 15 patients (12%), and cortical dysplasia in eight patients (7%). Postoperative follow-up of at least 2 years was available for 106 patients and ranged up to 13.0 years. Seventy-four percent of patients had an Engel Class I or II outcome. Patients with temporal lobe lesions had better outcomes compared with those without lesions (P < 0.05). Patients without a history of secondary generalization of seizures also had a better outcome when compared with those with secondary generalization. Complications in the form of contralateral homonymous hemianopsia, dysphasia, and infection were found in 5% of patients. Twelve patients had a second temporal lobe procedure for intractable recurrent seizures. After a second procedure, seven patients returned to a seizure-free state. CONCLUSION: Temporal lobe resections for epilepsy in children are effective and safe procedures, with a favorable impact on seizure control. Repeat temporal resections for recurrent seizures may also be effective in restoring a seizure-free outcome to children.

    Title Alpha 2,3-sialyltransferase-iv is Essential for L-selectin Ligand Function in Inflammation.
    Date February 2007
    Journal European Journal of Immunology
    Excerpt

    L-selectin belongs to the C-type lectin family of glycoproteins and is constitutively expressed on most leukocytes. L-selectin mediates leukocyte rolling in inflamed microvessels and high endothelial venules (HEV) via binding to specific carbohydrate structures on selectin ligands. Previous studies using sialidase treatment suggested a role of sialic acid residues in L-selectin-dependent rolling. To investigate the role of the alpha2,3-sialyltransferase (ST3Gal)-IV on L-selectin ligand activity in vivo, we studied leukocyte rolling in inflamed venules of the cremaster muscle and in Peyer's patch HEV of ST3Gal-IV-deficient mice and littermate control mice. In cremaster muscle venules with or without TNF-alpha treatment, L-selectin-dependent rolling was almost completely abolished in ST3Gal-IV(-/-) mice. In both models, L-selectin interacts with P-selectin glycoprotein ligand-1 (PSGL-1) presented by adherent leukocytes and leukocyte fragments, but not with endothelial L-selectin ligands. In contrast, L-selectin-dependent rolling in Peyer's patch HEV, which is mediated by unknown endothelial L-selectin ligands, was not impaired in the absence of ST3Gal-IV. Our in vivo data show that PSGL-1, the molecule responsible for L-selectin-mediated leukocyte interactions in inflammation, is dependent on ST3Gal-IV, while alpha2,3-sialylation by ST3Gal-IV is not necessary for L-selectin ligand activity on high endothelial cells of Peyer's patch HEV.

    Title Use of Physician-specific Data and Flow Sheets to Improve Compliance with Preventive and Screening Health Care Measures.
    Date February 2007
    Journal Connecticut Medicine
    Excerpt

    BACKGROUND: The benefits of preventive and screening health-care measures have been well documented, but physician compliance with these measures has been imperfect. This investigation sought to measure and improve compliance of seven internists with a range of health-care measures. METHODS: This study had two parts. Part 1: Office medical records of seven internists were scored on 36 measures. Physicians were given their individual and group scores to determine if such data would improve future compliance with these measures. A second record review was performed six months later, and the two compliance scores for both individual physician and the group were compared. Part 2: A flow sheet utilizing these 36 measures was custom designed for each physician to determine if this tool would increase compliance rates over those determined in Part 1. RESULTS: Part 1: Baseline compliance with health measures by these internists was approximately 75%. Providing individual and group scores to physicians had no significant effect on compliance with these health-care measures as measured by the second record review. Part 2: Custom designed flow sheets provided comparable compliance rates and were as effective as record review in assessing compliance, with some measures improving and some declining in comparison scores on Part 1. The flow sheet itself, however, did not increase overall compliance scores either for individual physicians or the group as a whole. CONCLUSIONS: Baseline compliance with health-care measures was higher in this investigation than reported elsewhere. Neither data feedback nor redesigned flow sheets increased overall compliance rates, but flow sheets were superior in documenting some frequently updated items, such as medication lists. Flow sheets were inexpensive and easy to implement. Additionally, flow sheets allowed for more rapid assessment of physician performance than time-consuming chart review. Until superior methods are widely available, the use of flow sheets in ambulatory care should be encouraged.

    Title Role of Advocates in Research: the Research Advocate Network (ran) As a Model for Advocate Participation.
    Date January 2007
    Journal Journal of the National Comprehensive Cancer Network : Jnccn
    Title Tmv-peptide Fusion Vaccines Induce Cell-mediated Immune Responses and Tumor Protection in Two Murine Models.
    Date January 2007
    Journal Vaccine
    Excerpt

    Fusion of peptides to viral carriers has proven an effective method for improving cellular immunity. In this study we explore the ability of a plant virus, Tobacco mosaic virus (TMV), to stimulate cellular immunity by interacting directly with immune cells. Fluorescently labeled TMV was incubated in vitro with murine spleen or lymph node cells, and near quantitative labeling of lymphocytes was achieved after 2 h, which persisted for up to 48 h. Direct TMV uptake and upregulation of the CD86 activation marker was measured in nearly all dendritic cells (DCs) by flow cytometry. To demonstrate that TMV can also provide functional antigen delivery and immune stimulation in vivo, two well-characterized T-cell epitopes that provide protection against tumor challenge in mice were fused to TMV coat protein by genetic manipulation, or by chemical conjugation. Vaccination of C57BL/6 mice elicited measurable cellular responses by interferon gamma (IFN gamma) ELISpot and resulted in significantly improved protection from tumor challenge in both the EG.7-Ova and B16 melanoma models. From these results we conclude that TMV was an effective antigen carrier for inducing cellular immune responses to less than 1 microg of peptide.

    Title Cyanide and Thiocyanate in Human Saliva by Gas Chromatography-mass Spectrometry.
    Date December 2006
    Journal Journal of Analytical Toxicology
    Excerpt

    A method is described for simultaneous determination of cyanide (CN) and thiocyanate (SCN) in human saliva, or oral fluid. SCN concentrations in body fluids appeared to be important in classifying patients as smokers or nonsmokers, in determining some clinical conditions, and in specimen validity testing in forensic drug testing. The human saliva samples were diluted and the anions were separated by an extractive alkylation technique. Tetrabutylammonium sulfate was used as phase-transfer catalyst and pentafluorobenzyl bromide as the derivatizing agent. The products were analyzed by a gas chromatography-mass spectrometry (GC-MS) with selected ion monitoring method. 2,5-Dibromotoluene was used as internal standard for quantitation of CN and SCN in saliva. The calibration plot was linear over the concentration range from 1 to 100 micromol/L (0.026-2.60 microg/mL) for CN (R=0.9978) and 5 to 200 micromol/L (0.29-11.6 microg/mL) for SCN (R=0.9996). The method was used to examine 10 saliva specimens. The concentration ranged from 4.8 to 29 micromol/L (0.13-0.75 microg/mL) for CN and 293 to 1029 micromol/L (17-59.7 microg/mL) for SCN. The SCN results were similar to those obtained from a method using oxidation of SCN to CN with colorimetric detection (R=0.9882). The proposed GC-MS confirmatory method was found useful when the concentrations of CN and SCN in saliva needed to be accurately determined.

    Title Impact of a Palliative Care Service on In-hospital Mortality in a Comprehensive Cancer Center.
    Date December 2006
    Journal Journal of Palliative Medicine
    Excerpt

    Palliative care services provide symptom control and psychosocial support for dying patients and their families. These services are not available in many cancer centers and tertiary hospitals. The purpose of this study was to review the impact of a palliative care program, established in 1999, on overall in-hospital mortality.

    Title A Nonself Recognition Gene Complex in Neurospora Crassa.
    Date November 2006
    Journal Genetics
    Excerpt

    Nonself recognition is exemplified in the fungal kingdom by the regulation of cell fusion events between genetically different individuals (heterokaryosis). The het-6 locus is one of approximately 10 loci that control heterokaryon incompatibility during vegetative growth of N. crassa. Previously, it was found that het-6-associated incompatibility in Oak Ridge (OR) strains involves two contiguous genes, het-6 and un-24. The OR allele of either gene causes "strong" incompatibility (cell death) when transformed into Panama (PA)-background strains. Several remarkable features of the locus include the nature of these incompatibility genes (het-6 is a member of a repetitive gene family and un-24 also encodes the large subunit of ribonucleotide reductase) and the observation that un-24 and het-6 are in severe linkage disequilibrium. Here, we identify "weak" (slow, aberrant growth) incompatibility activities by un-24PA and het-6PA when transformed separately into OR strains, whereas together they exhibit an additive, strong effect. We synthesized strains with the new allelic combinations un-24PA het-6OR and un-24OR het-6PA, which are not found in nature. These strains grow normally and have distinct nonself recognition capabilities but may have reduced fitness. Comparing the Oak Ridge and Panama het-6 regions revealed a paracentric inversion, the architecture of which provides insights into the evolution of the un-24-het-6 gene complex.

    Title Estimating Time of Last Oral Ingestion of Cannabis from Plasma Thc and Thccooh Concentrations.
    Date November 2006
    Journal Therapeutic Drug Monitoring
    Excerpt

    Estimating the time of last cannabis use is important in assessing possible impairment of drivers involved in accidents, in verifying accuracy of court testimony and in the future, helpful in therapeutic monitoring of cannabis agonists. In 1992, Huestis et al developed model 1, based on plasma Delta-tetrahydrocannabinol (THC) concentrations, and model 2, on plasma 11-nor-9-carboxy-Delta(9)-tetrahydrocannbinol/THC ratios, that predicted 95% confidence intervals for time of last cannabis use. These models seemed to be valuable when applied to the small amount of data from published studies of oral ingestion, a route of administration more popular with the advent of cannabis therapies. A study was designed to further validate the models after oral ingestion of THC, and to determine whether they could predict last usage after multiple oral doses. Eighteen subjects in IRB-approved studies participated after providing informed consent. Each of 12 subjects in one group received a single 10 mg oral dose of dronabinol (synthetic THC). In another protocol, 6 subjects received 4 different oral daily doses, divided into thirds and administered with meals for 5 consecutive days. There was a 10-day washout period between each dosing regimen. Daily doses were 0.39, 0.47, and 14.8 mg THC in hemp oil and 7.5 mg dronabinol. Blood specimens were collected throughout the study and analyzed for plasma THC and 11-nor-9-carboxy-Delta(9)-tetrahydrocannbinol by gas chromatography/mass spectrometry with limits of quantification (LOQs) of 0.5 and 1.0 ng/mL, respectively. Actual times between ingestion of THC and blood collection spanned 0.5 to 16 hours. All plasma specimens with analyte concentrations >LOQ (n=90) were evaluated. Models 1 and 2 correctly predicted time of last THC ingestion for 74.4% and 90.0% of plasma specimens, respectively. 96.7% of predicted times were correct with one overestimate and 2 underestimates using the time interval defined by the lowest and highest 95% confidence limit of both models. These results provide further evidence of the usefulness of the predictive models in estimating the time of last oral THC ingestion after single or multiple doses.

    Title Protection of Rabbits Against Cutaneous Papillomavirus Infection Using Recombinant Tobacco Mosaic Virus Containing L2 Capsid Epitopes.
    Date October 2006
    Journal Vaccine
    Excerpt

    Cottontail rabbit papillomavirus (CRPV) and rabbit oral papillomavirus (ROPV) represent distantly related, cutaneous and mucosal tissue tropic papillomaviruses respectively that can infect the same host. These two viruses were used to test the effectiveness of an L2 peptide-based vaccine (aa 94-122) that was delivered on the surface of recombinant tobacco mosaic virus (rTMV) particles. Groups of NZW rabbits received combinations of CRPVL2, ROPVL2 and CRPV+ROPVL2 rTMV vaccines, and were then challenged with infectious CRPV and ROPV. The rabbits developed antibodies that reacted to whole L2 protein and these sera were able to neutralize CRPV pseudovirions at half-maximal titers that were between 50 and 500. Rabbits receiving the CRPV L2 vaccine alone or in combination with ROPV L2 vaccines were completely protected against CRPV infections. Those rabbits vaccinated with the ROPV L2 vaccines showed a weak response in some rabbits against CRPV infection. These studies demonstrate that L2-based vaccines provide strong protection against experimental papillomavirus infection that is most likely based upon the induction of virus-neutralizing antibody. Notably, we observed some limited cross-protection induced by the L2 sequences tested in these vaccines. Finally, the study demonstrated that rTMV were excellent agents for the induction of strong protection in a pre-clinical disease model of papillomavirus infection.

    Title Breast Cancer Screening and Diagnosis.
    Date October 2006
    Journal Journal of the National Comprehensive Cancer Network : Jnccn
    Title Should Possible Disparities and Distrust Trump Do-no-harm?
    Date October 2006
    Journal The American Journal of Bioethics : Ajob
    Title Phytochemistry and Antifungal Properties of the Newly Discovered Tree Pleodendron Costaricense.
    Date September 2006
    Journal Journal of Natural Products
    Excerpt

    Gas chromatography analysis of the essential oils of leaves and bark collected from the newly discovered tree Pleodendron costaricense identified alpha-pinene, beta-pinene, beta-myrcene, beta-thujene, and beta-caryophyllene as their major constituents. Phytochemical analysis of P. costaricense parts led to the isolation and identification of delta-tocotrienol, beta-sitosterol, four known drimane-type sesquiterpenes, cinnamodial (1), cinnamosmolide (2), polygodial (3), and mukaadial (4), and two new compounds, a drimane-type sesquiterpene, parritadial (5), and an eremophilane-type sesquiterpene, pleodendione (6). Antifungal assays with the two major compounds, 1 and 2, were carried out, and results showed a high activity of 1 against Alternaria alternata (MIC = 3.9 microg/mL), Candida albicans azole-resistant strain D10, and Wangiella dermatitides (MICs = 15.6 microg/mL). Compound 2 showed less potent antifungal activities than 1 but was more effective against Candida albicans azole-resistant strain CN1A (MIC = 23.4 microg/mL) and Pseudallescheria boydii (MIC = 78.1 microg/mL). A combination of the dialdehyde sesquiterpenes with dillapiol showed a synergistic antifungal effect with 1 and an additive effect with 4 and 5.

    Title Development of Aflp-derived, Functionally Specific Markers for Environmental Persistence Studies of Fungal Strains.
    Date August 2006
    Journal Canadian Journal of Microbiology
    Excerpt

    The ability to rapidly identify and quantify a microbial strain in a complex environmental sample has widespread applications in ecology, epidemiology, and industry. In this study, we describe a rapid method to obtain functionally specific genetic markers that can be used in conjunction with standard or real-time polymerase chain reaction (PCR) to determine the abundance of target fungal strains in selected environmental samples. The method involves sequencing of randomly cloned AFLP (amplified fragment length polymorphism) products from the target organism and the design of PCR primers internal to the AFLP fragments. The strain-specific markers were used to determine the fate of three industrially relevant fungi, Aspergillus niger, Aspergillus oryzae, and Chaetomium globosum, during a 4 month soil microcosm experiment. The persistence of each of the three fungal strains inoculated separately into intact soil microcosms was determined by PCR analyses of DNA directly extracted from soil. Presence and absence data based on standard PCR and quantification of the target DNA by real-time PCR showed that all three strains declined after inoculation (approximately 14-, 32-, and 4-fold for A. niger, A. oryzae, and C. globosum, respectively) but remained detectable at the end of the experiment, suggesting that these strains would survive for extended periods if released into nature.

    Title Heterokaryon Incompatibility Function of Barrage-associated Vegetative Incompatibility Genes (vic) in Cryphonectria Parasitica.
    Date August 2006
    Journal Mycologia
    Excerpt

    Six vegetative incompatibility (vic) loci have been identified in Cryphonectria parasitica based on barrage formation during mycelial interactions. We used hygromycin B- and benomyl-resistance as forcing markers in C. parasitica strains to test whether heteroallelism at each vic locus prevents heterokaryon formation following mycelial interactions. Paired strains that had allelic differences at any of vic1, 2, 3, 6 or 7 but not vic4 displayed heterokaryon incompatibility function, as recognized by slow growth or aberrant morphology. While clearly forming barrages in mycelial interactions, paired strains with different alleles at vic4 formed stable heterokaryons. With examples from other fungi, this inconsistency at vic4 suggests that barrage formation and heterokaryon incompatibility are not different manifestations of the same process. Rather, the evidence indicates that heterokaryon incompatibility represents a component of a vegetative incompatibility system that may also use cell-surface or extracellular factors to trigger programmed cell death to modulate nonself recognition in fungi.

    Title Loss of Lag-response Curvilinearity of Indices of Heart Rate Variability in Congestive Heart Failure.
    Date August 2006
    Journal Bmc Cardiovascular Disorders
    Excerpt

    BACKGROUND: Heart rate variability (HRV) is known to be impaired in patients with congestive heart failure (CHF). Time-domain analysis of ECG signals traditionally relies heavily on linear indices of an essentially non-linear phenomenon. Poincaré plots are commonly used to study non-linear behavior of physiologic signals. Lagged Poincaré plots incorporate autocovariance information and analysis of Poincaré plots for various lags can provide interesting insights into the autonomic control of the heart. METHODS: Using Poincaré plot analysis, we assessed whether the relation of the lag between heart beats and HRV is altered in CHF. We studied the influence of lag on estimates of Poincaré plot indices for various lengths of beat sequence in a public domain data set (PhysioNet) of 29 subjects with CHF and 54 subjects with normal sinus rhythm. RESULTS: A curvilinear association was observed between lag and Poincaré plot indices (SD1, SD2, SDLD and SD1/SD2 ratio) in normal subjects even for a small sequence of 50 beats (p value for quadratic term 3 x 10-5, 0.002, 3.5 x 10-5 and 0.0003, respectively). This curvilinearity was lost in patients with CHF even after exploring sequences up to 50,000 beats (p values for quadratic term > 0.5). CONCLUSION: Since lagged Poincaré plots incorporate autocovariance information, these analyses provide insights into the autonomic control of heart rate that is influenced by the non-linearity of the signal. The differences in lag-response in CHF patients and normal subjects exist even in the face of the treatment received by the CHF patients.

    Title Molecular Systematics of Hispaniolan Pupfishes (cyprinodontidae: Cyprinodon): Implications for the Biogeography of Insular Caribbean Fishes.
    Date July 2006
    Journal Molecular Phylogenetics and Evolution
    Excerpt

    We used sequence variation in the mtDNA control-region and ND2 and cyt b genes to assess the systematics and biogeography of the five species of pupfish (Cyprinodon) on Hispaniola. These include four endemics, the relatively large-bodied Cyprinodon bondi, Cyprinodon nichollsi, and Cyprinodon sp., each from a separate lake in southwestern Hispaniola, and Cyprinodon higuey from a coastal lake in eastern Hispaniola. The fifth species consists of coastal populations referable to Cyprinodon variegatus riverendi. The results indicate that Hispaniola has been invaded by at least two forms, first by a late Pliocene progenitor of Cyprinodon variegatus ovinus and the large-bodied Hispaniolan species, and, more recently, by one or more ancestral forms allied with Cyprinodon variegatus variegatus and C. v. riverendi. Levels of divergence indicate that large expanses of open sea have not acted as long-term barriers to inter-island dispersal of cyprinodontiform fishes. This study, together with the molecular systematics of other insular Caribbean fishes, indicates that most insular groups originated from late Neogene dispersal from the mainland. The patterns of mtDNA variation in Cyprinodon showed little congruence with the species/subspecies taxonomy.

    Title Induction of Lfa-1-dependent Neutrophil Rolling on Icam-1 by Engagement of E-selectin.
    Date July 2006
    Journal Microcirculation (new York, N.y. : 1994)
    Excerpt

    To study rolling of mouse neutrophils on E-selectin and ICAM-1 in an ex vivo flow chamber system.

    Title The Copy-number of Plasmids and Other Genetic Elements Can Be Determined by Sybr-green-based Quantitative Real-time Pcr.
    Date July 2006
    Journal Journal of Microbiological Methods
    Excerpt

    In this study, we explored whether SYBR Green-based quantitative real-time PCR (qPCR) could be used to determine the copy number of a plasmid and whether the method was broadly applicable to chromosomally encoded genetic elements often occurring in multiple copies, such as rRNA genes and insertion sequences (IS). Three different template sources (whole cells, total DNA, and restriction-enzyme digested total DNA) derived from the bacterium Comamonas sp. strain JS46 were analyzed by qPCR using primer-pairs targeting plasmid pJS46 and three chromosomally encoded sequences (16S rDNA, ISCsp1, and IS1071). The difference between threshold cycle values, C(T), of amplicons targeting these elements and of an amplicon targeting the single-copy reference element mnbA (chromosomally encoded) was used to establish DeltaC(T). DeltaC(T) values were then used to derive copy number. For pJS46, qPCR analyses of whole cells and total DNA underestimated the copy number of pJS46 approximately 7-fold and approximately 2.5-fold, respectively, whereas copy number values derived from qPCR analyses of digested total DNA were comparable to those derived from Southern blot (SB) analyses. In contrast, for the chromosomally encoded elements, qPCR analyses of all three template sources gave copy number values that were virtually identical to or differed by approximately 2 from copy number values derived by SB analysis. These data indicate that qPCR can be used to estimate the copy number of various genetic elements but that the accuracy of qPCR-derived values is affected by the template source.

    Title Modified Tobacco Mosaic Virus Particles As Scaffolds for Display of Protein Antigens for Vaccine Applications.
    Date June 2006
    Journal Virology
    Excerpt

    Display of peptides or proteins in an ordered, repetitive array, such as on the surface of a virus-like particle, is known to induce an enhanced immune response relative to vaccination with the "free" protein antigen. The coat protein of Tobacco mosaic virus (TMV) can accommodate short peptide insertions into the primary sequence, but the display of larger protein moieties as genetic fusions to the capsid protein has not been possible. We employed a randomized library approach to introduce a reactive lysine at the externally located amino terminus of the coat protein, which facilitated biotinylation of the capsid. To characterize display of heterologous proteins on the virion surface, we bound a model antigen (green fluorescent protein (GFP)-streptavidin (SA), expressed and purified from plants) to the biotinylated TMV particles, creating a GFP-SA decorated virus particle. A GFP-SA tetramer loading of 26% was obtained, corresponding to approximately 2200 GFP moieties displayed per intact virion. We evaluated the immunogenicity of GFP decorated virions in both mice and guinea pigs and found augmented humoral IgG titers in both species, relative to unbound GFP-SA tetramer. Next, we fused an N-terminal fragment of the Canine oral papillomavirus L2 protein to streptavidin. With TMV display, the L2 protein fragment was significantly more immunogenic than uncoupled antigen when tested in mice. By demonstrating the presentation of whole proteins, this study expands the utility of TMV as a vaccine scaffold beyond that which is possible by genetic manipulation.

    Title Perceptual Moments of Conscious Visual Experience Inferred from Oscillatory Brain Activity.
    Date June 2006
    Journal Proceedings of the National Academy of Sciences of the United States of America
    Excerpt

    Transient periods of synchronized oscillating neuronal discharges in the brain have been proposed to support the discrete perceptual moments underlying conscious visual experience. However, the information content of these perceptual moments remains a critical challenge to the understanding of consciousness. We uncovered this information content in four observers who consciously perceived each interpretation of the ambiguous Dali painting Slave Market with the Disappearing Bust of Voltaire. For each individual observer, we isolated the stimulus spatial frequency (SF) features underlying their overt judgments of the input as "the nuns" and "Voltaire". Every 2 ms between stimulus onset and overt response, we derived the sensitivity of the observer's oscillatory brain activity (in the theta, alpha, and beta bandwidths) to these SF features. Then, in each bandwidth, we estimated the moments (between stimulus onset and perceptual judgment) when perception-specific SF features were maximally integrated, corresponding to perceptual moments. We show that the centroparietal beta oscillations support perceptual moments underlying the conscious perception of the nuns, whereas theta oscillations support the perception of Voltaire. For both perceptions, we reveal the specific information content of these perceptual moments.

    Title Selenium Protection from Dna Damage Involves a Ref1/p53/brca1 Protein Complex.
    Date May 2006
    Journal Anticancer Research
    Excerpt

    Selenium, in the form of seleno-L-methionine (SeMet), induced Redox-factor-1 (Ref1) and p53 proteins in normal human and mouse fibroblasts. Ref1 and p53 are known to be associated with each other, resulting in enhanced sequence-specific DNA binding by p53 and transactivation of p53-regulated effector genes. SeMet preferentially induced the DNA repair branch of the p53 pathway, while apoptosis and cell cycle arrest were unaffected. Accordingly, pretreatment with SeMet protected normal fibroblasts from subsequent DNA damage. In the current study, Brca1 and Ref1 were shown to interact concurrently with p53 in targeting a SeMet-induced DNA repair response. Moreover, like p53 and Ref1, Brca1 was required for SeMet-mediated DNA damage protection, as brca1 -/- mouse fibroblasts were not protected from UV-radiation by SeMet treatment. These findings indicate that besides p53 and Ref1, Brca1 is required for selenium protection from DNA damage. The data are consistent with selective induction of the DNA repair branch of the p53 pathway by SeMet.

    Title Development of a Quantitative Real-time Polymerase Chain Reaction Method for Monitoring Cebpa Mutations in Normal Karyotype Acute Myeloid Leukaemia.
    Date May 2006
    Journal British Journal of Haematology
    Title A Novel K509i Mutation of Kit Identified in Familial Mastocytosis-in Vitro and in Vivo Responsiveness to Imatinib Therapy.
    Date April 2006
    Journal Leukemia Research
    Excerpt

    KIT mutation has been implicated in sporadic mastocytosis, yet clusters in only a few sites in the molecule. For those malignancies associated with KIT mutation or over-expression, imatinib offers a specific therapeutic option, yet it has no effect on D816V mutation commonly seen in sporadic mastocytosis. The majority of cases of familial mastocytosis seem to lack KIT mutation. We report a kindred with mastocytosis in whom in vitro and in vivo sensitivity to imatinib was demonstrated. Mutation analysis of the KIT coding region in this family identified a novel A>T mutation at nucleotide 1547 [K509I] in exon 9 in both of the affected patients.

    Title Does Prosopagnosia Take the Eyes out of Face Representations? Evidence for a Defect in Representing Diagnostic Facial Information Following Brain Damage.
    Date March 2006
    Journal Journal of Cognitive Neuroscience
    Excerpt

    One of the most impressive disorders following brain damage to the ventral occipitotemporal cortex is prosopagnosia, or the inability to recognize faces. Although acquired prosopagnosia with preserved general visual and memory functions is rare, several cases have been described in the neuropsychological literature and studied at the functional and neural level over the last decades. Here we tested a brain-damaged patient (PS) presenting a deficit restricted to the category of faces to clarify the nature of the missing and preserved components of the face processing system when it is selectively damaged. Following learning to identify 10 neutral and happy faces through extensive training, we investigated patient PS's recognition of faces using Bubbles, a response classification technique that sampled facial information across the faces in different bandwidths of spatial frequencies [Gosselin, F., & Schyns, P. E., Bubbles: A technique to reveal the use of information in recognition tasks. Vision Research, 41, 2261-2271, 2001]. Although PS gradually used less information (i.e., the number of bubbles) to identify faces over testing, the total information required was much larger than for normal controls and decreased less steeply with practice. Most importantly, the facial information used to identify individual faces differed between PS and controls. Specifically, in marked contrast to controls, PS did not use the optimal eye information to identify familiar faces, but instead the lower part of the face, including the mouth and the external contours, as normal observers typically do when processing unfamiliar faces. Together, the findings reported here suggest that damage to the face processing system is characterized by an inability to use the information that is optimal to judge identity, focusing instead on suboptimal information.

    Title Lc/ms/ms Measurement of Penicillin G in Bovine Plasma, Urine, and Biopsy Samples Taken from Kidneys of Standing Animals.
    Date March 2006
    Journal Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences
    Excerpt

    Methods for the measurement of penicillin concentration in bovine plasma, kidney and urine were developed and validated. Detection was based on liquid chromatography/tandem mass spectrometry (LC/MS/MS). Phenethecillin was used as an internal standard. Plasma was extracted with acetonitrile using a method with a calculated limit of quantitation (LOQ) of 12 ng/mL. Kidney samples were homogenized in water and acetonitrile, then cleaned up on C18-bonded silica SPE cartridges. The LOQ of this procedure was 10 ng/g. Urine samples were diluted, filtered, and analyzed directly. The LOQ of this procedure was 63 ng/mL. The overall accuracy for plasma was 103% with coefficient of variation (CV) of 3%; for kidney, 96% and 11%, respectively, and for urine, 98% and 4%, respectively. These methods were applied to the analysis of plasma, urine, and kidney biopsy samples taken from standing animals that had been dosed with penicillin.

    Title A Rare Ganglioneuroblastoma Secreting Dopamine and the Value of Its Measurement in Diagnosis and Prognosis.
    Date March 2006
    Journal Annals of Clinical Biochemistry
    Excerpt

    A case is described of a patient with a ganglioneuroblastoma, initially located in the right adrenal, which produced an excess of dopamine (7646 and 7959 nmol/24 h), approximately two and a half times the upper limit of the normal daily urine output. The urinary excretion of noradrenaline, adrenaline and methylated derivatives was always within the normal reference ranges. The patient was generally well, with normal blood pressure and only mild flushes. Two years after surgical resection, recurrence was indicated by an increase in urinary dopamine (8507 nmol/24 h); it was located in the tumour bed and left side of the neck by CT and (123)I MIBG scans. The patient was treated with a high dose of (131)I MIBG, with subsequent reduction in dopamine production. This was repeated on four other occasions, the latest being in January 2005. The output of dopamine was thus used as a marker of tumour diagnosis and progression and it is recommended that the assay of dopamine be included in the screening of catecholamine-secreting tumours to avoid possible misdiagnosis.

    Title Detection of Penicillin Residues in Bovine Oral Fluid (saliva) by Liquid Chromatography/tandem Mass Spectrometry.
    Date February 2006
    Journal Rapid Communications in Mass Spectrometry : Rcm
    Title Comparing Language Lateralization Determined by Dichotic Listening and Fmri Activation in Frontal and Temporal Lobes in Children with Epilepsy.
    Date February 2006
    Journal Brain and Language
    Excerpt

    We investigated the relationship between ear advantage scores on the Fused Dichotic Words Test (FDWT), and laterality of activation in fMRI using a verb generation paradigm in fourteen children with epilepsy. The magnitude of the laterality index (LI), based on spatial extent and magnitude of activation in classical language areas (BA 44/45, 21/22, 39) differed significantly for patients classified with unilateral left, compared to bilateral, language representation based on FDWT scores. Concordance with fMRI was higher for those classified with unilateral left, than bilateral language representation on the FDWT. Of note, asymmetry in temporal lobe, rather than frontal lobe, activation was more strongly related to the LI from the dichotic listening test. This study shows that the FDWT can provide a quick and valid estimate of lateralization in pre-surgical candidates, which can be readily adopted for other clinical or research purposes when an estimate of language dominance is desired.

    Title I Just Want to Be Normal: a Qualitative Study Exploring How Children and Adolescents View the Impact of Intractable Epilepsy on Their Quality of Life.
    Date February 2006
    Journal Epilepsy & Behavior : E&b
    Excerpt

    This qualitative study explores how children and adolescents with medically refractory seizures experience the impact of epilepsy on their quality of life (QOL) within the domains of physical, emotional/behavioral, social, and cognitive/academic function. Semi-structured, open-ended interviews were conducted with 49 participants (7-18 years old). These narratives constituted our data source. Analyses involved inductive generation of themes/subthemes and connection of these themes to generate a theoretical representation of their relationships. These themes reflected the negative impact of epilepsy on QOL: physical-excessive fatigue as a barrier to academic and social pursuits; emotional/behavioral-intermittent emotional distress heightened by epilepsy-related factors such as unpredictability of seizures; social-profound social isolation; and cognitive/academic-discontinuous, fragmented learning. Youths perceive seizures as the major barrier to their sense of normalcy, setting them apart from others. Findings provide direction for assessment and evidence for developing or enhancing clinical interventions and community/school-based programs that might mitigate some of these negative experiences.

    Title Psychosocial Comorbidity in Epilepsy.
    Date February 2006
    Journal Advances in Neurology
    Title Neuropsychological Profiles.
    Date February 2006
    Journal Advances in Neurology
    Title Optical Spectra of Lactoperoxidase As a Function of Solvent.
    Date January 2006
    Journal Biochemistry
    Excerpt

    The iron of lactoperoxidase is predominantly high-spin at ambient temperature. Optical spectra of lactoperoxidase indicate that the iron changes from high-spin to low-spin in the temperature range from room temperature to 20 K. The transformation is independent of whether the enzyme is in glycerol/water or solid sugar glass. Addition of the inhibitor benzohydroxamic acid increases the amount of the low-spin form, and again the transformation is independent of whether the protein is in an aqueous solution or a nearly anhydrous sugar. In contrast to lactoperoxidase, horseradish peroxidase remains high-spin over the temperature excursion in both solvents and with addition of benzohydroxamic acid. We conclude that details of the heme pocket of lactoperoxidase allow ligation changes with temperature that are dependent upon the apoprotein but independent of solvent fluctuations. At low pH, lactoperoxidase shows a solvent-dependent transition; the high-spin form is predominant in anhydrous sugar glass, but in the presence of water, the low-spin form is also present in abundance. The active site of lactoperoxidase is not as tightly constrained at low pH as at neutrality, though the enzyme is active over a wide pH range.

    Title Production of Fumaric Acid in 20-liter Fermentors.
    Date January 2006
    Journal Applied Microbiology
    Excerpt

    The conditions necessary for the production of fumaric acid in 20-liter fermentors by fermentation of glucose with Rhizopus arrhizus strain NRRL 2582 were determined. Continuous neutralization of fumaric acid was necessary for optimal yields. Yields of the calcium salt were in excess of 65 g of fumaric acid from 100 g of sugar consumed during fermentation of sugar concentrations of 10 to 16%. Conditions established for calcium fumarate production include a simple mineral salts medium, 0.5 v:v:min aeration rate, 300 rev/min agitation rate in a baffled tank, 33 C incubation temperature, CaCO(3) to neutralize the acid formed, and a 4 to 5% (v/v) vegetative inoculum. A suitable procedure and medium for the preparation of a vigorous vegetative inoculum were established. The tendency for calcium fumarate fermentations to foam excessively was controlled with a proper antifoam agent added prior to sterilization of the medium and again at daily intervals during fermentation. The production of soluble sodium or potassium fumarates was inhibited when the concentration of fumarates reached 3.5 to 4.0%. No means of overcoming this inhibition was found. Starches and certain other grain-derived carbohydrates were fermented to form calcium fumarate in flask experiments with approximately the same efficiency as was glucose.

    Title Estimating the Time of Last Cannabis Use from Plasma Delta9-tetrahydrocannabinol and 11-nor-9-carboxy-delta9-tetrahydrocannabinol Concentrations.
    Date January 2006
    Journal Clinical Chemistry
    Excerpt

    Knowing the time cannabis was last used is important for determining impairment in accident investigations and clinical evaluations. Two models for predicting time of last cannabis use from single plasma cannabinoid concentrations-model I, using Delta(9)-tetrahydrocannabinol (THC), and model II, using the concentration ratio of 11-nor-9-carboxy-THC (THCCOOH) to THC-were developed and validated from controlled drug administration studies. Objectives of the current study were to extend the validation by use of a large number of plasma samples collected after administration of single and multiple doses of THC and to examine the effectiveness of the models at low plasma cannabinoid concentrations.

    Title Association Between Acquired Uniparental Disomy and Homozygous Gene Mutation in Acute Myeloid Leukemias.
    Date December 2005
    Journal Cancer Research
    Excerpt

    Genome-wide single nucleotide polymorphism analysis has revealed large-scale cryptic regions of acquired homozygosity in the form of segmental uniparental disomy in approximately 20% of acute myeloid leukemias. We have investigated whether such regions, which are the consequence of mitotic recombination, contain homozygous mutations in genes known to be mutational targets in leukemia. In 7 of 13 cases with uniparental disomy, we identified concurrent homozygous mutations at four distinct loci (WT1, FLT3, CEBPA, and RUNX1). This implies that mutation precedes mitotic recombination which acts as a "second hit" responsible for removal of the remaining wild-type allele, as has recently been shown for the JAK2 gene in myeloproliferative disorders.

    Title Functional Dyspepsia Pathogenesis and Therapeutic Options--implications for Management.
    Date December 2005
    Journal Digestive and Liver Disease : Official Journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver
    Excerpt

    Functional dyspepsia is far more common than dyspepsia due to organic disease, both in the community and general practice. Proposed aetiopathogenic factors include gastric acid, Helicobacter pylori infection, delayed emptying, hypersensitivity or impaired accommodation of the stomach, dysfunction of the duodenum or brain-gut axis, psychosocial morbidity and post-infective mucosal damage. More effective therapy will depend on the development of drugs targeted at these putative pathophysiological mechanisms. On current evidence tricyclic antidepressants appear to be more effective than either acid suppressants or H. pylori eradication.

    Title Lack of Prognostic Importance of Reverse-transcriptase Polymerase Chain Reaction Detection of Circulating Messenger Rna in Patients with Melanoma.
    Date November 2005
    Journal Plastic and Reconstructive Surgery
    Excerpt

    BACKGROUND: Molecular serologic markers for detecting early melanoma metastases have been described. The objective of this study was to determine whether reverse-transcriptase polymerase chain reaction detection of circulating tyrosinase messenger RNA (mRNA) can identify the presence of subclinical metastases and predict subsequent clinical recurrence in surgically treated melanoma patients who are at significant risk for relapse. METHODS: Preoperative peripheral blood samples of disease-free melanoma patients, disease stage ranging from I to IV, were analyzed for the presence of tyrosinase mRNA by semiquantitative reverse-transcriptase polymerase chain reaction as a putative marker for circulating melanoma cells. Multivariate analysis was performed to evaluate the prognostic value of tyrosinase mRNA in the blood and in the correlating pathologic stage of disease with recurrence and survival. RESULTS: The study group consisted of 96 patients. The mean age was 54 years (range, 24 to 83 years). The mean Breslow thickness was 3 mm (range, 0.9 to 21 mm). Circulating melanoma cells were detected in 66 patients (69 percent). Blood polymerase chain reaction positivity by American Joint Committee on Cancer stage was as follows: stage I, 19 of 28 patients (68 percent); stage II, 17 of 25 patients (68 percent); stage III, 28 of 41 patients (68 percent); and stage IV, two of two patients (100 percent). Tyrosinase detection was not associated with stage of disease (p = 0.77). At a median follow-up of 30 months, disease recurred in 21 patients (22 percent), and 15 patients (16 percent) died. Disease stage of the patients correlated with recurrence (p < 0.0001) and death (p < 0.0001). The finding of mRNA tyrosinase in peripheral blood samples was not associated with recurrence (p = 0.1) or death (p = 0.77). CONCLUSIONS: The use of polymerase chain reaction to detect circulating tyrosinase mRNA in peripheral blood does not correlate with traditional prognostic indicators in patients with cutaneous melanoma and does not appear to be an effective prognostic tool.

    Title Breast Cancer.
    Date September 2005
    Journal Journal of the National Comprehensive Cancer Network : Jnccn
    Title Phosphorylation of Human P53 at Serine 46 Determines Promoter Selection and Whether Apoptosis is Attenuated or Amplified.
    Date September 2005
    Journal The Journal of Biological Chemistry
    Excerpt

    The capacity of DNA damaging agents to induce apoptosis is regulated by target gene induction by p53. We found that p53 targeted MDM2 in cells in which DNA repair was occurring, but persistent DNA damage induced by chemotherapy led p53 to selectively target PTEN. High dose chemotherapy induced the phosphorylation of p53 on serine 46, whereas low dose chemotherapy did not. A nonphosphorylatable serine 46 to alanine p53 mutant (S46A) targeted the MDM2 promoter in preference to that for PTEN. A serine 46 to aspartate mutant (S46D, a phosphorylation mimic) targeted PTEN in preference to MDM2. These observations show that phosphorylation of serine 46 in p53 is sufficient for it to induce the PTEN (phosphatase and tensin homolog deleted on chromosome ten) tumor suppressor protein in preference to MDM2. S46A induced significantly less cell death than the S46D in cells. The phosphorylation-induced change of p53 promoter targeting suppresses the induction of MDM2 and the formation of the autoregulatory feedback loop. Induction of PTEN by p53 followed by expression of PTEN inhibits AKT-induced translocation of MDM2 into the nucleus and sustains p53 function. The protection of p53 from MDM2 by PTEN and the damage-induced activation of PTEN by phosphorylated p53 leads to the formation of an apoptotic amplification cycle in which p53 and PTEN coordinately increase cellular apoptosis.

    Title Intrapersonal and Extrapersonal Space: Performance of Older Adults on Ecologically Valid Orientation Tasks.
    Date August 2005
    Journal Experimental Aging Research
    Excerpt

    This experiment examined performance of 20 older adults (64 to 76 years) and 20 young adults (18 to 35 years) on two orientation tasks: The Intrapersonal task required participants to point to parts of their body corresponding to those on a line drawing; and, the Extrapersonal task involved translating a route indicated on paper to walking a route on a corresponding floor map. Older adults were found to be slower at completing both tasks, although accuracy of performance was comparable between age groups. The results were interpreted in terms of a speed-accuracy tradeoff that increases with age.

    Title Lc/ms/ms Measurement of Gentamicin in Bovine Plasma, Urine, Milk, and Biopsy Samples Taken from Kidneys of Standing Animals.
    Date August 2005
    Journal Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences
    Excerpt

    Methods for the measurement of gentamicin concentration in several bovine tissues were developed and validated. A novel liquid chromatographic (LC) technique employed trifluoroacetic acid in the mobile phase so that all gentamicin components co-eluted. Analytes were ionized by positive-ion pneumatically assisted electrospray and detected by selected reaction monitoring (SRM) with an LC-tandem mass spectrometer (LC/MS/MS). Calibration of plasma and urine samples was based on tobramycin internal standard. Calibration of milk and kidney samples was based on external standard, due to variability of tobramycin response in these matrices. The extraction technique employed treatment with aqueous trichloroacetic acid to both precipitate protein and liberate gentamicin from the matrix. Milk samples had to be defatted by centrifugation prior to extraction. Urine samples were further cleaned up with C-18 solid phase extraction (SPE). These methods were validated for use in several residue depletion studies (reported elsewhere) to monitor the depletion of gentamicin in tissues under various dosing conditions. The plasma method was calibrated from 1 to 5000 ng/mL in two ranges, with a limit of quantitation (LOQ) in the low range calculated at 3.3 ng/mL. The milk method was calibrated from 2.5 to 2500 ng/mL with an LOQ calculated at 4.5 ng/mL. The urine method was designed for use at low levels, and was calibrated from 1 to 100 ng/mL with an LOQ of 3.8 ng/mL. The kidney method was primarily designed for analysis of small samples (approximately 100mg). This method was calibrated from 10 to 50,000 ng/g with an LOQ of 26 ng/g.

    Title A Radiation-induced Acute Apoptosis Involving Tp53 and Bax Precedes the Delayed Apoptosis and Neoplastic Transformation of Cgl1 Human Hybrid Cells.
    Date August 2005
    Journal Radiation Research
    Excerpt

    Exposing CGL1 (HeLa x fibroblast) hybrid cells to 7 Gy of X rays results in the onset of a delayed apoptosis in the progeny of the cells 10 to 12 cell divisions postirradiation that correlates with the emergence of neoplastically transformed foci. The delayed apoptosis begins around day 8 postirradiation and lasts for 11 days. We now demonstrate that the delayed apoptosis is also characterized by the appearance of approximately 50-kb apoptotic DNA fragments and caspase 3 activation postirradiation. In addition, we confirm that stabilization of TP53 and transactivation of pro-apoptosis BAX also occurs during the delayed apoptosis and show that anti-apoptosis BCL-X(L) is down-regulated. To test whether the delayed apoptosis was due to a nonfunctional acute TP53 damage response in CGL1 cells, studies of acute apoptosis were completed. After irradiation, CGL1 cells underwent an acute wave of apoptosis that involves TP53 stabilization, transactivation of BAX gene expression, and a rapid caspase activation that ends by 96 h postirradiation. In addition, the acute onset of apoptosis correlates with transactivation of a standard wild-type TP53-responsive reporter (pG13-CAT) in CGL1 cells after radiation exposure. We propose that the onset of the delayed apoptosis is not the result of a nonfunctional acute TP53 damage response pathway but rather is a consequence of X-ray-induced genomic instability arising in the distant progeny of the irradiated cells.

    Title Regional Hippocampal Alteration Associated with Cognitive Deficit Following Experimental Brain Injury: a Systems, Network and Cellular Evaluation.
    Date July 2005
    Journal Neuroscience
    Excerpt

    Cognitive deficits persist in patients who survive traumatic brain injury (TBI). Lateral fluid percussion brain injury in the mouse, a model of human TBI, results in hippocampal-dependent cognitive impairment, similar to retrograde amnesia often associated with TBI. To identify potential substrates of the cognitive impairment, we evaluated regional neuronal loss, regional hippocampal excitability and inhibitory synaptic transmission. Design-based stereology demonstrated an approximate 40% loss of neurons through all subregions of the hippocampus following injury compared with sham. Input/output curves recorded in slices of injured brain demonstrated increased net synaptic efficacy in the dentate gyrus in concert with decreased net synaptic efficacy and excitatory postsynaptic potential-spike relationship in area CA1 compared with sham slices. Pharmacological agents modulating inhibitory transmission partially restored regional injury-induced alterations in net synaptic efficacy. Both evoked and spontaneous miniature inhibitory postsynaptic currents (mIPSCs) recorded in surviving dentate granule neurons were smaller and less frequent in injured brains than in uninjured brains. Conversely, both evoked and spontaneous mIPSCs recorded in surviving area CA1 pyramidal neurons were larger in injured brains than in uninjured brains. Together, these alterations suggest that regional hippocampal function is altered in the injured brain. This study demonstrates for the first time that brain injury selectively disrupts hippocampal function by causing uniform neuronal loss, inhibitory synaptic dysfunction, and regional, but opposing, shifts in circuit excitability. These changes may contribute to the cognitive impairments that result from brain injury.

    Title Antifungal Constituents of Northern Prickly Ash, Zanthoxylum Americanum Mill.
    Date July 2005
    Journal Phytomedicine : International Journal of Phytotherapy and Phytopharmacology
    Excerpt

    Leaf, fruit, stem, bark and root of Zanthoxylum americanum were investigated for antifungal activity with 11 strains of fungi representing diverse opportunistic and systemic pathogens, including Candida albicans, Cryptococcus neoformans and Aspergillus fumigatus. All extracts demonstrated a broad spectrum of antifungal activity and inhibited at least eight fungal species in a disk diffusion assay (600 microg/disk). Antifungal activity was light-dependent, with fruit and leaf extracts most active in general. The presence of light-mediated compounds, such as psoralen, 8-methoxypsoralen and imperatorin in extracts of different organs was confirmed by RP-HPLC. A high furanocoumarin content was detected in fruit and leaf and low furanocoumarin levels were found in bark and wood. A high positive correlation was observed between total furanocoumarin content and fungal inhibition zones (r2=0.902, p<0.001). The results provide a phytochemical basis for the very widespread use of Z. americanum in indigenous North American ethnomedical tradition for conditions that may be related to fungal infections.

    Title Biventricular Pacing Reduces the Induction of Monomorphic Ventricular Tachycardia: a Potential Mechanism for Arrhythmia Suppression.
    Date June 2005
    Journal Heart Rhythm : the Official Journal of the Heart Rhythm Society
    Excerpt

    OBJECTIVES: The aim of the present study was to evaluate in a prospective randomized fashion the electrophysiologic effects of acute biventricular (BV) pacing. We hypothesized that (1) the local coupling interval in the left ventricle in response to right-sided ventricular premature beats is prolonged when BV pacing is applied during the drive train compared with right ventricular (RV) pacing, and (2) BV programmed electrical stimulation (PES) decreases the induction of ventricular arrhythmias compared with standard RV-PES, regardless of the presence of intraventricular conduction delay. BACKGROUND: Previous studies have suggested that BV pacing might decrease the frequency of ventricular arrhythmias; however, the mechanism of arrhythmia suppression remains unclear. METHODS: Eighteen patients with coronary artery disease were randomized to RV-PES or BV-PES with a repeat study using the other pacing mode. The RV effective refractory periods were measured during RV-PES and BV-PES. In addition, the local LV S(1)-S(2) coupling interval was measured at 600/450 ms and 400/350 ms during RV-PES and BV-PES. RESULTS: BV-PES had no effect on RV effective refractory periods. On the other hand, the local LV S(1)-S(2) coupling intervals increased significantly during BV-PES compared with RV-PES (P < .0001). Ventricular tachycardia was induced in six patients using RV-PES but in only one patient with BV-PES (RR = 83%, P = .01). No difference was observed in the induction of ventricular fibrillation. CONCLUSIONS: BV-PES significantly reduced the induction of ventricular tachycardia compared to RV-PES, with no significant effect on ventricular fibrillation induction. Our findings may help explain the reduced incidence of ventricular arrhythmias noted with chronic BV pacing.

    Title Using 3d Animations to Teach Intracellular Signal Transduction Mechanisms: Taking the Arrows out of Cells.
    Date June 2005
    Journal Journal of Veterinary Medical Education
    Excerpt

    Traditional methods of teaching intracellular biological processes and pathways use figures or flowcharts with the names of molecules linked with arrows. Many veterinary students, presented with such material, simply memorize the names or chemical structures of the molecules and are then likely to forget the material once the examination is completed. To address this problem, the authors designed, created, and field-tested new teaching media that incorporate realistic three-dimensional (3D) animations depicting the dynamic changes that occur in intracellular molecules during cellular activation. Testing found that veterinary students taught using traditional teaching media (e.g., lectures, handouts, textbooks) are proficient in memorizing the names and order of intracellular molecules but unable to appreciate the interactions between these elements or their spatial relationships within cells. In contrast, more than 90% of veterinary students taught using 3D animations not only recall the facts about the intracellular elements but also develop accurate mental images of the interactions among these molecules and their spatial relationships. These findings strongly suggest that the comprehension of complex biological processes by veterinary students can be enhanced by the use of dynamic 3D depictions of these processes in the classroom.

    Title Cranial Manipulation Can Alter Sleep Latency and Sympathetic Nerve Activity in Humans: a Pilot Study.
    Date May 2005
    Journal Journal of Alternative and Complementary Medicine (new York, N.y.)
    Excerpt

    OBJECTIVE: To determine if cranial manipulation is associated with altered sleep latency. Furthermore, we investigated the effects of cranial manipulation on muscle sympathetic nerve activity (MSNA) as a potential mechanism for altered sleep latency. DESIGN: Randomized block design with repeated measures. SETTING: The Integrative Physiology and Manipulative Medicine Departments, University of North Texas Health Science Center, Fort Worth, TX. SUBJECTS: Twenty (20) healthy volunteers (12 male, 8 female; age range, 22-35 years) participated in this investigation. INTERVENTIONS: Subjects were exposed to 3 randomly ordered treatments: compression of the fourth ventricle (CV4), CV4 sham (simple touch), and control (no treatment). OUTCOME MEASURES: Sleep latency was assessed during each of the treatments in 11 subjects, using the standard Multiple Sleep Latency Test protocol. Conversely, directly recorded efferent MSNA was measured during each of the treatments in the remaining 9 subjects, using standard microneurographic technique. RESULTS: Sleep latency during the CV4 trial was decreased when compared to both the CV4 sham or control trials (p < 0.05). MSNA during the CV4-induced temporary halt of the cranial rhythmic impulse (stillpoint) was decreased when compared to prestillpoint MSNA (p < 0.01). During the CV4 sham and control trials MSNA was not different between CV4 time-matched measurements (p > 0.05). Moreover, the change in MSNA prestillpoint to stillpoint during the CV4 trial was different compared to the CV4 sham and control trials (p < 0.05). However, this change in MSNA was similar between the CV4 sham and control trials (p > 0.80). CONCLUSIONS: The current study is the first to demonstrate that cranial manipulation, specifically the CV4 technique, can alter sleep latency and directly measured MSNA in healthy humans. These findings provide important insight into the possible physiologic effects of cranial manipulation. However, the mechanisms behind these changes remain unclear.

    Title Coronary Angioplasty in Emergency Treatment of Myocardial Infarction in a Community-hospital Setting.
    Date May 2005
    Journal Texas Heart Institute Journal / from the Texas Heart Institute of St. Luke's Episcopal Hospital, Texas Children's Hospital
    Excerpt

    From July 1986 through June 1988, 135 consecutive patients with myocardial infarction, including 23 in cardiogenic shock, were treated with percutaneous transluminal coronary angioplasty in a community-hospital setting. In 109 (81%) of the cases, angioplasty was successful, resulting in brisk anterograde flow and in residual stenosis of less than 50%. The success rate was 88% (99/112) for patients not in cardiogenic shock and 43% (10/23) for those in shock. During the term of hospitalization, clinically evident total reocclusion occurred in 5 (4%) patients not in shock on presentation (2 of these experienced anterior infarction, and 3 inferior infarction); repeat angioplasty was performed successfully in all 5. No clinical reocclusion was detected in the smaller group of patients admitted in shock. Eleven patients (8%) underwent emergency coronary artery bypass grafting following the coronary angioplasty procedure: 4 for failed angioplasty in the infarct-related artery, and the other 7 for severe triple-vessel disease. Hospital mortality was 0.9% (1/112) for patients not in cardiogenic shock and 52% (12/23) for those admitted in shock, for an overall rate of 10% (13/135). Among patients whose balloon angioplasty was successful, hospital mortality was 0% for those not in shock and 30% (3/10) for those in shock. Among patients whose angioplasty failed, however, mortality was 8% (1/13) for those not in shock and 69% (9/13) for those admitted in shock.

    Title Subarachnoid Hemorrhage on Computed Tomography Scanning and the Development of Cerebral Vasospasm: the Fisher Grade Revisited.
    Date April 2005
    Journal Surgical Neurology
    Excerpt

    BACKGROUND: The Fisher grade (FG) is widely used to predict cerebral vasospasm after aneurysmal subarachnoid hemorrhage (SAH). We revisited the grading scale to determine its validity in the era of modern management. METHODS: We retrospectively reviewed the records of 134 patients with SAH. The amount and distribution of subarachnoid blood on admission computed tomography (CT) scan was quantified according to the FG and compared with development of symptomatic vasospasm. RESULTS: We reviewed 134 patients (median age, 54) who presented with aneurysmal SAH. Six (5%) were FG 1, 34 (25%) were FG 2, 25 (19%) were FG 3, and 69 (51%) were FG 4. Symptomatic vasospasm developed in no (0%) FG 1, 8 (24%) FG 2, 7 (28 %) FG 3, and 13 (19%) FG 4 patients (28 of 134 total patients; 21%). Development of symptomatic vasospasm was not associated with admission FG, Hunt and Hess grade, age, sex, or location of blood on presenting CT scan. Elevated transcranial Doppler blood flow velocity was associated with blood in the basal cisterns (P = .0047), lateral ventricles (P = .026), or blood in any ventricle (P = .04). Postoperative angiograms were obtained in 57 patients; moderate to severe vasospasm was observed in 5 (15%) FG 2, 6 (24%) FG 3, and 14 (20%) FG 4 patients. Twenty patients (71%) with symptomatic vasospasm had moderate or severe angiographic vasospasm. Angiographic vasospasm was associated with intraventricular blood (P = .054) but not with FG. CONCLUSIONS: Symptomatic vasospasm occurred in 21% of cases. The FG correlated with symptomatic vasospasm in only half the patients. A new predictive CT grading scale for vasospasm may be necessary.

    Title The Dna Sequence of the Human X Chromosome.
    Date March 2005
    Journal Nature
    Excerpt

    The human X chromosome has a unique biology that was shaped by its evolution as the sex chromosome shared by males and females. We have determined 99.3% of the euchromatic sequence of the X chromosome. Our analysis illustrates the autosomal origin of the mammalian sex chromosomes, the stepwise process that led to the progressive loss of recombination between X and Y, and the extent of subsequent degradation of the Y chromosome. LINE1 repeat elements cover one-third of the X chromosome, with a distribution that is consistent with their proposed role as way stations in the process of X-chromosome inactivation. We found 1,098 genes in the sequence, of which 99 encode proteins expressed in testis and in various tumour types. A disproportionately high number of mendelian diseases are documented for the X chromosome. Of this number, 168 have been explained by mutations in 113 X-linked genes, which in many cases were characterized with the aid of the DNA sequence.

    Title Development of a Human Acute Myeloid Leukaemia Screening Panel and Consequent Identification of Novel Gene Mutation in Flt3 and Ccnd3.
    Date March 2005
    Journal British Journal of Haematology
    Excerpt

    A study was undertaken to develop an acute myeloid leukaemia (AML) screening panel to uncover novel recurring gene mutations. Analysis was performed on six genes known to be mutated in AML (RUNX1, FLT3, KIT, CEBPA, PTPN11 and NRAS) and an additional two candidate genes (CCND3 and FES) in a panel of 175 primary human AML samples that included all French-American-British types except M3, and all cytogenetic risk groups. One hundred and fifteen mutations were identified in 97 (55%) patients comprising 81 patients (46%) with one mutation, 14 patients (8%) with two mutations and two patients (1%) with three mutations. Fifty-five of 88 (63%) patients with normal karyotype AML had at least one mutation. Correlation was observed between KIT mutation and 'favourable risk' cytogenetics (P <0.001), CEBPA mutation and 'intermediate risk' cytogenetics (P=0.045), and PTPN11 mutation and 'poor risk' disease (P <0.001). The frequency of individual gene mutation was in accordance with previously published studies. Three novel mutations of FLT3 were detected (Y589D, D839G, Y842H) that would have been overlooked by conventional gel electrophoresis. A 51-bp deletion was detected in CCND3 in a patient with normal karyotype AML. This validated panel now provides an important tool to evaluate other candidate genes in the genesis of myeloid malignancy.

    Title Dynamic Carotid Baroreflex Control of the Peripheral Circulation During Exercise in Humans.
    Date February 2005
    Journal The Journal of Physiology
    Excerpt

    We sought to determine the dynamic relationship between carotid baroreflex (CBR)-mediated control and local control of the skeletal muscle vasculature during dynamic exercise. In 12 subjects (18-35 years old), oscillatory neck pressure (NP, +40 mmHg) was applied at 0.1 Hz (i.e. 5 s on, 5 s off) for 5 min to determine the degree of CBR control over heart rate (HR), arterial blood pressure (ABP), muscle sympathetic nerve activity (MSNA), femoral blood velocity and skeletal muscle tissue oxygenation at rest and during 7 W dynamic knee-extension exercise. Skeletal muscle tissue oxygenation measurements of both the exercising and nonexercising leg were evaluated. Fast Fourier transformation was performed on 5 min segments to calculate spectral power of the R-R interval (RRI), ABP, MSNA, femoral blood velocity and tissue oxygenation time series, and the low-frequency (LF, 0.085-0.115 Hz) power spectra were compared to evaluate the degree of CBR-mediated entrainment for each variable. At rest, sinusoidal NP significantly increased LF spectral power of RRI, ABP, MSNA and femoral blood velocity. During exercise, sinusoidal NP provoked a similar increase in spectral power for RRI and MSNA, while CBR-mediated changes in ABP and femoral blood velocity were attenuated compared to rest. Changes in spectral power of skeletal muscle tissue oxygenation during sinusoidal NP were similar between the exercising and nonexercising leg at rest. However, during exercise the changes in skeletal muscle tissue oxygenation power were significantly less in the exercising leg, while changes in the nonexercising leg were similar to rest. We have demonstrated simultaneous entrainment of all CBR end-organ measurements, ranging from cardiac chronotropic effects to alterations at the level of the skeletal muscle microcirculation. Moreover, we have identified a significant and specific attenuation of end-organ responsiveness to CBR-mediated sympathoexcitation in the vasculature of the exercising muscle. However, despite a shift towards more predominant local control over the exercising muscle vasculature, systemic arterial blood pressure was well preserved.

    Title Cxcr2- and E-selectin-induced Neutrophil Arrest During Inflammation in Vivo.
    Date December 2004
    Journal The Journal of Experimental Medicine
    Excerpt

    The signaling events leading to the activation of integrins and firm arrest of rolling neutrophils in inflamed venules have yet to be elucidated. In vitro assays suggest that both E-selectin and chemokines can trigger arrest of rolling neutrophils, but E-selectin(-/-) mice have normal levels of adherent neutrophils in inflamed venules. To test whether chemokine-induced neutrophil arrest in vivo can be unmasked by blocking E-selectin, we investigated neutrophil adhesion in inflamed cremaster muscle venules in tumor necrosis factor (TNF)-alpha-treated CXCR2(-/-) or wild-type (WT) mice injected with E-selectin blocking monoclonal antibody (mAb) 9A9. To block chemokine receptor signaling, we investigated E-selectin(-/-) or WT mice treated with pertussis toxin (PTx) intravenously. Neutrophil adhesion was unchanged in CXCR2(-/-), E-selectin(-/-), PTx-treated WT, or mAb 9A9-treated WT mice. However, TNF-alpha-induced neutrophil adhesion was almost completely abrogated in E-selectin(-/-) mice treated with PTx and significantly reduced in CXCR2(-/-) mice treated with the E-selectin blocking mAb. In thioglycollate-induced peritonitis, PTx treatment blocked neutrophil recruitment into the peritoneum of E-selectin(-/-) mice, but had only a partial effect in WT animals. These data show that E-selectin- and chemokine-mediated arrest mechanisms are overlapping in this model and identify CXCR2 as an important neutrophil arrest chemokine in vivo.

    Title Periods of Intermittent Hypoxic Apnea Can Alter Chemoreflex Control of Sympathetic Nerve Activity in Humans.
    Date November 2004
    Journal American Journal of Physiology. Heart and Circulatory Physiology
    Excerpt

    Obstructive sleep apnea is associated with sustained elevation of muscle sympathetic nerve activity (MSNA) and altered chemoreflex control of MSNA, both of which likely play an important role in the development of hypertension in these patients. Additionally, short-term exposure to intermittent hypoxic apneas can produce a sustained elevation of MSNA. Therefore, we tested the hypothesis that 20 min of intermittent hypoxic apneas can alter chemoreflex control of MSNA. Twenty-one subjects were randomly assigned to one of three groups (hypoxic apnea, hypercapnic hypoxia, and isocapnic hypoxia). Subjects were exposed to 30 s of the perturbation every minute for 20 min. Chemoreflex control of MSNA was assessed during baseline, 1 min posttreatment, and every 15 min throughout 180 min of recovery by the MSNA response to a single hypoxic apnea. Recovery hypoxic apneas were matched to a baseline hypoxic apnea with a similar nadir oxygen saturation. A significant main effect for chemoreflex control of MSNA was observed after 20 min of intermittent hypoxic apneas (P <0.001). The MSNA response to a single hypoxic apnea was attenuated 1 min postexposure compared with baseline (P <0.001), became augmented within 30 min of recovery, and remained augmented through 165 min of recovery (P <0.05). Comparison of treatment groups revealed no differences in the chemoreflex control of MSNA during recovery (P=0.69). These data support the hypothesis that 20 min of intermittent hypoxic apneas can alter chemoreflex control of MSNA. Furthermore, this response appears to be mediated by hypoxia.

    Title Active Recovery Attenuates the Fall in Sweat Rate but Not Cutaneous Vascular Conductance After Supine Exercise.
    Date September 2004
    Journal Journal of Applied Physiology (bethesda, Md. : 1985)
    Excerpt

    The purpose of this study was to identify whether baroreceptor unloading was responsible for less efficient heat loss responses (i.e., skin blood flow and sweat rate) previously reported during inactive compared with active recovery after upright cycle exercise (Carter R III, Wilson TE, Watenpaugh DE, Smith ML, and Crandall CG. J Appl Physiol 93: 1918-1929, 2002). Eight healthy adults performed two 15-min bouts of supine cycle exercise followed by inactive or active (no-load pedaling) supine recovery. Core temperature (T(core)), mean skin temperature (T(sk)), heart rate, mean arterial blood pressure (MAP), thoracic impedance, central venous pressure (n = 4), cutaneous vascular conductance (CVC; laser-Doppler flux/MAP expressed as percentage of maximal vasodilation), and sweat rate were measured throughout exercise and during 5 min of recovery. Exercise bouts were similar in power output, heart rate, T(core), and T(sk). Baroreceptor loading and thermal status were similar during trials because MAP (90 +/- 4, 88 +/- 4 mmHg), thoracic impedance (29 +/- 1, 28 +/- 2 Omega), central venous pressure (5 +/- 1, 4 +/- 1 mmHg), T(core) (37.5 +/- 0.1, 37.5 +/- 0.1 degrees C), and T(sk) (34.1 +/- 0.3, 34.2 +/- 0.2 degrees C) were not significantly different at 3 min of recovery between active and inactive recoveries, respectively; all P > 0.05. At 3 min of recovery, chest CVC was not significantly different between active (25 +/- 6% of maximum) and inactive (28 +/- 6% of maximum; P > 0.05) recovery. In contrast, at this time point, chest sweat rate was higher during active (0.45 +/- 0.16 mg.cm(-2).min(-1)) compared with inactive (0.34 +/- 0.19 mg.cm(-2).min(-1); P < 0.05) recovery. After exercise CVC and sweat rate are differentially controlled, with CVC being primarily influenced by baroreceptor loading status while sweat rate is influenced by other factors.

    Title Hypoxia-mediated Prolonged Elevation of Sympathetic Nerve Activity After Periods of Intermittent Hypoxic Apnea.
    Date September 2004
    Journal Journal of Applied Physiology (bethesda, Md. : 1985)
    Excerpt

    Obstructive sleep apnea (OSA) is associated with transient elevation of muscle sympathetic nerve activity (MSNA) during apneic events, which often produces elevated daytime MSNA in OSA patients. Hypoxia is postulated to be the primary stimulus for elevated daytime MSNA in OSA patients. Therefore, we studied the effects of 20 min of intermittent voluntary hypoxic apneas on MSNA during 180 min of recovery. Also, we compared MSNA during recovery after either 20 min of intermittent voluntary hypoxic apneas, hypercapnic hypoxia, or isocapnic hypoxia. Consistent with our hypothesis, both total MSNA and MSNA burst frequency were elevated after 20 min of intermittent hypoxic apnea compared with baseline (P < 0.05). Both total MSNA and MSNA burst frequency remained elevated throughout the 180-min recovery period and were statistically different from time control subjects throughout this period (P < 0.05). Finally, MSNA during recovery from intermittent hypoxic apnea, hypercapnic hypoxia, and isocapnic hypoxia were not different (P = 0.50). Therefore, these data support the hypothesis that short-term exposure to intermittent hypoxic apnea results in sustained elevation of MSNA and that hypoxia is the primary mediator of this response.

    Title Poor Baroreflex Gain is a Marker of Heightened Sympathetic Activity Post-tachycardia Termination in Humans.
    Date August 2004
    Journal Clinical Autonomic Research : Official Journal of the Clinical Autonomic Research Society
    Excerpt

    We hypothesized that sympathetic nerve activity (SNA) remains elevated after tachycardia termination in patients with low baroreflex gain (BRG), and decreased to or below baseline in patients with high BRG. In a cohort of patients who participated in a previously published study [3], BRG, SNA, blood pressure, and central venous pressure were measured immediately after the termination of simulated tachycardia. While the hemodynamic responses following tachycardia termination were similar in both groups, SNA remained elevated in patients with low BRG compared to a decrease below baseline levels in patients with high BRG (p = 0.04). Increased sympathetic activity following tachycardia termination could be arrhythmogenic and might play a role in the genesis of recurrent ventricular arrhythmias following tachycardia termination.

    Title Does Pulsatile and Sustained Neck Pressure or Neck Suction Produce Differential Cardiovascular and Sympathetic Responses in Humans?
    Date June 2004
    Journal Experimental Physiology
    Excerpt

    Although square-wave sustained and R wave-triggered pulsatile stimuli have been used to assess carotid baroreflex (CBR) function in humans, it remains unclear whether these different stimulus protocols elicit comparable responses and whether CBR responses adapt during prolonged stimulation. Thus, we measured muscle sympathetic nerve activity (MSNA), heart rate (HR) and mean arterial pressure (MAP) in response to +30 Torr neck pressure (NP) and -30 Torr neck suction (NS) delivered for 20 s either as a sustained or pulsatile stimulus. CBR-mediated changes in MSNA, HR and MAP were similar with sustained and pulsatile stimuli. The time course of MSNA and HR responses identified that significant changes occurred during the initial 5 s and were better maintained over 20 s with NP than with NS. Changes in MAP exhibited a slower onset with the peak increase during NP occurring at 10 s (sustained, 7 +/- 1 mmHg; pulsatile, 7 +/- 1 mmHg; P > 0.05) and the nadir during NS occurring at 20 s (sustained, -7 +/- 1 mmHg; pulsatile, -9 +/- 2 mmHg; P > 0.05). These data demonstrate that sustained and pulsatile NP and NS produce comparable CBR-mediated responses. Furthermore, despite MSNA and HR returning towards baseline during NS, CBR-mediated changes in MAP are well maintained over 20 s of NS and NP.

    Title Sympathoexcitation is Attenuated During Low Level Lower Body Negative Pressure in Subjects Who Develop Pre-syncope.
    Date April 2004
    Journal Clinical Autonomic Research : Official Journal of the Clinical Autonomic Research Society
    Excerpt

    The purpose of this study was to compare the hemodynamic and sympathetic nerve activity (SNA) responses to graded lower body negative pressure (LBNP) in healthy subjects with either a positive (n = 24, SNA in 8) or a negative (n = 18, SNA in 6) LBNP response. A positive LBNP response was defined as an abrupt drop in systolic blood pressure associated with a decrease in heart rate and/or a decrease in SNA. All positive responses were accompanied by symptoms common to pre-syncope, defined as lightheadedness, diaphoresis, tunnel vision and/or nausea. If subjects tolerated 30 minutes of LBNP, this was considered a negative response. Comparisons were made between baseline, -10 mmHg (low-level LBNP) and -60 mmHg (high-level LBNP). Baseline SNA and arterial baroreflex sensitivity were not different between the 2 groups. However, subjects with pre-syncope had a significantly attenuated SNA response during low-level LBNP (p < 0.05) compared to subjects who did not experience pre-syncope. The hemodynamic data during high-level LBNP were similar until the occurrence of pre-syncope. Pre-syncope was preceded by a significant decrease in heart rate and SNA. Our findings suggest that subjects with LBNP induced pre-syncope might have an impairment in the cardiopulmonary baroreflex gain function in the setting of a preserved arterial baroreflex gain.

    Title Intramyocardial and Intracoronary Basic Fibroblast Growth Factor in Porcine Hibernating Myocardium: a Comparative Study.
    Date March 2004
    Journal The Journal of Thoracic and Cardiovascular Surgery
    Excerpt

    OBJECTIVE: Therapeutic angiogenesis is an alternative method of revascularization for end-stage coronary artery disease. We determined the effects of intramyocardial and intracoronary basic fibroblast growth factor 2 on myocardial blood flow and function in a porcine model of hibernating myocardium. METHODS: Twenty-four mini-swine with 90% left circumflex artery stenosis and documented hibernating myocardium by positron emission tomography and dobutamine stress echocardiography were randomized to intramyocardial basic fibroblast growth factor 2 at 0.6 microg/kg (mid-dose, n = 6, 30 injections/animal), 6 microg/kg (high-dose, n = 6, 30 injections/animal), or intramyocardial vehicle control (n = 6). The intracoronary group received 6 microg/kg basic fibroblast growth factor 2 (n = 6) into the right and left circumflex artery coronary arteries. Positron emission tomography and dobutamine stress echocardiography were repeated at 1 and 3 months. RESULTS: In the vehicle group, normalized left circumflex artery myocardial blood flow was 0.74 +/- 0.04 at 1 month and 0.75 +/- 0.07 at 3 months compared with 0.68 +/- 0.03 at baseline. In the intracoronary group, myocardial blood flow was 0.71 +/- 0.03 at 1 month and 0.72 +/- 0.04 at 3 months compared with 0.67 +/- 0.04 at baseline. In the mid group, myocardial blood flow was 0.73 +/- 0.06 at 1 month and 0.85 +/- 0.05 at 3 months (P <.001) compared with 0.67 +/- 0.04 at baseline. In the high group, myocardial blood flow was 0.81 +/- 0.06 at 1 month and 0.83 +/-.04 at 3 months (P =.03) compared with 0.71 +/- 0.02 at baseline. No significant improvements in ischemia were demonstrated in any of the groups by dobutamine stress echocardiography at 1 or 3 months. CONCLUSIONS: In porcine hibernating myocardium, intramyocardial basic fibroblast growth factor 2 significantly improved regional myocardial blood flow 3 months after treatment. There was no significant change in function in any of the 4 groups. These data suggest that intramyocardial dosing of basic fibroblast growth factor 2 (0.6 microg/kg) may be an optimal dose for improving perfusion in the treatment of end-stage coronary artery disease.

    Title The Significance of Ear Plugging in Localization-related Epilepsy.
    Date February 2004
    Journal Epilepsia
    Excerpt

    PURPOSE: The localizing value of ear plugging in the treatment of auditory onset partial seizures, to our knowledge, has not been previously described. We propose that ear plugging is a clinical response to a sensory seizure manifested as an auditory hallucination and a tool for identifying the seizure focus in the auditory cortex on the superior temporal gyrus. METHODS: We report on three children who had prior epilepsy surgery for recurrent symptomatic localization-related epilepsy and who, subsequent to their surgery, displayed stereotyped unilateral or bilateral ear plugging at the onset of partial seizures. We studied scalp video electroencephalography (VEEG), magnetoencephalography (MEG), and magnetic resonance imaging (MRI) in all three. Additionally, we used electrocorticography (ECoG) in two patients, intracranial VEEG monitoring in one patient, and functional MRI language mapping in two patients. RESULTS: All three patients plugged their ears with their hands during auditory auras that localized to the superior temporal gyrus and were followed by partial seizures that spread to a wider field, as shown on scalp and intracranial VEEG. All three patients had MEG interictal discharges in the superior temporal gyrus. One patient who was nonverbal and unable to describe an auditory phenomenon plugged the ear contralateral to where temporal lobe-onset seizures and MEG interictal discharges occurred. CONCLUSIONS; Ear-plugging seizures indicate an auditory aura and may also lateralize seizure onset to the contralateral temporal lobe auditory cortex. Stereotyped behaviors accompanied by epileptic seizures in children who have poor communication skills are important in the seizure semiology of localization-related epilepsy.

    Title Carotid Baroreflex Function During and Following Voluntary Apnea in Humans.
    Date December 2003
    Journal American Journal of Physiology. Heart and Circulatory Physiology
    Excerpt

    Muscle sympathetic nerve activity (MSNA) and arterial pressure increase concomitantly during apnea, suggesting a possible overriding of arterial baroreflex inhibitory input to sympathoregulatory centers by apnea-induced excitatory mechanisms. Apnea termination is accompanied by strong sympathoinhibition while arterial pressure remains elevated. Therefore, we hypothesized that the sensitivity of carotid baroreflex control of MSNA would decrease during apnea and return upon apnea termination. MSNA and heart rate responses to -60-Torr neck suction (NS) were evaluated during baseline and throughout apnea. Responses to +30-Torr neck pressure (NP) were evaluated during baseline and throughout 1 min postapnea. Apnea did not affect the sympathoinhibitory or bradycardic response to NS (P > 0.05); however, whereas the cardiac response to NP was maintained postapnea, the sympathoexcitatory response was reduced for 50 s (P < 0.05). These data demonstrate that the sensitivity of carotid baroreflex control of MSNA is not attenuated during apnea. We propose a transient rightward and upward resetting of the carotid baroreflex-MSNA function curve during apnea and that return of the function curve to, or more likely beyond, baseline (i.e., a downward and leftward shift) upon apnea termination may importantly contribute to the reduced sympathoexcitatory response to NP.

    Title Assessing Community Child Passenger Safety Efforts in Three Northwest Tribes.
    Date December 2003
    Journal Injury Prevention : Journal of the International Society for Child and Adolescent Injury Prevention
    Excerpt

    To identify strengths and weaknesses in community based child passenger safety programs by developing a scoring instrument and conducting observations of child restraint use in three Native American communities.

    Title Evaluation of Vacuum-assisted Closure in the Treatment of Poststernotomy Mediastinitis.
    Date October 2003
    Journal The Journal of Thoracic and Cardiovascular Surgery
    Excerpt

    OBJECTIVE: Poststernotomy mediastinitis, although infrequent, is a potentially life-threatening complication of cardiac surgery that continues to have a significant morbidity and mortality despite aggressive therapy. Vacuum-assisted closure uses controlled suction to provide evacuation of wound fluid, decrease bacterial colonization, stimulate granulation tissue, and reduce the need for dressing changes. METHODS: One hundred two patients from Duke University Hospital, The Durham Veterans Administration Hospital, and referring institutions underwent vacuum-assisted closure treatment. There were 63 men and 39 women, with a mean age of 67. The infection was noticed between postoperative days 8 and 34, at which time the wounds were opened and debrided. RESULTS: Ninety-six of the 102 patients received vacuum-assisted therapy while the remaining 6 underwent daily multiple dressing changes without vacuum-assisted therapy. Fifty-three of the 96 patients required only sternal debridement, followed by wound vacuum therapy and closure by secondary intention, while the remaining 43 had an additional procedure. Of these, 33 patients underwent omental transposition and 10 patients had a pectoralis flap. The length of stay for all patients was 27 +/- 12 days. This was related in part to intravenous antibiotics. Hospital mortality for all patients was 3.7% (4 patients). Two of these patients underwent vascular flap and succumbed to multisystemic organ failure, while the other 2 received only wound vacuum therapy following debridement and succumbed to overwhelming sepsis. CONCLUSION: Vacuum-assisted drainage is an effective therapy for mediastinitis following debridement or before placement of a vascularized tissue flap.

    Title Carotid Baroreflex Control of Leg Vascular Conductance at Rest and During Exercise.
    Date July 2003
    Journal Journal of Applied Physiology (bethesda, Md. : 1985)
    Excerpt

    We sought to test the hypothesis that the carotid baroreflex (CBR) alters mean leg blood flow (LBF) and leg vascular conductance (LVC) at rest and during exercise. In seven men and one woman, 25 +/- 2 (SE) yr of age, CBR control of LBF and LVC was determined at rest and during steady-state one-legged knee extension exercise at approximately 65% peak O(2) uptake. The application of 5-s pulses of +40 Torr neck pressure and -60 Torr neck suction significantly altered mean arterial pressure (MAP) and LVC both at rest and during exercise. CBR-mediated changes in MAP were similar between rest and exercise (P > 0.05). However, CBR-mediated decreases in LVC (%change) to neck pressure were attenuated in the exercising leg (16.4 +/- 1.6%) compared with rest (33 +/- 2.1%) and the nonexercising leg (23.7 +/- 1.9%) (P < 0.01). These data suggest CBR control of blood pressure is partially mediated by changes in leg vascular tone both at rest and during exercise. Furthermore, despite alterations in CBR-induced changes in LVC during exercise, CBR control of blood pressure was well maintained.

    Title Pancan Pals--patient and Liaison Services: an Innovative Model for Informed Patient Decision-making, Including Patient Information and Clinical Trials.
    Date June 2003
    Journal Oncology (williston Park, N.y.)
    Title P-selectin Glycoprotein Ligand-1 Mediates L-selectin-dependent Leukocyte Rolling in Venules.
    Date June 2003
    Journal The Journal of Experimental Medicine
    Excerpt

    Leukocyte rolling in postcapillary venules of inflamed tissues is reduced in L-selectin-deficient mice and mice treated with L-selectin blocking antibodies, but the glycoprotein ligand for L-selectin in inflamed venules is unknown. Here, we show that L-selectin-dependent rolling after P-selectin blockade is completely absent in P-selectin glycoprotein ligand-1 (PSGL-1)-/- mice or wild-type mice treated with a PSGL-1 blocking monoclonal antibody. Immunohistochemistry and flow cytometry failed to show PSGL-1 expression on resting or inflamed endothelium or on platelets. To investigate whether leukocyte-expressed PSGL-1 is mediating L-selectin-dependent rolling, we reconstituted lethally irradiated wild-type mice with PSGL-1-/- bone marrow cells. These chimeric mice showed no L-selectin-dependent rolling, suggesting that leukocyte-expressed PSGL-1 mediates L-selectin-dependent rolling. Frame-to-frame video analysis of L-selectin-dependent rolling in wild-type mice showed that the majority of observed L-selectin-dependent leukocyte rolling was between free flowing leukocytes and already adherent leukocytes or possibly leukocyte fragments, followed by E-selectin-dependent leukocyte rolling along the endothelium. Leukocyte rolling was significantly slower for leukocyte-endothelial than leukocyte-leukocyte interactions. We conclude that leukocyte-expressed PSGL-1 serves as the main L-selectin ligand in inflamed postcapillary venules. L-selectin binding to PSGL-1 initiates tethering events that enable L-selectin-independent leukocyte-endothelial interactions. These findings provide a molecular mechanism for the inflammatory defects seen in L-selectin-deficient mice.

    Title Effects of Mode of Exercise Recovery on Thermoregulatory and Cardiovascular Responses.
    Date May 2003
    Journal Journal of Applied Physiology (bethesda, Md. : 1985)
    Excerpt

    To identify the effects of exercise recovery mode on cutaneous vascular conductance (CVC) and sweat rate, eight healthy adults performed two 15-min bouts of upright cycle ergometry at 60% of maximal heart rate followed by either inactive or active (loadless pedaling) recovery. An index of CVC was calculated from the ratio of laser-Doppler flux to mean arterial pressure. CVC was then expressed as a percentage of maximum (%max) as determined from local heating. At 3 min postexercise, CVC was greater during active recovery (chest: 40 +/- 3, forearm: 48 +/- 3%max) compared with during inactive recovery (chest: 21 +/- 2, forearm: 25 +/- 4%max); all P < 0.05. Moreover, at the same time point sweat rate was greater during active recovery (chest: 0.47 +/- 0.10, forearm: 0.46 +/- 0.10 mg x cm(-2) x min(-1)) compared with during inactive recovery (chest: 0.28 +/- 0.10, forearm: 0.14 +/- 0.20 mg x cm(-2) x min(-1)); all P < 0.05. Mean arterial blood pressure, esophageal temperature, and skin temperature were not different between recovery modes. These data suggest that skin blood flow and sweat rate during recovery from exercise may be modulated by nonthermoregulatory mechanisms and that sustained elevations in skin blood flow and sweat rate during mild active recovery may be important for postexertional heat dissipation.

    Title Effect of Atrial Fibrillation and an Irregular Ventricular Response on Sympathetic Nerve Activity in Human Subjects.
    Date April 2003
    Journal Circulation
    Excerpt

    BACKGROUND: Although the hemodynamic changes associated with atrial fibrillation (AF) have been extensively studied, the neural changes remain unclear. We hypothesized that AF is associated with an increase in sympathetic nerve activity (SNA) and that the irregular ventricular response contributes to this state of sympathoexcitation. METHODS AND RESULTS: In 8 patients referred for an electrophysiological study, SNA, blood pressure (BP), central venous pressure (CVP), and heart rate were recorded during 3 minutes of normal sinus rhythm (NSR) and 3 minutes of induced AF. In 5 of 8 patients who converted to NSR, right atrial (RA) pacing was performed for 3 minutes in atrial pacing triggered by ventricular sensing mode triggered by playback of an FM tape previously recorded from the right ventricle during AF (RA-irregular) and atrial pacing inhibited by atrial sensing mode at a rate equal to the mean heart rate obtained during AF (RA-regular). SNA data were expressed as percentage of baseline during NSR. SNA increased in all 8 patients during induced AF compared with NSR (171+/-40% versus 100%, respectively; P<0.01). This was associated with a trend for a decrease in BP and an increase in CVP (P=0.02). Similarly, SNA was significantly higher during RA-irregular pacing compared with RA-regular pacing (124+/-24% versus 91+/-20%, respectively; P=0.03). BP and CVP were not significantly different between the 2 pacing modes. CONCLUSIONS: Induced AF results in a significant increase in SNA, which is in part attributable to the irregular ventricular response. Our findings suggest that restoring NSR or regularity might be beneficial, particularly in patients with heart failure.

    Title Cardiovascular and Sympathetic Neural Responses to Handgrip and Cold Pressor Stimuli in Humans Before, During and After Spaceflight.
    Date April 2003
    Journal The Journal of Physiology
    Excerpt

    Astronauts returning to Earth have reduced orthostatic tolerance and exercise capacity. Alterations in autonomic nervous system and neuromuscular function after spaceflight might contribute to this problem. In this study, we tested the hypothesis that exposure to microgravity impairs autonomic neural control of sympathetic outflow in response to peripheral afferent stimulation produced by handgrip and a cold pressor test in humans. We studied five astronauts approximately 72 and 23 days before, and on landing day after the 16 day Neurolab (STS-90) space shuttle mission, and four of the astronauts during flight (day 12 or 13). Heart rate, arterial pressure and peroneal muscle sympathetic nerve activity (MSNA) were recorded before and during static handgrip sustained to fatigue at 40 % of maximum voluntary contraction, followed by 2 min of circulatory arrest pre-, in- and post-flight. The cold pressor test was applied only before (five astronauts) and during flight (day 12 or 13, four astronauts). Mean (+/- S.E.M.) baseline heart rates and arterial pressures were similar among pre-, in- and post-flight measurements. At the same relative fatiguing force, the peak systolic pressure and mean arterial pressure during static handgrip were not different before, during and after spaceflight. The peak diastolic pressure tended to be higher post- than pre-flight (112 +/- 6 vs. 99 +/- 5 mmHg, P = 0.088). Contraction-induced rises in heart rate were similar pre-, in- and post-flight. MSNA was higher post-flight in all subjects before static handgrip (26 +/- 4 post- vs. 15 +/- 4 bursts min(-1) pre-flight, P = 0.017). Contraction-evoked peak MSNA responses were not different before, during, and after spaceflight (41 +/- 4, 38 +/- 5 and 46 +/- 6 bursts min(-1), all P > 0.05). MSNA during post-handgrip circulatory arrest was higher post- than pre- or in-flight (41 +/- 1 vs. 33 +/- 3 and 30 +/- 5 bursts min(-1), P = 0.038 and 0.036). Similarly, responses of MSNA and blood pressure to the cold pressor test were well maintained in-flight. We conclude that modulation of muscle sympathetic neural outflow by muscle metaboreceptors and skin nociceptors is preserved during short duration spaceflight.

    Title Do Vestibular Otolith Organs Participate in Human Orthostatic Blood Pressure Control?
    Date December 2002
    Journal Autonomic Neuroscience : Basic & Clinical
    Excerpt

    We hypothesized that vestibular otolith organ stimulation contributes to human orthostatic responses. Twelve subjects underwent three 60 degrees upright tilts: (1) with the neck flexed from 0 degrees to 30 degrees relative to the body during 60 degrees tilt, such that the head moved from horizontal to 90 degrees above horizontal (0 to 1 Gz otolith stimulation); (2) with the head and body aligned, such that they tilted together to 60 degrees (0 to 0.87 Gz otolith stimulation); and (3) with the neck flexed 30 degrees relative to the body during supine conditions, and the neck then extended to -30 degrees during 60 degrees body tilting, such that the head remained at 30 degrees above horizontal throughout body tilting (constant 0.5 Gz otolith stimulation). All three tilt procedures increased thoracic impedance, sympathetic nerve activity (N = 8 of 12), arterial pressure, and heart rate relative to supine conditions (all P < 0.04). Within the first 20 s of tilt, arterial pressure increased most obviously in the 0 to 1 Gz otolith condition. Thoracic impedance tended to increase more in otolith-constant conditions, but no dependent variable differed significantly between tilt conditions, and no significant time x tilt interactions emerged. Otolith inputs may contribute to early transient adjustments to orthostasis. However, lack of significant main effects of tilt condition and time x tilt interactions suggests that potential otolith effects on the variables we studied are relatively subtle and ephemeral, or that other mechanisms compensate for a lack of change in otolith input with orthostasis.

    Title Vegf-c Mediates Cyclic Pressure-induced Endothelial Cell Proliferation.
    Date December 2002
    Journal Physiological Genomics
    Excerpt

    Mechanical forces modulate endothelial cell functions through several mechanisms including regulation of gene transcription. In the present study, gene transcription by human umbilical vein endothelial cells (HUVEC) either maintained under control pressure (that is, standard cell culture conditions equivalent to 0.15 mmHg sustained hydrostatic pressure) or exposed to 60/20 mmHg sinusoidal pressures at 1 Hz were compared using Affymetrix GeneChip microarrays to identify cellular/molecular mechanisms associated with endothelial cell responses to cyclic pressure. Cyclic pressure selectively affected transcription of 14 genes that included a set of mechanosensitive proteins involved in hemostasis (tissue plasminogen activator), cell adhesion (integrin-alpha2), and cell signaling (Rho B, cytosolic phospholipase A2), as well as a unique subset of cyclic pressure-sensitive genes such as vascular endothelial growth factor (VEGF)-C and transforming growth factor (TGF)-beta2. The present study also provided first evidence that VEGF-C, the most highly induced gene under 60/20 mmHg, mediated HUVEC proliferation in response to this cyclic pressure. Cyclic pressure is, therefore, a mechanical force that modulates endothelial cell functions (such as proliferation) by activating a specific transcriptional program.

    Title Basic Fibroblast Growth Factor is Upregulated in Hibernating Myocardium.
    Date November 2002
    Journal The Journal of Surgical Research
    Excerpt

    BACKGROUND: Ischemia is known to be a potent stimulus for the upregulation of angiogenic growth factors, such as basic fibroblast growth factor (bFGF). While previous investigations have shown that many angiogenic growth factors are upregulated in animal models of myocardial ischemia, the models used are limited in their ability to produce stable ischemia beyond a few weeks. Our laboratory uses a stable model of hibernating myocardium where later time points may be examined. Therefore, the goal of this study was to examine bFGF protein levels in the myocardium at baseline and 3 or 6 months following the onset of myocardial ischemia. METHODS: A total of 18 miniswine were studied. Basal endogenous levels of bFGF were measured in control animals (n = 6) immediately following sacrifice, while 12 other pigs underwent a 90% left circumflex artery occlusion with documented hibernating myocardium by positron emission tomography ((13)N-ammonia) and dobutamine stress echocardiography. These animals were studied at 3 (n = 7) and 6 months (n = 5) postoperatively. At sacrifice, six 3 x 3 mm samples were harvested from the left circumflex (hibernating) myocardium. Basic FGF levels (picograms per microgram of protein) were determined using ELISA kits. RESULTS: Basic FGF protein levels 3 months after the creation of hibernating myocardium were three times greater than in nonischemic control animals (P < 0.05), while levels at 6 months were increased sixfold compared to control animals (P < 0.05 versus both control and 3-month groups). CONCLUSIONS: Endogenous bFGF production is upregulated at 3 and 6 months in hibernating porcine myocardium. The angiogenic effects of exogenous bFGF delivered into ischemic myocardium with varying levels of endogenous growth factors must be determined.

    Title National Practices Regarding Payment to Research Subjects for Participating in Pediatric Research.
    Date October 2002
    Journal Pediatrics
    Excerpt

    OBJECTIVE: Payment to subjects for participation in research is reportedly common, but no published data documents the nature of this practice. Institutional review boards (IRBs) are responsible for ensuring both the safety and voluntary participation of research subjects, yet guidance from federal and expert pediatric sources regarding appropriate payment approaches is conflicting. Ethical issues of payment for participation of adult versus pediatric research subjects may differ. This empirical study sought to examine current payment practices for participation in pediatric research as reported by IRBs. DESIGN: An 18-question survey regarding payment practices for participation in pediatric research was sent to IRB chairs at member institutions of the National Association of Children's Hospitals and Related Institutions, and to a systematic random sample of IRB chairs listed with the Office for Protection From Research Risks. Descriptive, nonparametric, and qualitative analyses were used to describe institution types, payment practices, and correlations among responses. RESULTS: Data from 128 institutions that conduct pediatric research revealed that payment for participation in pediatric research was allowed by 66% of responding institutions, and practices varied widely among institutions. Most responding IRBs that allowed payment required disclosure of payment before enrollment (during the consent process), following federal guidelines more closely than American Academy of Pediatrics guidelines. An IRB's perception of potential benefits or harms of a study correlated with the amount of payment approved. CONCLUSIONS: IRBs must balance the need to recruit pediatric research subjects against the risk of undue influence during the recruitment process. Federal guidelines and expert pediatric opinion differ in recommendations regarding payment; responding IRBs appeared to follow federal guidelines more closely than guidelines proposed by the American Academy of Pediatrics.

    Title Serotonin Reuptake Inhibitor (paxil) Does Not Prevent the Vasovagal Reaction Associated with Carotid Sinus Massage And/or Lower Body Negative Pressure in Healthy Volunteers.
    Date October 2002
    Journal Circulation
    Excerpt

    BACKGROUND: The purpose of this study was to assess the effect of the serotonin reuptake inhibitor paroxetine hydrochloride (Paxil, SmithKline Beecham) on cardiovascular reflexes. We hypothesized that Paxil prevents neurally mediated syncope (NMS) by attenuating the sympathoinhibition and vagotonia associated with a vasovagal reaction. METHODS AND RESULTS: In a double-blind randomized study, 25 healthy subjects with a positive response to either carotid sinus massage (CSM) or lower body negative pressure (LBNP) received Paxil (20 mg/d) or placebo for 6 weeks. Arterial baroreflex sensitivity (BRS), muscle sympathetic nerve activity (SNA), baroreflex control of SNA, blood pressure, and heart rate responses to CSM and LBNP were measured at baseline and at 6 weeks. Nineteen subjects completed the study (Paxil, n=9; placebo, n=10). In the Paxil group, BRS decreased significantly compared with baseline (15.8+/-4.0 ms/mm Hg versus 11.0+/-2.6 ms/mm Hg, P=0.05); however, all 9 subjects continued to have a positive response to LBNP with presyncope. Paxil did not attenuate the sympathoinhibition or vagotonia associated with a positive LBNP response and had no significant effect on baroreflex control of SNA. In the control group, no significant change in BRS was noted compared with baseline. Seven out of 9 subjects who had a positive LBNP response at baseline had a repeat positive LBNP response, and the subject with a positive CSM at baseline had a negative response at 6 weeks. CONCLUSIONS: Paxil decreases arterial BRS but does not prevent the presyncope associated with LBNP. The effect of Paxil on the autonomic reflexes in patients with neurally mediated syncope remains unclear.

    Title Sleep Apnea: from the Nose to the Heart.
    Date September 2002
    Journal The Journal of the American Board of Family Practice / American Board of Family Practice
    Excerpt

    BACKGROUND: Obstructive sleep apnea (OSA) is a disorder consisting of repetitive obstruction of the upper airway during sleep accompanied by ineffective respiratory effort. METHODS: We developed this clinical review using an extensive MEDLINE review of the literature and data from our laboratories. This review examines (1) the prevalence of OSA; (2) the pathophysiology involved including the causes of obstruction, the physiologic stimuli, and resulting autonomic changes; (3) the cardiovascular manifestations; and (4) the therapeutic approaches to patients with OSA with emphasis on arrhythmia management. RESULTS AND CONCLUSIONS: OSA is highly prevalent and largely underdiagnosed. As part of a much broader spectrum of respiratory disturbances during sleep, OSA can result in a multitude of systemic manifestations. Structural changes occur in the airway to obstruct airflow during OSA, and the resulting apnea activates hypoxic and hypercapnic reflexes, which in turn lead to profound elevation in sympathetic nerve activity and cyclical changes in parasympathetic nerve activity. These autonomic effects are thought to contribute to the associated cardiovascular diseases (eg, hypertension) and frequently observed brady- and tachyarrhythmias. The ultimate goal in the treatment of OSA is to restore airway patency and sleep continuity and to improve daytime functioning and quality of life. Treatment usually results in improvement of clinical symptoms.

    Title Interactive Effects of Mental and Physical Stress on Cardiovascular Control.
    Date June 2002
    Journal Journal of Applied Physiology (bethesda, Md. : 1985)
    Excerpt

    Physiological responses to mental tasks and physical exercise were studied independently and combined. We hypothesized that combined mental and physical stresses produce a synergistic interaction. We studied cardiovascular responses to 5 min of static handgrip, mental arithmetic, and the combined stimuli in random order in 12 healthy subjects. Muscle sympathetic nerve activity (SNA) and mean arterial blood pressure (MAP) responses to handgrip and the combined stimuli exceeded responses to mental arithmetic, yet no significant difference existed between responses to handgrip and the combined stimuli. Peak changes in SNA (in %) were greatest during handgrip (188 +/- 41), followed by the combined stimuli (166 +/- 31) and mental arithmetic (51 +/- 9). Peak changes in MAP (in mmHg) were also greatest during handgrip (26 +/- 4), followed by the combined stimuli (23 +/- 3) and then mental arithmetic (8 +/- 2). Peak changes in heart rate (in beats/min) followed the same trend: handgrip (15 +/- 2), combined (13 +/- 2), and mental arithmetic (10 +/- 2). Mental stimulation did not synergistically interact with or add to the responses elicited by handgrip exercise; in fact, a trend existed for math during handgrip to reduce responses relative to handgrip alone.

    Title Effects of Resynchronization Therapy on Sympathetic Activity in Patients with Depressed Ejection Fraction and Intraventricular Conduction Delay Due to Ischemic or Idiopathic Dilated Cardiomyopathy.
    Date May 2002
    Journal The American Journal of Cardiology
    Excerpt

    This study assesses the effect of biventricular pacing on sympathetic nerve activity (SNA) in patients with depressed ejection fraction and intraventricular conduction delay (IVCD). Biventricular pacing has been shown to result in hemodynamic improvement in patients with depressed ejection fraction and IVCD. The effect of biventricular pacing on SNA, however, remains unclear. A total of 15 men with a mean ejection fraction of 25 +/- 4% were enrolled. Arterial pressure, central venous pressure and SNA were recorded during 3 minutes of right atrial (RA) pacing and RA-biventricular pacing. Pacing was performed at a rate 5 to 10 beats faster than sinus rhythm, with an atrioventricular interval equal to 100 ms during RA-biventricular pacing. RA-biventricular pacing resulted in greater arterial pressures (p <0.05) than RA pacing (146 +/- 15/83 +/- 11 vs 141 +/- 15/80 +/- 10 mm Hg). There were no differences in central venous pressures between the 2 pacing modes (p = 0.76). SNA was significantly less during RA-biventricular pacing (727 +/- 242 U) than during RA pacing (833 +/- 332 U) (p <0.02). Furthermore, there was a positive correlation between baseline QRS duration and the decrease in SNA noted with RA-biventricular pacing (r = 0.58, p = 0.03). Biventricular pacing results in improved hemodynamics and a decrease in SNA compared with intrinsic conduction in patients with left ventricular dysfunction and IVCD. If the current findings are also present with chronic biventricular pacing, then this form of therapy may have a positive impact on mortality.

    Title Coordination Chemistry of Silver(i) with the Nitrogen-bridged Ligands (c(6)h(5))(2)pn(h)p(c(6)h(5))(2) and (c(6)h(5))(2)pn(ch(3))p(c(6)h(5))(2): the Effect of Alkylating the Nitrogen Bridge on Ligand Bridging Versus Chelating Behavior.
    Date May 2002
    Journal Inorganic Chemistry
    Excerpt

    The coordination chemistry of silver(I) with the nitrogen-bridged ligands (C(6)H(5))(2)PN(R)P(C(6)H(5))(2) [R = H (dppa); R = CH(3) (dppma)] has been investigated by (31)P NMR and electrospray mass spectrometry (ESMS). Species observed by (31)P NMR include Ag(2)(mu-dppa)(2+), Ag(2)(mu-dppa)(2)(2+), Ag(2)(mu-dppa)(3)(2+), Ag(2)(mu-dppma)(2+), Ag(2)(mu-dppma)(2)(2+), and Ag(eta(2)-dppma)(2)(+). Species observed by ESMS at low cone voltages were Ag(2)(dppa)(2)(2+), Ag(2)(dppa)(3)(2+), Ag(2)(dppma)(2)(2+), and Ag(dppma)(2)(+). (C(6)H(5))(2)PN(CH(3))P(C(6)H(5))(2) showed a strong tendency to chelate, while (C(6)H(5))(2)PN(H)P(C(6)H(5))(2) preferred to bridge. Differences in the bridging versus chelating behavior of the ligands are assigned to the Thorpe-Ingold effect, where the methyl group on nitrogen sterically interacts with the phenyl groups on phosphorus. The crystal structure of the three-coordinate dinuclear silver(I) complex (Ag(2)[(C(6)H(5))(2)PN(H)P(C(6)H(5))(2)](3))(BF(4))(2) has been determined. Bond distances include Ag-Ag = 2.812(1) A, Ag(1)-P(av) = 2.492(3) A, and Ag(2)-P(av) = 2.509(3) A. The compound crystallizes in the monoclinic space group Cc at 294 K, with a = 18.102(4)(o), Z = 4, V = 7261(3) A(3), R = 0.0503, and R(W) = 0.0670.

    Title Robotically Assisted Versus Conventional Freehand Technique During Beating Heart Anastomoses of Left Internal Thoracic Artery to Left Anterior Descending Artery.
    Date March 2002
    Journal The Annals of Thoracic Surgery
    Excerpt

    BACKGROUND: Although robotically assisted coronary arterial anastomoses are being performed clinically, the short-term and long-term quality and integrity of the left internal thoracic artery (LITA) to left anterior descending artery (LAD) anastomosis remains unknown. The goal of this study was to perform a histologic and angiographic assessment of porcine beating heart LITA to LAD anastomoses using either robotic assistance or a conventional freehand technique. METHODS: Twelve pigs underwent beating heart LITA to LAD anastomoses using either the robotically assisted (n = 6) or conventional freehand techniques (n = 6). Quantitative histologic analysis was performed in all animals in order to determine the degree of vascular wall damage. Selective coronary arteriography was performed in all animals immediately after the procedure in order to evaluate anastomotic patency. The unpaired Student's t test was used for all comparisons between groups. RESULTS: There were no differences in vascular wall damage between the robotically assisted and freehand techniques. Postoperative angiography revealed no stenoses in either group. CONCLUSIONS: Use of the robotically assisted technique for creation of a LITA to LAD anastomosis was not associated with increased histologic damage when compared with the freehand technique in a beating heart porcine model. Furthermore, there was no difference between the two techniques in postoperative patency rate. These results support further clinical investigation of robotically assisted coronary bypass surgery.

    Title Human Muscle Sympathetic Neural and Haemodynamic Responses to Tilt Following Spaceflight.
    Date March 2002
    Journal The Journal of Physiology
    Excerpt

    Orthostatic intolerance is common when astronauts return to Earth: after brief spaceflight, up to two-thirds are unable to remain standing for 10 min. Previous research suggests that susceptible individuals are unable to increase their systemic vascular resistance and plasma noradrenaline concentrations above pre-flight upright levels. In this study, we tested the hypothesis that adaptation to the microgravity of space impairs sympathetic neural responses to upright posture on Earth. We studied six astronauts approximately 72 and 23 days before and on landing day after the 16 day Neurolab space shuttle mission. We measured heart rate, arterial pressure and cardiac output, and calculated stroke volume and total peripheral resistance, during supine rest and 10 min of 60 deg upright tilt. Muscle sympathetic nerve activity was recorded in five subjects, as a direct measure of sympathetic nervous system responses. As in previous studies, mean (+/- S.E.M.) stroke volume was lower (46 +/- 5 vs. 76 +/- 3 ml, P = 0.017) and heart rate was higher (93 +/- 1 vs. 74 +/- 4 beats min(-1), P = 0.002) during tilt after spaceflight than before spaceflight. Total peripheral resistance during tilt post flight was higher in some, but not all astronauts (1674 +/- 256 vs. 1372 +/- 62 dynes s cm(-5), P = 0.32). No crew member exhibited orthostatic hypotension or presyncopal symptoms during the 10 min of postflight tilting. Muscle sympathetic nerve activity was higher post flight in all subjects, in supine (27 +/- 4 vs. 17 +/- 2 bursts min(-1), P = 0.04) and tilted (46 +/- 4 vs. 38 +/- 3 bursts min(-1), P = 0.01) positions. A strong (r(2) = 0.91-1.00) linear correlation between left ventricular stroke volume and muscle sympathetic nerve activity suggested that sympathetic responses were appropriate for the haemodynamic challenge of upright tilt and were unaffected by spaceflight. We conclude that after 16 days of spaceflight, muscle sympathetic nerve responses to upright tilt are normal.

    Title Expression of Nicotinamide N-methyltransferase (e.c. 2.1.1.1) in the Parkinsonian Brain.
    Date March 2002
    Journal Journal of Neuropathology and Experimental Neurology
    Excerpt

    Nicotinamide N-methyltransferase (NNMT) has been proposed as a link between the environmental and genetic factors of Parkinson disease (PD). Therefore, we explored the hypothesis that high levels of NNMT expression may predispose to the development of PD. Regions of high mRNA expression were shown in the spinal cord, medulla, and temporal lobe, with lowest expression in the cerebellum, subthalamic nucleus, and caudate nucleus. Using 2 NNMT antibodies, the protein was shown to be expressed in multipolar neurons in the temporal lobe, caudate nucleus, and spinal cord, granular neurons of the cerebellum, dopaminergic neurons in the substantia nigra, and in the axons of the third nerve. Expression of NNMT was compared in PD and non-PD control cerebella and caudate nucleus. PD tissue exhibited significantly increased levels of NNMT protein and activity. PD disease duration was inversely correlated with the level of expression in cerebellum. This is the first demonstration that patients with PD have higher levels of NNMT activity and protein in brain tissue than those without PD and that NNMT expression is associated with neurons that degenerate in PD.

    Title The Dna Sequence and Comparative Analysis of Human Chromosome 20.
    Date January 2002
    Journal Nature
    Excerpt

    The finished sequence of human chromosome 20 comprises 59,187,298 base pairs (bp) and represents 99.4% of the euchromatic DNA. A single contig of 26 megabases (Mb) spans the entire short arm, and five contigs separated by gaps totalling 320 kb span the long arm of this metacentric chromosome. An additional 234,339 bp of sequence has been determined within the pericentromeric region of the long arm. We annotated 727 genes and 168 pseudogenes in the sequence. About 64% of these genes have a 5' and a 3' untranslated region and a complete open reading frame. Comparative analysis of the sequence of chromosome 20 to whole-genome shotgun-sequence data of two other vertebrates, the mouse Mus musculus and the puffer fish Tetraodon nigroviridis, provides an independent measure of the efficiency of gene annotation, and indicates that this analysis may account for more than 95% of all coding exons and almost all genes.

    Title Gender Differences in Cardiovascular Regulation During Recovery from Exercise.
    Date December 2001
    Journal Journal of Applied Physiology (bethesda, Md. : 1985)
    Excerpt

    Are women more susceptible to acute postexercise orthostatic hypotension compared with men? We hypothesized that decreases in arterial pressure during recovery from dynamic exercise are greater in women compared with men. We studied 8 men and 11 women during inactive and active recovery from cycling exercise. Heart rate, stroke volume (SV), cardiac output, mean arterial pressure (MAP), and total peripheral resistance (TPR) were measured during and after 3 min of exercise at 60% of calculated maximum heart rate. At 1 min after exercise, MAP decreased less (P < 0.05) during inactive recovery in men (-18 +/- 2 mmHg) compared with women (-30 +/- 2 mmHg). This difference was due to greater decreases in SV and less increase in TPR during inactive recovery from exercise in women compared with men. These differences persisted for 5 min after exercise. MAP decreased less during active recovery in men compared with women. These findings suggest that women may have increased risk of postexercise orthostatic hypotension and that active recovery from exercise may reduce this risk.

    Title Malignant Rolandic-sylvian Epilepsy in Children: Diagnosis, Treatment, and Outcomes.
    Date September 2001
    Journal Neurology
    Excerpt

    OBJECTIVE: To describe the diagnosis, treatment, and outcomes in children with malignant rolandic-sylvian epilepsy (MRSE), defined as a form of epilepsy characterized by sensorimotor seizures, medical refractoriness, normal MRI, frontocentrotemporal EEG spikes, rolandic-sylvian spike sources on magnetoencephalography (MEG), and cognitive problems. METHODS: A retrospective chart analysis of seven patients who had shown these characteristics and undergone extensive diagnostic testing, including MEG and intracranial video-EEG was performed. RESULTS: Interictal scalp EEG spikes were seen over the frontocentrotemporal regions bilaterally (6) and unilaterally (1). MEG showed spike sources in the perisylvian region in two patients (both bilateral) and in the perirolandic fissure in five (two bilateral). Three patients required bilateral subdural strips to lateralize seizures before electrocorticography. Final electrocorticograms showed an ictal onset zone around the rolandic (four cases) and rolandic-sylvian regions (three cases). Six patients showed neuropsychological deficits. After cortical excision and multiple subpial transection, three were seizure free and four had seizures rarely (30 months' mean follow-up). No child had a permanent deficit in sensorimotor or cognitive functions, although two showed exacerbation of preexisting attentional deficits. Tissue analysis showed definite evidence of neuronal migration disorders (3) and gliosis (2). CONCLUSIONS: MEG was helpful for localizing both malignant rolandic-sylvian neuronal activities and functional cortex. Successive neuropsychological assessments are necessary to detect cognitive deterioration and indicate remedial programming. If, after careful observation over at least 5 years, surgery is considered to control refractory seizures, intracranial video-EEG is needed to localize the epileptogenic zone.

    Title Just Whose Autonomy is It?
    Date September 2001
    Journal Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
    Title A Cd2-green Fluorescence Protein-transgenic Mouse Reveals Very Late Antigen-4-dependent Cd8+ Lymphocyte Rolling in Inflamed Venules.
    Date August 2001
    Journal Journal of Immunology (baltimore, Md. : 1950)
    Excerpt

    Intravital microscopy allows detailed analysis of leukocyte trafficking in vivo, but fails to identify the nature of leukocytes investigated. Here, we describe the development of a CD2-enhanced green fluorescence protein (EGFP)-transgenic mouse to characterize lymphocyte trafficking during inflammation in vivo. A CD2-EGFP plasmid construct including the CD2 promoter, the EGFP transgene, and the CD2 locus control region was injected into B6CBA/F1 pronuclei. EGFP+ offspring were backcrossed into C57BL/6 mice for six generations. Flow cytometry demonstrated that all peripheral blood EGFP+ cells were positive for CD2 and negative for the granulocyte Ag Ly 6-G (GR-1). EGFP(high) cells stained positive for CD2, CD3, CD8, TCR beta-chain, and NK1.1 but did not express the B cell and monocyte markers CD45RA, CD19, and CD11b. In vitro stimulation assays revealed no difference in lymphocyte proliferation and IL-2 secretion between EGFP+ and EGFP- mice. Intravital microscopy of untreated or TNF-alpha-treated cremaster muscle venules showed EGFP+ cells in vivo, but these cells did not roll or adhere to the vessel wall. In cremaster muscle venules treated with both TNF-alpha and IFN-gamma, EGFP(high) cells rolled, adhered, and transmigrated at a rolling velocity slightly higher (11 microm/s) than that of neutrophils (10 microm/s). Blocking alpha4 integrin with a mAb increased rolling velocity to 24 microm/s. These findings show that CD8+ T cells roll in TNF-alpha/IFN-gamma-pretreated vessels in vivo via an alpha4 integrin-dependent pathway.

    Title Hox Genes and the Phylogeny of the Arthropods.
    Date July 2001
    Journal Current Biology : Cb
    Excerpt

    The arthropods are the most speciose, and among the most morphologically diverse, of the animal phyla. Their evolution has been the subject of intense research for well over a century, yet the relationships among the four extant arthropod subphyla - chelicerates, crustaceans, hexapods, and myriapods - are still not fully resolved. Morphological taxonomies have often placed hexapods and myriapods together (the Atelocerata) [1, 2], but recent molecular studies have generally supported a hexapod/crustacean clade [2-9]. A cluster of regulatory genes, the Hox genes, control segment identity in arthropods, and comparisons of the sequences and functions of Hox genes can reveal evolutionary relationships [10]. We used Hox gene sequences from a range of arthropod taxa, including new data from a basal hexapod and a myriapod, to estimate a phylogeny of the arthropods. Our data support the hypothesis that insects and crustaceans form a single clade within the arthropods to the exclusion of myriapods. They also suggest that myriapods are more closely allied to the chelicerates than to this insect/crustacean clade.

    Title Necrotic Arachnidism.
    Date June 2001
    Journal Journal of the American Academy of Dermatology
    Excerpt

    Necrotic arachnidism is the potential cutaneous reaction to spider bite venom. In the United States, members of 7 spider families may be responsible for envenomation sufficiently severe to warrant treatment. Characteristics of several spiders, in particular Loxosceles spiders, whose bite is toxic to humans are described, and diagnostic standards, preventive measures, and treatment options are reviewed. (J Am Acad Dermatol 2001;44:561-73.) LEARNING OBJECTIVE: After the completion of this learning activity, participants should be familiar with the characteristics of several different spider families endemic to the United States. Furthermore, this learning activity should aid in the prevention and diagnosis of spider bites as well as in the classification and treatment of specific bites.

    Title Biventricular Pacing Decreases the Inducibility of Ventricular Tachycardia in Patients with Ischemic Cardiomyopathy.
    Date June 2001
    Journal The American Journal of Cardiology
    Title Nccn Practice Guidelines for Breast Cancer.
    Date March 2001
    Journal Oncology (williston Park, N.y.)
    Excerpt

    The therapeutic options for patients with noninvasive or invasive breast cancer are complex and varied. In many situations, the patient and physician have the responsibility to jointly explore and ultimately select the most appropriate option from among the available alternatives. With rare exception, the evaluation, treatment, and follow-up recommendations contained within these guidelines were based largely on the results of past and present clinical trials. However, there is not a single clinical situation in which the treatment of breast cancer has been optimized with respect to either maximizing cure or minimizing toxicity and disfigurement. Therefore, patient and physician participation in prospective clinical trials allows patients not only to receive state-of-the-art cancer treatment but also to contribute to the improvement of treatment of future patients.

    Title Effect of P-wave Timing During Supraventricular Tachycardia on the Hemodynamic and Sympathetic Neural Response.
    Date January 2001
    Journal Circulation
    Excerpt

    BACKGROUND: Previous studies have shown the importance of the timing of atrial and ventricular systole on the hemodynamic response during supraventricular tachycardia (SVT). However, the reflex changes in autonomic tone during SVT remain poorly understood. METHODS AND RESULTS: Eleven patients with permanent dual-chamber pacemakers were enrolled in the study. Arterial blood pressure (BP), central venous pressure (CVP), and peripheral muscle sympathetic nerve activity (SNA) were recorded during DDD pacing at a rate of 175 bpm (cycle length 343 ms) with an atrioventricular (AV) interval of 30, 200 and 110 ms, simulating tachycardia with near-simultaneous atrial and ventricular systole, short-RP tachycardia (RP<PR), and long-RP tachycardia (RP>PR). Each pacing run was performed for 3 minutes separated by a 5-minute recovery period. All patients demonstrated an abrupt fall in BP, an increase in CVP, and an increase in SNA regardless of the AV interval. The decreases in SBP, DBP, and MAP and the increase in CVP were significantly less during long-RP tachycardia (AV interval 110 ms) than during the other 2 pacing modes (P:<0.05), and the increase in SNA in 7 of the 11 patients was significantly greater during closely coupled atrial and ventricular systole than during long-RP tachycardia (P:<0.05). CONCLUSIONS: These data suggest that the superior maintenance of hemodynamic stability during long-RP tachycardia is accompanied by reduced sympathoexcitation, which is primarily mediated by the arterial baroreceptors, with a modest cardiopulmonary vasodepressor effect.

    Title Biventricular Pacing Decreases Sympathetic Activity Compared with Right Ventricular Pacing in Patients with Depressed Ejection Fraction.
    Date September 2000
    Journal Circulation
    Excerpt

    BACKGROUND: Although there have been few studies in which the hemodynamic effects of right ventricular (RV) and left ventricular (LV) pacing were compared with those of biventricular (BV) pacing, the autonomic changes during these different pacing modes remain unknown. We hypothesized that BV pacing results in improved hemodynamics and a decrease in sympathetic nerve activity (SNA) compared with single-site pacing. METHODS AND RESULTS: Thirteen men with a mean ejection fraction of 0.28+/-0.7 were enrolled in the study. Arterial blood pressure (BP), central venous pressure (CVP), and SNA were recorded during 3 minutes of right atrial (RA)-RV, RA-LV, and RA-BV pacing at a rate 10 beats faster than sinus rhythm. BP was greater during LV (151+/-7/85+/-3 mm Hg) and BV (151+/-6/85+/-3 mm Hg) pacing than during RV pacing (146+/-7/82+/-3 mm Hg) (P:<0.05). There were no differences in CVP among all pacing modes (P:=0.27). SNA was significantly less (P:<0.02) during both LV (606+/-35 U) and BV (582+/-41 U) pacing compared with RV pacing (685+/-32 U) (P:<0.02). Although not statistically significant (P:=0. 08 to 0.14), there was a trend for patients with a narrow QRS to have a lower mean BP and higher SNA during LV pacing than during BV pacing (r=0.42 to 0.49). CONCLUSIONS: LV-based pacing results in improved hemodynamics and a decrease in SNA compared with RV pacing in patients with LV dysfunction regardless of the QRS duration.

    Title Increased Sympathetic Activity After Atrioventricular Junction Ablation in Patients with Chronic Atrial Fibrillation.
    Date July 2000
    Journal Journal of the American College of Cardiology
    Excerpt

    OBJECTIVES: The aim of this study was to determine the changes in sympathetic nerve activity (SNA) after atrioventricular junction (AVJ) ablation in patients with chronic atrial fibrillation (AF). BACKGROUND: Polymorphic ventricular tachycardia (PMVT) has been reported after AVJ ablation in patients paced at a rate of < or =70 beats/min. We hypothesized that AVJ ablation results in sympathetic neural changes that favor the occurrence of PMVT and that pacing at 90 beats/min attenuates these changes. METHODS: Sympathetic nerve activity, 90% monophasic cardiac action potential duration (APD90), right ventricular effective refractory period (ERP) and blood pressure measurements were obtained in 10 patients undergoing AVJ ablation. Sympathetic nerve activity was analyzed at baseline and during and after successful AVJ ablation for at least 10 min. Data were also collected after ablation at pacing rates of 60 and 90 beats/min. The APD90 and ERP were measured before and after AV block during pacing at 120 beats/min. RESULTS: Sympathetic nerve activity increased to 134 +/- 16% of the pre-ablation baseline value (p < 0.01) after successful AVJ ablation plus pacing at 60 beats/min and decreased to 74 +/- 8% of baseline (p < 0.05) with subsequent pacing at 90 beats/min. Both APD90 and ERP increased significantly. CONCLUSIONS: 1) Ablation of the AVJ followed by pacing at 60 beats/min is associated with an increase in SNA. 2) Pacing at 90 beats/min decreases SNA to or below the pre-ablation baseline value. 3) Cardiac APD and ERP increase after AVJ ablation. The increase in SNA, along with the prolongation in APD, may play a role in the pathogenesis of ventricular arrhythmias that occur after AVJ ablation.

    Title Refill Program Using Pharmacy Student Interns in a Primary Care Clinic.
    Date June 2000
    Journal American Journal of Health-system Pharmacy : Ajhp : Official Journal of the American Society of Health-system Pharmacists
    Title The Effect of Non-steroidal Anti-inflammatory Drugs on Human Colorectal Cancer Cells: Evidence of Different Mechanisms of Action.
    Date June 2000
    Journal European Journal of Cancer (oxford, England : 1990)
    Excerpt

    Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit proliferation and induce apoptosis in human colorectal cancer cells in vitro. It remains unclear whether individual NSAIDs act by cyclooxygenase-2 (COX-2) inhibition and how NSAIDs exert their anti-proliferative effects. We investigated the effects of NS-398 (a selective COX-2 inhibitor), indomethacin (a non-selective COX inhibitor) and aspirin on four human colorectal cancer cell lines (HT29.Fu, HCA-7, SW480 and HCT116). NS-398 completely inhibited proliferation, induced G1 arrest and promoted apoptosis in COX-2-expressing cells (HT29.Fu and HCA-7). However, indomethacin had similar effects on all cells, regardless of COX-2 expression. NS-398 also had anti-proliferative activity on COX-2-negative cell lines (SW480 and HCT116). Aspirin inhibited proliferation of all cell lines but did not induce apoptosis. Indomethacin decreased beta-catenin protein expression in all cells (unlike NS-398 or aspirin). NSAIDs act on human colorectal cancer cells via different mechanisms. Decreased beta-catenin protein expression may mediate the anti-proliferative effects of indomethacin.

    Title P53-mediated Dna Repair Responses to Uv Radiation: Studies of Mouse Cells Lacking P53, P21, And/or Gadd45 Genes.
    Date May 2000
    Journal Molecular and Cellular Biology
    Excerpt

    Human cells lacking functional p53 exhibit a partial deficiency in nucleotide excision repair (NER), the pathway for repair of UV-induced DNA damage. The global genomic repair (GGR) subpathway of NER, but not transcription-coupled repair (TCR), is mainly affected by p53 loss or inactivation. We have utilized mouse embryo fibroblasts (MEFs) lacking p53 genes or downstream effector genes of the p53 pathway, gadd45 (Gadd45a) or p21 (Cdkn1a), as well as MEFs lacking both gadd45 and p21 genes to address the potential contribution of these downstream effectors to p53-associated DNA repair. Loss of p53 or gadd45 had a pronounced effect on GGR, while p21 loss had only a marginal effect, determined by measurements of repair synthesis (unscheduled DNA synthesis), by immunoassays to detect removal of UV photoproducts from genomic DNA, and by assays determining strand-specific removal of CPDs from the mouse dhfr gene. Taken together, the evidence suggests a role for Gadd45, but relatively little role for p21, in DNA repair responses to UV radiation. Recent evidence suggests that Gadd45 binds to UV-damaged chromatin and may affect lesion accessibility. MEFs lacking p53 or gadd45 genes exhibited decreased colony-forming ability after UV radiation and cisplatin compared to wild-type MEFs, indicating their sensitivity to DNA damage. We provide evidence that Gadd45 affects chromatin remodelling of templates concurrent with DNA repair, thus indicating that Gadd45 may participate in the coupling between chromatin assembly and DNA repair.

    Title Selective Parasympathetic Denervation Following Posteroseptal Ablation for Either Atrioventricular Nodal Reentrant Tachycardia or Accessory Pathways.
    Date April 2000
    Journal The American Journal of Cardiology
    Excerpt

    Baroreflex gain and coronary sinus norepinephrine and epinephrine levels were measured before and immediately after radiofrequency ablation in the posteroseptal region in 9 patients with atrioventricular nodal reentrant tachycardia or posteroseptal accessory pathways. Arterial baroreflex gain was significantly reduced after radiofrequency ablation (p = 0.046), whereas coronary sinus epinephrine and norepinephrine levels did not change significantly compared with preablation levels.

    Title Screening Postmortem Blood and Tissues for Nine Classes [correction of Cases] of Drugs of Abuse Using Automated Microplate Immunoassay.
    Date February 2000
    Journal Forensic Science International
    Excerpt

    A commercially available enzyme-linked immunosorbant assay (ELISA) was evaluated as a screening procedure for the detection of nine classes of abused drugs in postmortem blood and tissue specimens. Specifically, postmortem blood, fluid and/or tissue homogenates were screened for amphetamine (AMP), methamphetamine (MET), barbiturates (BARB), benzodiazepines (BZD), cannabinoids (CNB), cocaine (benzoylecgonine; BE), morphine-specific (MOR), opiates (class; OPI), phencyclidine (PCP) and lysergic acid diethylamide (LSD) by ELISA and by coated tube radioimmunoassay (CTR) (BARB, BE, OPI, PCP, LSD) or double-antibody radioimmunoassay (DAR) (AMP/METH, BZD, CNB). Specimens that screened 'positive' by any method were confirmed and quantitated by gas chromatography/mass spectrometry (GC/MS). The only assay that appeared to perform less optimally than RIA was the MOR assay (five false negatives). However, this assay is very specific for free morphine while the GC/MS confirmation method provided a total morphine value. The OPI assay was more sensitive, producing fewer false negatives, and is recommended for broad class opiate screening. EIA is an adequate alternative to RIA for screening postmortem specimens, including blood and tissue, for nine major classes of drugs.

    Title Tissue Distribution of Mirtazapine (remeron) in Postmortem Cases.
    Date November 1999
    Journal Journal of Analytical Toxicology
    Excerpt

    Mirtazapine (Remeron) is a member of the relatively new class of tetracyclic antidepressants. There are published cases of mirtazapine's detection as an incidental finding in postmortem cases; however, case reports with associated tissue concentrations and interpretations are not available. This report documents the tissue distribution of mirtazapine in eight postmortem cases in which it was identified but did not contribute to the cause or manner of death. The following mean mirtazapine concentrations (milligrams per liter or milligrams per kilogram) were found: heart blood 0.12 (range, < 0.01-0.33, n = 7); peripheral blood 0.09 (< 0.01-0.14, n = 4); urine 0.61 (0.01-3.2, n = 7); liver 0.88 (0.04-3.6, n = 6), kidney 0.21 (0.02-0.48, n = 5); and bile 0.62 (0.11-1.6, n = 6). In each case, the mirtazapine concentration in heart blood was approximately equal to that of peripheral blood, indicating that postmortem redistribution was not a factor in evaluating postmortem blood concentrations in these cases. However, because the liver mirtazapine concentrations were 5-30 times the blood concentrations, the potential for postmortem redistribution cannot be excluded. Additionally, because urine concentrations of the parent compound were consistently greater than the blood concentrations, urine is an adequate screening specimen for mirtazapine.

    Title An Examination of Ethical Issues Raised in the Pretreatment of Normal Volunteer Granulocyte Donors with Granulocyte Colony-stimulating Factor.
    Date September 1999
    Journal Archives of Pathology & Laboratory Medicine
    Excerpt

    OBJECTIVE: To explore some of the ethical issues surrounding the administration of granulocyte colony-stimulating factor (G-CSF) to healthy individuals for the purpose of retrieval of granulocytes. DESIGN: Review of the historical precedent of drug administration to normal blood donors and review of the literature concerning the side effects of G-CSF administration to healthy individuals, particularly as related to granulocyte collection. We identify and discuss some of the ethical questions regarding this issue. RESULTS: Although the short-term side effects of G-CSF use in normal donors are generally felt to be benign, little is known about the long-term side effects. Ethical questions regarding the administration of this drug to normal donors for the purpose of collecting large numbers of granulocytes include the following: Does the potential benefit to a patient/recipient justify the unknown risks to the medicated granulocyte donor? Who should act as an advocate for donors so that their best interests are protected? What is the role and quality of informed consent for donors undergoing G-CSF administration? Is monetary compensation appropriate for donors administered G-CSF as part of a research protocol? CONCLUSIONS: We recommend the establishment of a donor registry to collect the needed data on the side effects of G-CSF on normal donors. Until adequate data are collected, the use of G-CSF and similar agents in normal donors should be regarded as experimental and subject to review by institutional review boards.

    Title Reflex Control of Sympathetic Activity During Simulated Ventricular Tachycardia in Humans.
    Date September 1999
    Journal Circulation
    Excerpt

    BACKGROUND: Ventricular tachyarrhythmias present a unique set of stimuli to arterial and cardiopulmonary baroreceptors by increasing cardiac filling pressures and decreasing arterial pressure. The net effect on the control of sympathetic nerve activity (SNA) in humans is unknown. The purpose of this study was to determine the relative roles of cardiopulmonary and arterial baroreceptors in controlling SNA and arterial pressure during ventricular pacing in humans. METHODS AND RESULTS: Two experiments were performed in which SNA and hemodynamic responses to ventricular pacing were compared with nitroprusside infusion (NTP) in 12 patients and studied with and without head-up tilt or phenylephrine to normalize the stimuli to either the arterial or cardiopulmonary baroreceptors in 9 patients. In experiment 1, the slope of the relation between SNA and mean arterial pressure was greater during NTP (-4.7+/-1.4 U/mm Hg) than during ventricular pacing (-3.4+/-1.1 U/mm Hg). Comparison of NTP doses and ventricular pacing rates that produced comparable hypotension showed that SNA increased more during NTP (P=0.03). In experiment 2, normalization of arterial pressure during pacing resulted in SNA decreasing below baseline (P<0.05), whereas normalization of cardiac filling pressure resulted in a greater increase in SNA than pacing alone (212+/-35% versus 189+/-37%, P=0. 04). Conclusions--These data demonstrate that in humans arterial baroreflex control predominates in mediating sympathoexcitation during ventricular tachyarrhythmias and that cardiopulmonary baroreceptors contribute significant inhibitory modulation.

    Title Baroreflex Gain Predicts Blood Pressure Recovery During Simulated Ventricular Tachycardia in Humans.
    Date August 1999
    Journal Circulation
    Excerpt

    BACKGROUND: Despite similar degrees of left ventricular dysfunction and similar tachycardia or pacing rate, blood pressure (BP) response and symptoms vary greatly among patients. Sympathetic nerve activity (SNA) increases during sustained ventricular tachycardia (VT), and the magnitude of this sympathoexcitatory response appears to contribute to the net hemodynamic outcome. We hypothesize that the magnitude of sympathoexcitation and thus arterial baroreflex gain is an important determinant of the hemodynamic outcome of VT. METHODS AND RESULTS: We evaluated the relation between arterial baroreflex sympathetic gain and BP recovery during rapid ventricular pacing (VP) in patients referred for electrophysiological study. Efferent postganglionic muscle SNA, BP, and central venous pressure (CVP) were measured in 14 patients during nitroprusside infusion and during VP at 150 (n=12) or 120 (n=2) bpm. Arterial baroreflex gain was defined as the slope of the relationship of change in SNA to change in diastolic BP during nitroprusside infusion. Recovery of mean arterial pressure (MAP) during VP was measured as the increase in MAP from the nadir at the onset of pacing to the steady-state value during sustained VP. Arterial baroreflex gain correlated positively with recovery of MAP (r=0.57, P=0.034). No significant correlation between ejection fraction and baroreflex gain (r=0.48, P=0.08) or BP recovery (r=0.41, P=0.15) was found. When patients were separated into high versus low baroreflex gain, the recovery of MAP during simulated VT was significantly greater in patients with high gain. CONCLUSIONS: These data strongly suggest that arterial baroreflex gain contributes significantly to hemodynamic stability during simulated VT. Knowledge of baroreflex gain in individual patients may help the clinician tailor therapy directed toward sustained VT.

    Title Association with Cdc2 and Inhibition of Cdc2/cyclin B1 Kinase Activity by the P53-regulated Protein Gadd45.
    Date June 1999
    Journal Oncogene
    Excerpt

    Recently Gadd45, a p53-regulated stress protein, has been implicated in the activation of a G2/M checkpoint after damage by UV radiation and alkylating agents. While inhibitory phosphorylation of Cdc2 and suppression of cyclin B1 levels are known to be involved in G2 delays after genotoxic stress, Gadd45 has now been found to directly inhibit the activity of Cdc2/Cyclin B1 complex, while it had no appreciable effect on Cdk2/ Cyclin E activity even at very high levels of Gadd45. In contrast, p21CiP1/Waf1 is an universal cdk/cyclin inhibitor and inhibited both of the cyclin complexes tested here. Gadd45 was also able to physically interact with Cdc2, but not Cyclin B1. Addition of Gadd45 to immunoprecipitated Cdc2/Cyclin B1 in vitro led to a dissociation of this complex, and thus may represent a new checkpoint mechanism whereby Cdc2/Cyclin B1 can be inhibited. With the use of an antisense approach, reduced Gadd45 expression attenuated the suppression of Cdc2/Cyclin B1 activity in UV-irradiated human cells. Taken together, these results implicate Gadd45 in the control of G2/M cell cycle progression after certain stresses.

    Title A Macrolactam Inhibitor of T Helper Type 1 and T Helper Type 2 Cytokine Biosynthesis for Topical Treatment of Inflammatory Skin Diseases.
    Date June 1999
    Journal The Journal of Investigative Dermatology
    Excerpt

    T lymphocytes play a critical part in inflammatory skin diseases but are targeted by available therapies that have only partial efficacy, significant side-effects, or both. Because psoriasis, atopic dermatitis, and allergic contact hypersensitivity are associated with T helper type 1 (Th1), T helper type 2 (Th2), or mixed Th1-Th2 cell subsets and cytokine types, respectively, there is a need for a better broad-based inhibitor. The macrolactam ascomycin analog, ABT-281, was found to inhibit potently T cell function across species and to inhibit expression of multiple cytokines in human peripheral blood leukocytes which have been found in human skin disease cells and tissues. These included immunoregulatory Th1 (interleukin-2 and interferon-gamma) and Th2 (interleukin-4 and interleukin-5) cytokines. ABT-281 was shown to have potent topical activity (ED50 = 0.6% in acetone/olive oil) in a stringent swine model of allergic contact hypersensitivity, but its potency was markedly reduced compared with ascomycin when administered systemically due to more rapid clearance. Topical application of 3% ABT-281 in acetone/olive oil over 25% of the body surface in swine resulted in undetectable blood levels. Compared with a wide potency range of topical corticosteroids in clinical formulations, 0.3% and 1% ABT-281 ointments profoundly inhibited dinitrochlorobenzene-induced contact hypersensitivity in the pig by 78% and 90%, respectively, whereas super-potent steroids such as clobetasol propionate only inhibited in the 50% range and mild to moderate potency steroids such as fluocinolone acetonide were inactive. The potent topical activity of ABT-281 in swine, its superior efficacy, its rapid systemic clearance following uptake into the bloodstream, and its ability to inhibit cytokine biosynthesis of both Th1 and Th2 cell subsets, suggests that it will have a broad therapeutic value in inflammatory skin diseases, including psoriasis, atopic dermatitis, and allergic contact dermatitis.

    Title Desmoplastic Fibroma of the Zygoma.
    Date June 1999
    Journal Plastic and Reconstructive Surgery
    Excerpt

    Desmoplastic fibroma is an exceedingly rare primary bone tumor. Previous reports have not included the presentation of this tumor associated with the zygoma. This report describes the unusual presentation and surgical management of a desmoplastic fibroma of the zygoma.

    Title Identification of a Neuronal Calmodulin-binding Peptide, Cap-19, Containing an Iq Motif.
    Date June 1999
    Journal Brain Research. Molecular Brain Research
    Excerpt

    Neurons produce polypeptides which can bind the calcium-poor or pre-activated form of calmodulin. It is expected that this class of peptide will serve an important role in maintaining cellular homeostasis since it would modulate calcium-dependent target regulation and redirect intracellular signaling. The lack of conserved sequence has made the identification of these peptides difficult, consequently leading us to exploit their property of binding calcium-poor calmodulin as a means of finding new species. A new peptide termed Calmodulin-Associated Peptide-19 (CAP-19) was purified and characterized. The protein-sequence information was employed in order to recover a cDNA clone from rat which included the entire reading frame for the peptide. Like its counterparts, neuromodulin (GAP-43), neurogranin (RC3) and PEP-19, it contains an IQ motif although the remainder of the peptide is quite different. Northern blot analysis of ribonucleic acid (RNA) from animals of differing ages indicated that the message appears at birth and then persists into adulthood. Antibodies to synthetic peptide were employed for localizing CAP-19. The results indicated that the peptide was localized to neurons in several brain regions. CAP-19 is similar to other calmodulin-binding proteins in that the domain spanning the IQ motif was demonstrated to participate in binding to calmodulin. Database searching showed CAP-19 to be homologous to the silkworm protein, multiprotein bridging factor 1 (MBF1). This homology suggests a potential new role for calmodulin-associated proteins in cellular homeostasis.

    Title Tissue Distribution of Tramadol and Metabolites in an Overdose Fatality.
    Date June 1999
    Journal The American Journal of Forensic Medicine and Pathology : Official Publication of the National Association of Medical Examiners
    Excerpt

    Tramadol (Ultram) is a centrally acting, synthetic analgesic agent. Although it has some affinity for the opiate receptors, tramadol is believed to exert its analgesic effect by inhibiting the re-uptake of norepinephrine and serotonin. There are several published cases of tramadol's involvement in drug-related deaths and impairment. Reports of deaths involving tramadol alone with associated tissue concentrations are rare. This report documents a case in which tramadol overdose was identified as the cause of death. The following tramadol concentrations were found in various tissues: blood, 20 mg/L; urine, 110.2 mg/L; liver, 68.9 mg/kg; and kidney, 37.5 mg/kg. Tissue distributions of the two primary metabolites, N-desmethyl and O-desmethyl tramadol, are also reported. In each tissue or fluid except urine, the tramadol concentration was greater than either metabolite, consistent with other reports of drug-impaired drivers and postmortem cases. The O-desmethyl metabolite concentration was greater than the N-desmethyl metabolite concentration in all tissues; this is in contrast to other postmortem reports, in which the majority of cases report concentrations of O-desmethyl as less than those of N-desmethyl. This may be useful as an indicator of time lapse between ingestion and death.

    Title Regulation of the C-met Proto-oncogene Promoter by P53.
    Date February 1999
    Journal The Journal of Biological Chemistry
    Excerpt

    In the present study, we have investigated the possible involvement of p53 in the transcriptional regulation of the c-met gene. Cotransfection of various c-met promoter reporter vectors with p53 expression plasmids demonstrated that only wild-type p53 but not tumor-derived mutant forms of p53 resulted in a significant enhancement of c-met promoter activity. Functional assays revealed that the p53 responsive element in the c-met promoter region is located at position -278 to -216 and confers p53 responsiveness not only in the context of the c-met promoter but also in the context of a heterologous promoter. Electrophoretic mobility shift assays using purified recombinant p53 protein showed that the p53 binding element identified within the c-met promoter specifically binds to p53 protein. Induction of p53 by UV irradiation in RKO cells that express wild-type p53 increased the level of the endogenous c-met gene product and p21(WAF1/CIP1), a known target of p53 regulation. On the other hand, in RKO cells in which the function of p53 is impaired either by stable transfection of a dominant negative form of p53 or by HPV-E6 viral protein, no induction of the endogenous c-met gene or p21(WAF1/CIP1) was noted by UV irradiation. These results suggest that the c-met gene is also a target of p53 gene regulation.

    Title Amelioration by Cyclosporin A of Brain Damage in Transient Forebrain Ischemia in the Rat.
    Date February 1999
    Journal Brain Research
    Excerpt

    The immunosuppressant drug cyclosporin A (CsA) is considered to be inherently protective in conditions of ischemia, e.g. in hepatic and cardiac tissue. However, investigations of effects of CsA on neuronal tissue have been contradictory, probably because the blood-brain barrier (BBB) is virtually impermeable to CsA. In the present study, we exploited the finding that the insertion of a syringe needle into brain parenchyma obviously disrupts the BBB and allows influx of CsA, and explored whether CsA, given as intraperitoneal injections daily for 1 week before and 1 week after forebrain ischemia of 7 or 10 min duration, ameliorates the damage incurred to the hippocampal CA 1 sector. In other experiments, the needle insertion and the first i.p. injection of CsA were made 30 min after the start of recirculation, with continued daily administration of CsA during the postinsult week. In animals which were injected with CsA in daily doses of 10 mg kg-1, but in which no needle was inserted, the drug failed to ameliorate CA1 damage, whether the ischemia had a duration of 7 or 10 min. Likewise, needle insertion had no effect on CA1 damage if CsA was not administered. In contrast, when CsA was given to animals with a needle insertion, CA1 damage was dramatically ameliorated, whether treatment was initiated 1 week before ischemia, or 30 min after the start of recirculation. The effect of CsA seemed larger than that of any other drug proposed to have an anti-ischemic effect in forebrain/global ischemia. Injection of tritiated CsA in one animal with BBB disruption lead to detectable radioactivity throughout the ventricular system, suggesting a generalised increase of the entry of CsA across the BBB. The results demonstrate that immunosuppressants of the type represented by CsA markedly ameliorate delayed neuronal damage after transient forebrain ischemia, provided that they can pass the BBB. It is discussed whether the effect of the drug is one involving calcineurin, a protein phosphatase, or if CsA counteracts a permeability transition of the inner mitochondrial membrane, assumed to occur in response to adverse conditions, e.g. gradual accumulation of Ca2+ in the mitochondria in the postischemic period.

    Title Neurodevelopmental Outcomes in Children Surviving D-transposition of the Great Arteries.
    Date February 1999
    Journal Journal of Developmental and Behavioral Pediatrics : Jdbp
    Excerpt

    We investigated the prevalence of neurological abnormalities and learning problems in a population cohort of children with dextro-transposition of the great arteries (d-TGA) born between January 1, 1981 and July 1, 1990. Fifty-seven of the 60 survivors and 35 siblings in the control group underwent neurodevelopmental assessments. As compared with population norms, children with d-TGA were more likely to have abnormal neurological examination findings, learning disabilities, and behavioral disorders. There was no significant difference in IQ or frequency of abnormal neurological examination results between children undergoing atrial as compared with arterial switch procedures. Compared with their siblings, the children with d-TGA had more neurological findings and learning disabilities. The siblings of children with d-TGA had more learning problems than expected. The findings suggest that ongoing surveillance is indicated for children surviving d-TGA. Furthermore, a familial tendency for learning differences should to be taken into consideration when neurodevelopmental outcomes of various perioperative parameters are examined.

    Title Reduction Mammaplasty: Its Role in Breast Conservation Surgery for Early-stage Breast Cancer.
    Date December 1998
    Journal Annals of Plastic Surgery
    Excerpt

    Segmental resection and radiotherapy is an accepted alternative over mastectomy for small, staged breast malignancies. However, women with large, pendulous breasts have been documented to have poorer cosmetic outcomes when undergoing irradiation after breast conservative surgery compared with women with small- or medium-size breasts, thought to be caused by dose inhomogeneity. The purpose of this study was to evaluate the efficacy of combining reduction mammaplasty with breast conservative surgery to facilitate postoperative irradiation. Between 1988 and 1996, 10 women have undergone bilateral reduction mammaplasty for breast malignancy followed by radiation therapy at our center. All women wished to avoid mastectomy (average age, 59 years). All lesions were detected preoperatively on mammography. The average amount of tissue removed was 945 g per breast. A variety of reduction techniques were employed to include the malignant lesions. All patients received 50 Gy of radiation therapy delivered in 25 fractions following reduction mammaplasty during a 5-week period. Radiation therapy was usually initiated within 4 weeks following surgery. Follow-up is currently 37 months, with all patients being followed for at least 8 months. No patients have had complications from the surgery or radiation therapy. No local recurrent malignancies have been detected. Cosmesis has been good to excellent in all patients. Despite equivalent survival outcomes for mastectomy for early-stage breast cancer, certain women are not good candidates for breast conservation and radiation therapy. An alternative for women with large, pendulous breasts that combines breast conservation therapy and concurrent bilateral reduction mammaplasty should be considered. This combination, in selected women, provides good functional and cosmetic results, and at the same time minimizes the potential difficulties of radiation therapy.

    Title Diabetes and Mitochondrial Encephalomyopathy with Lactic Acidosis and Stroke-like Episodes (melas): Radiolabeled Polymerase Chain Reaction is Necessary for Accurate Detection of Low Percentages of Mutation.
    Date October 1997
    Journal The Journal of Clinical Endocrinology and Metabolism
    Excerpt

    A 6-yr-old boy presented with muscle weakness, lactic acidemia, and insulin-dependent diabetes mellitus (IDDM). Using PCR and restriction enzyme analysis, he was found to have the classical A3248G mitochondrial DNA (mtDNA) mutation frequently associated with mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS). The mutation was confirmed by sequencing muscle mtDNA. The mutation in mtDNA from muscle, lymphoblasts, and blood was clearly demonstrable by standard methods using ethidium bromide staining. His mother also had IDDM, but no A3243G mutation could be detected in her blood or transformed lymphoblasts using the same PCR technique. When PCR was carried out in the presence of [32P]deoxycytidine triphosphate, subsequent autoradiography detected the presence of the mutation at low levels in mtDNA from the mother's lymphoblasts and blood. Study of the mother's muscle showed a mitochondrial myopathy, despite the fact that she was asymptomatic. We emphasize that the increased sensitivity of radiolabeled PCR may be necessary to detect small percentages of heteroplasmic A3243G mtDNA mutation in blood from diabetic subjects. Otherwise the incidence of mtDNA mutations in both IDDM and non-insulin dependent diabetes may be underestimated.

    Title Rise in Sexually Transmitted Diseases During Democratization and Economic Crisis in Mongolia.
    Date July 1997
    Journal International Journal of Std & Aids
    Excerpt

    In 1990, democratic changes and loss of Soviet economic subsidies led to enormous social upheaval in Mongolia. The objective of this study is to map sexually transmitted disease (STD) trends in Mongolia from 1983-1995 and review human immunodeficiency virus (HIV) surveillance data since 1987. Data for syphilis show a decreasing trend from 1983-1993 with a decline in cases from 70 to 18/100,000 population, followed by a rise in cases to 32/100,000 population in 1995. Data suggest a 1.5-3.0 fold higher rate of syphilis for ages 15-24 than for any other group. Data for gonorrhoea show an upward trend in the rate of cases, from 51/100,000 population in 1983 to 142/100,000 in 1995. The majority of cases are aged 15-44. Trichomonas rates also show an upward trend in the number of cases, from 47/100,000 population in 1983 to 155/100,000 cases in 1995. Like gonorrhoea the majority of cases are in the 15-44 year age range. For children aged 0-14, the 1983-1993 rate remained below 4.5/100,000; however, in 1994 and 1995 the rate increased reaching 53 and 48/100,000 respectively. Since 1987, more than 176,000 HIV tests have been done with only one confirmed positive result. Rises in STD rates coincide with deterioration in STD services and reduced active surveillance, suggesting that these data reflect a minimum estimation of the problem. Changes in business and social circumstances may have resulted in increasing HIV and STD risk behaviour.

    Title Immediate Breast Reconstruction in Patients with Locally Advanced Disease.
    Date June 1997
    Journal Annals of Plastic Surgery
    Excerpt

    Immediate breast reconstruction for patients with early-stage disease is well established. This study evaluates a consecutive series of 22 patients with locally advanced disease (stage IIB or III) who underwent mastectomy and immediate breast reconstruction. All patients received several cycles of neoadjuvant chemotherapy (average, 3.5 cycles) followed by completion of chemotherapy beginning approximately 3 weeks following surgery. The perioperative morbidity was 14% and no patient suffered a delay in the resumption of chemotherapy. Patients have been particularly grateful about being offered reconstruction in this setting. Our preliminary results with this technique have been encouraging and further study is warranted.

    Title Evidence That Therapy Works in Clinically Representative Conditions.
    Date June 1997
    Journal Journal of Consulting and Clinical Psychology
    Excerpt

    This article reports a secondary analysis of past therapy outcome meta-analysis. Fifteen meta-analysis provided effect sizes from 56 studies in previous reviews that met 1 of 3 increasingly stringent levels of criteria for clinical representativeness. The effect sizes were synthesized and compared with results from the original meta-analyses. Effect sizes from more clinically representative studies are the same size at all 3 criteria levels as in past meta-analyses. Almost no studies exist that meet the most stringent level of criteria. Results are interpreted cautiously because of controversy about what criteria best capture the notion of clinical representativeness, because so few experiments have tested therapy in clinical conditions, and because other models for exploring the generalizability of therapy outcome research to clinical conditions might yield different results.

    Title Neural Monitoring of Vasovagal Syncope.
    Date June 1997
    Journal Pacing and Clinical Electrophysiology : Pace
    Excerpt

    Head-up tilt testing has become a valuable and widely accepted diagnostic tool for evaluation of patients with vasovagal syncope. This test has afforded clinical researchers the opportunity to focus on the hemodynamic, humoral, and neural changes that accompany syncope. We review the animal and clinical studies that provide insight into the possible pathophysiological mechanisms involved in vasovagal syncope. Hemodynamic measurements in patients with vasovagal syncope suggest that a relative decrease in ventricular size and increase in cardiac contractility may be seen in many patients with vasovagal syncope. Patients with vasovagal syncope have also demonstrated numerous "exaggerated" neurohumoral responses to syncope. Differential changes in plasma levels of epinephrine, renin, endothelin, vasopressin, cortisol, prolactin, beta endorphins, and substance P have been reported by some investigators either prior to or during a syncopal episode in patients with vasovagal syncope. The precise pathophysiological significance of these measurements is unknown at the present time. Measurements of autonomic tone may be accomplished indirectly with analysis of heart rate variability or baroreflex slope, or directly by sympathetic neural recordings of the peroneal nerve. We have demonstrated decreased baroreflex slopes in patients with vasovagal syncope. Using microneurography, we and others have demonstrated decreased sympathetic nerve activity occurring 11 +/- 3 seconds prior to syncope during head-up tilt table testing. A variety of other abnormal reflexes, including blunted forearm blood flow responses during exercise, have been demonstrated by others. These observations suggest that pacing instituted after the event may not be as helpful as the use of a hemodynamic sensor that will result in the initiation of pacing prior to sympathetic withdrawal or modify the decrease in sympathetic tone that occurs prior to syncope.

    Title Evaluation of the Role of Routine Serial Cranial Computed Tomography in the Management of Children with Human Immunodeficiency Virus Infection.
    Date April 1997
    Journal Pediatric Aids and Hiv Infection
    Excerpt

    OBJECTIVE: To review the impact of routine follow-up cranial computed tomography (CT) scans on the management of children with human immunodeficiency virus (HIV) infection. DESIGN: Longitudinal data collected from 58 HIV-infected children followed in one center for mean of 3.8 +/- 1.8 years. SETTING: HIV/AIDS pediatric program following over 90% of the identified HIV-infected children in one region in Canada. RESULTS: The baseline CT scans showed intracranial abnormalities in 35 of 58 children (60%). In five children with basal ganglia calcifications (BGC) without cerebral atrophy, there has not been progressive encephalopathy. For the 43 children who had serial CT scans for routine follow-up, 34 (79%) had changes in the scans that were concordant with the clinical assessment. In all but five children with progressive ventricular and sulcal dilatation on CT scan, there was simultaneous clinical evidence of encephalopathy. Those five children were already on antiretroviral therapy, and therapy was not changed in response to the CT scan findings. CONCLUSION: Baseline CT scans provide useful diagnostic and prognostic information. Further research is needed to evaluate the role of cranial CT imaging in the management of pediatric HIV encephalopathy.

    Title Microsurgery in a Rat Lung Transplant Model: Analysis of Benefit.
    Date February 1997
    Journal Microsurgery
    Excerpt

    With the use of microsurgery, we have developed a method of measuring hemodynamic parameters in a rat not possible with previous technology. Three groups of rats were studied: a chemically induced pulmonary hypertensive group (PH); a chemically induced pulmonary hypertensive group treated with single lung transplantation (LT); and an untreated, control group (C). Cardiac output, heart rate, and pulmonary vascular resistance were then calculated in each group from data obtained by 1 mm high fidelity micromanometers and an ultrasonic flow probe. The results show that the data collected from the rodent model are reproducible within each group, and data quality is comparable to large animal models. With this new method, data can be collected in a small animal model at a fraction of the time and cost of large animal studies. Additionally, the complications of graft rejection in large animal studies are eliminated in an isogenic rodent model.

    Title Escape from Het-6 Incompatibility in Neurospora Crassa Partial Diploids Involves Preferential Deletion Within the Ectopic Segment.
    Date February 1997
    Journal Genetics
    Excerpt

    Self-incompatible het-6OR/het-6PA partial diploids of Neurospora crassa were selected from a cross involving the translocation strain, T(IIL-->IIIR)AR18, and a normal sequence strain. About 25% of the partial diploids exhibited a marked increase in growth rate after 2 weeks, indicating that "escape" from het-6 incompatibility had occurred. Near isogenic tester strains with different alleles (het-6OR and het-6PA) were constructed and used to determine that 80 of 96 escape strains tested were het-6PA, retaining the het-6 allele found in the normal-sequence LGII position; 16 were het-6OR, retaining the allele in the translocated position. Restriction fragment length polymorphisms in 45 escape strains were examined with probes made from cosmids that spanned the translocated region. Along with electrophoretic analysis of chromosomes from three escape strains, RFLPs showed that escape is associated with deletion of part of one or the other of the duplicated DNA segments. Deletions ranged in size from approximately 70 kbp up to putatively the entire 270-kbp translocated region but always included a 35-kbp region wherein we hypothesize het-6 is located. The deletion spectrum at het-6 thus resembles other cases where mitotic deletions occur such as of tumor suppressor genes and of the hprt gene (coding for hypoxanthine-guanine phosphoribosyl-transferase) in humans.

    Title The Product of the Het-c Heterokaryon Incompatibility Gene of Neurospora Crassa Has Characteristics of a Glycine-rich Cell Wall Protein.
    Date January 1997
    Journal Genetics
    Excerpt

    Filamentous fungi are capable of hyphal fusion, but heterokaryon formation between different isolates is controlled by specific loci termed het loci. Heterokaryotic cells formed between strains of different het genotype are rapidly destroyed or strongly inhibited in their growth. In Neurospora crassa, at least 11 loci, including the mating type locus, affect the capacity to form a heterokaryon between different isolates. In this report, we describe the molecular characterization of the vegetative incompatibility locus, het-C. The het-COR allele was cloned by genetically identifying the het-C locus in a chromosome walk, and the activity of clones containing the het-COR allele was tested in a functional transformation assay. The het-COR allele encodes a 966-amino acid polypeptide with a putative signal peptide, a coiled-coil motif and a C-terminal glycine-rich domain, similar to glycine-rich domains detected in various extracellular and structural cell envelope proteins. Both the coiled-coil and one-third of the glycine-rich carboxyl terminal domains were required for full het-COR activity. Mutants of het-COR were obtained by repeat-induced point mutation (RIP); these mutants were indistinguishable from wild type during vegetative growth and sexual reproduction but displayed dual compatibility with both of two mutually incompatible het-COR and het-cPA strains.

    Title Valsalva's Maneuver Revisited: a Quantitative Method Yielding Insights into Human Autonomic Control.
    Date December 1996
    Journal The American Journal of Physiology
    Excerpt

    Seventeen healthy supine subjects performed graded Valsalva maneuvers. In four subjects, transesophageal echographic aortic cross-sectional areas decreased during and increased after straining. During the first seconds of straining, when aortic cross-sectional area was declining and peripheral arterial pressure was rising, peroneal sympathetic muscle neurons were nearly silent. Then, as aortic cross-sectional area and peripheral pressure both declined, sympathetic muscle nerve activity increased, in proportion to the intensity of straining. Poststraining arterial pressure elevations were proportional to preceding increases of sympathetic activity. Sympathetic inhibition after straining persisted much longer than arterial and right atrial pressure elevations. Similarly, R-R intervals changed in parallel with peripheral arterial pressure, until approximately 45 s after the onset of straining, when R-R intervals were greater and arterial pressures were smaller than prestraining levels. Our conclusions are as follows: opposing changes of carotid and aortic baroreceptor inputs reduce sympathetic muscle and increase vagal cardiac motor neuronal firing; parallel changes of barorsensory inputs provoke reciprocal changes of sympathetic and direct changes of vagal firing; and pressure transients lasting only seconds reset arterial pressure-sympathetic and -vagal response relations.

    Title Abrogation of P53 Function Affects Gadd Gene Responses to Dna Base-damaging Agents and Starvation.
    Date December 1996
    Journal Dna and Cell Biology
    Excerpt

    The tumor suppressor p53 is required for induction of its downstream effector genes such as GADD45 and CIP1/WAF1 by ionizing radiation (IR). This response is probably mediated through defined p53 binding sites located in the promoter of CIP1/WAF1 and in the third intron of GADD45. In contrast, the gadd gene stress response to base-damaging agents, such as methylmethane sulfonate (MMS) or UV radiation, or medium depletion (starvation) occurs in all mammalian cells examined to date regardless of p53 status for both GADD45 and also GADD153, which is not IR-responsive in many lines with functional p53. These agents strongly induce the p53 protein and raise the possibility that, although p53 is not required for the typical "gadd" response to these agents, p53 may contribute to these non-IR stress responses. This possibility was confirmed by the finding that disruption of p53 function by transfection with dominant-negative vectors expressing HPV E6, mutant p53, or SV40 T Ag reduced the induction of GADD45 and GADD153 as measured by increases in mRNA and protein levels in human lines with wild-type p53. Similarly, induction of these genes by MMS or UV radiation was consistently stronger in the parental mouse embryo fibroblasts compared to cells derived from mice where both p53 alleles had been deleted. Similar qualitative responses were also seen for CIP1/WAF1. In agreement with reduced induction of p53-regulated genes, the G1 checkpoint activated by MMS or UV radiation was markedly abrogated in p53-wt human MCF-7 breast carcinoma cells by E6 expression. Interestingly, induction of reporter constructs driven by the GADD45 or GADD153 promoters was substantially reduced in human cells transfected with mutant p53 or E6 expression vectors or in cells lacking p53 following treatment with MMS, UV radiation, or starvation. Because neither promoter is inducible by IR, and neither contains a strong p53 binding site, these results indicate that p53 has a synergistic or cooperative role in these non-IR stress responses for both GADD45 and GADD153, and that this role is not mediated through identifiable p53-binding sites.

    Title Role of Hypoxemia in Sleep Apnea-induced Sympathoexcitation.
    Date October 1996
    Journal Journal of the Autonomic Nervous System
    Excerpt

    The importance of hypoxemia in determining sympathoexcitation during obstructive sleep apnea was examined by comparing changes in efferent sympathetic nerve activity (SNA) during spontaneous obstructive apneas with hypoxemia alone of similar magnitude and duration induced by 1-4 breaths of 100% nitrogen in six patients with obstructive sleep apnea and with spontaneous apneas while breathing 100% oxygen (apnea without hypoxemia) in three patients. In addition, eight control subjects were studied during induced hypoxemia. The magnitude of sympathoexcitation during spontaneous apneas (103 +/- 15%) was more than twice that observed during induced hypoxemia (47 +/- 14%) during episodes in which the nadir of oxygen desaturation (78 +/- 2 and 75 +/- 2%, respectively) and duration of hypoxemia (27 +/- 3 and 33 +/- 3 s, respectively) were the same (P > 0.20). Similarly, in three patients SNA increased 115% during normoxic spontaneous obstructive apneas, but increased only 43% during hyperoxic spontaneous obstructive apneas in which oxygen saturation did not decrease significantly. Sympathetic neural responses to induced hypoxemia in control subjects (17 +/- 7%) were significantly less than that of the sleep apnea patients. We conclude that hypoxemia contributes importantly, but is not the sole determinant of the sympathoexcitation provoked during episodes of obstructive sleep apnea.

    Title Characterization of the Gadd45 Response to Ionizing Radiation in Wi-l2-ns Cells, a P53 Mutant Cell Line.
    Date August 1996
    Journal Mutation Research
    Excerpt

    We have previously reported that WI-L2-NS, a human lymphoblastoid cell line, has very high basal levels of GADD45 mRNA and protein in spite of a p53 mutation at amino acid 237. Regardless of the amount of Gadd45 in this cell line, no growth suppression activity was detected. We report here that in WI-L2-NS, the mutated p53 protein adopts predominantly a wild type (wt) conformation and binds to the p53 binding site in the GADD45 third intron. In this cell line, the already high levels of mutated p53 protein can be induced further by ionizing radiation (IR) but the response of the p53 downstream effector genes is altered. Induction of GADD45 and CIP1/WAF1 is reduced compared to p53 wt cell lines but is still substantially higher than the average fold induction obtained from 39 p53 mutant cell lines. Induction of the MDM2 gene was not detected in WI-L2-NS following IR. The induction pattern of the three p53 effector genes by the alkylating agent methylmethane sulfonate (MMS) was also attenuated in WI-L2-NS cells. In TK6 cells, a WI-L2-NS sister cell line having a p53 wt genotype, the induction of the p53 downstream effectors is normal, i.e. induced, both at the protein and the mRNA levels. These results indicate that the DNA binding activity of the mutated p53 protein in WI-L2-NS might be responsible, at least in part, for the high basal levels of GADD45 but can not mediate the full induction of the p53 downstream effector genes. The reason(s) for the inability of Gadd45 to suppress growth in this cell line remains however unknown.

    Title Mapping Translocation Breakpoints by Orthogonal Field Agarose-gel Electrophoresis.
    Date April 1996
    Journal Current Genetics
    Excerpt

    Orthogonal field agarose-gel electrophoresis (OFAGE) of chromosomes from translocation-bearing and normal Neurospora crassa strains was utilized, first, to recover cosmids from a translocated region, and second, to map translocation breakpoints. Surprisingly, the right breakpoints in two independently derived, interstitial translocations, T(II-->III) AR18 and T(II-->VI)P2869, are within about 5.6 kbp of each other suggesting that this region of linkage group (LG) II may be fragile or otherwise subject to chromosome breakage. Mapping translocation breakpoints through OFAGE, or other similar methods, should allow for DNA sequencing across breakpoints that are not associated with mutant phenotypes or that are not within walking distance of cloned markers.

    Title The Neurochemical and Metabolic Cascade Following Brain Injury: Moving from Animal Models to Man.
    Date April 1996
    Journal Journal of Neurotrauma
    Excerpt

    Experimental traumatic brain injury produces a series of cellular events contributing to a neurochemical and neurometabolic cascade. This cascade is defined by the release of neurotransmitters resulting in a massive ionic flux, which, consequently, produces an increase in glycolysis. This increase in glycolysis is followed by a metabolic diaschisis, which is related to the degree and extent of behavioral deficits. Clinical efforts have now determined that a similar cascade occurs in human head injury, validating the animal model as well as providing new assessment strategies for the management and treatment of brain injury.

    Title Patterns of Htlv-i Infection Among Family Members of Patients with Adult T-cell Leukemia/lymphoma and Htlv-i Associated Myelopathy/tropical Spastic Paraparesis.
    Date February 1996
    Journal International Journal of Cancer. Journal International Du Cancer
    Title Enalaprilat Augments Arterial and Cardiopulmonary Baroreflex Control of Sympathetic Nerve Activity in Patients with Heart Failure.
    Date February 1996
    Journal Journal of the American College of Cardiology
    Excerpt

    OBJECTIVES. This study sought to determine the effects of enalaprilat on reflex control of sympathetic nerve activity. BACKGROUND. Angiotensin-converting enzyme inhibitors decrease mortality in patients with congestive heart failure. Their efficacy appears to be related importantly to antiadrenergic effects, the mechanism for which has not been determined. Because baroreflexes tonically inhibit sympathetic outflow, and baroreflexes are blunted in heart failure, we hypothesized that these agents reduce sympathetic activity by augmenting baroreflexes. METHODS. We assessed baroreflex control of sympathetic nerve activity and heart rate in patients with congestive heart failure and in control subjects before and after enalaprilat (0.02 mg/kg body weight intravenously). Arterial baroreflexes were perturbed by bolus administration of sodium nitroprusside and phenylephrine. Cardiopulmonary baroreflexes were perturbed by lower body negative pressure and head-down tilt. Muscle sympathetic nerve activity was recorded by microneurography. RESULTS. Enalaprilat decreased systolic blood pressure in patients with heart failure and control subjects. Sympathetic nerve activity increased in control subjects but decreased in patients with heart failure after enalaprilat despite reductions in central venous pressure in this group. Baroreflex control of sympathetic nerve activity was unchanged by enalaprilat in control subjects. In patients with heart failure, both arterial and cardiopulmonary baroreflex control of sympathetic nerve activity was enhanced by enalaprilat. Baroreflex control of heart rate was unchanged by enalaprilat in either group. CONCLUSIONS. Enalaprilat augments both arterial and cardiopulmonary baroreflex control of sympathetic activity in heart failure. These augmented inhibitory influences are associated with a reduction in sympathetic outflow and may contribute to the beneficial effects of angiotensin-converting enzyme inhibitors in heart failure.

    Title The Production and Characterization of Murine Monoclonal Antibodies to Human Gadd45 Raised Against a Recombinant Protein.
    Date January 1996
    Journal Hybridoma
    Excerpt

    The production of two different murine monoclonal antibodies to human Gadd45, a protein that is induced in response to DNA damage, is reported. Antibodies were generated in a SJL mouse using a recombinant form of the human Gadd45 protein. Monoclonal antibody 4TCYA1, which recognizes the denatured form of human Gadd45 in Western blots, was selected based upon the recognition of Gadd45 induced by functional p53 in the human myeloid leukemia cell line, ML-1. A second monoclonal antibody, designated 30T.14, immunoprecipitates native human Gadd45 in lysates produced from RKO cells, a colorectal carcinoma cell line that expresses relatively high basal levels of Gadd45, as well as from cell lysates made from ML-1 cells after exposure to ionizing irradiation (IR). Since 4TCYA1 fails to immunoprecipitate Gadd45, and 30T.14 fails to bind to IR-induced Gadd45 in immunoblotting, these two monoclonal antibodies probably recognize different epitopes.

    Title Psychosocial Correlates of Immune Responsiveness and Illness Episodes in Us Air Force Academy Cadets Undergoing Basic Cadet Training.
    Date November 1995
    Journal Journal of Psychosomatic Research
    Excerpt

    This study examined psychosocial correlates of immune function and illness in 89 male first-year US Air Force Academy cadets. A psychosocial questionnaire was administered to cadets prior to their arrival at the academy and was readministered during cadet orientation and during the stressful environment of Basic Cadet Training (BCT). Immune responsiveness was analyzed by PHA-, PMA-, or anti-CD3-stimulated thymidine uptake in mononuclear leucocytes. Illness episodes were assessed via medical chart review and self-reported symptoms. There were significant increases in distress levels as cadets entered BCT. No psychosocial measure assessed prior to arrival at the academy predicted level of PHA-, PMA-, and anti-CD3-stimulated thymidine uptake or risk of illness. However, hostility levels reported during BCT predicted risk of illness in the four weeks following psychosocial assessment (odds ratio = 7.1; 95% confidence interval: 1.4-36.1). Elevated response to environmental stressors and lower well-being levels also predicted impending illness, but only in the cohort of cadets who had not contracted food poisoning prior to assessment during BCT (OR = 9.3, CI = 1.9-46.7; OR = 0.09, CI = 0.02-0.53). These results suggest that self-report measures of hostility, response to environmental stressors and well-being may be useful predictors of impending illness episodes in males encountering high stress environments.

    Title Baseline Arterial Pressure Affects Sympathoexcitatory Responses to Ventricular Premature Beats.
    Date August 1995
    Journal The American Journal of Physiology
    Excerpt

    The seconds to minutes before sudden cardiac death are characterized by fluctuations of arterial pressure, cardiac rhythm, and probably sympathetic nerve activity. We explored the interrelations among these factors in seven patients undergoing clinical electrophysiological testing. We measured muscle sympathetic nerve activity (SNA) and arterial pressure responses to ventricular premature beats induced throughout the cardiac cycle under three conditions: 1) lowered arterial pressure and elevated SNA produced by intravenous nitroprusside, 2) baseline arterial pressure and SNA during saline infusion, and 3) elevated arterial pressure and decreased SNA activity produced by intravenous phenylephrine. Sympathetic responses to premature beats were inversely related to diastolic pressure. The magnitude of the sympathetic response was directly related to the prevailing arterial pressure and inversely related to baseline SNA. These data demonstrate that sympathoexcitation evoked by ventricular dysrhythmias is determined importantly by the prevailing arterial pressure and possibly by the background R-R interval and level of sympathetic activity. This effect may influence hemodynamic and electrophysiological stability during dysrhythmias.

    Title Modulation of Human Sympathetic Periodicity by Mild, Brief Hypoxia and Hypercapnia.
    Date August 1995
    Journal Journal of Physiology and Pharmacology : an Official Journal of the Polish Physiological Society
    Excerpt

    We determined the influence of brief mild normocapnic hyperoxia, hypoxia, and hyperoxic hypercapnia on human muscle sympathetic nerve activity and R-R intervals, as quantified by both time- and frequency-domain analyses. We obtained measurements in nine healthy young adult men and women during uncontrolled and frequency (but not tidal volume) controlled breathing. Responses were evaluated with forward selection and backward elimination statistical models, with muscle sympathetic nerve activity as the dependent variable, and power spectral techniques. Hyperoxia and hypoxia did not alter arterial pressure; hypercapnia increased diastolic pressure modestly. Average R-R intervals tended to increase during hyperoxia, and decrease during hypoxia and hypercapnia. During uncontrolled breathing, changes of inspiratory gases exerted only minor effects on muscle sympathetic nerve activity; during controlled breathing, both hypoxia and hypercapnia tended to increase muscle sympathetic nerve activity. Statistical modeling suggested that chemoreceptor stimulation increased muscle sympathetic neural outflows, but that increases of sympathetic traffic were opposed by secondary increases of ventilation. Inspiratory gases modulated the frequency distribution of muscle sympathetic nerve activity strikingly: hypoxia increased sympathetic power at respiratory frequencies and hypercapnia increased sympathetic power at both respiratory and (primarily in one subject) cardiac frequencies. Our data suggest that mild brief hypoxia and hypercapnia increase human muscle sympathetic nerve activity, but that this tendency is opposed by chemoreflex-induced increases of ventilation. Our results suggest also that chemoreceptor activity exerts important influences on the frequency content, as well as the quantity of sympathetic neural outflow.

    Title Disruption of P53 Function Sensitizes Breast Cancer Mcf-7 Cells to Cisplatin and Pentoxifylline.
    Date May 1995
    Journal Cancer Research
    Excerpt

    The possibility that appropriately designed chemotherapy could act selectively against p53-defective tumor cells was explored in MCF-7 human breast cancer cells. These cells were chosen because they have normal p53 function but are representative of a tumor cell type that does not readily undergo p53-dependent apoptosis. Two sublines (MCF-7/E6 and MCF-7/mu-p53) were established in which p53 function was disrupted by transfection with either the human papillomavirus type-16 E6 gene or a dominant-negative mutant p53 gene. p53 function in MCF-7/E6 and MCF-7/mu-p53 cells was defective relative to control cells in that there were no increases in p53 or p21Waf1/Cip1 protein levels and no G1 arrest following exposure to ionizing radiation. Survival assays showed that p53 disruption sensitized MCF-7 cells to cisplatin (CDDP) but not to several other DNA-damaging agents. CDDP sensitization was not limited to MCF-7 cells since p53 disruption in human colon carcinoma RKO cells also enhanced sensitivity to CDDP. Contrary to the other DNA-damaging agents tested, CDDP-induced DNA lesions are repaired extensively by nucleotide excision, and in agreement with a defect in this process, MCF-7/E6 and MCF-7/mu-p53 cells exhibited a reduced ability to repair a CDDP-damaged chloramphenicol acetyltransferase-reporter plasmid transfected into the cells. Therefore, we attributed the increased CDDP sensitivity of MCF-7 cells with disrupted p53 to defects in G1 checkpoint control, nucleotide excision repair, or both. The G2 checkpoint inhibitor pentoxifylline exhibited synergism with CDDP in killing MCF-7/E6 cells but did not affect sensitivity of the control cells. Moreover, pentoxifylline inhibited G2 checkpoint function to a greater extent in MCF-7/E6 than in the parental cells. These results suggested that, in the absence of p53 function, cancer cells are more vulnerable to G2 checkpoint abrogators. Our results show that a combination of CDDP and pentoxifylline is capable of synergistic and preferential killing of p53-defective tumor cells that do not readily undergo apoptosis.

    Title Reconsidering "psychosurgery": Issues of Informed Consent and Physician Responsibility.
    Date March 1995
    Journal The Journal of Clinical Ethics
    Title Interaction of the P53-regulated Protein Gadd45 with Proliferating Cell Nuclear Antigen.
    Date December 1994
    Journal Science (new York, N.y.)
    Excerpt

    GADD45 is a ubiquitously expressed mammalian gene that is induced by DNA damage and certain other stresses. Like another p53-regulated gene, p21WAF1/CIP1, whose product binds to cyclin-dependent kinases (Cdk's) and proliferating cell nuclear antigen (PCNA), GADD45 has been associated with growth suppression. Gadd45 was found to bind to PCNA, a normal component of Cdk complexes and a protein involved in DNA replication and repair. Gadd45 stimulated DNA excision repair in vitro and inhibited entry of cells into S phase. These results establish GADD45 as a link between the p53-dependent cell cycle checkpoint and DNA repair.

    Title Mitochondrial Dnas of the Fungus Armillaria Ostoyae: Restriction Map and Length Variation.
    Date October 1994
    Journal Current Genetics
    Excerpt

    A restriction-enzyme-site map is presented for the 147-kb mtDNA of North American Armillaria ostoyae. The locations of five structural genes, atp6, atp8, coxI, coxIII, and cob, along with the location and orientation of the large and small ribosomal RNA genes, were determined through Southern hybridizations with cloned genes from other fungal mtDNAs. Based on this map, the variation in mtDNA suggested geographic structure at two different levels. On a large geographic scale, 17 mtDNA types from North America were distinct, with respect to both size and restriction maps, from three mtDNA types from Europe. At the local scale, identical mtDNA types were evident among several different genetic individuals located no more than 1 km apart at a site in Michigan. No mtDNA type occurred more than once among genetic individuals from different regions of North America, although the occurrence of similar mtDNAs in isolates from distant regions suggested that this may occur at a low frequency with large sample sizes. Among the North American mtDNA types, analysis of discrete length variants was inconsistent with the hypothesis that the mtDNA of A. ostoyae evolves as a clonal lineage in which each length mutation represents a unique event. The two remaining hypotheses, that similar mutational events have occurred independently and that genetic exchange and recombination occurs among mtDNAs in natural populations of this species, remain to be tested.

    Title Rapid Adaptation of Vagal Baroreflexes in Humans.
    Date June 1994
    Journal Journal of the Autonomic Nervous System
    Excerpt

    We evaluated the time course of carotid baroreflex adaptation to arterial pressure elevations induced by phenylephrine infusion (1 microgram/kg per min) in 13 normotensive volunteers. Vagally-mediated carotid baroreceptor-cardiac reflex responses were assessed serially with a staircase pressure/suction sequence delivered to a neck chamber. Carotid baroreflex stimulus-response relations shifted up the response (R-R interval) axis and to the right on the stimulus (pressure) axis (determined as the carotid distending pressure at saturation) within 90-120 s (time between measurements) during the first 10 min. The shifts in position of the reflex relation were sustained throughout the infusion. The position of operational point pressure, relative to carotid distending pressure at saturation, was unchanged throughout the infusion period. These data suggest that human carotid baroreceptor reflex relations change within minutes to retain beat-to-beat pressure regulation as the prevailing pressure increases.

    Title Renal Sympathetic Responses to Conflicting Baroreceptor Inputs: Rapid Ventricular Pacing in Dogs.
    Date April 1994
    Journal The Journal of Physiology
    Excerpt

    1. Ventricular tachycardia generates complex changes in baroreceptor input to the central nervous system: arterial baroreceptors are unloaded while cardiopulmonary receptors are stimulated. In humans with heart diseases, muscle sympathetic nerve activity increases during ventricular tachycardia. This suggests that arterial baroreceptor-mediated sympathoexcitation overrides cardiopulmonary receptor-mediated sympathoinhibition. However, the relative roles of each reflex are difficult to determine in humans. 2. We measured efferent renal sympathetic neural responses to simulated ventricular tachycardia, to determine what pathophysiological mechanisms are invoked when inputs from different baroreceptive areas change in opposite directions. In alpha-chloralose anaesthetized, mechanically ventilated dogs, we recorded the electrocardiogram, mean left atrial and arterial pressures and multifibre efferent renal sympathetic nerve activity (RSNA) during 1 min of right ventricular pacing at 214 beats min-1. Pacing was repeated after either sinoaortic or vagal cardiopulmonary denervation and again after both sinoaortic and cardiopulmonary denervation. 3. With all afferent baroreceptor pathways intact, right ventricular pacing elicited transient sympathoinhibition (delta RSNA, -19 +/- 10%, mean +/- S.E.M.). After sinoaortic denervation (cardiopulmonary receptors intact), right ventricular pacing elicited abrupt and sustained sympathoinhibition (delta RSNA, -53 +/- 8%, P < 0.05 vs. intact). After vagal cardiopulmonary denervation (sinoaortic receptors intact), right ventricular pacing elicited abrupt and sustained sympathoexcitation (delta RSNA, + 56 +/- 19%, P < 0.05 vs. intact). After both sinoaortic and vagal cardiopulmonary denervation, right ventricular pacing elicited a gradual increase in sympathetic outflow (delta RSNA, + 16 +/- 6%, P < 0.05 vs. intact). 4. We conclude that interactions between vagal cardiopulmonary and arterial baroreflexes determine renal sympathetic outflow during simulated ventricular tachycardia. In healthy anaesthetized dogs, the balance of the two opposing reflexes is weighted towards vagal cardiopulmonary-mediated sympathoinhibition.

    Title An Assessment of a Formal Ethics Committee Consultation Process.
    Date April 1994
    Journal Hec Forum : an Interdisciplinary Journal on Hospitals' Ethical and Legal Issues
    Title A Multiple Drug Intoxication Involving Cyclobenzaprine and Ibuprofen.
    Date March 1994
    Journal The American Journal of Forensic Medicine and Pathology : Official Publication of the National Association of Medical Examiners
    Excerpt

    A 19-year-old black man presented to the emergency room with superficial cuts on the anterior wrists, lethargy, tachycardia, and metabolic acidosis. Multiple containers of medication were found at the scene. Dysrhythmias developed and the patient died 7 h after admission. No anatomic cause of death was identifiable at autopsy. Toxicologic analysis identified the following drugs in the blood (mg/L): cyclobenzaprine (0.3), phenylpropanolamine (2.5), chlorpheniramine (0.2), lidocaine (6.6), phenytoin (19), and ibuprofen (130). Lidocaine and phenytoin had been administered therapeutically. The major symptoms displayed by the patient were tachycardia and metabolic acidosis, symptoms consistent with cyclobenzaprine and ibuprofen intoxication, respectively. Therefore, the medical examiner ruled that the cause of death was multiple drug intoxication and that the manner of death was suicide.

    Title Naloxone Does Not Prevent Vasovagal Syncope During Simulated Orthostasis in Humans.
    Date December 1993
    Journal Journal of the Autonomic Nervous System
    Excerpt

    The mechanism of vasovagal syncope during orthostasis in humans is unknown. Opioid receptors have been implicated in the vasovagal-like responses to hemorrhagic hypotension in conscious animals. We sought to determine if opioid receptor blockade with naloxone (mu receptor antagonist) would prevent or delay the onset of vasovagal syncope in humans. Three protocols were performed in which heart rate, arterial pressure, sympathetic nerve activity, thoracic impedance and forearm vascular resistance were measured during stepwise steady-state increments of lower body negative pressure (LBNP) in nine healthy volunteers. In protocol 1, duplicate trials of LBNP to syncope or -60 mmHg were performed with a 30-45 minute rest period separating the trials. No significant differences in any physiologic responses or cumulative stress tolerance were found. In protocol 2, graded LBNP was repeated after administration of saline or naloxone (0.1 mg/kg) in six subjects in which vasovagal syncope occurred prior to -60 mmHg LBNP. The peak increase of sympathetic nerve activity during LBNP was augmented after naloxone (P = 0.02), but the occurrence of vasovagal syncope was not prevented nor was the cumulative stress tolerated affected (P = 0.42). The heart rate and arterial pressure responses to LBNP were not affected by naloxone. Similarly, in protocol 3, naloxone given just prior to the onset of pre-syncopal symptoms did not alter the physiologic response or the occurrence of vasovagal syncope. These data show that naloxone does not prevent or delay the onset of vasovagal syncope in humans which suggests that mu opioid receptors do not mediate the vasovagal response.

    Title Abnormalities of Baroreflex Control in Heart Failure.
    Date October 1993
    Journal Journal of the American College of Cardiology
    Excerpt

    This brief review summarizes abnormalities of arterial and cardiopulmonary baroreflex control of heart rate and sympathetic nerve activity. The potential role of these abnormalities in the development of the neurohumoral excitatory state associated with heart failure is discussed. Major emphasis is placed on the identification of important issues still to be investigated in this area. The potential importance of altered cardiovascular reflexes in the context of the interaction of the patient with heart failure and environmental stresses is discussed. The use of the canine rapid ventricular pacing model of biventricular failure in the investigation of abnormalities of baroreflexes in heart failure is emphasized. Insights obtained from this model should be extended to human investigations.

    Title Influence of Cigarette Smoking on Human Autonomic Function.
    Date September 1993
    Journal Circulation
    Excerpt

    Although cigarette smoking is known to lead to widespread augmentation of sympathetic nervous system activity, little is known about the effects of smoking on directly measured human sympathetic activity and its reflex control.

    Title Changes in Bone Density with Lactation.
    Date July 1993
    Journal Jama : the Journal of the American Medical Association
    Excerpt

    To test the a priori hypotheses that significant bone loss occurs in lactation of greater than 5 months' duration and that bone mass returns to baseline levels when breast-feeding ceases.

    Title Medical Decisions Concerning the End of Life in Children in The Netherlands.
    Date July 1993
    Journal American Journal of Diseases of Children (1960)
    Title Abnormalities in the P53 Gene in Tumors and Cell Lines of Human Squamous-cell Carcinomas of the Head and Neck.
    Date June 1993
    Journal International Journal of Cancer. Journal International Du Cancer
    Excerpt

    Abnormalities in the p53 gene were studied in a series of cell lines of human squamous-cell carcinoma of the head and neck (SCCHN) and in tumor tissues. Restriction-fragment-length polymorphism (RFLP), quantitative hybridization and immunochemical analysis of mutant p53 proteins were combined to detect and characterize 3 different phases in the p53 gene alteration: mutation (in 9/9 cases), 17p13 deletion (9/10 cases) and amplification of the non-deleted allele (9/31 cases). In SCCHN, deletion of the p53 gene was nearly always accompanied by mutation, only one cell line studied having mutation without deletion. Alterations in the p53 gene are common in SCCHN, and involve a series of genetic events which occur in sequence during tumor progression.

    Title Sympathoinhibition and Hypotension in Carotid Sinus Hypersensitivity.
    Date March 1993
    Journal Clinical Autonomic Research : Official Journal of the Clinical Autonomic Research Society
    Excerpt

    Carotid sinus reflex hypersensitivity is a known cause of syncope in humans. The condition is characterized by cardioinhibition and vasodepression, each to varying degrees. The extent and importance of sympathoinhibition has not been determined in patients with carotid sinus hypersensitivity. This study reports on the extent of sympathoinhibition measured directly directly during carotid massage with and without atrioventricular sequential pacing, in a patient with symptomatic carotid sinus reflex hypersensitivity. Carotid massage elicited asystole, hypotension and complete inhibition of muscle sympathetic nerve activity. Carotid massage during atrioventricular pacing produced similar sympathoinhibition, but with minimal hypotension. Therefore, sympathoinhibition did not contribute importantly to the hypotension during carotid massage in the supine position in this patient. Further investigations are required to elucidate the relation of sympathoinhibition to hypotension in patients with carotid sinus hypersensitivity in the upright position.

    Title Pediatric Euthanasia.
    Date January 1993
    Journal American Journal of Diseases of Children (1960)
    Excerpt

    Pediatric euthanasia is currently practiced in the Netherlands on newborns, infants, children, and adolescents, although exact numbers are not known. Euthanasia in the Netherlands is generally assumed to be active and voluntary, but some cases of pediatric euthanasia would have to be characterized as nonvoluntary. Much of the motivation behind the euthanasia movement and the performance of pediatric euthanasia in the Netherlands is a genuine, compassionate desire to alleviate pain and suffering. In this study, we review the Dutch experience, with particular attention to the current practice of euthanasia on newborns, infants, children, and adolescents. We discuss pediatric euthanasia from an ethical point of view. We assert that more effective pain control, better symptom management, and psychosocial support of the dying and their families would alleviate the perception of suffering, and reduce the perceived need to resort to euthanasia.

    Title Toxicologic Findings in the Uss Iowa Disaster.
    Date November 1992
    Journal Journal of Forensic Sciences
    Excerpt

    The toxicologic results from the 47 victims of the explosion on the USS Iowa are presented. Good correlation between carboxyhemoglobin saturations and cause of death was found. There were no correlations between blood cyanide concentrations and causes of death. Volatile analysis suggested postmortem ethanol production rather than antemortem ethanol ingestion. No drugs except nicotine were detected in any of the victims.

    Title Influence of Lidocaine on Human Muscle Sympathetic Nerve Activity During Programmed Electrical Stimulation and Ventricular Tachycardia.
    Date October 1992
    Journal American Heart Journal
    Excerpt

    Lidocaine directly affects conduction and refractoriness of ventricular myocardium, and may also indirectly affect these electrophysiologic properties by inhibition of cardiac sympathetic nerve traffic. Both effects may play important roles in preventing ventricular arrhythmias in humans. To determine if lidocaine has a direct effect on sympathetic nerve activity, the effects of a 100 mg lidocaine bolus followed by a 2 mg/min infusion of lidocaine on muscle sympathetic nerve activity was assessed in seven patients during programmed ventricular stimulation with single extrastimuli (premature ventricular contractions [PVCs]) in sinus rhythm, and in seven patients during induced hemodynamically stable monomorphic ventricular tachycardia. During single extrastimuli, the mean (+/- SEM) area of PVC-associated bursts of sympathetic nerve activity was unaffected by lidocaine (1101 +/- 16 units pre-lidocaine versus 1075 +/- 19 units following lidocaine; p = 0.30). Likewise, the transient decrease in blood pressure with induced PVCs was similar before and after lidocaine infusion (p = 0.46). In seven patients with induced monomorphic ventricular tachycardia, tachycardia cycle length did not change after the lidocaine bolus (393 +/- 18 versus 399 +/- 17 msec; p = 0.34) but increased during lidocaine maintenance infusion (428 +/- 17 msec; p = 0.01). After induction of ventricular tachycardia, systolic pressure decreased from 150 +/- 6 to 117 +/- 9 mm Hg at 1 minute of tachycardia, to 109 +/- 6 mm Hg during the lidocaine bolus, and rebounded to 126 +/- 8 mm Hg during the lidocaine maintenance infusion (p = 0.04, bolus versus infusion).(ABSTRACT TRUNCATED AT 250 WORDS)

    Title Alteration in Human Mononuclear Leucocytes Following Space Flight.
    Date October 1992
    Journal Immunology
    Excerpt

    Reduced in vitro mitogen-stimulated proliferative responses have routinely been observed from astronauts' mononuclear leucocytes following space flight. This study investigated the effect of space flight on subpopulations of peripheral blood mononuclear cells from 30 shuttle astronauts prior to launch, upon landing and 3 days after flight. The total number of peripheral blood leucocytes, granulocytes and monocytes were increased after space flight (5.7 +/- 0.2 versus 7.0 +/- 0.2; 3.1 +/- 0.1 versus 5.0 +/- 0.1; and 0.16 +/- 0.02 versus 0.25 +/- 0.28 x 10(3) cells/mm3, respectively) whereas lymphocytes were decreased (2.2 +/- 0.1 versus 1.7 +/- 0.1 x 10(3) cells/mm3). Flow cytometry analysis on Ficoll-Hypaque isolated mononuclear cells upon landing revealed significant decreases in T-inducer (CD4+, Leu-8+; 32 +/- 2 versus 23 +/- 2%) and T-cytotoxic lymphocytes (CD8+, CD11b-; 17 +/- 1 versus 12 +/- 1%), and increases in monocytes (CD14+; 13 +/- 1 versus 21 +/- 1%) compared to pre-flight and post-flight samples whereas B cells (CD19+), T-helper (CD4+, Leu-8-) and T-suppressor (CD8+, CD11b+) populations did not change. Additional phenotypic analysis of these mononuclear leucocytes from 10 crew members upon landing revealed a reduction in natural killer (NK) cells (CD16+ or CD56+; 9 +/- 1 versus 3 +/- 1%) and an increase in monocytes that were negative for insulin and insulin-like growth factor-1 (IGF-1) receptor expression. Flow cytometric analysis indicated these hormone receptor negative monocytes were smaller and less granular than receptor positive monocytes. Therefore, a novel population of monocytes may be released into the peripheral blood during the stress of space flight or upon landing. These findings may explain some of the diverse in vitro immunological and endocrine changes observed in crew members following space flight.

    Title Immune Responsiveness and Risk of Illness in U.s. Air Force Academy Cadets During Basic Cadet Training.
    Date October 1992
    Journal Aviation, Space, and Environmental Medicine
    Excerpt

    It has been proposed, but not confirmed, that environmental stressors alter immune function and increase the risk of viral infection among healthy individuals. We evaluated this hypothesis, examining the relationship among stress, immune function, and illness in 96 first-year U.S. Air Force Academy cadets during orientation and 4 weeks later during the stressful environment of Basic Cadet Training (BCT). Perceived stress and well-being levels of cadets were assessed via questionnaire. Immune responsiveness was analyzed by PHA-stimulated thymidine uptake in mononuclear leucocytes and by serologic evidence of reactivation of the Epstein-Barr virus (EBV). We documented significant declines in in vitro PHA-induced lymphocyte transformation (-35%; p less than 0.05) and subjective well-being (-19%; p less than 0.05) from orientation to BCT with corresponding, significant increases in perceived stress (+32%; p less than 0.05). Despite significantly altered in vitro immune responsiveness, there was no serologic evidence of EBV reactivation nor was there an association between these measures and risk of illness as determined by medical chart review and self-reported symptoms. These results suggest that reduced in vitro immune responsiveness during a moderate stressor may not necessarily lead to an increased risk of infection and/or reactivation of EBV in normal individuals.

    Title A Survey on Awareness and Effectiveness of Bioethics Resources.
    Date September 1992
    Journal Hec Forum : an Interdisciplinary Journal on Hospitals' Ethical and Legal Issues
    Title Early Occurrence of End-stage Renal Disease in a Patient with Infantile Nephropathic Cystinosis.
    Date April 1992
    Journal The Journal of Pediatrics
    Excerpt

    We report the case of a patient with infantile nephropathic cystinosis who required renal transplantation at age 30 months. Exhaustive evaluation did not identify a cause of progressive renal failure other than cystinosis. The patient's genetic lesion was allelic with those of other patients with cystinosis; fusion of this patient's fibroblasts with fibroblasts from another patient with infantile nephropathic cystinosis did not demonstrate complementation of the biochemical defect.

    Title Nalbuphine After Major Gynecologic Surgery. Comparison of Patient-controlled Analgesia and Intramuscular Injections.
    Date March 1992
    Journal The Journal of Reproductive Medicine
    Excerpt

    A randomized investigation compared the efficacy and safety of nalbuphine administered by two methods, a patient-controlled infuser system and intramuscular (IM) injections, after major gynecologic surgery. Forty-seven patients were randomly assigned to receive nalbuphine by either method. The 22 patients using the infuser were given a 2.0-mg, incremental dose with a 10-minute lock-out interval between doses. A similar group receiving 10-15 mg IM every three hours served as the control. Misprogramming, overdosage, depressed respiration and drug dependence were not encountered. Self-administration provided equally satisfactory sedation and more immediate pain relief without painful injections. Although patients with the infuser had the ability to self-administer more medication, they did not use higher doses of nalbuphine than did the IM group. The additional cost of the infuser system was offset by the satisfaction expressed by the patients and by the improved nursing efficiency. Nalbuphine administered with a patient-controlled infuser provided an effective balance between analgesia and sedation and offered advantages over IM injections.

    Title Chloroquine Distribution in Postmortem Cases.
    Date January 1992
    Journal Journal of Forensic Sciences
    Excerpt

    Chloroquine concentrations in blood and tissues were examined in overdose and non-overdose cases to determine appropriate ranges for interpretation. Twenty-nine literature overdose cases and 8 non-overdose literature cases were compared with this laboratory's findings. The results indicate significant postmortem redistribution of chloroquine. Combining this laboratory's results and the literature results indicates that using a liver concentration of 150 mg/kg as a cutoff between overdose and non-overdose concentrations properly identified 30 of the 34 published cases containing liver chloroquine and 19 of the 20 presented cases.

    Title Cutaneous Manifestations of Acquired Immunodeficiency Syndrome in Children.
    Date December 1991
    Journal International Journal of Dermatology
    Excerpt

    Cutaneous disorders are among the most common manifestations of HIV infection in both children and adults. Because of the obvious visibility of the integument, these lesions are often the presenting manifestation of HIV-related disease. The cutaneous afflictions are frequently related to the sequelae of impaired immunity and include opportunistic infections and neoplasms as well as dramatic exacerbations and/or the development of rapidly progressive and severe manifestations in pre-existing, normally benign dermatoses. In many cases of AIDS, iatrogenic cutaneous disorders associated with toxic or allergic drug reactions are seen. With the increasing incidence of pediatric HIV infection and with therapeutic prolongation of survival, certain cutaneous manifestations (especially drug reactions) are likely to become more common. Kaposi sarcoma and other neoplasms may be recognized with increased frequency in HIV-infected children. New or previously unrecognized cutaneous manifestations of pediatric AIDS are likely to emerge. Familiarity with the various dermatologic presentations of pediatric AIDS can result in the earlier diagnosis and treatment of the disease and, hopefully, the prolongation of the patient's life.

    Title Hemodynamic Responses to 6 Degree Head-down Rest in Dogs: Effect of Aerobic Conditioning.
    Date December 1991
    Journal Medicine and Science in Sports and Exercise
    Excerpt

    The -6 degree head-down position is used in humans to produce fluid shifts that resemble those occurring in microgravity. Alternative animal models of microgravity may be helpful for extensive exploration of this unique condition. The dog may be a viable candidate. Sixteen dogs were assigned to one of three conditions: anesthetized open chest, anesthetized closed chest, and awake. Dogs in groups 1 (N = 6) and 2 (N = 6) were divided into an exercise or a sedentary treatment, and dogs in group 3 (N = 4) served as their own controls. Following instrumentation the dogs were put in the head-down position for 1 h. Measurements included right atrial pressure, heart rate, and mean arterial pressure for all groups, left ventricular pressure and LV dp/dt for group 1, and cardiac output and iliac flow for group 2. Right atrial pressure increased for all groups. Heart rate demonstrated non-significant changes over time or group. Significant differences were noted for mean arterial pressure, left ventricular pressure and LV dp/dt for exercise condition in response to HDR. It appears that -6 degrees of head-down rest produces similar cardiovascular responses in dogs as those observed in humans and that exercise has a minor effect on those responses.

    Title Sympathetic Neural Responses to Induced Ventricular Tachycardia.
    Date October 1991
    Journal Journal of the American College of Cardiology
    Excerpt

    Although sympathetic mechanisms play a major role in buffering abrupt arterial pressure reductions, including those that occur during tachyarrhythmias, human sympathetic nervous system responses to ventricular tachycardia have not been measured. Muscle sympathetic nerve activity was recorded directly from the peroneal nerve in 16 patients during diagnostic induction of 19 episodes of sustained monomorphic ventricular tachycardia (average rate 189 beats/min, range 130 to 250). Average systolic and diastolic pressures decreased from 149/78 to 61/49 mm Hg by 10 s and increased toward baseline levels to 88/64 mm Hg by 1 min of ventricular tachycardia. Average sympathetic nerve activity increased by 92% at 10 s in direct proportion to arterial pressure reductions and in inverse proportion to ventricular rate and remained 83% above baseline levels at 1 min. The late recovery of arterial pressure during ventricular tachycardia was related significantly to the magnitude of early sympathetic responses. Sympathetic activity tended to lose its discrete bursting pattern during ventricular tachycardia, and power spectral analysis showed that the large sympathetic peaks at the heart rate frequency present during sinus rhythm are absent during ventricular tachycardia. This study is the first to delineate human sympathetic nervous system responses to ventricular tachycardia. The results suggest that in the patients studied, large early sympathetic surges differed from those that occur during sinus rhythm and contributed to hemodynamic stability during ventricular tachycardia.

    Title Biochemical and Genetic Analysis of a Child with Cystic Fibrosis and Cystinosis.
    Date September 1991
    Journal American Journal of Medical Genetics
    Excerpt

    We have studied a child with cystic fibrosis (CF), nephropathic cystinosis, and manifestations of Bartter syndrome, a finding reported previously in both of these diseases (CF and cystinosis). The chance of an individual inheriting a mutant allele for both CF and cystinosis from each of his parents by independent segregation is very small. Therefore, other mechanisms of inheritance were investigated, including whether his diseases were caused by a chromosome deletion or rearrangement that caused defects in both genes, whether his phenotype was caused by a new mutation or variant of either disease, or whether both diseases were inherited together due to inheritance of 2 copies of the same chromosome from one of the parents (uniparental disomy). An investigation was made of whether having mutations for both CF and cystinosis resulted in a different phenotype for either disease and whether the child was a heterozygote rather than a homozygote for one of the mutations. The results suggest that neither disease influenced the expression of the defect in the other and that this child inherited a mutant allele for both diseases independently from each parent.

    Title Phenytoin Treatment and Folate Supplementation Affect Folate Concentrations and Methylation Capacity in Rats.
    Date August 1991
    Journal The Journal of Nutrition
    Excerpt

    Phenytoin (PHT) has long been known to cause folate depletion with chronic use. In animal models PHT has been shown to interfere with folate-dependent one-carbon metabolism. Folic acid supplementation in humans has been shown to restore blood levels of folates to normal, but the effects of folic acid supplementation on the PHT-induced effects on one-carbon metabolism have not been addressed. In the present study rats were treated for 8 wk with 1) PHT, 2) folic acid, 3) PHT plus folic acid or 4) vehicle (propylene glycol). Phenytoin treatment caused a decrease in weight gain over the 8 wk of treatment. This effect on weight gain was reversed by folic acid supplementation, but the decrease in brain folate concentration caused by PHT was not reversed by folic acid supplementation, which by itself apparently caused a decrease in brain folate concentration. Phenytoin treatment tended to increase methylation capacity (S-adenosylmethionine:S-adenosylhomocysteine ratio) in the brain and decrease methylation capacity in the liver. Folate supplementation by itself increased methylation capacity in the liver but had no effect in the brain. Folic acid and PHT apparently had independent but opposite effects in the liver, leading to a normalization of methylation capacity. These data suggest that folic acid supplementation in PHT therapy may be effective in reversing the peripheral effects of chronic PHT treatment on one-carbon metabolism but not the central effects.

    Title Acidosis-induced Ischemic Brain Damage: Are Free Radicals Involved?
    Date July 1991
    Journal Journal of Cerebral Blood Flow and Metabolism : Official Journal of the International Society of Cerebral Blood Flow and Metabolism
    Excerpt

    Substantial evidence exists that reactive oxygen species participate in the pathogenesis of brain damage following both sustained and transient cerebral ischemia, adversely affecting the vascular endothelium and contributing to the formation of edema. One likely triggering event for free radical damage is delocalization of protein-bound iron. The binding capacity for some iron-binding proteins is highly pH sensitive and, consequently, the release of iron is enhanced by acidosis. In this study, we explored whether enhanced acidosis during ischemia triggers the production of reactive oxygen species. To that end, enhanced acidosis was produced by inducing ischemia in hyperglycemic rats, with normoglycemic ones serving as controls. Production of H2O2, estimated from the decrease in catalase activity after 3-amino-1,2,4-triazole (AT) administration, was measured in the cerebral cortex, caudoputamen, hippocampus, and substantia nigra (SN) after 15 min of ischemia followed by 5, 15, and 45 min of recovery, respectively (in substantia nigra after 45 min of recovery only). Free iron in cerebrospinal fluid (CSF) was measured after ischemia and 45 min of recovery. Levels of total glutathione (GSH + GSSH) in cortex and hippocampus, and levels of alpha-tocopherol in cortex, were also measured after 15 min of ischemia followed by 5, 15, and 45 min of recovery. The results confirm previous findings that brief ischemia in normoglycemic animals does not measurably increase H2O2 production in AT-injected animals. Ischemia under hyperglycemic conditions likewise failed to induce increased H2O2 production. No difference in free iron in CSF was observed between animals subjected to ischemia under hyper- and normoglycemic conditions. The moderate decrease in total glutathione or alpha-tocopherol levels did not differ between normo- and hyperglycemic animals in any brain region or at any recovery time. Thus, the results failed to give positive evidence for free radical damage following brief periods of ischemia complicated by excessive acidosis. However, it is possible that free radical production is localized to a small subcellular compartment within the tissue, thereby escaping detection. Also, the results do not exclude the possibility that free radicals are pathogenetically important after ischemia of longer duration.

    Title Intestinal Vitamin D-dependent Calbindin-d9k and Alkaline Phosphatase in Spontaneously Hypertensive Rats.
    Date June 1991
    Journal The American Journal of Physiology
    Excerpt

    Intestinal Ca2+ malabsorption has been described in spontaneously hypertensive rats (SHRs), but the molecular basis for this defect is unknown. In this study, we measured intestinal alkaline phosphatase and vitamin D-dependent Ca(2+)-binding protein (calbindin-D9k), two proteins implicated in the active pathway of intestinal Ca2+ absorption. Both proteins were measured in the small intestines of SHRs and their normotensive controls, Wistar-Kyoto rats, before, during, and after development of hypertension (4, 9, 14, 18, and 28 wk of age). At all ages, alkaline phosphatase activity in duodenum (0-6 cm) was decreased by 30-57% (P less than 0.001) and by 47-75% in the 2nd intestinal segment (6-12 cm) (P less than 0.001-0.05). Calbindin-D9k was decreased similarly. The decreases of calbindin were statistically significant (P less than 0.001-0.05) in the duodena at 4, 14, 18, and 28 wk (9-30% decreases) and in the 2nd segment at 4, 14, and 18 wk (38-69% decreases; P less than 0.001-0.005). Decreased calbindin in SHRs was documented in animals from two suppliers. The deficiencies of calbindin-D9k and alkaline phosphatase could not be attributed to malnutrition or to a generalized brush-border defect as indicated by body weights and the intestinal marker enzyme sucrase. Although calbindin-D9k was decreased in young SHRs, the serum 1,25-dihydroxycholecalciferol [1,25(OH)2D3] was increased by 59 and 129% in 4- and 9-wk-old SHRs (P less than 0.001), respectively; by contrast, serum 1,25(OH)2D3 was unchanged or decreased in older SHRs.(ABSTRACT TRUNCATED AT 250 WORDS)

    Title Photochemotherapy of Dominant, Diffuse, Cutaneous Mastocytosis.
    Date April 1991
    Journal Pediatric Dermatology
    Excerpt

    Diffuse, cutaneous mastocytosis is a rare variant of cutaneous mast cell infiltration that can arise in neonates or infants as a generalized bullous eruption. The mode of transmission is suggested as autosomal dominant. We report four infants from two unrelated families with diffuse cutaneous mastocytosis whose cutaneous disease was not controlled by initial therapies. Treatment of the four infants with photochemotherapy dramatically reduced or eliminated symptoms. One course of therapy resulted in improvement, and retreatment has not been required two to six years later.

    Title Differential Baroreflex Modulation of Human Vagal and Sympathetic Activity.
    Date April 1991
    Journal The American Journal of Physiology
    Excerpt

    We compared baroreflex modulation of human vagal-cardiac and sympathetic muscle activity in healthy volunteers by measuring R-R interval and peroneal nerve responses to a profile of positive and negative (40-65 mmHg) R-wave-triggered neck pressure steps during held expiration. R-R interval responses were sigmoid. Sympathetic activity increased abruptly with 40 mmHg pressure but returned to baseline levels as this pressure was maintained. The first decremental pressure step reduced sympathetic activity to below baseline, and the next three steps inhibited activity. During the final three steps, sympathetic activity increased to baseline, and after the return of neck pressure to ambient levels sympathetic activity increased to the highest levels recorded. Our results suggest that on a second-by-second basis human vagal-cardiac responses are determined simply by the net level of baroreceptor stimulation. Sympathetic muscle responses are determined complexly by the direction of changes (rising or falling) more than absolute arterial pressure levels and importantly by inputs from both carotid and aortic baroreceptors.

    Title Cigarette Smoking and Extracranial Carotid Atherosclerosis.
    Date March 1991
    Journal Advances in Experimental Medicine and Biology
    Title Quality Assurance in Drug Testing Laboratories.
    Date January 1991
    Journal Clinics in Laboratory Medicine
    Excerpt

    Drug testing is currently regulated for Department of Defense and other federal agency programs and many of the QA actions listed in this article are mandated in the regulations cited. This trend will probably continue in an effort to ensure high-quality test results and may expand into private sector testing. Also, more drugs may be added to the list of the five currently mandated for federal agencies. It remains to be seen if the certified DTLs avoid the pitfalls of past programs. A good QA program will undoubtedly be the key to success.

    Title Postmortem Forensic Toxicology.
    Date January 1991
    Journal Clinics in Laboratory Medicine
    Excerpt

    After all of the analytic data have been accumulated, the final step in the toxicologic process is to assess the meaning of the results. In suspected drug intoxications, one must determine if the amount of toxicant or toxicants present in the appropriate specimens is consistent with producing lethality. This decision ultimately must be made by the medical examiner or coroner, who must also consider the history, scene investigation, and gross and microscopic autopsy findings in reaching this decision. Once the cause of death has been determined, the manner of death needs to be decided. This can produce another group of questions to be addressed by the toxicologist. Items such as route of administration, acute versus chronic dose, and consistency between drug concentrations and behavioral effects may be critical factors in assessing the manner of death. These questions may arise even if the cause of death is ruled not to be drug related.

    Title Mitochondrial Genetics in a Natural Population of the Plant Pathogen Armillaria.
    Date January 1991
    Journal Genetics
    Excerpt

    Transmission and propagation of mitochondrial genotypes in fungi have not been previously investigated in the field. This study examined the distribution of nuclear and mitochondrial genotypes in a natural, local population of the fungal (Basidiomycetes) root-rot pathogen, Armillaria. Six vegetative clones, ranging in size up to 635 m, were identified on the basis of mating-type alleles. Mitochondrial DNA (mtDNA) restriction fragment patterns indicated that each vegetative clone has one, unique mtDNA type. However, as in other basidiomycetous fungi, biparental transmission of mitochondria following laboratory matings of sexually compatible haploid isolates of Armillaria resulted in a uniformly diploid mycelium that was a mosaic for both parental mitochondrial types. Therefore, either matings between monosporous, haploid isolates are uncommon in nature, or when mating does occur, cytoplasmic markers of one partner predominate during subsequent vegetative growth.

    Title Subnormal Parasympathetic Activity After Cardiac Transplantation.
    Date December 1990
    Journal The American Journal of Cardiology
    Excerpt

    Heart period variability (standard deviation of 120 consecutive RR or PP intervals) was used to assess baseline parasympathetic activity in 18 patients with congestive heart failure before and after orthotopic cardiac transplantation, and was compared to that of 16 age-matched control subjects. Mean heart period variability (+/- standard error of the mean) was significantly greater (p less than 0.05) in control subjects (58 +/- 5 ms) than in the patients at any time before or after transplantation. Heart period variability of innervated recipient atria did not change significantly early (1 to 4 weeks) after transplantation (16 +/- 2 to 24 +/- 5 ms; p = 0.11), but increased significantly between weeks 15 and 37 after transplantation (30 +/- 5 ms, p less than 0.002 versus before transplantation). A stepwise regression model (R2 = 0.35; p = 0.01) showed that heart period variability was directly related to time after transplantation and inversely related to systolic arterial pressure after transplantation and degree of rejection. Heart period variability of the denervated donor atria did not change from early to late periods after transplantation, suggesting that vagal reinnervation of the donor heart had not occurred. These data indicate that baseline parasympathetic activity does not increase significantly during the first month after transplantation but increases significantly between months 3 and 6.

    Title Autonomic Pathophysiology in Heart Failure: Carotid Baroreceptor-cardiac Reflexes.
    Date October 1990
    Journal The American Journal of Physiology
    Excerpt

    We evaluated reflex cardiac responses mediated by carotid baroreceptors in 14 patients with treated congestive heart failure and 14 age-matched healthy subjects. We used a neck chamber to deliver two types of pressure change: 5 s of continuous 50-mmHg suction and an R wave triggered, ramped neck pressure-suction sequence. Reflex latencies (functions of baroreflex arc duration) were comparable in heart failure patients and healthy subjects. However, the average maximum baroreflex slope (gain) was less in heart failure patients than healthy subjects (2.0 vs. 3.5 ms/mmHg, P less than 0.010), the R-R interval response range was smaller (91 vs. 188 ms, P = 0.002), and the resting R-R interval position on stimulus-response relation (operational point) was significantly (13 vs. 40%, P = 0.001) closer to threshold. Stepwise regression analysis suggested that baseline R-R interval variability, used as an index of ongoing vagal-cardiac nerve traffic, and the inverse of antecubital vein plasma norepinephrine level, used as an index of sympathetic nerve activity, contributed significantly to the prediction of abnormal carotid baroreceptor-cardiac reflex responses. Thus our results suggest that in heart failure patients, carotid baroreceptor-cardiac reflex abnormalities are related significantly to ongoing abnormalities of vagal and sympathetic cardiovascular outflow.

    Title Three-dimensional Comparison of Peripheral Benzodiazepine Binding and Histological Findings in Rat Brain Tumor.
    Date September 1990
    Journal Neurosurgery
    Excerpt

    Experiments were undertaken to determine the in vivo utility of the mixed benzodiazepine ligand [3H]flunitrazepam and the selective peripheral benzodiazepine ligand [3H]PK 11195 [1-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinoline carboxamide] to outline the borders of rat C6 glial tumors in three dimensions. Intravenous injection of [3H]flunitrazepam resulted in a tumor/cortex ratio of radioactive densities between 2.7 and 1.5 within the first 60 minutes after injection. [3H]PK 11195 demonstrated a higher tumor/cortex ratio (5.3) than [3H]flunitrazepam. For three-dimensional studies, images were generated from thionin-stained histological sections and autoradiograms. The mixed type benzodiazepine ligand [3H]flunitrazepam was superior in showing some of the normal anatomical structures surrounding the tumor, whereas [3H]PK 11195, a specific peripheral ligand, demonstrated higher tumor/brain contrast and superior topographical correlation between histological and autoradiographic images. Implications of peripheral benzodiazepine receptor ligands for positron emission tomography are discussed.

    Title Effects of Diphenhydramine on Immunoassays of Phencyclidine in Urine.
    Date July 1990
    Journal Clinical Chemistry
    Title Imaging Peripheral Benzodiazepine Receptors in Brain Tumors in Rats: in Vitro Binding Characteristics.
    Date July 1990
    Journal Journal of Cerebral Blood Flow and Metabolism : Official Journal of the International Society of Cerebral Blood Flow and Metabolism
    Excerpt

    Peripheral benzodiazepine binding constants for transplanted RG-2 gliomas and HD and LK Walker 256 tumors (metastatic breast carcinoma) were determined in Wistar rats using autoradiography. In addition, Kd and Bmax parameters for peripheral benzodiazepine receptors on RG-2 tumors were directly visualized using digital image analysis of autoradiograms. High specific binding of [3H]PK11195, a selective peripheral benzodiazepine ligand, had excellent topographical correlation to areas of histologically verified tumor. Scatchard analysis suggested a single class of peripheral binding sites with similar binding affinities in RG-2 and LK Walker 256 tumors and normal cortex. Bmax was 20-fold greater in glial tumors and 11.6- and 10.6-fold greater in LK and HK Walker 256 tumors, respectively, compared to normal cortex. The location of metastatic tumors, either intracerebrally or subcutaneously, did not effect their Kd or Bmax values. Kd and Bmax values for RG-2 tumors were similar whether determined densitometrically or by direct visualization with image analysis. Binding parameters within normal brain were difficult to visualize by image analysis due to the low level of specific binding. The ability to label specifically intracerebral tumor cells and to characterize the binding parameters shown in this study suggest that peripheral benzodiazepine receptor ligands could be utilized by PET to analyze directly a variety of tumors in humans.

    Title Changes in Regional Adrenergic Tone During Sustained Ventricular Tachycardia Associated with Coronary Artery Disease or Idiopathic Dilated Cardiomyopathy.
    Date June 1990
    Journal The American Journal of Cardiology
    Excerpt

    The hemodynamic tolerance of an episode of ventricular tachycardia (VT) can vary widely from no decrease in systolic blood pressure to severe hypotension. Little is known about the factors responsible for these different responses in man. Previous animal studies have suggested an important role for vasoconstriction mediated by the alpha-adrenergic nervous system. To determine the magnitude and time course of changes in alpha-adrenergic tone during symptomatic sustained monomorphic VT, VT cycle length, mean and phasic arterial pressure, forearm blood flow (by venous occlusion plethysmography) and forearm vascular resistance were measured in 15 patients. Nine of these patients were studied before and after regional intraarterial alpha blockade with phentolamine. After the induction of VT (350 +/- 68 ms), mean forearm blood flow decreased from 3.2 +/- 1.1 to 2.2 +/- 0.8 ml/min/100 ml (p = 0.0002) and the forearm vascular resistance increased from 32 +/- 14 to 40 +/- 14 units (p = 0.01). There were no significant differences for forearm vascular resistance during the first and last 30 seconds of VT (41.3 +/- 14 vs 37 +/- 13 units). After the infusion of intraarterial phentolamine, there were no significant changes in the VT cycle length or mean arterial pressure, but the forearm vascular resistance increase during VT was blunted by 60 to 70%. Most patients with symptomatic VT demonstrate sympathetic vasoconstriction and these changes are maximal during the first 30 seconds of VT. This sympathoexcitatory response is due largely to stimulation of alpha-adrenoreceptors and may be mediated by arterial baroreflexes.

    Title Increased Vagal Cardiac Nerve Traffic Prolongs Ventricular Refractoriness in Patients Undergoing Electrophysiology Testing.
    Date June 1990
    Journal The American Journal of Cardiology
    Excerpt

    Stimulation of the vagus nerve in animals causes prolongation of sinus cycle length, atrioventricular nodal conduction and ventricular refractoriness. Vagal stimulation appears to have a protective effect in animal models of sudden death. The electrophysiologic effects of enhanced vagal activity on right ventricular (RV) refractoriness in man have not been studied previously. The comparative effects of enhanced vagal tone (neck suction to -60 mm Hg) on sinus cycle length and RV refractoriness were assessed in 26 patients. The electrophysiologic effects of vagal activation by stimulation of carotid baroreceptors with neck suction were compared to the effect of carotid and aortic baroreceptor stimulation with phenylephrine infusion in 12 patients. During neck suction, mean sinus cycle length (819 +/- 32 ms) was prolonged by 146 +/- 20 ms (p less than 0.0001). The mean RV effective refractory period (ERP) and functional refractory period (FRP) were prolonged by 4 +/- 1 ms and 5 +/- 1 ms (p = 0.0001 and 0.0002, respectively). The mean change in RV ERP and FRP correlated with the peak change in sinus cycle length during neck suction (r = 0.46 and r = 0.58, respectively). During intravenous phenylephrine infusion, the mean change in RV ERP and FRP was 5 +/- 2 ms (p less than 0.04) and 10 +/- 3 ms (p less than 0.01), respectively. These results show that reflex vagal stimulation with neck suction or phenylephrine infusion causes a small but significant prolongation in RV refractoriness. These findings imply that the potential benefits of enhanced vagal tone in preventing sudden death may be indirectly mediated by changes in ventricular refractoriness.

    Title Cystine Exodus from Lysosomes: Cystinosis.
    Date May 1990
    Journal Methods in Enzymology
    Title Radon-222 Levels in New York State Homes.
    Date March 1990
    Journal Health Physics
    Excerpt

    Results are presented from a statewide survey that measured annual 222Rn concentrations in over 2000 single-family, owner-occupied homes in New York state. The participants were selected by a random-digit-dialing telephone interview approach developed by Mitofsky-Waksberg which allows inferences to be made from the sample to the statewide population. After completing a telephone questionnaire and agreeing to have their homes monitored, eligible households were mailed alpha-track detectors with instructions to place one detector in the main living area for 2 mo (during the winter heating season), a second in the main living area for 1 y, and a third in the basement (if applicable) for 1 y. The statewide median concentration for the heating-season, living-area readings was 31.6 Bq m-3, with a median of 24.0 Bq m-3 for the annual living-area readings and 51.8 for the annual basement readings. For the state, approximately 95% of the living-area concentrations and 86% of the basement concentrations were below 148 Bq m-3 (4 pCi L-1). In addition, only 1.4% of the readings in the basement were above 740 Bq m-3 (20 pCi L-1).

    Title Seizure-induced Damage to Substantia Nigra and Globus Pallidus is Accompanied by Pronounced Intra- and Extracellular Acidosis.
    Date December 1989
    Journal Journal of Cerebral Blood Flow and Metabolism : Official Journal of the International Society of Cerebral Blood Flow and Metabolism
    Excerpt

    Status epilepticus of greater than 30-min duration in rats gives rise to a conspicuous lesion in the substantia nigra pars reticulata (SNPR) and globus pallidus (GP). The objective of the present study was to explore whether the lesion, which encompasses necrosis of both neurons and glial cells, is related to intra- and extracellular acidosis. Using the flurothyl model previously described to produce seizures, we assessed regional pH values with the autoradiographic 5,5-dimethyl[2-14C]oxazolidine-2,4-dione technique. Regional pH values were assessed in animals with continuous seizures for 20 and 60 min, as well as in those allowed to recover for 30 and 120 min after seizure periods of 20 or 60 min. In additional animals, changes in extracellular fluid pH (pHe) were measured with ion-selective microelectrodes, and extracellular fluid (ECF) volume was calculated from the diffusion profile for electrophoretically administered tetramethylammonium. In structures such as the neocortex and the hippocampus, which show intense metabolic activation during seizures, status epilepticus of 20- and 60-min duration was accompanied by a reduction of the "composite" tissue pH (pHt) of 0.2-0.3 unit. Recovery of pHt was observed upon termination of seizures. In SNPR and in GP, the acidosis was marked to excessive after 20 and 60 min of seizures (delta pHt approximately 0.6 after 60 min).(ABSTRACT TRUNCATED AT 250 WORDS)

    Title Milialike Idiopathic Calcinosis Cutis in Down's Syndrome.
    Date December 1989
    Journal Archives of Dermatology
    Title Diagnosis of Cystinosis with Use of Placenta.
    Date August 1989
    Journal The New England Journal of Medicine
    Title Subnormal Heart Period Variability in Heart Failure: Effect of Cardiac Transplantation.
    Date August 1989
    Journal Journal of the American College of Cardiology
    Excerpt

    Heart period variability and arterial baroreceptor-cardiac reflex function were studied in cardiac transplant patients to determine if correction of heart failure restores parasympathetic control mechanisms toward normal. Heart period variability (standard deviation [SD] of 120 consecutive RR or PP intervals) was measured at supine rest in 34 patients with congestive heart failure (23 patients receiving diuretics, digoxin or vasodilators and 11 patients weaned from all medications), 30 cardiac transplant patients (both innervated recipient and denervated donor atrial rates) and 16 age-matched healthy control subjects. Arterial baroreflex gain was evaluated with intravenous bolus injections of phenylephrine in 22 transplant patients. Mean heart period variability (+/- SEM) was significantly lower (p less than 0.05) in the heart failure groups (22 +/- 3 ms for medicated and 17 +/- 3 ms for nonmedicated) than in the transplant patients (41 +/- 5 ms) or control subjects (58 +/- 5 ms). Heart period variability of the transplant patients was less than that of the control patients (p less than 0.05). A stepwise regression model revealed that heart period variability was inversely related to systolic arterial pressure and directly related to time after transplantation (R2 = 0.39; p = 0.03) in the transplant patients. Baroreflex gain of normotensive transplant patients was normal (11.7 +/- 1.0 ms/mm Hg) and correlated directly with heart period variability (r = 0.62; p less than 0.001). These data suggest that subnormal levels of cardiac parasympathetic activity at rest associated with congestive heart failure can be restored progressively toward normal by correction of congestive heart failure after cardiac transplantation. Post-transplant hypertension opposes this correction of baseline parasympathetic activity.

    Title Salmonella Meningitis. Unusual Presentation and Successful Treatment with Cefuroxime.
    Date May 1989
    Journal North Carolina Medical Journal
    Title Exercise Training Bradycardia: the Role of Autonomic Balance.
    Date May 1989
    Journal Medicine and Science in Sports and Exercise
    Excerpt

    We used an algebraic model of resting heart rate (HRr), HRr-mn (HRo), to compare resting parasympathetic (n) and sympathetic (m) influence, intrinsic heart rate (HRo), and resting autonomic balance (Abal) in ten endurance-trained (ET) and ten nontrained (NT) men. The values of m, n, and Abal were determined by selective pharmacological blockade with atropine and metoprolol. HRo was obtained during double blockade with atropine and metoprolol. HRo and HRr were significantly lower (P less than or equal to 0.04 and P less than or equal to 0.01, respectively) in the ET subjects (79.5 +/- 2.8 beats.min-1 and 54.7 +/- 3.0 beats.min-1, respectively) when compared to the NT subjects (86.6 +/- 2.5 beats.min1 and 70.2 +/- 3.1 beats.min-1, respectively). Parasympathetic influence (n) was greater in the ET subjects (P less than or equal to 0.04), while sympathetic influence (m) was slightly (P less than or equal to 0.05) less in the ET subjects. Consequently, the value of Abal was significantly less in the ET subjects (P less than or equal to 0.02), indicating that resting parasympathetic predominance was significantly greater in the ET subjects. We concluded that the exercise training bradycardia, observed in this group of subjects, was due to both a lower HRo and an Abal with an augmented parasympathetic dominance.

    Title Effect of Etidronate Disodium on Bone Turnover Following Surgical Menopause.
    Date March 1989
    Journal Calcified Tissue International
    Excerpt

    A longitudinal study was performed to document the effect of surgical menopause and postmenopausal etidronate disodium therapy on several nonhistomorphometric indices of bone turnover. Twenty healthy, premenopausal women undergoing oophorectomy for nonmalignant conditions were studied preoperatively and at 3 monthly intervals postoperatively. Sequential measurements of serum calcium (Ca), alkaline phosphatase (AP), bone Gla protein (BGP), and urinary calcium and hydroxyproline excretion, expressed as a ratio of urinary creatinine (UCa/Cr and UOHp/Cr, respectively) were obtained. Twenty-four-hour whole body retention of diphosphonate (WBR) and radial bone density were also measured. When a postoperative increase in bone turnover was observed, patients were randomized to receive either 400 mg etidronate disodium daily or placebo for 3 months. Oophorectomy was associated with a significant increase in WBR, Ca, AP, and BGP and an insignificant rise in UCa/Cr. A variable pattern of UOHp/Cr was seen. Patients on placebo maintained these elevated levels of Ca, BGP, and UCa/Cr. WBR and AP continued to rise. Etidronate disodium therapy resulted in a fall towards premenopausal levels in WBR, Ca, and UCa/Cr. AP and BGP were unchanged. Three months after stopping etidronate, BGP fell significantly and the decrease in Ca was maintained; however, WBR and UCa/Cr had returned towards pretreatment values. Bone density measurements did not change significantly. An increase in several of the indices of bone turnover was seen following oophorectomy. Etidronate disodium suppressed this increase, affecting indices of both resorption and formation.(ABSTRACT TRUNCATED AT 250 WORDS)

    Title Rheumatoid Papules: Lesions Showing Features of Vasculitis and Palisading Granuloma.
    Date March 1989
    Journal Journal of the American Academy of Dermatology
    Excerpt

    Whether palisading granuloma formation occurs with leukocytoclastic vasculitis in rheumatoid nodules and in histopathologically similar conditions is debatable. Patients with high titers for rheumatoid factor and severe erosive rheumatoid arthritis are at risk for both rheumatoid vasculitis and rheumatoid nodules. A patient with all of these features developed a papular eruption. These papules showed clinicopathologic features both of leukocytoclastic vasculitis and of early palisading granuloma. Lesions resolved slowly with low-dose oral corticosteroid therapy. It is proposed that these lesions be called rheumatoid papules and that they may represent a link between vasculitis and the palisaded granulomatous reaction seen in rheumatoid nodules.

    Title Enhancement of Sympathetic Nerve Activity by Single Premature Ventricular Beats in Humans.
    Date February 1989
    Journal Journal of the American College of Cardiology
    Excerpt

    This is the first systematic study of the effects of ventricular premature beats on sympathetic nerve activity in humans. Microneurographic techniques were used to record efferent sympathetic activity from the peroneal nerve, and an intracardiac electrode catheter was used to introduce ventricular premature beats after every 6 to 10 sinus heartbeats. Studies were performed in eight patients, aged 22 to 74 years (mean 57), undergoing cardiac electrophysiologic studies. Three patients did not have apparent heart disease and five had coronary artery disease. During sinus rhythm, 19 to 93% (mean 42%) of heartbeats were followed by a pulse-synchronous burst of sympathetic activity. Provoked ventricular premature beats had obvious effects on this activity. Premature beats with coupling intervals less than 80% of sinus cycle length were consistently followed by a burst of sympathetic activity, and this activity was greater in amplitude, duration and area (all p less than 0.05) than were burst of such activity during sinus rhythm. The magnitude of this burst of activity increased as the coupling interval of the ventricular premature beat decreased (p less than 0.0001). In contrast, postextrasystolic beats were followed by nearly complete neural silence. These effects were seen in all patients regardless of baseline burst incidence and the presence or absence of heart disease. Total nerve activity per 10 heartbeats was 6,520 +/- 770 U during ventricular extrastimulation and 5,720 +/- 440 U during normal sinus rhythm (difference not significant). It is concluded that single ventricular premature beats provoke fluxes of muscle sympathetic nerve activity in humans, comprising surges of sympathetic activity larger than those occurring during sinus rhythm, followed by neural silence.

    Title Blood Pressure Regulation During Cardiac Autonomic Blockade: Effect of Fitness.
    Date December 1988
    Journal Journal of Applied Physiology (bethesda, Md. : 1985)
    Excerpt

    The purpose of this study was to determine the role of the autonomic nervous system's control of the heart in fitness-related differences in blood pressure regulation. The cardiovascular responses to progressive lower-body negative pressure (LBNP) were studied during unblocked (control) and full blockade (experimental) conditions in 10 endurance-trained (T) and 10 untrained (UT) men, aged 20-31 yr. The experimental conditions included beta 1-adrenergic blockade (metoprolol tartrate), parasympathetic blockade (atropine sulfate), or complete blockade (metoprolol and atropine). Heart rate, blood pressure, forearm blood flow, and cardiac output were measured at rest and -16 and -40 Torr LBNP. Forearm vascular resistance, peripheral vascular resistance, and stroke volume were calculated from these measurements at each stage of LBNP. Blood pressure was maintained, primarily by augmented vasoconstriction, equally in T and UT subjects during complete and atropine blockade. The fall in systolic and mean pressure from 0 to -40 Torr was greater (P less than 0.05) in the T subjects during the unblocked and metoprolol blockade conditions. This reduced blood pressure control during unblocked condition was attributable to attenuated vaso-constrictor and chronotropic responses in the T subjects. We hypothesize that an autonomic imbalance (elevated base-line parasympathetic activity) in highly trained subjects restricts reflex cardiac responses, which accompanied by an attenuated vasoconstrictor response, results in attenuated blood pressure control during a steady-state hypotensive stress.

    Title The Effect of 1 Alpha-hydroxyvitamin D3 on the Mineralization Defect in Disodium Etidronate-treated Paget's Disease--a Double-blind Randomized Clinical Study.
    Date October 1988
    Journal Journal of Bone and Mineral Research : the Official Journal of the American Society for Bone and Mineral Research
    Excerpt

    A double-blind randomized study of 29 patients with symptomatic Paget's disease was conducted comparing the clinical, biochemical, and histomorphometric responses to 3-month treatment with placebo (10 patients), low-dose disodium etidronate (EHDP) (5-7 mg/kg/day) (10 patients), and low-dose EHDP plus 1 alpha-hydroxyvitamin D3 (1 alpha D3) 0.5 mcg daily (9 patients). In placebo-treated patients no significant changes were observed in symptoms, biochemistry, or bone histomorphometry. Histologically apparent mineralization defects developed after 3 months of therapy in 90% of patients in the EHDP group, compared with 45% of patients in the EHDP/1 alpha D3 group. In 19% of the patients treated with active medication, the mineralization defects in pagetic bone were accompanied by histological evidence of continued osteoclastic resorption. The development of mineralization defects was not related to serum levels of vitamin D metabolites, alkaline phosphatase, or intestinal calcium absorption but did correlate with the occurrence of hyperphosphatemia during treatment, which was most marked in patients treated with EHDP alone. Although mineralization defects were less frequent in the EHDP/1 alpha D3 group, these patients also responded less well symptomatically, thus limiting the potential usefulness of this drug combination in Paget's disease.(ABSTRACT TRUNCATED AT 250 WORDS)

    Title Appearances on Computed Tomography Following Thoracoplasty for Pulmonary Tuberculosis.
    Date October 1988
    Journal The British Journal of Radiology
    Excerpt

    Thoracic computed tomography was performed in 32 patients who had undergone thoracoplasty as part of their treatment for pulmonary tuberculosis. Pleural thickening and the prevalence of bronchiectasis were more marked in the operated hemithorax. Bullae were more prevalent in the operated hemithorax but the difference was not statistically significant. In all but one patient, scoliosis was present. Illustrative examples are presented to demonstrate the range of appearances following this operation.

    Title Successful Pregnancy Despite Placental Cystine Crystals in a Woman with Nephropathic Cystinosis.
    Date August 1988
    Journal The New England Journal of Medicine
    Title Effect of Changes in Cardiac Autonomic Balance on Blood Pressure Regulation in Man.
    Date July 1988
    Journal Journal of the Autonomic Nervous System
    Excerpt

    The role of cardiac autonomic balance in fitness-related differences in blood pressure regulation was evaluated by comparing the cardiovascular responses to lower body negative pressure (LBNP) in 10 trained and 10 untrained men. Cardiac autonomic balance was quantified as the ratio of resting heart rate to intrinsic heart rate, and was significantly lower in the trained subjects (0.68 +/- 0.03) than the untrained subjects (0.81 +/- 0.03) indicating a greater parasympathetic dominance at rest in the trained subjects. Arterial pressure decreased significantly more during LBNP in the trained subjects and was due to lower chronotropic and vasoconstrictor responses in these trained subjects. 'Cardiac autonomic balance' was equilibrated between the groups by partial parasympathetic blockade with atropine sulfate in the trained subjects and partial sympathetic blockade with metoprolol tartrate in the untrained subjects. Equilibration of cardiac autonomic balance eliminated the group differences in blood pressure maintenance, and chronotropic and vasoconstrictor responsiveness during LBNP. It was hypothesized that the elevated tone of parasympathetic control of the heart rate of the trained subjects resulted in an attenuation of blood pressure regulation.

    Title Baroreflex Function in Endurance- and Static Exercise-trained Men.
    Date June 1988
    Journal Journal of Applied Physiology (bethesda, Md. : 1985)
    Excerpt

    The effect of exercise training mode on reflex cardiovascular control was studied in a cross-sectional design. We examined the cardiovascular responses to progressive incremental phenylephrine (PE) infusion to maximal rates of 120 micrograms/min and the delta heart rate/delta blood pressure responses to lower body negative pressure (LBNP) to -50 Torr in 30 men who were either endurance exercise trained (ET), untrained (UT), or weight trained (WT). During PE infusion, measures of blood pressures, forearm blood flow, heart rate and cardiac output, and calculations of forearm vascular resistance, stroke volume, and peripheral vascular resistance were made at each infusion rate when steady-state blood pressure was attained. No significant differences (P less than 0.05) in forearm blood flow or resistance were observed between the groups at any dose of PE, suggesting that the vasoconstrictor response was similar among the groups. Regression analyses of heart rate against mean blood pressure during the PE infusion were performed to evaluate baroreflex function. A linear model was used and correlation coefficients ranging from 0.82 to 0.96 were obtained (P less than 0.05). The slope of the line of best fit for the ET subjects (-0.57) was significantly less (P less than 0.05) than the slopes obtained for either the UT (-0.91) or WT (-0.88) subjects. In addition, the delta heart rate/delta blood pressure measurements obtained during LBNP reflected a similarly significant attenuation of reflex chronotropic control in the ET subjects.(ABSTRACT TRUNCATED AT 250 WORDS)

    Title Lack of Complementation in Somatic Cell Hybrids Between Fibroblasts from Patients with Different Forms of Cystinosis.
    Date June 1988
    Journal Proceedings of the National Academy of Sciences of the United States of America
    Excerpt

    Cystinosis is an autosomal recessive disease in which three clinical forms are recognized: infantile nephropathic, with renal tubular damage by 1 year of age and progressive glomerular insufficiency; intermediate, with tubular and glomerular insufficiency beginning at a later age; benign, with no kidney damage. Skin fibroblasts cultured from patients with all types of cystinosis show increased intralysosomal free (nonprotein) cystine; however, fibroblasts from heterozygotes have normal free-cystine values. To determine whether genetic complementation occurs between the different forms, somatic cell hybrids were constructed between cells from a patient with infantile nephropathic cystinosis and cells from patients with other types of cystinosis. If complementation occurred, the hybrids would be expected to have normal cystine levels. To construct hybrid cells, a "universal parent" cell type (TG1-neo), which was hypoxanthine/aminopterin/thymidine (HAT) sensitive and G418 resistant was constructed from an infantile nephropathic cystinosis fibroblast strain. Polyethylene glycol fusion of TG1-neo with other cells that are not HAT sensitive or G418 resistant allowed for selection of hybrid cells in a medium containing HAT and the aminoglycoside G418. As indicated by elevated cystine levels, complementation did not occur between TG1-neo and two different benign cystinosis strains, an intermediate cystinosis strain, or another nephropathic cystinosis cell strain. When a normal fibroblast strain was fused with TG1-neo, all 15 hybrid clones studied contained normal amounts of intracellular free cystine.

    Title Automated Quantitative Fluorescent Image Analysis of Cervical Cytology.
    Date January 1988
    Journal Gynecologic Oncology
    Excerpt

    Cervical cytology from 122 patients with histories of one or more abnormal Pap smears were studied using slide-based automated quantitative fluorescence image analysis (QFIA) in order to determine the usefulness of the QFIA technique in detecting neoplasias. The purpose of the study was to evaluate the accuracy and validity of QFIA as a cytological method for the early detection of cervical cancer, based on comparisons with the conventional Pap smear and histopathology. The results of the analysis demonstrated that the sensitivity of the automated QFIA cytology was 100% for high-grade neoplasms (CIN III and invasive carcinoma), compared with 82% for the Pap smear. Evaluation of lower grade neoplasms was also performed. Initial analyses of the data indicate that QFIA, which uses objective biochemical criteria to identify cells with increased nuclear nucleic acid content, is a more sensitive detector of cervical neoplasia of all grades than is conventional Pap cytology.

    Title Cystine Exodus from Normal Leucocytes is Stimulated by Mgatp.
    Date December 1987
    Journal The Biochemical Journal
    Excerpt

    Cystine exodus from partially purified granular fractions of normal leucocytes is stimulated by MgATP. N-Ethylmaleimide, an inhibitor of the lysosomal H+-translocating ATPase, eliminated the stimulated exodus, but had no effect on basal exodus. As the initial content of cystine was increased, the initial velocity of both the basal and ATP-stimulated egress increased. However, as saturation with substrate was approached, the ATP stimulation disappeared leaving only the N-ethylmaleimide-insensitive basal exodus. The increased initial velocity in the presence of ATP may represent improved binding of cystine to the partially saturated inner transporter as a result of conformational or charge optimization brought about by the action of the H+-translocating ATPase.

    Title Effect of Muscle Tension on the Cardiovascular Responses to Lower Body Negative Pressure in Man.
    Date December 1987
    Journal Medicine and Science in Sports and Exercise
    Excerpt

    The purpose of this investigation was to evaluate the effect of moderate (non-hypertensive) levels of muscle tension on the cardiovascular responses to progressive lower body negative pressure (LBNP) in eight healthy male volunteers. Subjects were presented with progressive LBNP to -50 torr or the occurrence of vasovagal symptoms during three different levels of electromyographic activity in the lower limbs represented by the relaxed state, 5 and 10% maximal voluntary contraction. The same procedure was also performed at the same three levels of electromyographic activity in the arms with concomitant relaxation of the abdomen and lower extremities. In 75% of the subjects, pre-syncopal reactions were observed during the relaxed state while no pre-syncopal responses occurred during the elevated muscle tension levels. Both levels of muscle tension in the legs attenuated the LBNP-induced decrease in blood pressure (P less than 0.05). The effect of the 5% maximal voluntary contraction tension level appeared to be due to a compressive effect on the vascular tree, because similar levels of tension in the forearm had minimal effect on the blood pressure response to LBNP. In addition to a compressive effect, the 10% maximal voluntary contraction tension level appeared to induce a reflex stimulation of the heart as evidenced by an augmented heart rate response to LBNP and an increase in cardiac output. The muscle tension appeared to induce a mechanical compression of the vascular tree which was accompanied by somatopressor reflex responses, resulting in a maintenance of blood pressure that was primarily mediated by a maintained cardiac output.

    Title Effect of 60-minute Head-down Tilt on Arterial Baroreflex Function in Anesthetized Dogs.
    Date November 1987
    Journal Journal of the Autonomic Nervous System
    Excerpt

    Arterial baroreflex control of heart rate was assessed in 6 anesthetized dogs with a bolus infusion of phenylephrine before and during cardiopulmonary receptor stimulation by 6 degrees head-down tilt (HDT) for 60 min. No difference in arterial baroreflex function was observed between the control and HDT conditions. It appears that the attenuation of baroreflex function that occurs during acute stimulation of cardiopulmonary baroreceptors disappears when cardiopulmonary baroreceptors reset after prolonged stimulation.

    Title Physical Fitness and Hemodynamic Response of Women to Lower Body Negative Pressure.
    Date October 1987
    Journal Medicine and Science in Sports and Exercise
    Excerpt

    Aerobic fitness as assessed by maximal aerobic capacity (VO2max) has been shown to be associated with an attenuated baroreflex function during lower body negative pressure (LBNP) in men. Sixteen women (mean age = 24.7 yrs) were evaluated during progressive LBNP to -50 torr. Each subject's VO2max was determined using indirect calorimetry during the Bruce protocol exercise test. Eight subjects [mean VO2max = 56.8 (ml O2 X min-1) X kg-1] were designated as trained, and eight subjects [mean VO2max = 39.4 (ml O2 X min-1) X kg-1] were designated as untrained. During LBNP, heart rate, blood pressure, cardiac index, forearm blood flow, and leg circumference were measured. All subjects completed the LBNP protocol without clinical symptoms of pre-syncope. The over-all hemodynamic responses of both groups to LBNP were qualitatively similar to previous findings reported for males. However, no significant differences in response of hemodynamic variables were observed between trained and untrained subjects during LBNP to -50 torr (P greater than 0.05) except for vascular resistance and diastolic blood pressure at -50 torr where the untrained value was greater than the trained value. This would suggest that a fitness-related difference may have been present at higher levels of LBNP. Furthermore, in contrast to previous reports in males, the index of baroreflex responsiveness (delta heart rate/delta systolic blood pressure) was similar for both groups (P greater than 0.05). When these data were compared with a similar subject pool of males, the females displayed a significantly greater (P less than 0.05) tolerance of LBNP to -50 torr regardless of fitness.(ABSTRACT TRUNCATED AT 250 WORDS)

    Title Development of an Enzyme-linked Immunosorbent Assay for the Detection of Phenothiazine Tranquillisers in Horses.
    Date August 1987
    Journal Research in Veterinary Science
    Excerpt

    An acepromazine (ACP) hapten was synthesised, coupled to bovine serum albumin and injected into a horse to produce antibodies to the drug. A competitive ELISA was developed whereby ACP attached to the solid phase via lysozyme competed with free ACP present in phosphate buffered saline, horse serum or horse urine for limiting amounts of antibody. The assay could detect the presence of ACP and, or, some of its metabolites in horse urine for at least 25 hours after intravenous injection of 0.1 mg kg-1 ACP maleate, but because of non-specific interference, horse serum could not be used. As little as 0.24 micrograms ml-1 ACP or its metabolites could be detected. The level of detection and the ease of performance of the assay make it an attractive alternative to the more complex methods currently available for the screening of horse urine samples at horse races, shows and sales.

    Title Colonization of Gnotobiotic Piglets with Campylobacter Pyloridis--an Animal Model?
    Date June 1987
    Journal The Journal of Infectious Diseases
    Title Uterus Didelphys with Unilateral Hematocolpos, Ipsilateral Renal Agenesis and Menses. A Case Report and Literature Review.
    Date May 1987
    Journal The Journal of Reproductive Medicine
    Excerpt

    A 13-year-old girl with signs and symptoms of an acute abdomen was found to have uterus didelphys, unilateral hematocolpos, ipsilateral renal agenesis and menses. A review of the literature in English revealed 115 reported cases. This complex congenital anomaly is seen most commonly in adolescents with dysmenorrhea of progressive severity, abdominal pain and a pelvic mass.

    Title The Effects of Exercise Training on Factors Affecting Orthostatic Tolerance.
    Date May 1987
    Journal The Physiologist
    Title Prenatal Diagnosis of Cystinosis Utilizing Chorionic Villus Sampling.
    Date March 1987
    Journal Prenatal Diagnosis
    Excerpt

    The prenatal diagnosis of cystinosis is currently based on the increased amount of free-cystine present in amniotic fluid cells. Amniocyte cultures must be grown for at least 2 weeks to obtain sufficient cells for such measurements. Thus, the diagnosis cannot be made until close to 20 weeks gestational age by this method. We report a case in which chorionic villi were used for direct cystine measurement resulting in the in utero diagnosis of cystinosis at 9 weeks gestational age. The diagnosis was confirmed by the study of cultured chorionic villus cells, and of the 10-week abortus.

    Title Lysosomal Cystine Transport. Effect of Intralysosomal Ph and Membrane Potential.
    Date March 1987
    Journal The Journal of Biological Chemistry
    Excerpt

    The regulation of lysosomal cystine transport was studied using cystine dimethyl ester-loaded lysosomes isolated from human diploid fibroblasts. Net efflux from normal fibroblast lysosomes was compared to that from lysosomes of cystinotic fibroblasts, which contain an inherited mutation decreasing lysosomal cystine transport. This exodus of cystine from normal fibroblast lysosomes was greater than from cystinotic fibroblast lysosomes. When lysosomes were incubated with both 5 mM MgCl2 and 2 mM ATP (Mg/ATP), the amount of lysosomal cystine lost from normal lysosomes doubled, but the amount of cystine lost from cystinotic lysosomes remained small. This effect of Mg/ATP on cystine loss from lysosomes isolated from normal fibroblasts was abolished when either carbonyl cyanide m-chlorophenylhydrazone or N-ethylmaleimide was present, suggesting that the effect of Mg/ATP was mediated by the action of a lysosomal proton-translocating ATPase. Addition of KCl, RbCl, or NaCl to normal lysosomes caused smaller increases in cystine exodus. A variety of experimental conditions altered lysosomal pH, membrane potential, and the cystine lost from normal fibroblast lysosomes. These same experimental conditions produced similar alterations in the lysosomal pH and membrane potential of cystinotic fibroblast lysosomes without a comparable alteration in cystine loss. These results have led us to propose a model in which the transport of cystine out of the normal lysosome is regulated by both the lysosomal membrane potential gradient and the transmembrane pH gradient.

    Title A 13c-nmr Study of Mutant Hemoglobins with Altered Oxygen Affinity.
    Date August 1986
    Journal Febs Letters
    Excerpt

    The 13CO-NMR spectra of carbonylhemoglobins Saint Mandé (beta 102Asn----Tyr), Malmö (beta 97His----Gln), Hôtel Dieu (beta 99Asp----Gly) and Ao have been determined. The positions of the 13CO resonances for hemoglobins Ao, Malmö and Hôtel Dieu were similar indicating similar ligand environments for all. The 13CO resonance for the beta-subunit of Saint Mandé was upfield-shifted compared to the others. This is evidence that structural changes at the beta 102 position directly affect iron-ligand bonding as well as quaternary structure.

    Title Initial Experience with a New Plethysmograph for Zero-g Use.
    Date June 1986
    Journal The Physiologist
    Title Lysosomal Cystine Storage in Cystinosis and Mucolipidosis Type Ii.
    Date January 1986
    Journal Pediatric Research
    Excerpt

    Cultured fibroblasts from mucolipidosis II (ML-II) patients demonstrated an elevated cystine content which increased with time in culture compared to fibroblasts from cystinotic patients or normal controls under the same conditions. In both cystinotic and ML-II cells the increased levels of cystine could be derived either from endogenous proteolysis or from in vitro supplementation of the cultured cells with cysteine-glutathione mixed disulfide. Cystine was depleted from both cell types by cysteamine. When cysteamine was replaced with complete medium, the cystine reaccumulated in both cystinotic and ML-II cells within 24 h, although a lag of 4 h was seen with ML-II cells. The intracellular location of the increased cystine in cultured fibroblasts was examined utilizing free-flow electrophoresis and found to be in the purified population of secondary lysosomes of both cystinotic and ML-II cells. White blood cell and hepatic cystine, which was greatly increased in cystinotic patients, was not elevated in ML-II patients. Compared to normal control fibroblasts the efflux of cystine from isolated granular fractions was virtually absent in cystinotic fibroblasts and considerably reduced in ML-II fibroblasts. The examination of such similarities and differences in cystine accumulation and transport in tissues from cystinotic and ML-II patients has provided some insight into the defects in these diseases.

    Title Lysosomal Transport of Cystine and Other Small Molecules.
    Date May 1985
    Journal Biochemical Society Transactions
    Title Correlation of Skeletal Uptake of 99mtc-diphosphonate and Alkaline Phosphatase Before and After Oral Diphosphonate Therapy in Paget's Disease.
    Date August 1984
    Journal Metabolic Bone Disease & Related Research
    Excerpt

    In Paget's disease of bone, quantitation of skeletal uptake of radiolabeled diphosphonate has been proposed as a means of monitoring response to therapy. However, the validity of such techniques has been questioned during oral diphosphonate therapy because of possible interaction between oral and radiolabeled diphosphonate. In the present study 18 patients with Paget's disease received a 6 month course of oral diphosphonate therapy. Measurements of 24 h whole body retention (WBR) of 99mTc-labeled hydroxyethylidene diphosphonate (HEDP), serum alkaline phosphatase (SAP), and urinary hydroxyproline excretion were obtained before, during, and after treatment. WBR correlated well with SAP and urinary hydroxyproline throughout the course of therapy. In addition, the relationship between WBR and SAP was maintained after cessation of oral diphosphonate. It would thus appear that in Paget's disease 24 h WBR of HEDP, a quantitative measure of skeletal uptake of diphosphonate, will reflect disease activity even in the presence of an oral diphosphonate load.

    Title Mutant Hemoglobin Stability Depends Upon Location and Nature of Single Point Mutation.
    Date June 1984
    Journal Febs Letters
    Excerpt

    The temperature dependence of the rates of heme release from the beta subunits of methemoglobin A and 5 beta mutant methemoglobins has been determined. The rates were largest for two hemoglobins with mutations distal to heme, previously known to be unstable. The other 3 mutants also released heme faster than A. These hemoglobins, with single point mutations at the alpha 1/beta 2 interface, were previously thought to be stable. The low reported yields of the 5 mutant proteins covaries with the relative rates of heme release from the met species.

    Title Renal Cell Culture Using Autopsy Material from Children with Cystinosis.
    Date April 1984
    Journal In Vitro
    Excerpt

    Renal cell cultures were initiated using fresh autopsy material from two individuals with cystinosis, ages 5 and 8 yr. Cells obtained from collagenase treated autopsy material were grown in a selective kidney medium containing Coon's modified F12, 2.5% fetal bovine serum, transferrin, insulin, selenium, hydrocortisone, PGE1, and fibronectin. These cells had an epithelial appearance, formed domes, and were periodic acid-Schiff positive. Both tight junctions and microvilli were seen by electron microscopy. Fibroblasts had a cloning efficiency of zero in the selective medium and grew poorly compared to their growth in Coon's F12 with 10% fetal bovine serum. The lysosomal cystine content of the renal cells was greatly elevated and comparable to that of fibroblasts from cystinotic patients. Renal cell lysosomal cystine levels were only partially reduced by exposure to either pantethine or the aminothiol, cysteamine. However, exposure to either compound effectively depleted cystinotic cultured fibroblasts of their lysosomal cystine. Study of cultured renal material may have practical significance in pharmacologic considerations.

    Title Proton-translocating Atpase and Lysosomal Cystine Transport.
    Date November 1983
    Journal The Journal of Biological Chemistry
    Excerpt

    A proton-translocating ATPase was identified in highly purified lysosomes from Epstein-Barr virus-transformed human lymphoblasts. Activity of this ATPase caused acidification of highly purified, fluorescein isothiocyanate dextran-loaded lysosomes and correlated with the ATP-dependent efflux of lysosomal cystine. The lysosomal ATPase was distinct from mitochondrial F1-ATPase in its responses to a variety of inhibitors. Although ATP-dependent lysosomal cystine efflux is not demonstrable in cultured lymphoblasts from individuals with nephropathic cystinosis, ATPase activity and acidification in lysosomes from these cells is comparable to that in noncystinotic lysosomes. ATPase activity in lymphoblasts from normal individuals was 543 +/- 79 nmol/mg/min while in lymphoblasts from cystinotic individuals this activity was 541 +/- 25 nmol/mg/min. ATP-dependent acidification of lysosomes from normals was -0.5 +/- 0.1 pH units compared to -0.5 +/- 0.1 pH units in cystinotic lysosomes. Activity of the lysosomal proton-translocating ATPase is a necessary, but not sufficient, condition for lysosomal cystine efflux.

    Title Delayed Vaginal Reconstruction in the Fibrotic Pelvis Following Radiation or Previous Reconstruction.
    Date June 1983
    Journal Obstetrics and Gynecology
    Excerpt

    Vaginal reconstruction was performed in 14 patients who had developed vaginal stenosis secondary to extensive pelvic fibrosis after pelvic radiation therapy (12 patients) or prior vaginal reconstruction (2 patients). Sixteen procedures were performed using a split-thickness skin graft. All patients had satisfactory vaginal restoration, and 12 patients reported good vaginal function. No fistula developed as a result of the operative procedure, but one patient later developed a rectovaginal fistula resulting from tumor recurrence. Successful vaginal reconstruction can be achieved even years after initial therapy in patients who develop an obliterated vagina from previous radiation or surgery.

    Title Atp-dependent Lysosomal Cystine Efflux is Defective in Cystinosis.
    Date January 1983
    Journal The Journal of Biological Chemistry
    Excerpt

    Lysosomes containing large amounts of the amino acid, cystine, were obtained from transformed, cultured, human lymphoblasts which had been exposed to cystine dimethyl ester. Lysosomal cystine efflux was greatly enhanced by exogenous ATP in cell lines from normal individuals. Cystine efflux was unresponsive to ATP in lysosomes from individuals with the disorder, cystinosis. Efflux of cystine from normal cell lysosomes was inhibited by both the ATP analog, 5-adenylylimidodiphosphate, and the proton translocator, carbonyl cyanide m-chlorophenylhydrazone. Efflux was not affected by ouabain or oligomycin. Thus, lysosomal cystine efflux is dependent upon the functioning of a proton-pump ATPase. ATPase-dependent cystine efflux appears to be aberrant in cystinotic cell lysosomes.

    Title Cystine Accumulation and Loss in Normal, Heterozygous, and Cystinotic Fibroblasts.
    Date December 1982
    Journal Proceedings of the National Academy of Sciences of the United States of America
    Excerpt

    Cystinotic fibroblasts contain approximately 100 times more cystine than do normal control fibroblasts. When cystinotic fibroblasts were placed in the presence of 30 mM cysteine-glutathione mixed disulfide (CSSG) for 24 hr, their cystine content increased about 3-fold. Similar treatment of normal fibroblasts and fibroblasts from patients heterozygous for cystinosis resulted in a 6- to 7-fold increase in cystine content. In all three cell types, the intracellular free cystine is located within lysosomes. When placed in cystine-free medium after 24 hr in CSSG-containing medium, the normal and heterozygous fibroblasts rapidly lost their lysosomal cystine (t 1/2 = 20 min), but the cystine content of the cystinotic cells remained stable for over 90 min. In contrast to the findings in intact fibroblasts, cystine loss could not be demonstrated from isolated, cystine-loaded lysosomes from any of the three cell types.

    Title Regulation of Nucleotide and Pentose Synthesis in Resting and Stimulated 3t6 Fibroblasts.
    Date October 1982
    Journal Advances in Enzyme Regulation
    Excerpt

    A two-step procedure has been used to follow the activation of one metabolic system involved in the return of cells to a proliferative state after resting in a Go state as a result of serum limitation. One feature of the resting state is a limited capacity to synthesize nucleotides. The limitation apparently is in the rate of synthesis of 5-phosphoribosylpyrophosphate from glucose and indirectly in the capacity of the resting cells to turn over the triphosphopyridine nucleotide pair, NADPH:NADP+. A reaction utilizing NADPH is apparently greatly diminished in resting cells and is substantially increased by only brief contact of cells with the hormonal elements in dialyzed calf serum. Insulin together with platelet-derived growth factor can substitute for calf serum. Aside from stimulating the turnover of the pyridine nucleotide coenzyme pair, serum also stimulates the utilization and reformation of ATP, principally from AMP. Among the NADPH-linked reactions that have been examined for their physiological significance in the initiation of growth stimulation are two steps in the conversion of glutamate to proline in the cytoplasm. Pyrroline 5-carboxylate, an intermediate in this metabolic pathway, has been shown to stimulate PRPP synthesis when added to cultures of resting 3T6 cells. Proline, the product of the reduction of this 5-membered heterocycle is also a stimulant of PRPP synthesis. In addition, dehydroascorbic acid is a potent stimulant of PRPP synthesis. As a working hypothesis, we are exploring the role of a series of reactions that form a pyrroline 5-carboxylate/proline cycle operating between the cytoplasm and mitochondria. The net result is the oxidation of NADPH by molecular oxygen to yield NADP+ and water. The NADP+ is then used in the hexose monophosphate pathway for the conversion of glucose to PRPP. We wish to determine whether dehydroascorbate is operating in this cycle as an oxidant of proline in the mitochondria or whether it participates in some other reaction in the cell that redistributes the ratio of NADPH to NADP.

    Title Chromosome-bound Mitotic Factors: Release by Endonucleases.
    Date October 1982
    Journal Nucleic Acids Research
    Excerpt

    Additional evidence is presented to support our recently reported conclusion that the mitotic factors of mammalian cells, which induce germinal vesicle breakdown and chromosome condensation when injected into fully grown Xenopus laevis oocytes, are localized on metaphase chromosomes. Chromosomes isolated from mitotic HeLa cells were further purified on sucrose gradients and digested for varying periods with either the micrococcal nuclease or DNase II. At each time point of digestion the amount of mitotic factors released was determined by injecting a supernatant of these fractions, obtained by high-speed centrifugation, into oocytes. The amount of DNA rendered acid soluble under the conditions of digestion used was 3% ot 5% of the total chromosomal DNA. The extent of release of mitotic factors with both nucleases was estimated to be about 30% to 40% as evidenced by the reextraction of the undigested chromosomal pellet with 0.2 M NaC1. Similar results were obtained when nuclei from G2 cells were digested under identical conditions. The release of these chromosome-bound mitotic factors by mild digestion with these nucleases though only partial, clearly demonstrates that a significant proportion of these factors are localized on metaphase chromosomes.

    Title Failure to Produce Blood Pressure Changes Following Pharmacological or Surgical Depletion of Brain Serotonin in the Spontaneously Hypertensive Rat.
    Date December 1981
    Journal Clinical and Experimental Hypertension
    Excerpt

    Spontaneously hypertensive (SH) and normotensive (Wistar-Kyoto, WKY) rats were examined for blood pressure changes following depletion of CNS serotonin (5-HT) by 3 separate techniques: (1) p-chlorophenylalanine, (2) 5,7-dihydroxytryptamine, and (3) a lesion of the dorsal and median raphe nuclei. All of these procedures failed to alter blood pressure in either hypertensive or normotensive rats, despite marked reductions (75-85%) in forebrain 5-HT. Moreover, treatment of 10 day-old hypertensive rat pups with intracisternal injections of 5,7-DHT (10 microgram) failed to alter the development of hypertension despite a 75-80% decrease in spinal cord 5-HT. These findings, which show that 5-HT depletion does not alter blood pressure in the SH or the WKY rat, do not lend support to the idea that 5-HT is involved in the regulation of blood pressure or in the development and maintenance of hypertension in the SH rat.

    Title Seminal Fluid Androgen Binding Protein.
    Date November 1981
    Journal Andrologia
    Excerpt

    The following study was undertaken to determine the presence of an androgen binding protein (ABP) in the ejaculate. Seminal fluid was obtained from ten fertile subjects. Sperm counts ranged from 20 x 106/cc to 80 x 106/cc. Each sample was preincubated with tritiated dihydrotestosterone (DHT) and examined by polyacrylamide gel electrophoresis (PAGE). Second, after preincubation of the samples with tritiated DHT, the samples were mixed with Concanavalin-A bound to sepharose-D (C-S) and the supernate separated and counted. Finally, saturation analysis of the samples using dextran-coated charcoal for separation and counted. Finally, saturation analysis of the samples using dextran-coated charcoal for separation was performed and Scatchard analysis was used to determine the concentration of ABP present. PAGE demonstrated ABP in seven of ten samples studied. The bound counts of DHT were removed by C-S. The concentrations of ABP ranged from 0.132 to 0.468 nanomoles ABP/dl semen. These data indicate there is an ABP in seminal fluid similar to that from the Sertoli cell.

    Title The Effect of Intravenous Therapy During Labour on Maternal and Cord Serum Sodium Levels.
    Date August 1981
    Journal British Journal of Obstetrics and Gynaecology
    Excerpt

    A total of 113 women in labour were studied prospectively to determine the relation between maternal and cord serum sodium levels and the effect of intravenous infusions of glucose solutions and oxytocin during labour on the mother and infant. Maternal and cord sodium levels were correlated, with no systematic difference between the two, which is consistent with passive diffusion of sodium across the placenta. Glucose infusions and oxytocin caused statistically significant depression of maternal and cord serum sodium levels, but with the quantities used this did not adversely affect the mothers or infants. It is recommended that caution should be exercised in prescribing intravenous therapy during labour and, if more than 500 ml of fluid is required, sodium should be included.

    Title Mode of Delivery and Survival in Babies Weighing Less Than 2000 G at Birth.
    Date January 1981
    Journal British Medical Journal
    Excerpt

    A retrospective study of babies weighing less than 2000 g at birth admitted over a four-year period to Nottingham City Hospital Neonatal Unit showed a higher incidence of lower Apgar scores and the need for intubation in babies born by caesarean section and breech deliveries. Mortality in those delivered by the breech (35%) was statistically higher than those by caesarean section (10%) or vertex (14%). It is concluded that small babies born by breech delivery have a higher mortality than when delivered vaginally and should have the benefit of caesarean section.

    Title Dedifferentiation of Endolymphatic Stromal Myosis to Poorly Differentiated Uterine Stromal Sarcoma.
    Date April 1980
    Journal Gynecologic Oncology
    Title Nucleotide and Pentose Synthesis After Serum-stimulation of Resting 3t6 Fibroblasts.
    Date February 1980
    Journal Journal of Cellular Physiology
    Title Tissue Testosterone and Dihydrotestosterone from Bilateral Testis Biopsies in Males with Varicocele.
    Date December 1979
    Journal Fertility and Sterility
    Excerpt

    Nine males with varying degrees of subfertility with left varicocele underwent bilateral testicular biopsy for determination of testicular testosterone (T) and dihydrotestosterone (DHT) content. Testicular tissue T and DHT levels varied greatly, and there was no significant difference when the group T and DHT content of the left testis was compared with that of the right testis. When the respective mean preoperative sperm count was compared with the bilateral tissue T and DHT content, no consistent relationship was found.

    Title Uterine Cervical and Vaginal Verrucous Squamous Cell Carcinoma.
    Date September 1979
    Journal Gynecologic Oncology
    Title In Vivo Rate of Serotonin Synthesis in Brain and Spinal Cord of Young, Spontaneously Hypertensive Rats.
    Date March 1979
    Journal European Journal of Pharmacology
    Excerpt

    The accumulation of 5-hydroxytryptophan (5-HTP) following decarboxylase inhibition was measured in hypothalamus (HYP), pons-medulla (PM) and spinal cord (SC) of 4- and 8-week-old spontaneously hypertensive (SH) and normotensive (WKY) rats. Using this method, a significant increase in the in vivo activity of tryptophan hydroxylase was observed in the PM and SC of 4-week-old, but not 8-week-old SH rats. These findings show a transient elevation in rate of 5-HT synthesis prior to the onset of hypertension, which does not appear to continue during the maintenance phase.

    Title Mortality in Unionized Truck Drivers.
    Date February 1979
    Journal Journal of Occupational Medicine. : Official Publication of the Industrial Medical Association
    Excerpt

    To determine occupational mortality in the Central States Teamster population, all death certificates for a three-month period in 1976 were collected and coded. With the exception of respiratory tract cancer and motor vehicle accident deaths, mortality rates were lower than those found in the U.S. population and comparable to those found in other employed populations. It was not possible to separate the effect of cigarette smoking from environmental exposure to explain the excess respiratory tract cancer death. Unexpectedly, the majority of accident mortalities occurred away from work rather than at work.

    Title Continent Vesicostomy. Application in a Patient.
    Date October 1978
    Journal Obstetrics and Gynecology
    Excerpt

    Continent vesicostomy, as performed in the laboratory animal, allows the severely dysfunctional bladder to be emptied at predetermined intervals by transabdominal catheterization. The formation of a continent vesicostomy in a patient with markedly impaired bladder function secondary to an extended pelvic operation for the treatment of cancer is described. This technique provides a possible alternative to the construction of a urinary conduit in patients disabled from the treatment of a pelvic malignancy.

    Title Analysis of the Effect of Dilution on the Necrotic Tissue Dissolution Property of Sodium Hypochlorite.
    Date October 1978
    Journal Journal of Endodontics
    Title Modification of Erythrocyte Abnormalities in Hodgkin's Disease After Chemotherapy.
    Date May 1978
    Journal Lancet
    Title Enteroperineal Fistulae Following Pelvic Exenteration: a 10-point Program of Management.
    Date February 1977
    Journal Gynecologic Oncology
    Title Visual Resolution in Young Kittens.
    Date September 1976
    Journal Vision Research
    Title Vaginal Reconstruction Following Extensive Treatment for Pelvic Cancer.
    Date September 1976
    Journal American Journal of Obstetrics and Gynecology
    Excerpt

    Since 1970, 23 patients at UCLA and The City of Hope who have undergone extensive treatment for pelvic malignancy have had vaginal function successfully restored. A combination of methods, including split-thickness skin graft and the construction of an external vulvar pouch, is often necessary to obtain maximal functional results. The external vulvar pouch was very useful, although not as anatomically appealing as internal methods of reconstruction. In young patients who required an exenteration, a new technique using part of the anterior bladder fundus was developed. Preliminary experience with this method was promising. Among the gorup of 23 patients, there have been no overt failures. By combining restoration of rectal function with vaginal reconstruction, two major steps have been taken toward total rehabilitation of the patient undergoing extensive treatment for pelvic malignancy. Persistence, ingenuity, and planning by the surgeon are essential to obtain a maximum functional result for each patient.

    Title Radioprotection of the Digestive Tract by Intravenous Infusion of Vasopressin.
    Date February 1976
    Journal Gynecologic Oncology
    Title Combination Adriamycin and Radiation Therapy in Gynecologic Cancers.
    Date September 1975
    Journal Gynecologic Oncology
    Excerpt

    Anthracyclic antibiotics, of which Adriamycin is representative, have the ability to bind to cellular DNA and thereby interfere with the X-ray repair process. When radiation survival curves of tissue cultures were studied, increased cell-killing was noted in those cultures with Adriamycin over those without the drug. The mechanism by which this occurs may be related to a reduced rate of DNA strand break rejoining, as demonstrated by use of alkaline sucrose gradient techniques. A preliminary clinical Phase I study, in which patients with advanced gynecologic malignancy were treated by simultaneous Adriamycin and X radiation, suggests that combined therapy is well-tolerated, and that such combinations may prove useful in selected patients.

    Title The Effect of Radiation Therapy on Pelvic Lymph Node Involvement in Stage I Carcinoma of the Cervix.
    Date July 1974
    Journal American Journal of Obstetrics and Gynecology
    Title Use of Sigmoid Colon for Rectal Substitution Following Pelvic Exenteration.
    Date June 1973
    Journal American Journal of Obstetrics and Gynecology
    Title Standards for Prosthetic Devices Containing Radionuclide Power Sources.
    Date April 1972
    Journal Medical Research Engineering
    Title Corrigendum to "screening Postmortem Blood and Tissues for Nine Classes of Drugs of Abuse Using Automated Microplate Immunoassay"
    Date
    Journal Forensic Science International
    Title Net Primary Productivity of Forest Stands in New Hampshire Estimated from Landsat and Modis Satellite Data.
    Date
    Journal Carbon Balance and Management
    Excerpt

    ABSTRACT:

    Title Heart Rate Variability Measures During Sinus Rhythm Predict Cycle Length Entropy During Atrial Fibrillation.
    Date
    Journal Journal of Cardiovascular Electrophysiology
    Excerpt

    INTRODUCTION: Several noninvasive measures of cardiac risk such as heart rate variability (HRV) cannot be used in patients with atrial fibrillation (AF). One promising exception is the measure of ventricular cycle length entropy (VCLE) where initial data suggest that a reduction in VCLE portends an increased risk of cardiac death in patients with chronic AF. In this study, we hypothesized that measures of short-term HRV during sinus rhythm would correlate with measures of cycle length entropy during paroxysms of AF. METHODS: We tested 25 Holter recordings of paroxysmal AF from the Physionet AF Prediction Database. We calculated HRV parameters including standard deviation of all NN intervals (SDNN), the root mean square root of the differences between adjacent NN intervals (RMSSD), standard deviation of 5-minute averages of NN intervals (SDANN), percentage of adjacent NN interval differences >50 ms (pNN50), and interbeat correlation coefficient (ICC) from 30 minutes of normal sinus rhythm, and entropy measures (the Shannon Informational Entropy [ShEn] and Average of Approximate Entropy [ApEn]) from 5 minutes of AF that occurred during the same 24-hour monitor. Pairwise correlations were used to assess associations, as regression residuals were normally distributed. RESULTS: The mean entropy measures during AF were: ShEn: 4.78 +/- 0.82, ApEn: 0.198 +/- 0.21. When assessed during the 30 minutes immediately preceding AF onset, ICC showed a significant negative correlation with both ShEn (r =-0.65, P < 0.001) and ApEn (r =-0.60, P < 0.01). RMSSD also correlated with both ShEn (r = 0.41, P = 0.04) and ApEn (r = 0.39, P = 0.05), but other HRV measures showed no correlation with VCLE during AF. CONCLUSION: Reductions in RMSSD or increases in ICC, two short-term HRV measures that are known to reflect parasympathetic function in sinus rhythm, are correlated with reductions in the entropy of ventricular response intervals during AF. Our findings suggest that entropy during AF may be modulated, in part, by vagal innervation.

    Title Nccn Task Force Report: Breast Cancer in the Older Woman.
    Date
    Journal Journal of the National Comprehensive Cancer Network : Jnccn
    Excerpt

    Breast cancer is common in older women, and the segment of the U.S. population aged 65 years and older is growing rapidly. Consequently, awareness is increasing of the need to identify breast cancer treatment recommendations to assure optimal, individualized treatment of older women with breast cancer. However, the development of these recommendations is limited by the heterogeneous nature of this population with respect to functional status, social support, life expectancy, and the presence of comorbidities, and by the underrepresentation of older patients with breast cancer in randomized clinical trials. The NCCN Breast Cancer in the Older Woman Task Force was convened to provide a forum for framing relevant questions on topics that impact older women with early-stage, locally advanced, and metastatic breast cancer. The task force is a multidisciplinary panel of 18 experts in breast cancer representing medical oncology, radiation oncology, surgical oncology, geriatric oncology, geriatrics, plastic surgery, and patient advocacy. All task force members were from NCCN institutions and were identified and invited solely by NCCN. Members were charged with identifying evidence relevant to their specific expertise. During a 2-day meeting, individual members provided didactic presentations; these presentations were followed by extensive discussions during which areas of consensus and controversy were identified on topics such as defining the "older" breast cancer patient; geriatric assessment tools in the oncology setting; attitudes of older patients with breast cancer and their physicians; tumor biology in older versus younger women with breast cancer; implementation of specific interventions in older patients with breast cancer, such as curative surgery, surgical axillary staging, radiation therapy, reconstructive surgery, endocrine therapy, chemotherapy, HER2-directed therapy, and supportive therapies; and areas requiring future studies.

    Title Loss of Nadph Quinone Oxidoreductase in the Prostate and Enhanced Serum Levels of Cytokine-induced Neutrophil Chemoattractant 2alpha in Hormone-stimulated Noble Rats: Potential Role in Prostatic Intraepithelial Neoplasia Development.
    Date
    Journal Translational Oncology
    Excerpt

    The Noble rat is an established model for studying hormone-induced development of prostatic intraepithelial neoplasia and prostatic adenocarcinoma. It is known that for a period, hormones in the prostate generate reactive molecules that have the capacity to overwhelm intracellular defenses, damage macromolecules, and modulate redox-regulated signaling pathways leading to increased oxidative stress. Such hormone-induced imbalance in the oxidative stress/antioxidant defense enzymes may lead to neoplastic transformation of the prostate. We investigated alteration in the expression of critical antioxidant defense enzymes, a redox-regulated transcription factor nuclear factor kappaB (NFkappaB) and its downstream target inflammation-associated cyclooxygenase 2 (Cox-2) in the prostate from hormone-stimulated Noble rats using immunohistochemistry. Further, we also analyzed serum levels of cytokines and chemokines associated with inflammation using multiplex immunoassay. Our results show that there was no significant change in the expression of glutathione peroxidase, glutathione S-transferase pi, superoxide dismutase, or catalase. However, the level of NADPH quinone oxidoreductase decreased in hormone-stimulated animals compared with their unstimulated counterparts. Further, the prostate from hormone-stimulated rats showed very strong expressions of p65, Cox-2, and NFkappaB DNA binding activity. In addition, the cytokine-induced neutrophil chemoattractant 2alpha was significantly upregulated by more than 10-fold (P = .001) in serum from animals stimulated with hormones. Although further studies are required, we speculate that activation of NFkappaB/cytokine-induced neutrophil chemoattractant 2alpha/Cox-2 along with modulation of antioxidant defense mechanisms may create a proinflammatory environment suitable for tumor growth and survival.

    Title Seleno-l-methionine Modulation of Nucleotide Excision Dna Repair Relevant to Cancer Prevention and Chemotherapy.
    Date
    Journal Molecular and Cellular Pharmacology
    Excerpt

    Organic selenium compounds are known to prevent certain cancers although mechanisms may be complex. A widely-held view is that selenium compounds can induce apoptosis in cancer cells, or more precisely, in aberrant cells that are undergoing clonal evolution somewhere along the carcinogenesis process. There are at least 20 different selenium compounds, inorganic as well as organic, that have been used in various published studies. Extrapolation between studies should therefore be undertaken with caution. Similarly, it will be important to ascertain the physiological relevance of the selenium concentrations used in some studies. While cancer prevention by selenium is well-established, recently, organic selenium in the form of pure seleno-L-methionine (SeMet) has been used in combination with cancer chemotherapy drugs. SeMet can induce a DNA repair response in some cell types including bone marrow. Cancer cells generally lack a SeMet-inducible DNA repair response. Thus, SeMet appears to selectively regulate a DNA repair pathway and thereby potentially alter responses to cancer chemotherapy drugs. The specific pathway implicated, nucleotide excision DNA repair (NER) is required for repair of cisplatin or carboplatin DNA damage relevant to chemotherapy. Moreover, some studies have implicated NER as a factor in carcinogenesis processes. Thus, the capacity of SeMet to selectively regulate NER may prove useful in both therapeutic and preventive contexts.

    Title The "two Faces" of Tumor Suppressor P53-revisited.
    Date
    Journal Molecular and Cellular Pharmacology
    Excerpt

    About 15 years ago, several groups including ours had used matched pairs of cell lines carrying wild type or mutant p53 genes to ascertain a role for p53 in cell survival. These were isogenic cell lines differing only by p53 status. The trend at that time was to support p53-mediated apoptosis. Accordingly, p53-wildtype cells were sensitive to DNA damage compared to p53-mutant cells which were thought to evade apoptosis. However, this finding was not universal. In particular, after UV-radiation, p53-mutant cells were more sensitive than their wild type p53 counterparts in several studies. The finding that p53 controlled a major DNA repair pathway, nucleotide excision repair (NER) which repairs UV-damage, provided a mechanism for the observations. We coined the term "the two faces of tumor suppressor p53" to illustrate that p53 can on one hand induce apoptosis leading to cell sensitivity, but p53 can also enhance the rate of DNA repair thereby protecting cells from DNA damage. This concept has gained acceptance and has been expanded to other DNA-damaging agents. New insights into how p53 is "switched" from a protective function to an apoptotic function are reviewed.

    Title Cancer Genomics: Conducting Exemplary Trials with Biospecimen and Biomarker Components.
    Date
    Journal Journal of Oncology Practice / American Society of Clinical Oncology
    Excerpt

    Translating research on genomic changes into novel interventions for patients with cancer requires increased analysis of biospecimens and biomarkers in cancer clinical trials, which involve certain procedural requirements.

    Title The Threshold of Insulin-induced Hypophagia is Lower in Chicks Selected for Low Rather Than High Juvenile Body Weight.
    Date
    Journal Behavioural Brain Research
    Excerpt

    Chicks genetically selected for low juvenile body weight had a lower threshold of central insulin-induced decreased food and water intake and whole blood glucose concentration than those selected for juvenile high body weight. Plasma corticosterone concentration was increased but not differently between lines. Therefore, selection may have affected insulin sensitivity which may have then contributed to their hypo- and hyperphagia and differential body weights.

    Title Associations Between Health Care Factors and Self-reported Health Status Among Individuals with Diabetes: Results from a Community Assessment.
    Date
    Journal Journal of Community Health
    Excerpt

    To identify the influence of select health care variables on self-reported physical and mental health status of individuals with diabetes. Data from the 2006 Brazos Valley Health Status Assessment (BVHSA) were analyzed. Aspects of health care were defined through exploratory factor analysis. Structural equation modeling was used to create relationships between health care aspects, personal characteristics of the participants, and self-reported physical and mental health status of individuals with diabetes. The significant predictors of self-reported physical health status were the number of co-morbid chronic diseases (β = 0.27, P = .002), and medical system access (β = -0.20, P = .035). The significant predictor of self-reported mental health status was the number of co-morbid chronic diseases (β = 0.35, P < .001). Self-reported physical (β = 0.27, P = .028) and mental (β = 0.29, P = .020) health status were both predictive of physician communication of mental health issues. Communication about mental health issues strongly relates to both self-reported physical and mental health status and should be an important part of physicians' care for individuals with diabetes. Further, the nuances of medical system access for diabetes care should be further examined.

    Title Variations in Body Mass Index Among Older Americans: the Roles of Social and Lifestyle Factors.
    Date
    Journal Journal of Aging and Health
    Excerpt

    To investigate the correlates of body mass index (BMI) among a national sample of older adults in the United States.

    Title Identification of the J and K Genes in the Bacteriophage Mu Genome Sequence.
    Date
    Journal Fems Microbiology Letters
    Excerpt

    Bacteriophage Mu was the first transposable phage to be discovered and still serves as the model for a large family of related transposable phages and prophages. The Mu genome sequence is known (NC-000929.1 GI:9633494), but not all of the genes have been assigned to the ORFs in the genome sequence. For this paper, we have sequenced an approximately 3-kb DNA region containing four predicted ORFs, Mup35-Mup38, from lysogens containing amber mutant prophages defective in either the J or the K gene. Amber mutations in prophages with J gene mutations mapped to the Mup36 ORF, and those in the K gene were found in Mup37, identifying the ORFs corresponding to these genes.

    Title Implementing and Disseminating an Evidence-based Program to Prevent Falls in Older Adults, Texas, 2007-2009.
    Date
    Journal Preventing Chronic Disease
    Excerpt

    Falls are a public health problem for the growing population of older adults. We describe a statewide effort to implement and disseminate A Matter of Balance/Volunteer Lay Leader model, an evidence-based fall-prevention program.

    Title The Evolutionary Origins of Ritualized Acoustic Signals in Caterpillars.
    Date
    Journal Nature Communications
    Excerpt

    Animal communication signals can be highly elaborate, and researchers have long sought explanations for their evolutionary origins. For example, how did signals such as the tail-fan display of a peacock, a firefly flash or a wolf howl evolve? Animal communication theory holds that many signals evolved from non-signalling behaviours through the process of ritualization. Empirical evidence for ritualization is limited, as it is necessary to examine living relatives with varying degrees of signal evolution within a phylogenetic framework. We examine the origins of vibratory territorial signals in caterpillars using comparative and molecular phylogenetic methods. We show that a highly ritualized vibratory signal-anal scraping-originated from a locomotory behaviour-walking. Furthermore, comparative behavioural analysis supports the hypothesis that ritualized vibratory signals derive from physical fighting behaviours. Thus, contestants signal their opponents to avoid the cost of fighting. Our study provides experimental evidence for the origins of a complex communication signal, through the process of ritualization.

    Title Beaddatapackr: A Tool to Facilitate the Sharing of Raw Data from Illumina Beadarray Studies.
    Date
    Journal Cancer Informatics
    Excerpt

    Microarray technologies have been an increasingly important tool in cancer research in the last decade, and a number of initiatives have sought to stress the importance of the provision and sharing of raw microarray data. Illumina BeadArrays provide a particular problem in this regard, as their random construction simultaneously adds value to analysis of the raw data and obstructs the sharing of those data.We present a compression scheme for raw Illumina BeadArray data, designed to ease the burdens of sharing and storing such data, that is implemented in the BeadDataPackR BioConductor package (http://bioconductor.org/packages/release/bioc/html/BeadDataPackR.html). It offers two key advantages over off-the-peg compression tools. First it uses knowledge of the data formats to achieve greater compression than other approaches, and second it does not need to be decompressed for analysis, but rather the values held within can be directly accessed.

    Title Issues Surrounding Biospecimen Collection and Use in Clinical Trials.
    Date
    Journal Journal of Oncology Practice / American Society of Clinical Oncology
    Excerpt

    As the need for patient participation in biospecimen and correlative research increases, challenging ethical and potentially legal questions are emerging.

    Title A Novel Series of Ikkβ Inhibitors Part Ii: Description of a Potent and Pharmacologically Active Series of Analogs.
    Date
    Journal Bioorganic & Medicinal Chemistry Letters
    Excerpt

    A novel series of (E)-1-((2-(1-methyl-1H-imidazol-5-yl) quinolin-4-yl) methylene) thiosemicarbazides was discovered as potent inhibitors of IKKβ. In this Letter we document our efforts at further optimization of this series, culminating in 2 with submicromolar potency in a HWB assay and efficacy in a CIA mouse model.

    Title A Novel Series of Ikkβ Inhibitors Part I: Initial Sar Studies of a Hts Hit.
    Date
    Journal Bioorganic & Medicinal Chemistry Letters
    Excerpt

    A novel series of (E)-1-((2-(1-methyl-1H-imidazol-5-yl) quinolin-4-yl) methylene) thiosemicarbazides was discovered as potent inhibitors of IKKβ. In this Letter we document our early efforts at optimization of the quinoline core, the imidazole and the semithiocarbazone moiety. Most potency gains came from substitution around the 6- and 7-positions of the quinoline ring. Replacement of the semithiocarbazone with a semicarbazone decreased potency but led to some measurable exposure.

    Title Independent Prognostic Variables in Acute Myeloid Leukaemia.
    Date
    Journal Blood Reviews
    Excerpt

    Acute myeloid leukaemia (AML) is one of the most common haematological malignancies and is increasing in frequency due to an ageing population. Whilst remission will be achieved in up to 80% of those receiving intensive chemotherapy, the main variables precluding cure are the treatment-related mortality and relapse rates. Decisions on intensification, de-escalation and allografting rely on the ability to divide an apparently homogeneous group according to risk. A wide range of clinical, cytogenetic and molecular variables may be used to inform this task. Cytogenetic and molecular characterisation has already identified subgroups, such as acute promyelocytic leukaemia (APL) with t(15;17)/PML-RARA and AML with FLT3 mutation for which targeted therapies are available, and further molecularly defined groups who may be potential candidates for this approach are likely to be identified in the future. This review examines the range of established clinical and diagnostic parameters that should be used in assessing prognosis for a patient with AML and looks ahead to an expanding repertoire of potential variables that are currently under evaluation.

    Title Characterization of Human Antigenic Proteins Schs21 and Schs34 from Stachybotrys Chartarum.
    Date
    Journal International Archives of Allergy and Immunology
    Excerpt

    Background:SchS21 and SchS34 are proteins from Stachybotrys chartarum sensu latto that are antigenic in goats, mice and humans. Monoclonal antibodies to these proteins react with spores of S. chartarum and S. chlorohalonata but do not cross-react with a diverse taxonomic and ecological array of other fungi. Methods: Based on partial sequences of the 21- and 34-kDa proteins, obtained from tandem mass spectra and Edman degradation, degenerate primers were designed for touchdown PCR and the resulting amplicons were sequenced. Subsequently, inverse-PCR was used to obtain genomic DNA sequences encoding SchS21 and SchS34. RT-PCR products were sequenced to predict the mature protein sequences of SchS21 and SchS34. Based on the speculation that SchS21 protein was a DNase, the enzymatic properties were investigated. Results: Sequences of 435 and 666 bp in length were obtained from SchS21 and SchS34 cDNAs. The SchS21 open reading frame encodes a mature protein of 144 amino acids, while that of SchS34 is 221 amino acids in length. SchS21 is a secretory, alkaline, Mg-dependent exodeoxyribonuclease, while SchS34 is a secretory protein of unknown function. His-tagged forms of the mature SchS21 and SchS34 proteins were separately overexpressed in Escherichia coli and purified using Ni-NTA columns (0.5 mg/l yield). Conclusions: Based on Western blots, the expressed proteins were similar in molecular weight and bound to the respective monoclonal antibodies to SchS21 and SchS34 proteins from S. chartarum. Interactions with human sera IgE confirmed the expressed forms of SchS21 and SchS34 as naturally occurring allergens.

    Title Stretching Fibronectin Fibres Disrupts Binding of Bacterial Adhesins by Physically Destroying an Epitope.
    Date
    Journal Nature Communications
    Excerpt

    Although soluble inhibitors are frequently used to block cell binding to the extracellular matrix (ECM), mechanical stretching of a protein fibre alone can physically destroy a cell-binding site. Here, we show using binding assays and steered molecular dynamics that mechanical tension along fibronectin (Fn) fibres causes a structural mismatch between Fn-binding proteins from Streptococcus dysgalactiae and Staphylococcus aureus. Both adhesins target a multimodular site on Fn that is switched to low affinity by stretching the intermodular distances on Fn. Heparin reduces binding but does not eliminate mechanosensitivity. These adhesins might thus preferentially bind to sites at which ECM fibres are cleaved, such as wounds or inflamed tissues. The mechanical switch described here operates differently from the catch bond mechanism that Escherichia coli uses to adhere to surfaces under fluid flow. Demonstrating the existence of a mechanosensitive cell-binding site provides a new perspective on how the mechanobiology of ECM might regulate bacterial and cell-binding events, virulence and the course of infection.

    Title Tissue/fluid Correlation Study for the Depletion of Sulfadimethoxine in Bovine Kidney, Liver, Plasma, Urine, and Oral Fluid.
    Date
    Journal Journal of Veterinary Pharmacology and Therapeutics
    Excerpt

    Chiesa, O. A., Li, H., Kijak, P. J., Li, J. X., Lancaster, V., Smith, M. L., Heller, D. N., Thomas, M. H., von Bredow, J. Tissue/fluid correlation study for the depletion of sulfadimethoxine in bovine kidney, liver, plasma, urine, and oral fluid. J. vet. Pharmacol. Therap. 35, 249-258. Sulfonamides are among the oldest, but still effective, antimicrobial veterinary medicines. In steers and dairy cows, the sulfonamides are effective in the treatment of respiratory disease and general infections. Sulfadimethoxine (SDM) has been approved by US Food and Drug Administration (FDA) for use in steers and dairy cows with a tolerance of 100 ng/g (ppb) in edible tissues and 10 ppb in milk. The detection of SDM residue above tolerance in the animal slaughtered for food process will result in the whole carcass being discarded. This report describes a comprehensive depletion study of SDM (and its main metabolite) in plasma, urine, oral fluid, kidney, and liver. In this study, nine steers were injected intravenously with the approved dose of SDM; the loading dose was 55 mg/kg, followed by 27.5 mg/kg dose at 24 h and again at 48 h. Fluids (blood, urine, and saliva) and tissue (liver and kidney) samples were collected at intervals after the last dose of SMD. The combination of laparoscopic serial sampling technique with the liquid chromatography/mass spectrometry method provided the data to establish the tissue/fluid correlation in the depletion of SMD. A strong correlation and linearity of the log-scale concentration over time in the depletion stage has been confirmed for kidney, liver, and plasma.

    Title Rapid Processing of Emotional Expressions Without Conscious Awareness.
    Date
    Journal Cerebral Cortex (new York, N.y. : 1991)
    Excerpt

    Rapid accurate categorization of the emotional state of our peers is of critical importance and as such many have proposed that facial expressions of emotion can be processed without conscious awareness. Typically, studies focus selectively on fearful expressions due to their evolutionary significance, leaving the subliminal processing of other facial expressions largely unexplored. Here, I investigated the time course of processing of 3 facial expressions (fearful, disgusted, and happy) plus an emotionally neutral face, during objectively unaware and aware perception. Participants completed the challenging "which expression?" task in response to briefly presented backward-masked expressive faces. Although participant's behavioral responses did not differentiate between the emotional content of the stimuli in the unaware condition, activity over frontal and occipitotemporal (OT) brain regions indicated an emotional modulation of the neuronal response. Over frontal regions this was driven by negative facial expressions and was present on all emotional trials independent of later categorization. Whereas the N170 component, recorded on lateral OT electrodes, was enhanced for all facial expressions but only on trials that would later be categorized as emotional. The results indicate that emotional faces, not only fearful, are processed without conscious awareness at an early stage and highlight the critical importance of considering categorization response when studying subliminal perception.

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