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Credentials

Education ?

Medical School Score
Midwestern University (2002) *
  •  
Residency
Philadelphia College of Osteopathic Medicine (2007) *
Orthopaedic Surgery
Fellowship
Pennsylvania Hospital University PA Health System (2008) *
Adult Reconstructive Orthopaedic Surgery
* This information was reported to Vitals by the doctor or doctor's office.

Awards & Distinctions ?

Awards  
Patients' Choice Award (2012 - 2014)
Compassionate Doctor Recognition (2012 - 2014)
Top 10 Doctor - City (2014)
Warren, MI
Family Practitioner
Appointments
Michigan State University College of Osteopathic Medicine (2010 - Present)
Clinical Assistant Professor - Orthopedic Surgery
Associations
American Osteopathic Association
American Osteopathic Academy of Orthopedics
American Association of Hip and Knee Surgeons

Affiliations ?

Dr. Hill is affiliated with 4 hospitals.

Hospital Affiliations

Score

Rankings

  • St. John Macomb-Oakland Hospital (Oakland Center)
    Orthopaedic Surgery
    27351 Dequindre Rd, Madison Heights, MI 48071
    •  
    Top 50%
  • St. John Macomb-Oakland Hospital (Macomb Center)
    Orthopaedic Surgery
    11800 E 12 Mile Rd, Warren, MI 48093
    •  
  • Henry Ford Macomb Hospitals *
    Orthopaedic Surgery
    15855 19 Mile Rd, Clinton Township, MI 48038
    •  
  • Oakland Regional Hospital
    22401 Foster Winter Dr, Southfield, MI 48075
  • Publications & Research

    Dr. Hill has contributed to 109 publications.
    Title Staying Connected: Native American Women Faculty Members on Experiencing Success.
    Date May 2010
    Journal Academic Medicine : Journal of the Association of American Medical Colleges
    Excerpt

    To document how medical school faculty who are Native American women describe their sense of personal and professional success, so that mentoring can be better informed and diversity increased.

    Title Continuous Infusion of 17-hydroxyprogesterone Caproate into Either the Fetoplacental or Intervillous Circulation of a Placental Cotyledon Attenuates Vasoconstriction of the Fetoplacental Arteries by Thromboxane Mimetic U46619.
    Date February 2010
    Journal American Journal of Obstetrics and Gynecology
    Excerpt

    The objective of the study was to determine whether pretreatment of fetal or maternal placental vasculature with 17-hydroxyprogesterone caproate (17-P) attenuates the vasoactive effect of the thromboxane mimetic U46619.

    Title Comparison of Phantom and Registration Scaling Corrections Using the Adni Cohort.
    Date October 2009
    Journal Neuroimage
    Excerpt

    Rates of brain atrophy derived from serial magnetic resonance (MR) studies may be used to assess therapies for Alzheimer's disease (AD). These measures may be confounded by changes in scanner voxel sizes. For this reason, the Alzheimer's Disease Neuroimaging Initiative (ADNI) included the imaging of a geometric phantom with every scan. This study compares voxel scaling correction using a phantom with correction using a 9 degrees of freedom (9DOF) registration algorithm. We took 129 pairs of baseline and 1-year repeat scans, and calculated the volume scaling correction, previously measured using the phantom. We used the registration algorithm to quantify any residual scaling errors, and found the algorithm to be unbiased, with no significant (p=0.97) difference between control (n=79) and AD subjects (n=50), but with a mean (SD) absolute volume change of 0.20 (0.20) % due to linear scalings. 9DOF registration was shown to be comparable to geometric phantom correction in terms of the effect on atrophy measurement and unbiased with respect to disease status. These results suggest that the additional expense and logistic effort of scanning a phantom with every patient scan can be avoided by registration-based scaling correction. Furthermore, based upon the atrophy rates in the AD subjects in this study, sample size requirements would be approximately 10-12% lower with (either) correction for voxel scaling than if no correction was used.

    Title Chemoreception Scientists Gather Under the Florida Sun: The 31st Annual Association for Chemoreception Sciences Meeting.
    Date October 2009
    Journal Annals of the New York Academy of Sciences
    Excerpt

    The 31st Annual Association for Chemoreception Sciences (AChemS) met in Sarasota, Florida April 22-26, 2009, attracting approximately 600 registrants and nearly 400 abstracts. In addition to poster and platform presentations, the program offered symposia, special lectures, and various National Institutes of Health (NIH)-sponsored workshops, including one on computational approaches to olfaction.

    Title Longitudinal Regional Brain Volume Changes Quantified in Normal Aging and Alzheimer's App X Ps1 Mice Using Mri.
    Date July 2009
    Journal Brain Research
    Excerpt

    In humans, mutations of amyloid precursor protein (APP) and presenilins (PS) 1 and 2 are associated with amyloid deposition, brain structural change and cognitive decline, like in Alzheimer's disease (AD). Mice expressing these proteins have illuminated neurodegenerative disease processes but, unlike in humans, quantitative imaging has been little used to systematically determine their effects, or those of normal aging, on brain structure in vivo. Accordingly, we investigated wildtype (WT) and TASTPM mice (expressing human APP(695(K595N, M596L)) x PS1(M146V)) longitudinally using MRI. Automated global and local image registration, allied to a standard digital atlas, provided pairwise segmentation of 13 brain regions. We found the mature mouse brain, unlike in humans, enlarges significantly from 6-14 months old (WT 3.8+/-1.7%, mean+/-SD, P<0.0001). Significant changes were also seen in other WT brain regions, providing an anatomical benchmark for comparing other mouse strains and models of brain disorder. In TASTPM, progressive amyloidosis and astrogliosis, detected immunohistochemically, reflected even larger whole brain changes (5.1+/-1.4%, P<0.0001, transgenexage interaction P=0.0311). Normalising regional volumes to whole brain measurements revealed significant, prolonged, WT-TASTPM volume differences, suggesting transgene effects establish at <6 months old of age in most regions. As in humans, gray matter-rich regions decline with age (e.g. thalamus, cerebral cortex and caudoputamen); ventricles and white matter (corpus callosum, corticospinal tract, fornix system) increase; in TASTPMs such trends often varied significantly from WT (especially hippocampus). The pervasive, age-related structural changes between WT and AD transgenic mice (and mouse and human) suggest subtle but fundamental species differences and AD transgene effects.

    Title The Effects of Dietary Protein Restriction on Chorda Tympani Nerve Taste Responses and Terminal Field Organization.
    Date April 2009
    Journal Neuroscience
    Excerpt

    Prenatal dietary sodium restriction produces profound developmental effects on rat functional taste responses and formation of neural circuits in the brainstem. Converging evidence indicates that the underlying mechanisms for these effects are related to a compromised nutritional state and not to direct stimulus-receptor interactions. We explored whether early malnourishment produces similar functional and structural effects to those seen following dietary sodium restriction by using a protein deficient, sodium replete diet. To determine if early dietary protein-restriction affects the development of the peripheral gustatory system, multi-fiber neurophysiological recordings were made from the chorda tympani nerve and anterograde track tracing of the chorda tympani nerve into the nucleus of the solitary tract (NTS) was accomplished in rats fed a protein-restricted or a control diet (6% and 20%, respectively). The dietary regimens began on embryonic day 7 and continued until rats were used for neurophysiological recordings (postnatal days (P) 35-50) or for chorda tympani terminal field labeling (P40-50). Responses to a concentration series of NaCl, sodium acetate, KCl, and to 0.50 M sucrose, 0.03 M quinine-HCl, and 0.01 N HCl revealed attenuated responses (30-60%) to sodium-specific stimuli in rats fed the 6% protein diet compared with those fed the 20% protein diet. Responses to all other stimuli were similar between groups. Terminal field volumes were nearly twofold larger in protein-restricted rats compared with controls, with the differences located primarily in the dorsal-caudal zone of the terminal field. These results are similar to the results seen previously in rats fed a sodium-restricted diet throughout pre- and postnatal development, suggesting that dietary sodium- and protein-restriction share similar mechanisms in altering gustatory development.

    Title A Patient with Headache and Increased Intracranial Pressure.
    Date September 2008
    Journal Reviews in Neurological Diseases
    Excerpt

    These 2 cases presented with acutely raised intracranial pressure and had characteristic CT and MRI changes.

    Title A Patient with Headache and Increased Intracranial Pressure.
    Date September 2008
    Journal Reviews in Neurological Diseases
    Title The Alzheimer's Disease Neuroimaging Initiative (adni): Mri Methods.
    Date August 2008
    Journal Journal of Magnetic Resonance Imaging : Jmri
    Excerpt

    The Alzheimer's Disease Neuroimaging Initiative (ADNI) is a longitudinal multisite observational study of healthy elders, mild cognitive impairment (MCI), and Alzheimer's disease. Magnetic resonance imaging (MRI), (18F)-fluorodeoxyglucose positron emission tomography (FDG PET), urine serum, and cerebrospinal fluid (CSF) biomarkers, as well as clinical/psychometric assessments are acquired at multiple time points. All data will be cross-linked and made available to the general scientific community. The purpose of this report is to describe the MRI methods employed in ADNI. The ADNI MRI core established specifications that guided protocol development. A major effort was devoted to evaluating 3D T(1)-weighted sequences for morphometric analyses. Several options for this sequence were optimized for the relevant manufacturer platforms and then compared in a reduced-scale clinical trial. The protocol selected for the ADNI study includes: back-to-back 3D magnetization prepared rapid gradient echo (MP-RAGE) scans; B(1)-calibration scans when applicable; and an axial proton density-T(2) dual contrast (i.e., echo) fast spin echo/turbo spin echo (FSE/TSE) for pathology detection. ADNI MRI methods seek to maximize scientific utility while minimizing the burden placed on participants. The approach taken in ADNI to standardization across sites and platforms of the MRI protocol, postacquisition corrections, and phantom-based monitoring of all scanners could be used as a model for other multisite trials.

    Title Intensity Non-uniformity Correction Using N3 on 3-t Scanners with Multichannel Phased Array Coils.
    Date May 2008
    Journal Neuroimage
    Excerpt

    Measures of structural brain change based on longitudinal MR imaging are increasingly important but can be degraded by intensity non-uniformity. This non-uniformity can be more pronounced at higher field strengths, or when using multichannel receiver coils. We assessed the ability of the non-parametric non-uniform intensity normalization (N3) technique to correct non-uniformity in 72 volumetric brain MR scans from the preparatory phase of the Alzheimer's Disease Neuroimaging Initiative (ADNI). Normal elderly subjects (n=18) were scanned on different 3-T scanners with a multichannel phased array receiver coil at baseline, using magnetization prepared rapid gradient echo (MP-RAGE) and spoiled gradient echo (SPGR) pulse sequences, and again 2 weeks later. When applying N3, we used five brain masks of varying accuracy and four spline smoothing distances (d=50, 100, 150 and 200 mm) to ascertain which combination of parameters optimally reduces the non-uniformity. We used the normalized white matter intensity variance (standard deviation/mean) to ascertain quantitatively the correction for a single scan; we used the variance of the normalized difference image to assess quantitatively the consistency of the correction over time from registered scan pairs. Our results showed statistically significant (p<0.01) improvement in uniformity for individual scans and reduction in the normalized difference image variance when using masks that identified distinct brain tissue classes, and when using smaller spline smoothing distances (e.g., 50-100 mm) for both MP-RAGE and SPGR pulse sequences. These optimized settings may assist future large-scale studies where 3-T scanners and phased array receiver coils are used, such as ADNI, so that intensity non-uniformity does not influence the power of MR imaging to detect disease progression and the factors that influence it.

    Title Whole-heart Cine Mri Using Real-time Respiratory Self-gating.
    Date December 2007
    Journal Magnetic Resonance in Medicine : Official Journal of the Society of Magnetic Resonance in Medicine / Society of Magnetic Resonance in Medicine
    Excerpt

    Two-dimensional (2D) breath-hold cine MRI is used to assess cardiac anatomy and function. However, this technique requires cooperation from the patient, and in some cases the scan planning is complicated. Isotropic nonangulated three-dimensional (3D) cardiac MR can overcome some of these problems because it requires minimal planning and can be reformatted in any plane. However, current methods, even those that use undersampling techniques, involve breath-holding for periods that are too long for many patients. Free-breathing respiratory gating sequences represent a possible solution for realizing 3D cine imaging. A real-time respiratory self-gating technique for whole-heart cine MRI is presented. The technique enables assessment of cardiac anatomy and function with minimum planning or patient cooperation. Nonangulated isotropic 3D data were acquired from five healthy volunteers and then reformatted into 2D clinical views. The respiratory self-gating technique is shown to improve image quality in free-breathing scanning. In addition, ventricular volumetric data obtained using the 3D approach were comparable to those acquired with the conventional multislice 2D approach.

    Title Dexamethasone As a Chemosensitizer for Breast Cancer Chemotherapy: Potentiation of the Antitumor Activity of Adriamycin, Modulation of Cytokine Expression, and Pharmacokinetics.
    Date May 2007
    Journal International Journal of Oncology
    Excerpt

    Dexamethasone (DEX) is mainly used as an anti-emetic agent in cancer therapy. We have recently demonstrated that DEX pretreatment increases the antitumor activity of the cancer chemotherapeutic agents carboplatin and gemcitabine, and decreases host toxicity in nude mouse xenograft models of human cancer. However, the underlying mechanisms are not fully understood. The present study was designed to determine the effects of DEX pretreatment on the anticancer activity of adriamycin (ADR) in a syngeneic model of breast cancer (4T1), emphasizing the effects of DEX on cytokine expression and modulation of ADR pharmacokinetics. We have demonstrated five major new findings about DEX pretreatment: a) it enhances the therapeutic effect of ADR, inducing almost complete inhibition of tumor growth; b) it increases tumor ADR accumulation; c) it modulates the expression of cytokines produced by the tumor, increasing TNFalpha and decreasing IL-1beta and VEGF expression; d) it enhances the effects of ADR on induction of apoptosis and inhibition of cell proliferation; and e) it suppresses nuclear NFkappaB activation and inhibits ADR-induced NFkappaB activation, possibly via IkappaB up-regulation. These findings suggest that DEX can be used as a chemosensitizer and chemoprotectant. These results provide a rationale for the expanded clinical use of DEX for cancer therapy.

    Title Most Cases Labeled As "retinal Migraine" Are Not Migraine.
    Date May 2007
    Journal Journal of Neuro-ophthalmology : the Official Journal of the North American Neuro-ophthalmology Society
    Excerpt

    Monocular visual loss has often been labeled "retinal migraine." Yet there is reason to believe that many such cases do not meet the criteria set out by the International Headache Society (IHS), which defines "retinal migraine" as attacks of fully reversible monocular visual disturbance associated with migraine headache and a normal neuro-ophthalmic examination between attacks.

    Title Automatic Quantification of Changes in Bone in Serial Mr Images of Joints.
    Date February 2007
    Journal Ieee Transactions on Medical Imaging
    Excerpt

    Recent innovations in drug therapies have made it highly desirable to obtain sensitive biomarkers of disease progression that can be used to quantify the performance of candidate disease modifying drugs. In order to measure potential image-based biomarkers of disease progression in an experimental model of rheumatoid arthritis (RA), we present two different methods to automatically quantify changes in a bone in in-vivo serial magnetic resonance (MR) images from the model. Both methods are based on rigid and nonrigid image registration to perform the analysis. The first method uses segmentation propagation to delineate a bone from the serial MR images giving a global measure of temporal changes in bone volume. The second method uses rigid body registration to determine intensity change within a bone, and then maps these into a reference coordinate system using nonrigid registration. This gives a local measure of temporal changes in bone lesion volume. We detected significant temporal changes in local bone lesion volume in five out of eight identified candidate bone lesion regions, and significant difference in local bone lesion volume between male and female subjects in three out of eight candidate bone lesion regions. But the global bone volume was found to be fluctuating over time. Finally, we compare our findings with histology of the subjects and the manual segmentation of bone lesions.

    Title Determination of Desoxyepothilone B in Nude Mice Plasma by Liquid-liquid Extraction and Reversed-phase High-performance Liquid Chromatography.
    Date January 2007
    Journal Journal of Pharmaceutical and Biomedical Analysis
    Excerpt

    A novel reversed-phase high-performance liquid chromatographic (HPLC) method has been established for the determination of a newly developed anti-cancer agent desoxyepothilone B (dEpo B) in nude mice plasma. The sample preparation involved deproteination of 200 microl of plasma sample first, followed by liquid-liquid extraction of the resultant supernatant with chloroform. The compound taxol was used as the internal standard. Chromatographic separations were carried out on a 250 mm x 4.6 mm Zorbax SB-phenyl column with acetonitrile-0.25% orthophosphoric acid (50/50, v/v) as mobile phase and UV detection at 250 nm. For dEpo B and taxol at the concentration level of 10 microg/ml in nude mice plasma, the absolute extraction recoveries were 85.3 and 87.2%, respectively. The linear quantification range of the method was 0.1-100 microg/ml in nude mice plasma with linear correlation coefficients greater than 0.999. The within-day and between-day relative standard deviations (R.S.D.s) for dEpo B at 0.5, 2.5 and 10 microg/ml levels in nude mice plasma fell in the range of 2.8-4.8 and 1.5-4.6%, and the within-day and between-day recoveries were in the range of 96.5-101.7 and 97.7-101.2%, respectively.

    Title Subretinal Hemorrhage from a Peripapillary Choroidal Neovascular Membrane in Papilledema Caused by Idiopathic Intracranial Hypertension.
    Date October 2006
    Journal Journal of Neuro-ophthalmology : the Official Journal of the North American Neuro-ophthalmology Society
    Excerpt

    A 42-year-old man with idiopathic intracranial hypertension and chronic papilledema had severe visual loss in his left eye caused by subretinal bleeding from a peripapillary choroidal neovascular membrane (CNVM). After optic nerve sheath fenestration in his left eye, the papilledema improved, allowing improved visualization of the CNVM. Visual function did not improve after the surgery. CNVM can complicate chronic papilledema and account for sudden worsening of vision. The appropriate management of this type of CNVM is unresolved.

    Title Interactive Mr Imaging and Tracking of Catheters with Multiple Tuned Fiducial Markers.
    Date September 2006
    Journal Journal of Vascular and Interventional Radiology : Jvir
    Excerpt

    The lack of magnetic resonance (MR) safe catheters and guide wires remains an important obstacle to widespread clinical use of MR-guided endovascular procedures. The authors looked at the feasibility of using multiple tuned fiducial markers (TFM) and novel imaging sequences to track catheters reliably under MR and to evaluate the safety of such markers in terms of heating.

    Title A System for Real-time Xmr Guided Cardiovascular Intervention.
    Date January 2006
    Journal Ieee Transactions on Medical Imaging
    Excerpt

    The hybrid magnetic resonance (MR)/X-ray suite (XMR) is a recently introduced imaging solution that provides new possibilities for guidance of cardiovascular catheterization procedures. We have previously described and validated a technique based on optical tracking to register MR and X-ray images obtained from the sliding table XMR configuration. The aim of our recent work was to extend our technique by providing an improved calibration stage, real-time guidance during cardiovascular catheterization procedures, and further off-line analysis for mapping cardiac electrical data to patient anatomy. Specially designed optical trackers and a dedicated calibration object have resulted in a single calibration step that can be efficiently checked and updated before each procedure. An X-ray distortion model has been implemented that allows for distortion correction for arbitrary c-arm orientations. During procedures, the guidance system provides a real-time combined MR/X-ray image display consisting of live X-ray images with registered recently acquired MR derived anatomy. It is also possible to reconstruct the location of catheters seen during X-ray imaging in the MR derived patient anatomy. We have applied our registration technique to 13 cardiovascular catheterization procedures. Our system has been used for the real-time guidance of ten radiofrequency ablations and one aortic stent implantation. We demonstrate the real-time guidance using two exemplar cases. In a further two cases we show how off-line analysis of registered image data, acquired during electrophysiology study procedures, has been used to map cardiac electrical measurements to patient anatomy for two different types of mapping catheters. The cardiologists that have used the guidance system suggest that real-time XMR guidance could have substantial value in difficult interventional and electrophysiological procedures, potentially reducing procedure time and delivered radiation dose. Also, the ability to map measured electrical data to patient specific anatomy provides improved visualization and a path to investigation of cardiac electromechanical models.

    Title Simulation of Cardiac Pathologies Using an Electromechanical Biventricular Model and Xmr Interventional Imaging.
    Date December 2005
    Journal Medical Image Analysis
    Excerpt

    Simulating cardiac electromechanical activity is of great interest for a better understanding of pathologies and for therapy planning. Design and validation of such models is difficult due to the lack of clinical data. XMR systems are a new type of interventional facility in which patients can be rapidly transferred between X-ray and MR systems. Our goal is to design and validate an electromechanical model of the myocardium using XMR imaging. The proposed model is computationally fast and uses clinically observable parameters. We present the integration of anatomy, electrophysiology, and motion from patient data. Pathologies are introduced in the model and simulations are compared to measured data. Initial qualitative comparison on the two clinical cases presented is encouraging. Once fully validated, these models will make it possible to simulate different interventional strategies.

    Title Preclinical Pharmacology of 2-methoxyantimycin A Compounds As Novel Antitumor Agents.
    Date August 2005
    Journal Cancer Chemotherapy and Pharmacology
    Excerpt

    PURPOSE: The present study was designed to determine pharmacological and biochemical properties of 2-methoxyantimycin A analogs (OMe-A1, OMe-A2, OMe-A3, and OMe-A5), which are novel antitumor compounds, and provide a basis for future pharmaceutical development, preclinical evaluation, and clinical trials. METHODS: A high-performance liquid chromatography (HPLC) method was established and employed to assess the biostability of these analogs and to determine their pharmacokinetic properties in mice and rats. RESULTS: In vitro biostability of the 2-methoxyantimycin analogs was esterase-dependent, compound-dependent, and species-dependent. In the absence of esterase inhibitors, all of the analogs were relatively unstable. Stability was greater, however, in human and dog plasma than in rat and mouse plasma. In the presence of esterase inhibitors, OMe-A1 was stable at 37 degrees C for 60 min in mouse and rat plasma, moderately stable in human plasma, and unstable in dog plasma. OMe-A2 was generally stable in all types of plasma. OMe-A3 was stable in dog and rat plasma, but not in human or mouse plasma. OMe-A5 was stable in human and dog plasma, but not in mouse or rat plasma. Each of these analogs was highly bound to plasma proteins. Of S9 fractions from four species, human S9 was least efficient in metabolizing OMe-A3. Following an intravenous dose of OMe-A1 in mice, plasma levels decreased rapidly, with an initial half-life of 2.7 min and a terminal half life of 34 min. Following an intraperitoneal dose in mice, plasma levels decreased less rapidly with a terminal half-life of 215 min. Following an intravenous dose of OMe-A1 or OMe-A3 in rats, plasma levels decreased more rapidly with initial half-lives of about 1.0 min. At an equivalent dose, OMe-A3 had a faster clearance than OMe-A1. CONCLUSIONS: For 2-methoxyantimycin A analogs, species differences in biostability, metabolism, and pharmacokinetics may be pertinent in assessing their pharmacological and toxicological profiles and antitumor activity in humans.

    Title Tissue Deformation and Shape Models in Image-guided Interventions: a Discussion Paper.
    Date June 2005
    Journal Medical Image Analysis
    Excerpt

    This paper promotes the concept of active models in image-guided interventions. We outline the limitations of the rigid body assumption in image-guided interventions and describe how intraoperative imaging provides a rich source of information on spatial location of anatomical structures and therapy devices, allowing a preoperative plan to be updated during an intervention. Soft tissue deformation and variation from an atlas to a particular individual can both be determined using non-rigid registration. Established methods using free-form deformations have a very large number of degrees of freedom. Three examples of deformable models--motion models, biomechanical models and statistical shape models--are used to illustrate how prior information can be used to restrict the number of degrees of freedom of the registration algorithm and thus provide active models for image-guided interventions. We provide preliminary results from applications for each type of model.

    Title Novel Method of Quantifying Pulmonary Vascular Resistance by Use of Simultaneous Invasive Pressure Monitoring and Phase-contrast Magnetic Resonance Flow.
    Date February 2005
    Journal Circulation
    Excerpt

    Pulmonary vascular resistance (PVR) quantification is important in the treatment of children with pulmonary hypertension. The Fick principle, used to quantify pulmonary artery flow, may be a flawed technique. We describe a novel method of PVR quantification by the use of magnetic resonance (MR) flow data and invasive pressure measurements.

    Title Recent Advances in Experimental Molecular Therapeutics for Malignant Gliomas.
    Date December 2004
    Journal Current Medicinal Chemistry. Anti-cancer Agents
    Excerpt

    The current lack of effective therapy for malignant gliomas has prompted the development of three primary foci of molecular research: anti-angiogenesis therapy, immunotherapy, and DNA- and RNA-based therapies. Angiogenesis inhibitors, designed to exploit the highly vascularized nature of gliomas, target endothelial cells and/or the extracellular matrix and bypass many of the problems of conventional chemotherapy. There may be easy access to the molecular target (e.g. blood vessels), reduced induction of drug resistance, and general lack of host toxicity. The relatively immunoprivileged status of the brain has also prompted use of immune stimulation as an anti-glioma strategy. Lines of attack include global cytokine therapy, vaccination with specific tumor antigens, dosing with monoclonal antibodies conjugated to radioisotopes or toxins, and ex vivo priming of lymphocytes. With regard to DNA- and RNA-based therapy, numerous oncogenic proteins have been targeted by antisense molecules administered alone or in combination with conventional chemotherapy and radiation. In one tactic, termed "suicide" gene therapy, herpes simplex thymidine kinase has been transfected into glioma cells via a retrovirus; subsequent introduction of ganciclovir causes cytotoxicity in the transduced cells. Although considerable preclinical data have been accumulated, promising results for therapy of human glioma have only recently appeared.

    Title Catheter Tracking and Visualization Using 19f Nuclear Magnetic Resonance.
    Date December 2004
    Journal Magnetic Resonance in Medicine : Official Journal of the Society of Magnetic Resonance in Medicine / Society of Magnetic Resonance in Medicine
    Excerpt

    This work presents an investigation into catheter visualization and localization using 19F nuclear magnetic resonance (NMR) in conjunction with proton imaging. For this purpose, the imaging capabilities of a standard system were extended to allow for 19F excitation and signal detection. Two modes of operation were implemented: 1) a real-time tracking mode that provides tip tracking and automatic slice position updates interleaved with real-time, interactive proton imaging; and 2) a non-real-time catheter length visualization mode in which the entire length of a catheter can be assessed. Initial phantom experiments were conducted with the use of an angiographic balloon catheter filled with the blood substitute perfluorooctylbromide (PFOB). Using limited bandwidth excitation centered at the resonances of the CF2 groups of PFOB, we found that sufficient signal could be received to facilitate tip tracking during catheter motion and length visualization for various catheter configurations. The present approach is considered a promising alternative to existing methods, which either are associated with safety concerns (if active markers are employed) or suffer from insufficient, direction-dependent contrast (if passive visualization is used). Furthermore, our approach enables visualization of the entire length of the catheter. The proposed method provides a safe technique that, unlike electrical or optical devices, does not require modification of commercially available catheters.

    Title Visualization and Tracking of an Inflatable Balloon Catheter Using Ssfp in a Flow Phantom and in the Heart and Great Vessels of Patients.
    Date August 2004
    Journal Magnetic Resonance in Medicine : Official Journal of the Society of Magnetic Resonance in Medicine / Society of Magnetic Resonance in Medicine
    Excerpt

    Passive catheter tracking involves direct interaction between the device and its surroundings, creating a local signal loss or enhancement of the image. Using only standard balloon catheters filled with CO(2) and imaged with a steady-state free precession sequence, it was possible to visualize and passively track catheters in a flow phantom and in the heart and great vessels of 20 patients without any additional image processing. The phantom work demonstrated that it was advantageous to sacrifice spatial resolution in order to increase temporal resolution. Frame rates greater than 10/sec were necessary for ease of catheter manipulation. Although only the tip of the catheter was visualized, this technique proved to be effective in patients undergoing cardiac catheterization.

    Title Three-dimensional Magnetic Resonance Imaging of Congenital Cardiac Anomalies.
    Date April 2004
    Journal Cardiology in the Young
    Excerpt

    We describe a new method of three-dimensional magnetic resonance imaging of the heart that has been used to produce high quality diagnostic images in 274 patients with congenital cardiac disease, ranging in age from 1 day to 66 years. Using a steady state free precession gradient echo technique and parallel imaging, rapid acquisition of the entire cardiac volume is possible during 8 to 15 sequential breath-holds, each lasting between 8 and 15 s. We obtained high-resolution images, with a resolution of 1 mm3, at between 3 and 10 phases of the cardiac cycle. While images of diagnostic quality were obtained in all cases, in 52 patients there was some degradation due to various factors. Children under 8 years were ventilated, and ventilation was suspended for the breath-holds. For patients breathing spontaneously a novel respiratory navigator technique was developed, using a navigator echo placed over the right hemidiaphragm. This was used successfully in 20 patients, and reduced the misalignment of images obtained during different breath-holds. Images were analysed using multi-planar reformatting and volume rendering. Image processing took approximately five minutes for each study. End-diastolic images were processed for all patients. Systolic images were also processed in selected cases. Further improvements in parallel imaging should reduce imaging times further, so that it is possible to obtain the full volume image in a single breath-hold. This will enable imaging of complex anatomy to be obtained using a standard imaging protocol that does not require the operator to understand the cardiac malformation, making the magnetic resonance imaging of congenital cardiac disease faster and more effective.

    Title Registration and Tracking to Integrate X-ray and Mr Images in an Xmr Facility.
    Date April 2004
    Journal Ieee Transactions on Medical Imaging
    Excerpt

    We describe a registration and tracking technique to integrate cardiac X-ray images and cardiac magnetic resonance (MR) images acquired from a combined X-ray and MR interventional suite (XMR). Optical tracking is used to determine the transformation matrices relating MR image coordinates and X-ray image coordinates. Calibration of X-ray projection geometry and tracking of the X-ray C-arm and table enable three-dimensional (3-D) reconstruction of vessel centerlines and catheters from bi-plane X-ray views. We can, therefore, combine single X-ray projection images with registered projection MR images from a volume acquisition, and we can also display 3-D reconstructions of catheters within a 3-D or multi-slice MR volume. Registration errors were assessed using phantom experiments. Errors in the combined projection images (two-dimensional target registration error--TRE) were found to be 2.4 to 4.2 mm, and the errors in the integrated volume representation (3-D TRE) were found to be 4.6 to 5.1 mm. These errors are clinically acceptable for alignment of images of the great vessels and the chambers of the heart. Results are shown for two patients. The first involves overlay of a catheter used for invasive pressure measurements on an MR volume that provides anatomical context. The second involves overlay of invasive electrode catheters (including a basket catheter) on a tagged MR volume in order to relate electrophysiology to myocardial motion in a patient with an arrhythmia. Visual assessment of these results suggests the errors were of a similar magnitude to those obtained in the phantom measurements.

    Title Cardiac Catheterisation Guided by Mri in Children and Adults with Congenital Heart Disease.
    Date February 2004
    Journal Lancet
    Excerpt

    Fluoroscopically guided cardiac catheterisation is an essential tool for diagnosis and treatment of congenital heart disease. Drawbacks include poor soft tissue visualisation and exposure to radiation. We describe the first 16 cases of a novel method of cardiac catheterisation guided by MRI with radiographic support.

    Title 9cuab30, an Rxr Specific Retinoid, And/or Tamoxifen in the Prevention of Methylnitrosourea-induced Mammary Cancers.
    Date January 2004
    Journal Cancer Letters
    Excerpt

    Studies were performed in female Sprague-Dawley rats to determine the efficacy of a new RXR specific retinoid (9cUAB30) when combined with tamoxifen in the prevention of mammary cancers and to determine various pharmacokinetic parameters of the retinoid. When administered by gavage, 9cUAB30 was rapidly absorbed and had a serum t(1/2) of 13.5 h. Since the retinoid was administered in the diet for the chemoprevention study, a 28-day study in which 9cUAB30 was given at dose levels of 200, 400, and 600 mg/kg diet revealed fairly constant serum levels regardless of dose or length of treatment; possibly accounting for the observed low toxicity of this compound. When suboptimal doses of 9cUAB30 were given in the methylnitrosourea (MNU)-induced mammary cancer model, the following average number of mammary cancers were observed: 9cUAB30 (150 mg/kg diet), 4.3; tamoxifen (0.4 mg/kg diet), 4.6; 9cUAB30 (150 mg/kg diet)+tamoxifen (0.4 mg/kg diet), 2.6; and controls, 6.0. Thus, the combination of the agents resulted in an increased effect in preventing mammary cancers; suggesting that cancer cell proliferation was inhibited by the compounds blocking different pathways.

    Title Three- and Four-dimensional Reconstruction of Intra-cardiac Anatomy from Two-dimensional Magnetic Resonance Images.
    Date December 2003
    Journal The International Journal of Cardiovascular Imaging
    Excerpt

    The present study was designed to evaluate the feasibility and clinical usefulness of three-dimensional (3D) reconstruction of intra-cardiac anatomy from a series of two-dimensional (2D) MR images using commercially available software. Sixteen patients (eight with structurally normal hearts but due to have catheter radio-frequency ablation of atrial tachyarrhythmias and eight with atrial septal defects (ASD) due for trans-catheter closure) and two volunteers were imaged at 1T. For each patient, a series of ECG-triggered images (5 mm thick slices, 2-3 mm apart) were acquired during breath holding. Depending on image quality, T1- or T2-weighted spin-echo images or gradient-echo cine images were used. The 3D reconstruction was performed off-line: the blood pools within cardiac chambers and great vessels were semi-automatically segmented, their outer surface was extracted using a marching cube algorithm and rendered. Intra- and inter-observer variability, effect of breath-hold position and differences between pulse sequences were assessed by imaging a volunteer. The 3D reconstructions were assessed by three cardiologists and compared with the 2D MR images and with 2D and 3D trans-esophagal and intra-cardiac echocardiography obtained during interventions. In every case, an anatomically detailed 3D volume was obtained. In the two patients where a 3 mm interval between slices was used, the resolution was not as good but it was still possible to visualize all the major anatomical structures. Spin-echo images lead to reconstructions more detailed than those obtained from gradient-echo images. However, gradient-echo images are easier to segment due to their greater contrast. Furthermore, because images were acquired at least at ten points in the cardiac cycles for every slice it was possible to reconstruct a cine loop and, for example, to visualize the evolution of the size and margins of the ASD during the cardiac cycle. 3D reconstruction proved to be an effective way to assess the relationship between the different parts of the cardiac anatomy. The technique was useful in planning interventions in these patients.

    Title Conformationally Defined Retinoic Acid Analogues. 5. Large-scale Synthesis and Mammary Cancer Chemopreventive Activity for (2e,4e,6z,8e)-8-(3',4'-dihydro-1'(2'h)-naphthalen-1'-ylidene)-3,7-dimethyl-2,4,6-octatrienoic Acid (9cuab30).
    Date September 2003
    Journal Journal of Medicinal Chemistry
    Excerpt

    Retinoids that activate the nuclear retinoid X receptors (RXRs) display potential for chemoprevention of breast cancer. We previously reported that 9cUAB30 (1) is an RXR-selective retinoid. To explore its in vivo chemopreventive activity, multigram quantities of 1 were needed. Here, we describe a modified synthesis that yields up to 100 g of 1. We further demonstrate that 1 is very effective in the prevention of N-methyl-N-nitrosourea induced mammary cancers in rats without signs of toxicity.

    Title Measurement and Analysis of Brain Deformation During Neurosurgery.
    Date July 2003
    Journal Ieee Transactions on Medical Imaging
    Excerpt

    Recent studies have shown that the surface of the brain is deformed by up to 20 mm after the skull is opened during neurosurgery, which could lead to substantial error in commercial image-guided surgery systems. We quantitatively analyze the intraoperative brain deformation of 24 subjects to investigate whether simple rules can describe or predict the deformation. Interventional magnetic resonance images acquired at the start and end of the procedure are registered nonrigidly to obtain deformation values throughout the brain. Deformation patterns are investigated quantitatively with respect to the location and magnitude of deformation, and to the distribution and principal direction of the displacements. We also measure the volume change of the lateral ventricles by manual segmentation. Our study indicates that brain shift occurs predominantly in the hemisphere ipsi-lateral to the craniotomy, and that there is more brain deformation during resection procedures than during biopsy or functional procedures. However, the brain deformation patterns are extremely complex in this group of subjects. This paper quantitatively demonstrates that brain deformation occurs not only at the surface, but also in deeper brain structure, and that the principal direction of displacement does not always correspond with the direction of gravity. Therefore, simple computational algorithms that utilize limited intraoperative information (e.g., brain surface shift) will not always accurately predict brain deformation at the lesion.

    Title Is Gender Selection an Appropriate Use of Medical Resources?
    Date May 2003
    Journal Journal of Assisted Reproduction and Genetics
    Excerpt

    Gender selection by PGD is an appropriate use of medical resources. Children borne through PGD for gender determination would be welcome and would come into a couple's life at a planned, opportune time. If the practice were made more available through insurance coverage, the size and makeup of families could become a matter of choice rather than chance for couples favoring this approach.

    Title Measures of Folding Applied to the Development of the Human Fetal Brain.
    Date March 2003
    Journal Ieee Transactions on Medical Imaging
    Excerpt

    Previous work has suggested the existence of differences between the cerebral cortex of normal individuals, and those of patients with diseases such as epilepsy and schizophrenia. These shape abnormalities may be of developmental origin. Improved shape measures could provide useful tools for neuroscience research and patient diagnosis. We consider the theoretically desirable properties of measures of brain shape. We have implemented seven measures, three from the neuroscience literature, and four new to this field. Three of the measures are zero-order and four are second-order with respect to the surface. We validate the measures using simple geometrical shapes, and a collection of magnetic resonance scans of ten histologically normal ex vivo fetal brains with gestational ages from 19-42 weeks. We then apply the measures to MR scans from two histologically abnormal ex vivo brains. We demonstrate that our implementation of the measures is sensitive to anatomical variability rather than to the discreteness of the image data. All the measures were sensitive to changes in shape during fetal development. Several of the measures could distinguish between the normal and abnormal fetal brains. We propose a multivariate approach to studying the shape of the cerebral cortex, in which both zero-order and second-order measures are used to quantify folding.

    Title Radical Retropubic Prostatectomy and Blood Transfusion.
    Date January 2003
    Journal Mayo Clinic Proceedings. Mayo Clinic
    Excerpt

    OBJECTIVE: To determine whether there is a reduction in blood loss and blood transfusions associated with radical retropubic prostatectomy (RRP) by measuring the amount of blood loss and incidence of red blood cell (RBC) transfusions over time along with factors that may influence transfusions. PATIENTS AND METHODS: This is a retrospective study of patients who underwent RRP with and without the nerve-sparing dorsal venous complex (DVC) technique from 1985 to 1993 and in 1999. Transfusion rate, mean RBC loss, and preoperative and postoperative hemoglobin values were assessed. Univariate and multivariate regression analyses were performed. RESULTS: A total of 438 RRPs (276 DVC technique, 162 non-DVC technique) were reviewed and included in the study. The percentage of patients receiving allogeneic RBC transfusion decreased from 69% during 1985 to 1986 to 7.1% during 1999, and there was a decline in discharge hemoglobin values from 12.0 to 10.9 g/dL during this period. There was a significant reduction in mean hemoglobin concentration lost over time in the DVC technique group from 4.9 to 4.0 g/dL (P=.04) during the 1985 to 1990 study period, which persisted in 1999. CONCLUSION: Improvement in surgical technique and reduction in transfusion triggers resulted in large decreases of allogeneic RBC transfusions in patients undergoing RRP.

    Title Time Course of Morphological Alterations of Fungiform Papillae and Taste Buds Following Chorda Tympani Transection in Neonatal Rats.
    Date July 2002
    Journal Journal of Neurobiology
    Excerpt

    The time course of structural changes in fungiform papillae was analyzed in rats that received unilateral chorda tympani nerve transection at 10 days of age. Morphological differences between intact and denervated sides of the tongue were first observed at 8 days postsection, with an increase in the number of fungiform papillae that did not have a pore. In addition, the first papilla with a filiform-like appearance was noted on the denervated side at 8 days postsectioning. By 11 days after surgery, the total number of papillae and the number of papillae with a pore were significantly lower on the transected side of the tongue as compared to the intact side. At 50 days postsection, there was an average of 70.5 fungiform papillae on the intact side and a mean of only 20.8 fungiform papillae the denervated side. Of those few remaining papillae on the cut side, an average of 13.5 papillae were categorized as filiform-like, while no filiform-like papillae occurred on the intact side. Significant reduction in taste bud volume was noted at 4 days posttransection and further decrements in taste bud volume were noted at 8 and 30 days postsection. Electron microscopy of the lingual branch of the trigeminal nerve from adult rats that received neonatal chorda tympani transection showed normal numbers of both myelinated and unmyelinated fibers. Thus, in addition to the well-characterized dependence of taste bud maintenance on the chorda tympani nerve, the present study shows an additional role of the chorda tympani nerve in papilla maintenance during early postnatal development.

    Title Design and Evaluation of a System for Microscope-assisted Guided Interventions (magi).
    Date May 2001
    Journal Ieee Transactions on Medical Imaging
    Excerpt

    The problem of providing surgical navigation using image overlays on the operative scene can be split into four main tasks--calibration of the optical system; registration of preoperative images to the patient; system and patient tracking, and display using a suitable visualization scheme. To achieve a convincing result in the magnified microscope view a very high alignment accuracy is required. We have simulated an entire image overlay system to establish the most significant sources of error and improved each of the stages involved. The microscope calibration process has been automated. We have introduced bone-implanted markers for registration and incorporated a locking acrylic dental stent (LADS) for patient tracking. The LADS can also provide a less-invasive registration device with mean target error of 0.7 mm in volunteer experiments. These improvements have significantly increased the alignment accuracy of our overlays. Phantom accuracy is 0.3-0.5 mm and clinical overlay errors were 0.5-1.0 mm on the bone fiducials and 0.5-4 mm on target structures. We have improved the graphical representation of the stereo overlays. The resulting system provides three-dimensional surgical navigation for microscope-assisted guided interventions (MAGI).

    Title Retinoic Acid (ra) Receptor Transcriptional Activation Correlates with Inhibition of 12-o-tetradecanoylphorbol-13-acetate-induced Ornithine Decarboxylase (odc) Activity by Retinoids: a Potential Role for Trans-ra-induced Zbp-89 in Odc Inhibition.
    Date January 2001
    Journal International Journal of Cancer. Journal International Du Cancer
    Excerpt

    Evaluation of retinoic acid receptor (RAR) subtype-selective alpha and gamma agonists and antagonists and a retinoid X receptor (RXR) class-selective agonist for efficacy at inhibiting both induction of ornithine decarboxylase (ODC) by the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) in mouse epidermis and rat tracheal epithelial cells and the appearance of papillomas in mouse epidermis treated in the 2-stage tumor initiation-promotion model indicated that (i) RXR class-selective transcriptional agonists, such as MM11246, were not involved in ODC inhibition; (ii) RAR-selective agonists that induce gene transcription from RA-responsive elements (RAREs) were active at low concentrations; (iii) RAR-selective antagonists that bind RARs and inhibit AP-1 activation on the collagenase promoter but do not activate RAREs to induce gene transcription were less effective inhibitors; and (iv) RARgamma-selective retinoid agonists were more effective inhibitors of TPA-induced ODC activity than RARalpha-selective agonists. These results suggest that RARE activation has a more important role in inhibition of ODC activity than RXR activation or AP-1 inhibition and that RARgamma-selective agonists would be the most useful inhibitors of epithelial cell proliferation induced by tumor promoters. The natural retinoid all-trans-RA induced expression of transcription factor ZBP-89, which represses activation of the GC box in the ODC promoter by the transcription factor Sp1.

    Title Celecoxib Inhibits N-butyl-n-(4-hydroxybutyl)-nitrosamine-induced Urinary Bladder Cancers in Male B6d2f1 Mice and Female Fischer-344 Rats.
    Date November 2000
    Journal Cancer Research
    Excerpt

    Epidemiological studies have shown that nonsteroidal anti-inflammatory drugs (NSAIDs) may have a role in the prevention of human cancers. A number of preclinical studies have also suggested that inhibition of cyclooxygenase (COX) with NSAIDs has an anticancer effect in animal models of colon, urinary bladder, skin, and breast. In these studies, we evaluated the COX-2 inhibitor celecoxib in two rodent models of urinary bladder cancer. Male B6D2F1 mice treated with N-butyl-N-(4-hydroxybutyl)-nitrosamine (OH-BBN) developed transitional and squamous cell urinary bladder cancers, many of which grew rapidly and caused substantial morbidity that required sacrifice of the mice. Groups of mice received various daily doses of celecoxib in the diet (1250, 500, or 200 mg/kg of diet) beginning 7 days before the initiation of 12 weekly doses of OH-BBN. Mice were checked weekly for the presence of palpable urinary bladder masses. The study was terminated at 8 months following the initial treatment with OH-BBN. The percentage of mice with large palpable bladder lesions, which necessitated sacrifice of the mice, was 40% in the OH-BBN control group. In contrast, only 10% of all celecoxib-treated mice required sacrifice before the scheduled termination of the experiment, implying that all three doses of celecoxib inhibited the formation of large palpable lesions. Celecoxib did not significantly alter the incidence of preneoplastic bladder lesions, but did dose-dependently decrease the total number of urinary bladder cancers/mouse, palpable plus microscopic, by 77, 57, and 43% at dosages of 1250, 500, and 200 mg of celecoxib/kg of diet, respectively. In the second model, female Fischer-344 rats were administered OH-BBN twice/week for a period of 8 weeks. After 8 months, all rats developed preneoplastic lesions, whereas roughly 60% of the rats developed relatively small urinary bladder cancers. Rats were treated continually with celecoxib in the diet (500 or 1000 mg/kg of diet) beginning either 1 week prior to the initial OH-BBN treatment or beginning 1 week following the last OH-BBN treatment. Neither celecoxib treatment regimen significantly altered the number of preneoplastic lesions. Whereas celecoxib treatment initiated prior to OH-BBN administration decreased cancer incidence roughly 65%, celecoxib treatment initiated beginning 1 week after the last dose of OH-BBN profoundly decreased cancer incidence (>95%). Celecoxib did not alter the body weights of the mice or rats, or cause other signs of toxicity at any of the doses studied. Taken together these results demonstrate that: (a) celecoxib effectively inhibits tumor growth and enhances survival in the mouse model of urinary bladder cancer; and (b) celecoxib profoundly inhibits development of urinary bladder cancers in the rat model even when administered following the last dose of OH-BBN. Clinical trials will be necessary to determine whether COX-2 inhibitors will provide a clinical benefit in human bladder cancer.

    Title Sampling and Reconstruction Effects Due to Motion in Diffusion-weighted Interleaved Echo Planar Imaging.
    Date October 2000
    Journal Magnetic Resonance in Medicine : Official Journal of the Society of Magnetic Resonance in Medicine / Society of Magnetic Resonance in Medicine
    Excerpt

    Subject motion during diffusion-weighted interleaved echo-planar imaging causes k-space offsets which lead to irregular sampling in the phase-encode direction. For each image, the k-space shifts are monitored using 2D navigator echoes, and are shown to lead to a frequent violation of the Nyquist condition when an ungated sequence is used on seven subjects. Combining data from four repeat acquisitions allows the Nyquist condition to be satisfied in all but 1% of images. Reconstruction of the irregularly-sampled data can be performed using a matrix inversion technique. The repeated acquisitions make the inversion more stable and additionally improve the signal-to-noise ratio. The resultant isotropic diffusion-weighted images and average apparent diffusion coefficient (ADC) maps show high resolution and enable clear localization of a stroke lesion. Residual ADC artifacts with a slow spatial variation are observed and assumed to originate from non-rigid pulsatile brain motion. Magn Reson Med 44:101-109, 2000.

    Title Sources of Error in Comparing Functional Magnetic Resonance Imaging and Invasive Electrophysiological Recordings.
    Date August 2000
    Journal Journal of Neurosurgery
    Excerpt

    OBJECT: Several authors have recently reported studies in which they aim to validate functional magnetic resonance (fMR) imaging against the accepted gold standard of invasive electrophysiological monitoring. The authors have conducted a similar study, and in this paper they identify and quantify two characteristics of these data that can make such a comparison problematic. METHODS: Eight patients in whom surgery for epilepsy was performed and five healthy volunteers underwent fMR imaging to localize the part of the sensorimotor cortex responsible for hand movement. In the patient group subdural electrode mats were subsequently implanted to identify eloquent regions of the brain and the epileptogenic zone. The fMR imaging data were processed to correct for motion during the study and then registered with a postimplantation computerized tomography (CT) scan on which the electrodes were visible. The motion during imaging in the two groups studied, and the deformation of the brain between the preoperative images and postoperative scans were measured. The patients who underwent epilepsy surgery moved significantly more during fMR imaging experiments than healthy volunteers performing the same motor task. This motion had a particularly increased out-of-plane component and was significantly more correlated with the stimulus than in the volunteers. This motion was especially increased when the patients were performing a task on the side affected by the lesion. The additional motion is hard to correct and substantially degrades the quality of the resulting fMR images, making it a much less reliable technique for use in these patients than in others. Also, the authors found that after electrode implantation, the brain surface can shift more than 10 mm relative to the skull compared with its preoperative location, substantially degrading the accuracy of the comparison of electrophysiological measurements made in the deformed brain and fMR studies obtained preoperatively. CONCLUSIONS: These two findings indicate that studies of this sort are currently of limited use for validating fMR imaging and should be interpreted with care. Additional image analysis research is necessary to solve the problems caused by patients' motion and brain deformation.

    Title A System for Microscope-assisted Guided Interventions.
    Date August 2000
    Journal Stereotactic and Functional Neurosurgery
    Excerpt

    We present a system for surgical navigation using stereo overlays in the operating microscope aligned to the operative scene. This augmented reality system provides 3D information about nearby structures and offers a significant advancement over pointer-based guidance, which provides only the location of one point and requires the surgeon to look away from the operative scene. With a previous version of this system, we demonstrated feasibility, but it became clear that to achieve convincing guidance through the magnified microscope view, a very high alignment accuracy was required. We have made progress with several aspects of the system, including automated calibration, error simulation, bone-implanted fiducials and a dental attachment for tracking. We have performed experiments to establish the visual display parameters required to perceive overlaid structures beneath the operative surface. Easy perception of real and virtual structures with the correct transparency has been demonstrated in a laboratory and through the microscope. The result is a system with a predicted accuracy of 0.9 mm and phantom errors of 0.5 mm. In clinical practice errors are 0.5-1.5 mm, rising to 2-4 mm when brain deformation occurs.

    Title Voxel Similarity Measures for 3-d Serial Mr Brain Image Registration.
    Date July 2000
    Journal Ieee Transactions on Medical Imaging
    Excerpt

    We have evaluated eight different similarity measures used for rigid body registration of serial magnetic resonance (MR) brain scans. To assess their accuracy we used 33 clinical three-dimensional (3-D) serial MR images, with deformable extradural tissue excluded by manual segmentation and simulated 3-D MR images with added intensity distortion. For each measure we determined the consistency of registration transformations for both sets of segmented and unsegmented data. We have shown that of the eight measures tested, the ones based on joint entropy produced the best consistency. In particular, these measures seemed to be least sensitive to the presence of extradural tissue. For these data the difference in accuracy of these joint entropy measures, with or without brain segmentation, was within the threshold of visually detectable change in the difference images.

    Title The Easi Project--improving the Effectiveness and Quality of Image-guided Surgery.
    Date April 2000
    Journal Ieee Transactions on Information Technology in Biomedicine : a Publication of the Ieee Engineering in Medicine and Biology Society
    Excerpt

    In recent years, advances in computer technology and a significant increase in the accuracy of medical imaging have made it possible to develop systems that can assist the clinician in diagnosis, planning, and treatment. This paper deals with an area that is generally referred to as computer-assisted surgery, image-directed surgery, or image-guided surgery. We report the research, development, and clinical validation performed since January 1996 in the European Applications in Surgical Interventions (EASI) project, which is funded by the European Commission in their "4th Framework Telematics Applications for Health" program. The goal of this project is the improvement of the effectiveness and quality of image-guided neurosurgery of the brain and image-guided vascular surgery of abdominal aortic aneurysms, while at the same time reducing patient risks and overall cost. We have developed advanced prototype systems for preoperative surgical planning and intraoperative surgical navigation, and we have extensively clinically validated these systems. The prototype systems and the clinical validation results are described in this paper.

    Title The Identification of Cerebral Volume Changes in Treated Growth Hormone-deficient Adults Using Serial 3d Mr Image Processing.
    Date February 2000
    Journal Journal of Computer Assisted Tomography
    Excerpt

    PURPOSE: A pilot study to detect volume changes of cerebral structures in growth hormone (GH)-deficient adults treated with GH using serial 3D MR image processing and to assess need for segmentation prior to registration was conducted. METHOD: Volume MR scans of the brain were obtained in five patients and six control subjects. Patients were scanned before and after 3 and 6 months of therapy. Control subjects were scanned at the same intervals. A phantom was used to quantify scaling errors. Second and third volumes were aligned with the baseline by maximizing normalized mutual information and transformed using sinc interpolation. Registration was performed with and without brain segmentation and correction of scaling errors. Each registered, transformed image had the original subtracted, generating a difference image. Structural change and effects of segmentation and scaling error correction were assessed on original and difference images. The radiologists' ability to detect volume change was also assessed. RESULTS: Compared with control subjects, GH-treated subjects had an increase in cerebral volume and reduction in ventricular volume (p = 0.91 x 10(-3)). Scale correction and segmentation made no difference (p = 1 and p = 0.873). Structural changes were identified in the difference images but not in the original (p = 0.136). The radiologists detected changes >200 microm. CONCLUSION: GH treatment in deficient patients results in cerebral volume changes detectable by registration and subtraction of serial MR studies but not by standard assessment of images. This registration method did not require prior segmentation.

    Title Nonrigid Registration Using Free-form Deformations: Application to Breast Mr Images.
    Date November 1999
    Journal Ieee Transactions on Medical Imaging
    Excerpt

    In this paper we present a new approach for the nonrigid registration of contrast-enhanced breast MRI. A hierarchical transformation model of the motion of the breast has been developed. The global motion of the breast is modeled by an affine transformation while the local breast motion is described by a free-form deformation (FFD) based on B-splines. Normalized mutual information is used as a voxel-based similarity measure which is insensitive to intensity changes as a result of the contrast enhancement. Registration is achieved by minimizing a cost function, which represents a combination of the cost associated with the smoothness of the transformation and the cost associated with the image similarity. The algorithm has been applied to the fully automated registration of three-dimensional (3-D) breast MRI in volunteers and patients. In particular, we have compared the results of the proposed nonrigid registration algorithm to those obtained using rigid and affine registration techniques. The results clearly indicate that the nonrigid registration algorithm is much better able to recover the motion and deformation of the breast than rigid or affine registration algorithms.

    Title Comparison and Evaluation of Rigid, Affine, and Nonrigid Registration of Breast Mr Images.
    Date October 1999
    Journal Journal of Computer Assisted Tomography
    Excerpt

    PURPOSE: A new nonrigid registration method, designed to reduce the effect of movement artifact in subtraction images from breast MR, is compared with existing rigid and affine registration methods. METHOD: Nonrigid registration was compared with rigid and affine registration methods and unregistered images using 54 gadolinium-enhanced 3D breast MR data sets. Twenty-seven data sets had been previously reported normal, and 27 contained a histologically proven carcinoma. The comparison was based on visual assessment and ranking by two radiologists. RESULTS: When analyzed by two radiologists independently, all three registration methods gave better-quality subtraction images than unregistered images (p < 0.01), but nonrigid registration gave significantly better results than the rigid and affine registration methods (p < 0.01). There was no significant difference between rigid and affine registration methods. CONCLUSION: Nonrigid registration significantly reduces the effects of movement artifact in subtracted contrast-enhanced breast MRI. This may enable better visualization of small tumors and those within a glandular breast.

    Title Stereo Augmented Reality in the Surgical Microscope.
    Date August 1999
    Journal Studies in Health Technology and Informatics
    Excerpt

    We present an augmented reality system that allows surgeons to view features from preoperative radiological images accurately overlaid in stereo in the optical path of a surgical microscope. The purpose of the system is to show the surgeon structures beneath the viewed surface in the correct 3-D position. The technical challenges are registration, tracking, calibration and visualisation. For patient registration, or alignment to preoperative images, we use bone-implanted markers and a dental splint is used for patient tracking. Both microscope and patient are tracked by an optical localiser. Calibration uses an accurately manufactured object with high contrast circular markers which are identified automatically. All ten camera parameters are modelled as a bivariate polynomial function of zoom and focus. The overall system has a theoretical overlay accuracy of better than 1 mm. Implementations of the system have been tested on seven patients. Recent measurements in the operating room conformed to our accuracy predictions. For visualisation the system has been implemented on a graphics workstation to enable high frame rates with a variety of rendering schemes. Several issues of 3-D depth perception remain unsolved, but early results suggest that perception of structures in the correct 3-D position beneath the viewed surface is possible.

    Title Screening of Potential Cancer Preventing Chemicals As Aromatase Inhibitors in an in Vitro Assay.
    Date June 1999
    Journal Anticancer Research
    Excerpt

    The inhibition of human placental aromatase was used to rank a series of compounds, with the objective of selecting compounds for further evaluation as chemopreventive agents. (+/-)-p-Aminoglutethimide, introduced over two decades ago as a treatment for breast cancer, had an IC50 of 6.5 microM. Five compounds were more potent than aminoglutethimide in this assay: (+)- vorozole, 4-hydroxyandrostenedione, miconazole nitrate, plomestane, and 4-methoxy-androst-4-ene-3,17-dione. Other compounds with known chemoprevention activity, such as curcumin and genistein, were inactive. This assay for aromatase inhibitors is a rapid, economical way of ranking compounds for further development as chemoprevention agents.

    Title A Three-component Deformation Model for Image-guided Surgery.
    Date May 1999
    Journal Medical Image Analysis
    Excerpt

    In image-guided surgery it is necessary to align preoperative image data with the patient. The rigid-body approximation is usually applied, but is often not valid due to tissue deformation. Non-rigid deformation algorithms have been applied to related, but not identical problems, such as atlas matching and surgery simulation. In image-guided surgery we have the additional information that the deformation is constrained by the physical properties of the different tissues. The most important properties that must be incorporated are the rigidity of bone, the unconstrained nature of fluid regions and the relatively smooth deformation of soft tissue. Hence, we have developed a simplified model of tissue deformation based on a three-component system. Rigid regions are constrained by the rigid-body transformation and fluid regions are unconstrained. A number of energy models for deformable tissues have been compared. The model can be deformed using intraoperative data, in this case landmarks, using a technique similar to active contours. A novel strategy to avoid folding in the transformation is described. Our method was applied to MRI and CT data from a neurosurgery patient with epilepsy. Although the current implementation is only two dimensional, the initial results are promising. As the algorithm must ultimately run in or near 'real-time' an improved implementation of the energy minimization is underway. This paper presents the problem of tissue deformation, which has received little attention in the literature and outlines the framework we have developed for tackling this difficult subject.

    Title An Alpha-2-macroglobulin Insertion-deletion Polymorphism in Alzheimer Disease.
    Date May 1999
    Journal Nature Genetics
    Title Investigation of Intraoperative Brain Deformation Using a 1.5-t Interventional Mr System: Preliminary Results.
    Date March 1999
    Journal Ieee Transactions on Medical Imaging
    Excerpt

    All image-guided neurosurgical systems that we are aware of assume that the head and its contents behave as a rigid body. It is important to measure intraoperative brain deformation (brain shift) to provide some indication of the application accuracy of image-guided surgical systems, and also to provide data to develop and validate nonrigid registration algorithms to correct for such deformation. We are collecting data from patients undergoing neurosurgery in a high-field (1.5 T) interventional magnetic resonance (MR) scanner. High-contrast and high-resolution gradient-echo MR image volumes are collected immediately prior to surgery, during surgery, and at the end of surgery, with the patient intubated and lying on the operating table in the operative position. In this paper we report initial results from six patients: one freehand biopsy, one stereotactic functional procedure, and four resections. We investigate intraoperative brain deformation by examining threshold boundary overlays and difference images and by measuring ventricular volume. We also present preliminary results obtained using a nonrigid registration algorithm to quantify deformation. We found that some cases had much greater deformation than others, and also that, regardless of the procedure, there was very little deformation of the midline, the tentorium, the hemisphere contralateral to the procedure, and ipsilateral structures except those that are within 1 cm of the lesion or are gravitationally above the surgical site.

    Title Measurement of Intraoperative Brain Surface Deformation Under a Craniotomy.
    Date December 1998
    Journal Neurosurgery
    Excerpt

    OBJECTIVE: Several causes of spatial inaccuracies in image-guided surgery have been carefully studied and documented for several systems. These include error in identifying the external features used for registration, geometrical distortion in the preoperative images, and error in tracking the surgical instruments. Another potentially important source of error is brain deformation between the time of imaging and the time of surgery or during surgery. In this study, we measured the deformation of the dura and brain surfaces between the time of imaging and the start of surgical resection for 21 patients. METHODS: All patients underwent intraoperative functional mapping, allowing us to measure brain surface motion at two times that were separated by nearly an hour after opening the dura but before performing resection. The positions of the dura and brain surfaces were recorded and transformed to the coordinate space of a preoperative magnetic resonance image, using the Acustar surgical navigation system (manufactured by Johnson & Johnson Professional, Inc., Randolph, MA) (the Acustar trademark and associated intellectual property rights are now owned by Picker International, Highland Heights, OH). This system performs image registration with bone-implanted markers and tracks a surgical probe by optical triangulation. RESULTS: The mean displacements of the dura and the first and second brain surfaces were 1.2, 4.4, and 5.6 mm, respectively, with corresponding mean volume reductions under the craniotomy of 6, 22, and 29 cc. The maximum displacement was greater than 10 mm in approximately one-third of the patients for the first brain surface measurement and one-half of the patients for the second. In all cases, the direction of brain shift corresponded to a "sinking" of the brain intraoperatively, compared with its preoperative position. Analysis of the measurement error revealed that its magnitude was approximately 1 to 2 mm. We observed two different patterns of the brain surface deformation field, depending on the inclination of the craniotomy with respect to gravity. Separate measurements of brain deformation within the closed cranium caused by changes in patient head orientation with respect to gravity suggested that less than 1 mm of the brain shift recorded intraoperatively could have resulted from the change in patient orientation between the time of imaging and the time of surgery. CONCLUSION: These results suggest that intraoperative brain deformation is an important source of error that needs to be considered when using surgical navigation systems.

    Title Prolactin, a Pituitary Hormone That Modifies Immune Responses. Proceedings of the Mini-symposium on Prolactin and Sle, Held at the 5th International Conference on Systemic Lupus Erythematosus, Cancun, Mexico.
    Date November 1998
    Journal Lupus
    Title Screening of Potential Cancer Preventing Chemicals As Antioxidants in an in Vitro Assay.
    Date June 1998
    Journal Anticancer Research
    Excerpt

    We used an azo-initiated fluorescence assay to rank a series of antioxidants, with the objective of selecting compounds for further evaluation as chemopreventive agents. Trolox was the positive control for the assay and, with an IC50 of 0.50 microM, was more active than any of the other 16 compounds examined. Three compounds, U83836E, glutathione, and purpurgallin, were only slightly less active with IC50's in the 1-3 microM range. Four other compounds were almost as active: protochatechuic acid, N-acetyl-L-cysteine, U74389G, and lipoic acid (reduced). This fluorescence-based assay for antioxidant activity is a rapid, economical way of ranking antioxidants for further development in the National Cancer Institute's chemoprevention program.

    Title Conformationally Defined Retinoic Acid Analogues. 4. Potential New Agents for Acute Promyelocytic and Juvenile Myelomonocytic Leukemias.
    Date May 1998
    Journal Journal of Medicinal Chemistry
    Excerpt

    We recently synthesized several conformationally constrained retinoic acid (RA) analogues [8-(2'-cyclohexen-1'-ylidene)-3, 7-dimethyl-2,4,6-octatrienoic acids with different alkyl substituents at 2' (R1) and 3' (R2) positions on the cyclohexene ring] (Muccio et al. J. Med. Chem. 1996, 39, 3625) as cancer chemopreventive agents. UAB8 (R1 = Et; R2 = iPr), which contains sufficient steric bulk at the terminal end of the polyene chain to mimic the trimethylcyclohexenyl ring of RA, displayed biological properties similar to those of RA. To explore the efficacy of this retinoid in acute promyelocytic leukemia (APL) and juvenile myelomonocytic leukemia (JMML), we evaluated UAB8 isomers in in vitro assays which measure the capacity of retinoids to inhibit aberrant myeloid colony growth from blood or bone marrow cells obtained from human JMML patients and in assays measuring the potential of retinoids to differentiate NB4 cells (an APL cell line). Both (all-E)- and (13Z)-UAB8 were 2-fold more active than RA in the NB4 cell differentiation assay; however, only (all-E)-UAB8 had comparable activity to the natural retinoids in the JMML cell assays. These results were compared to the biological effectiveness of a new retinoid, UAB30 [8-(3', 4'-dihydro-1'(2'H)-naphthalen-1'-ylidene)-3,7-dimethyl-2,4, 6-octatrienoic acid], which had different nuclear receptor binding and transactivational properties than UAB8. Relative to (all-E)-RA and (all-E)-UAB8, (all-E)-UAB30 bound well to RARalpha but did not activate transcription-mediated RARalpha homodimers, even though it was effective in RARbeta- and RARgamma-mediated transactivational assays. In APL assays, this retinoid had much reduced activity and was only moderately effective in JMML assays and in cancer chemoprevention assays.

    Title Screening of Potential Cancer-preventing Chemicals for Inhibition of Induction of Ornithine Decarboxylase in Epithelial Cells from Rat Trachea.
    Date April 1998
    Journal Oncology Reports
    Excerpt

    Sixty-one selected chemicals were evaluated in rat tracheal epithelial (2C5) cells for their capacity to inhibit induction (or inhibit directly) the enzyme ornithine decarboxylase, the activity of which is associated with cell growth and division. a-Difluoromethylornithine (DFMO) was used as a positive control. At non-toxic concentrations, six test compounds had substantial activity (values for IC50 DFMO/IC50 compound >1): N-(2-carboxyphenyl)-all-trans-retinamide, ZK 119010 ¿2-(4-hydroxyphenyl)-3-methyl-1-[6-(1-pyrrolidinyl)hexyl]-1H-indol-5- ol¿, curcumin, 18-a-olean-12-ene-3 ,23,28-triol, genistein and phenethyl isothiocyanate. These should be considered for further development as cancer preventive agents.

    Title Screening of Potential Cancer Preventing Chemicals for Induction of Glutathione in Rat Liver Cells.
    Date April 1998
    Journal Oncology Reports
    Excerpt

    With BRL 3A hepatocytes, a series of selected, potentially chemopreventive chemicals was evaluated for their capacity to elevate glutathione (GSH) levels. Since sodium selenite consistently increased GSH levels by approximately 70%, it was selected as a positive control. Of 62 test chemicals, eighteen stimulated GSH levels by >30%, but eleven of these had only a modest effect or displayed considerable toxicity. At non-toxic concentrations, seven compounds had substantial activity: black tea extract (decaffeinated), trans-chalcone, N-ethyl-9-cis-retinamide, indole-3-carbinol, dehydroepiandrosterone (DHEA) curcumin and N-(4-carboxyphenyl)retinamide. These should be considered for further development as cancer preventive agents.

    Title Biologically Active Heteroarotinoids Exhibiting Anticancer Activity and Decreased Toxicity.
    Date December 1997
    Journal Journal of Medicinal Chemistry
    Excerpt

    A series of retinoids, containing heteroatoms in a cyclic ring and called heteroarotinoids, were synthesized, and their biological activity was evaluated using tissue culture lines that have measurable responses to trans-retinoic acid (t-RA). Transglutaminase (TGase) was assessed in the human erythroleukemia cell line (GMO6141A) as an indicator of differentiation and apoptosis. Proliferation was evaluated in a human cervical cell line, CC-1, which exhibits dose-dependent alterations in growth rate in response to treatment with trans-retinoic acid. Activation of nuclear retinoic acid receptors was determined in a reporter cell line established from CC-1. The reporter line, called CC-B, contains a reporter gene controlled by a retinoic acid responsive element (RARE) and a thymidine kinase (tk) promoter. Treatment of the CC-B line with the heteroarotinoids resulted in a dose-responsive and retinoid-dependent regulation of reporter gene expression. The heteroarotinoids exhibited activity in all assays and correlated in a statistically significant manner between assays. RARE transactivation activity in CC-B cells correlated with induction of TGase in GMO6141A (R = 0.96) and with a decrease in the growth rate of CC-1 cells (R = -0.90). The ability of the selected heteroarotinoids to induce differentiation, inhibit proliferation, and activate nuclear receptors demonstrates the chemotherapeutic potential of these agents. In view of the biological activity cited, an in vivo toxicity study was conducted on male B6D2F1 mice with three heteroarotinoids, namely 8 [(2E,4E,6E)-3,7-dimethyl-7-(1,2,3,4-tetrahydro-4,4-dimeth ylthiochroman-6-yl)-2,4,6-heptatrienoic acid], 10 [(2E,4E,6E)-3,7-dimethyl-7-(1,2,3,4-tetrahydro-4,4-dimeth ylchroman-6-yl)-2, 4,6-heptatrienoic acid], and 13 [(E)-p-[2-(4,4-dimethylchroman-6-yl)propenyl]benzoic acid]. The mice were used with gavage of heteroarotinoids in corn oil [0.1, 0.2, 0.4, or 0.8 mg/kg] and with 0.01 or 0.05 mg/kg of TTNPB (5) [(E)-4-[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-1- propenyl]benzoic acid] as reference controls. The target organs affected in the mice by the three heteroarotinoids were those typically associated with t-RA (1) toxicity. The maximum tolerated dose (MTD) of 13 was 9.4 mg/kg/day, which was equal in toxicity to that of t-RA (1) and 1000-fold less toxic than TTNPB (5). The MTDs of 8 and 10 were 34 and 32 mg/kg/day, respectively, which is 3-fold less toxic than t-RA (1) and 3000-fold less toxic than TTNPB (5). The 3000-fold reduced toxicity, compared with only a 27% reduction biological activity of 8 and 10 with respect to that of TTNPB, observed in our assays indicates a good therapeutic ratio of these heteroarotinoids over the parent compound. The biological activity and reduced toxicity of these heteroartinoids demonstrate the potential efficacy as anticancer agents.

    Title Toxicity of Cordycepin in Combination with the Adenosine Deaminase Inhibitor 2'-deoxycoformycin in Beagle Dogs.
    Date December 1997
    Journal Toxicology and Applied Pharmacology
    Excerpt

    For 3 consecutive days, the nucleoside cordycepin (3'-deoxyadenosine) was administered as 1-hr iv infusions (0, 1, 4, 8, 10, or 20 mg/kg/day) to dogs. These doses were given 1 hr after a bolus iv injection (0.25 mg/kg/day) of 2'-deoxycoformycin (dCF), a potent inhibitor of adenosine deaminase. The hypothesis was that dCF would affect the toxicity of cordycepin. Plasma adenosine deaminase activity was strongly inhibited during the dose period and for 5 days following the final dose of dCF. Dogs given cordycepin alone showed no drug-related toxicities. In dogs given only dCF, drug-related toxicity to lymphoid tissue (lymphopenia and thymus lymphoid depletion), thrombocytopenia, and decreases in food consumption were observed. Cordycepin in combination with dCF produced symptoms associated with severe gastrointestinal toxicity (decreased body weights, emesis, diarrhea, decreased food consumption, and necrosis of the gastrointestinal tract) and bone marrow toxicity (lymphopenia, thrombocytopenia, and depletion of hematopoietic cells). The gastrointestinal tract and bone marrow were sites associated with dose-limiting toxicities. In surviving dogs, most of the effects were reversible by Day 30. The maximum tolerated dose of cordycepin administered in combination with dCF was 8 mg/kg/day (160 mg/m2/day) given daily for 3 days.

    Title Analysis of Human T Cell and B Cell Responses Against U Small Nuclear Ribonucleoprotein 70-kd, B, and D Polypeptides Among Patients with Systemic Lupus Erythematosus and Mixed Connective Tissue Disease.
    Date September 1997
    Journal Arthritis and Rheumatism
    Excerpt

    OBJECTIVE: To analyze T and B cell reactivity with U small nuclear RNP (snRNP) 70-kd, B, and D polypeptides among patients with connective tissue disease (CTD) and to examine the functional characteristics of snRNP-reactive T cell clones. METHODS: We used an snRNP enzyme-linked immunosorbent assay and immunoblotting to characterize antibodies in patients' sera. We used human recombinant fusion proteins 70 kd, B, and D to stimulate and clone snRNP-reactive T cells from CTD patients. We analyzed the cell surface phenotype, antigenic specificity, and cytokine profiles of T cell clones. RESULTS: Patients showed T cell responsiveness to snRNP polypeptides that paralleled their autoantibody reactivities. A total of 256 clones were generated, and clones were identified which were specific for the 70-kd, B, or D polypeptides. Clones expressed a T helper cell phenotype, and were found to produce substantial quantities of both interleukin-4 (IL-4) and interferon-gamma, and lesser quantities of IL-2 and IL-6. CONCLUSION: These results show that CTD patients have clonable circulating snRNP-reactive T cells that parallel the specificity of snRNP-reactive antibodies in their sera. The snRNP-reactive T cells exhibit a helper cell phenotype and produce cytokines which are important in B cell help and differentiation.

    Title Comparison and Evaluation of Retrospective Intermodality Brain Image Registration Techniques.
    Date July 1997
    Journal Journal of Computer Assisted Tomography
    Excerpt

    PURPOSE: The primary objective of this study is to perform a blinded evaluation of a group of retrospective image registration techniques using as a gold standard a prospective, marker-based registration method. To ensure blindedness, all retrospective registrations were performed by participants who had no knowledge of the gold standard results until after their results had been submitted. A secondary goal of the project is to evaluate the importance of correcting geometrical distortion in MR images by comparing the retrospective registration error in the rectified images, i.e., those that have had the distortion correction applied, with that of the same images before rectification. METHOD: Image volumes of three modalities (CT, MR, and PET) were obtained from patients undergoing neurosurgery at Vanderbilt University Medical Center on whom bone-implanted fiducial markers were mounted. These volumes had all traces of the markers removed and were provided via the Internet to project collaborators outside Vanderbilt, who then performed retrospective registrations on the volumes, calculating transformations from CT to MR and/ or from PET to MR. These investigators communicated their transformations again via the Internet to Vanderbilt, where the accuracy of each registration was evaluated. In this evaluation, the accuracy is measured at multiple volumes of interest (VOIs), i.e., areas in the brain that would commonly be areas of neurological interest. A VOI is defined in the MR image and its centroid c is determined. Then, the prospective registration is used to obtain the corresponding point c' in CT or PET. To this point, the retrospective registration is then applied, producing c" in MR. Statistics are gathered on the target registration error (TRE), which is the distance between the original point c and its corresponding point c". RESULTS: This article presents statistics on the TRE calculated for each registration technique in this study and provides a brief description of each technique and an estimate of both preparation and execution time needed to perform the registration. CONCLUSION: Our results indicate that retrospective techniques have the potential to produce satisfactory results much of the time, but that visual inspection is necessary to guard against large errors.

    Title Craniotomy Guidance Using a Stereo-video-based Tracking System.
    Date March 1997
    Journal Stereotactic and Functional Neurosurgery
    Excerpt

    In open intracranial neurosurgery, it is desirable to minimize exposure and to approach the target in the most accurate way possible. The VISLAN system described here employs a completely passive hand-held locator which is tracked by a video system and does not require a mechanical linkage nor cables. The system also tracks easily recognizable, constant, anatomical landmarks of the patient. By this means the initial registration of pre-operative imaging and the detection of, and correction for, patient movement can be accomplished. High-resolution MRI segmented interactively is used to define external surface and brain anatomy. Thus, a pre-operative patient representation (POPR) is planned. During the surgical procedure the patient's head is illuminated by structured light and stereo-video pictures obtained from two television cameras mounted above the head. The system is calibrated and registered with the POPR using a chamfered matching algorithm. The locator is also tracked in space by the video system, and its tip position shown in relation to the POPR on the video monitor.

    Title Conformationally Defined 6-s-trans-retinoic Acid Analogs. 3. Structure-activity Relationships for Nuclear Receptor Binding, Transcriptional Activity, and Cancer Chemopreventive Activity.
    Date November 1996
    Journal Journal of Medicinal Chemistry
    Excerpt

    We recently demonstrated that conformationally defined 6-s-trans-retinoic acid (RA) analogs were effective in the prevention of skin papillomas (Vaezi et al. J. Med. Chem. 1994, 37, 4499-4507) and selective agonists for nuclear receptor binding and activation (Alam et al. J. Med. Chem. 1995, 38, 2302-2310). In order to probe important structure-activity relationships, we evaluated a homologous series of four 6-s-trans-retinoids that are 8-(2'-cyclohexen-1'-ylidene)-3,7-dimethyl-2,4,6-octatrienoic acids with different substituents at 2' (R2) and 3' (R1) positions on the cyclohexene ring. UAB1 (R1 = R2 = H), UAB4 (R1 = R2 = Me), UAB7 (R1 = Me, R2 = iPr), and UAB8 (R1 = Et, R2 = iPr) contain alkyl R groups that mimic, to different extents, portions of the trimethylcyclohexenyl ring of RA. Both 9Z- and all-E-isomers of these retinoids were evaluated in binding assays for cellular retinoic acid-binding proteins (CRABP-I and CRABP-II), a nuclear retinoic acid receptor (RAR alpha), and a nuclear retinoid X receptor (RXR alpha). The all-E-isomers of UAB retinoids bound tightly to CRABPs and RAR alpha, the binding affinity of the all-E-isomer increased systematically from UAB1 to UAB8, and binding for the latter was comparable to that of all-E-RA. In contrast to RA, the (9Z)-UAB retinoids were at least 200-fold less active than the all-E-isomers in binding to RAR alpha. The (9Z)-UAB isomers exhibited increasingly stronger binding to RXR alpha, and (9Z)-UAB8 was nearly as effective as (9Z)-RA in binding affinity. The retinoids were also evaluated in gene expression assays mediated by RAR alpha and RXR alpha homodimers or RAR alpha/RXR alpha heterodimers. Consistent with the binding affinities, the (all-E)-UAB retinoids activated gene transciption mediated by RAR alpha homodimers or RAR alpha/RXR alpha heterodimers, while the (9Z)-UAB isomers activated only the RXR alpha homodimer-mediated transcription. The all-E- and 9Z-isomers of the UAB retinoids were further evaluated for their capacity to prevent the induction of mouse skin papillomas. When compared to RA, only the (all-E)-UAB retinoids containing bulky R1 and R2 groups were effective in this chemoprevention assay. (9Z)-RA displayed equal capacity as RA to prevent papillomas, while the 9Z-isomers of the UAB retinoids were much less effective. Taken together, these studies demonstrate that the cyclohexenyl ring substituents of 6-s-trans-UAB retinoids are important for their biological activities and that the chemopreventive effect of the all-E-isomers of these retinoids correlates well with their capacity to bind to RARs and activate RAR/RXR-mediated transcription.

    Title A Conformationally Defined 6-s-trans-retinoic Acid Isomer: Synthesis, Chemopreventive Activity, and Toxicity.
    Date January 1995
    Journal Journal of Medicinal Chemistry
    Excerpt

    A conformationally defined retinoic acid analog (1) which contains a dimethylene bridge to maintain the 6-s-trans orientation for two terminal double bonds in the polyene chain was synthesized. A Reformatsky reaction was utilized to extend the polyene chain of the starting enone, which provided exclusively the 9Z-configuration for the intermediate aldehyde. A Horners-Emmons condensation with this aldehyde then produced retinoic acid analogs with both 9Z- and 9Z,13Z-configurations. An I2-catalyzed isomerization of the intermediate 9Z-aldehyde yielded the all-E-aldehyde, which was olefinated as above to yield the (all-E)- and (13Z)-retinoic acid analogs of 1. Each configurational isomer of 1 was evaluated for its ability to inhibit the binding of retinoic acid to CRABP (chick skin) and to inhibit the chemical induction of ornithine decarboxylase in mouse skin. In each assay (all-E)-1 was the most active isomer, and this activity was comparable to or better than that for (all-E)-retinoic acid. (all-E)-1 and (13Z)-1 were both shown to be equally effective as (13Z)-retinoic acid in suppressing the proliferation of human sebaceous cells in vitro. (all-E)-1 was further evaluated for its ability to prevent the induction of mouse skin papillomas and to induce signs of vitamin A toxicity in mice. The cancer chemopreventive activity of (all-E)-1 was comparable to that of (all-E)-retinoic acid, and the toxicity was comparable to or slightly better than that of the natural vitamin.

    Title Combined and Three-dimensional Rendered Multimodal Data for Planning Cranial Base Surgery: a Prospective Evaluation.
    Date January 1995
    Journal Neurosurgery
    Excerpt

    Magnetic resonance (MR), X-ray computed tomography (CT), and angiographic images best depict soft tissue, bone, and blood vessels respectively. No one on its own is sufficient in the preoperative assessment of cranial base lesions. We have developed and evaluated a computational technique for the three-dimensional (3D) combination and display of multimodality images for planning cranial base surgery. This evaluation was prospective and performed in such a way that the results could be quantified. Eight patients (three acoustic neuromas, four subfrontal and suprasellar meningiomas, and one petrous apex meningioma) underwent MR, CT, and MR angiographic investigations. These images were registered with anatomical landmarks rather than an external frame. Two techniques were used to display the resulting combined images: multiple slices in which bone from CT was overlaid on soft tissue from registered MR and pseudo-3D-rendered movie sequences showing bone from CT, lesions and optic nerves from MR, and blood vessels from MR angiography. The advantages of the combined displays compared with those of conventional methods of viewing were assessed prospectively by the operating surgeon and by an independent surgeon, and the results were compared with operative findings. The preoperative assessment showed a significant improvement (P < 0.05, sign test) in the depiction of both individual structures (lesion and bone from overlaid slices and lesion and vasculature from 3D-rendered displays) and structural relationships (tumor-bone relationships from overlaid slices and of tumor-vasculature relationships from 3D-rendered displays). The operative findings indicated that a more accurate interpretation of this information was possible from the combined images.

    Title Diazinon Toxicity in Broilers.
    Date November 1994
    Journal Avian Diseases
    Excerpt

    Ten 3-day-old chicks were submitted from a flock experiencing high mortality. Necropsy revealed lacrimation, diarrhea, pleural effusion, hemorrhage and ulceration of the proventriculus, and swollen, hemorrhagic livers. Numerous yellow granules were present in the crop. Assayed crop contents contained 39 ppm diazinon [O,O-diethyl O-(2-isopropyl-4-methyl-6-pyrimidyl)phosphorothioate]. The insecticide had been applied to the litter to control fire ants. The high mortality abated after new litter was added on top of the old litter. Diazinon toxicosis was traced to ingestion of diazinon-impregnated granules and was reproduced experimentally.

    Title Increased Frequency of Mutations in the Hprt Gene of T Cells Isolated from Patients with Anti-u1-70kd-autoantibody-positive Connective Tissue Disease.
    Date November 1994
    Journal International Archives of Allergy and Immunology
    Excerpt

    Mixed connective tissue disease (MCTD) is characterized by the presence of high titers of anti-U1-70kD autoantibodies which are the result of substantial B cell activation. The hprt gene encodes the constitutively expressed enzyme hypoxanthine-guanine phosphoribosyl transferase which is active in the purine salvage pathway. Rapidly dividing cells randomly accumulate gene mutations, including mutations in the hprt gene. These mutations may be used to identify activated cells. If activated T cells play a role in the pathogenesis of MCTD, an increased frequency of mutations in the hprt gene might be expected among T cells isolated from such patients. To examine this hypothesis, we isolated and cloned T cells from 10 anti-U1-70kD-autoantibody-positive MCTD patients and determined the precursor frequencies of cells possessing mutations in hprt by comparing the frequency of cells grown in the presence and absence of the purine analogue 6-thioguanine. We found that the frequency of 6-thioguanine-resistant hprt-negative T cells was significantly increased among MCTD patients (mean 566/10(6); range 122-2,845/10(6)) versus age- and sex-matched controls (mean 42/10(6); range 21-78/10(6); p < 0.003). These results demonstrate that there is an increase in the measured mutant frequency of T cells from MCTD patients. Such T cells may play a role in the pathogenesis of this disease.

    Title Treatment of Endometriosis by Carbon Dioxide Laser During Gamete Intrafallopian Transfer.
    Date October 1994
    Journal Journal of the American College of Surgeons
    Excerpt

    BACKGROUND: Endometriosis is often encountered during laparoscopy performed for gamete intrafallopian transfer (GIFT) procedures. STUDY DESIGN: A prospective randomized study involving 44 patients with endometriosis (American Fertility Society (AFS) stages I through IV) was conducted. All patients underwent controlled ovarian hyperstimulation followed by laparoscopic GIFT procedures. Twenty-one patients had no carbon dioxide laser vaporization of endometriosis and twenty-one patients did receive laser vaporization. Two patients could not have GIFT performed due to tubal and peritubal disease. RESULTS: The results showed a clinical pregnancy rate of 38.1 percent in the treatment groups versus 47.9 percent in the control group (not significant, Chi square, and Student's test). The live birth rate from both groups was identical, at 23.8 percent per group. CONCLUSIONS: We conclude that CO2 laser vaporization of AFS stages I to IV endometriosis at the time of the GIFT procedure does not significantly affect either the clinical pregnancy rate or live birth rate from this form of assisted reproductive technology.

    Title Accurate Frameless Registration of Mr and Ct Images of the Head: Applications in Planning Surgery and Radiation Therapy.
    Date May 1994
    Journal Radiology
    Excerpt

    PURPOSE: To evaluate the feasibility and efficacy of a three-dimensional image registration technique for planning skull base surgery, performing frameless image registration for stereotaxic neurosurgery, and staging nasopharyngeal carcinoma. MATERIALS AND METHODS: Computed tomographic (CT) and magnetic resonance (MR) images from 35 patients were registered by identifying 12-16 homologous landmarks with each modality. Images were displayed as overlaid sections or rendered three-dimensional scenes. The clarity of the combined images from 15 patients undergoing skull base surgery was compared with that of the conventional displays. RESULTS: Images were combined for three applications, with an accuracy of 1-2 mm. For the 15 patients undergoing skull base surgery, the combined images were significantly better at depicting the relationship between bone and lesion than conventional display (P < .01). CONCLUSION: MR and CT images of the head can be accurately registered without using external markers or substantially altering image acquisition protocols. The resulting images can show the radiologic information more clearly than conventional viewing.

    Title Accurate Combination of Ct and Mr Data of the Head: Validation and Applications in Surgical and Therapy Planning.
    Date March 1994
    Journal Computerized Medical Imaging and Graphics : the Official Journal of the Computerized Medical Imaging Society
    Excerpt

    A method is presented for the accurate combination of magnetic resonance (MR) and computed tomographic (CT) images of the head. Our technique is based on user identified 3D landmarks followed by data combination and display as adjacent slices, a single fused slice representation, colour overlay and three-dimensional (3D) rendered scenes. Validation with a point phantom and computer simulation has established the relationship of registration accuracy with point location accuracy, the number of points used and their spatial distribution. The technique is in clinical use in the planning of skull base surgery, transferring MR images acquired without a stereotaxic frame to stereotaxic space, and staging and planning therapy of nasopharyngeal tumours.

    Title Human T Cell Clones Reactive Against U-small Nuclear Ribonucleoprotein Autoantigens from Connective Tissue Disease Patients and Healthy Individuals.
    Date January 1994
    Journal Journal of Immunology (baltimore, Md. : 1950)
    Excerpt

    SLE and mixed connective tissue disease (MCTD) are characterized by the presence of high titers of autoantibodies against uridine-rich RNA-small nuclear ribonucleoprotein (snRNP) Ag. Because the presence of such snRNP-reactive autoantibodies has recently been shown to be associated with polymorphisms of HLA, this study was undertaken to determine whether snRNP-reactive T cells could be identified and characterized from patients. PBMC were stimulated with affinity-purified snRNP Ag and cloned by limiting dilution in the presence of rIL-2 and rIL-4, snRNP-reactive human T cell clones were generated from three patients and two healthy blood donors who possessed disease-associated HLA genotypes. The cell surface phenotype of clones determined by flow cytometry was CD3+, CD4+, CD45RO+, TCR V alpha beta+. TCR V beta analysis, performed using V beta-specific primers and polymerase chain reaction, revealed that the T cell lines generated were clonal; a limited number of TCR V beta genes were expressed among the clones tested. All clones tested by mAb blocking of Ag-induced proliferation were restricted by HLA-DR. Several T cell clones were identified that were specific for B'/B or D polypeptides. These results demonstrate that snRNP-reactive T cells can be isolated from SLE and MCTD patients in vitro, and that Ag-driven expansion of such T cells could play a role in the immunopathogenesis of these diseases in vivo.

    Title Multisystemic Adenovirus Infection in Broiler Chicks with Hypoglycemia and Spiking Mortality.
    Date September 1993
    Journal Avian Diseases
    Excerpt

    The search for a solitary cause of spiking mortality (so-called spiking mortality syndrome [SMS]) among broiler chicks has been thwarted by the fact that many agents will cause similar mortality histograms. Recently, severe hypoglycemia has been said to be a characteristic finding in chicks that die with SMS. In the present case study, we report adenovirus inclusions in the pancreas, small intestines, and liver of chicks with hypoglycemia and spiking mortality. We attributed the hypoglycemia and mortality to hepatic insufficiency.

    Title Treatment of a Bacterial (mycotic) Intracranial Aneurysm Using an Endovascular Approach.
    Date June 1993
    Journal Neurosurgery
    Excerpt

    The case of a patient with a bacterial intracranial aneurysm treated with antibiotics and endovascular obliteration is reported. The patient presented with dysphasia and right hemiparesis. A medical workup revealed endocarditis and associated heart valve dysfunction with no evidence of congestive heart failure. Computed tomography demonstrated subarachnoid hemorrhage, and a subsequent cerebral arteriogram showed a distal left middle cerebral aneurysm, which, as demonstrated by angiography, did not change in size in 2 weeks. An endovascular approach was used to obliterate the aneurysm and its parent vessel. Endovascular techniques may be used to obliterate certain bacterial intracranial aneurysms, particularly in patients who harbor distal aneurysms.

    Title Hla-dpb1*0401 is Associated with the Presence of Autoantibodies Reactive with the U1-70 Kd Polypeptide Antigen of U1-small Nuclear Ribonucleoprotein Among Connective Tissue Disease Patients.
    Date November 1992
    Journal Tissue Antigens
    Title Retinoyl Beta-glucuronide: Lack of Binding to Receptor Proteins of Retinoic Acid As Related to Biological Activity.
    Date April 1992
    Journal Biochemical Pharmacology
    Excerpt

    Retinoid beta-glucuronides have emerged as biologically active, water-soluble, natural retinoids with relatively few toxic and teratogenic effects. The mechanism of action of these glucuronides in the control of epithelial differentiation, growth, and tumorigenesis is unknown. Since retinoyl beta-glucuronide (RAG) contains a free carboxyl group, we studied the interactions of RAG with cellular retinoic acid-binding protein (CRABP) and nuclear receptors of retinoic acid (RARs), the possible mediators of the biological action of retinoic acid (RA). RAG did not exhibit any significant affinity to bind either CRABP or RARs. During 24- and 48-hr incubations of RAG in chick cytosol, detectable amounts of RA were generated which interacted with the RA receptors. In chick skin, the biological activity of RAG may be due to this slowly released RA. Other possible modes of action of RAG are suggested.

    Title Registration of Mr and Ct Images for Skull Base Surgery Using Point-like Anatomical Features.
    Date January 1992
    Journal The British Journal of Radiology
    Excerpt

    We have developed a registration technique for combining magnetic resonance imaging (MRI) and computed tomography (CT) images of the skull base for use in surgical planning. The technique is based on user identification of point-like landmarks visible in both modalities. The combination of images involves a small amount of expert interaction, is relatively quick and preliminary evaluation indicates that it is accurate to within 1.5 mm. Registered or fused images can be viewed either on an image processing workstation, or fused images can be printed onto conventional film for convenience in clinical use. We present one patient in order to demonstrate the technique's indications and advantages.

    Title Perceptual Characteristics of the Amiloride-suppressed Sodium Chloride Taste Response in the Rat.
    Date January 1991
    Journal Behavioral Neuroscience
    Excerpt

    The contribution of amiloride-sensitive membrane components to the perception of NaCl taste was assessed by using a conditioned taste aversion procedure. Eight independent groups of adult rats were conditioned to avoid either 0.1M NaCl, 0.5M NaCl; 0.1M NH4Cl, or 1.0M sucrose while their tongues were exposed either to water or to the sodium transport blocker amiloride hydrochloride. In contrast to rats exposed to water during conditioning, rats exposed to amiloride were unable to acquire a conditioned taste aversion to 0.1M NaCl. Differences in the acquisition of taste aversions between the amiloride- and nonamiloride-treated groups were not apparent when the conditioned stimulus (CS) was 0.5M NaCl, 0.1M NH4Cl, or 1.0M sucrose. Although the magnitude of the 0.5M NaCl aversion was similar between amiloride- and non-amiloride-treated rats, the perceptual characteristics of the CS differed between groups. Analyses of stimulus generalization gradients revealed that amiloride-treated rats generally avoided all monochloride salts after conditioning to 0.5M NaCl but not nonsodium salts or nonsalt stimuli. In contrast, rats not treated with amiloride only generalized the 0.5M NaCl aversion to sodium salts. No differences in generalization gradients occurred between groups when the CS was 0.1M NH4Cl or 1.0M sucrose. These findings suggest that the "salty" taste of NaCl is primarily related to the amiloride-sensitive portion of the functional taste response in rats. Conversely, the portion of the NaCl response insensitive to amiloride appears to have "sour-salty" perceptual characteristics and does not appear to be perceived as being salty.

    Title Electromagnetic Field Focusing Probe (effp)--a New Angioplasty Tool.
    Date December 1988
    Journal Angiology
    Excerpt

    An electromagnetic field focusing probe (EFFP) consists of a radiofrequency generator, solenoidal coil, and a hand-held or catheter probe. The probe is operated in the near field (distance within one wave length of an electromagnetic field source) of a coil, which induces eddy current in a biological tissue. The induced eddy current is converged maximally at the tip of the probe upon contact of the tip with the tissue. The probe produces very high temperatures depending on the wattage selected. In this study, the EFFP was used to evaporate atheromatous plaques in human cadaver abdominal aorta specimens, which were then studied histologically. Gas produced by this technique was analyzed and the volume found to be related to power delivered, but in such small amounts as to be of no embolic significance. While temperature varied with wattage and time of application, it was maximal at the probe tip and easily controlled, resulting in clean obliteration of plaque.

    Title Precision Surgery with an Electromagnetically Induced Current Convergence Probe Application in Aneurysm Treatment, Angioplasty, and Brain Tumor Resection in in Vivo and in Vitro Models.
    Date November 1988
    Journal Medical Instrumentation
    Excerpt

    A hand-held probe, or one introduced through a catheter, rapidly produces an extremely high, tissue-vaporizing temperature in a precisely defined manner enabling surgeons or interventional radiologists to perform angioplasty, thrombose aneurysms, and vaporize tumors. The probe is operated in a near field of an inductive coil, and the current induced in the biologic tissue is converged maximally at the tip of the probe at the resonance frequency of both the inductor and the probe, producing a maximum temperature in excess of 1400 degrees C. Radio-frequency power controls the probe-tip temperature. The operation of the probe is comparable to that of a CO2 or YAG laser and is complementary to laser-surgical techniques. The low cost relative to lasers and simplicity of the device including its disposable components make the prospect of commercialization of this device promising.

    Title Properties of Electromagnetic Field Focusing Probe.
    Date November 1988
    Journal Angiology
    Excerpt

    The electromagnetic field focusing (EFF) apparatus consists of a radio frequency generator, solenoidal coil, and a hand-held or catheter probe. Applications such as aneurysm treatment, angioplasty, and neurosurgery in various models have been reported. The probe is operated in the near field (within one wavelength of an electromagnetic field source) of a coil inducing eddy currents in biological tissues, producing maximal convergence of the induced current at the probe tip. The probe produces very high temperatures depending on the wattage selected for the given radio frequency of output power. The high temperature can be used in cutting, cauterizing, or vaporizing. The EFF probe is comparable to different types of lasers and to bipolar and monopolar cautery. The EFF probe can be used with catheters or endoscopes. Objectives of this study were to determine what the thermal properties of the EFF probe are and how instrument parameters can be varied to obtain different temperatures in the tissue near the probe tip. In this study an F2 catheter was used as an insulated sheath and the tip of the guide wire was used as the probe tip. Different powers, wave forms, coil-to-probe distances, and probe-tip lengths were tested on a phantom that simulates tissue electrical properties. Some of the experiments were conducted under normal saline to simulate treatment of tissue with body fluids such as blood vessels or brain tissue under normal physiologic conditions. It is concluded that the EFF probe has the advantages of easy manipulation, relative safety, cost effectiveness, and a high degree of spatial control.(ABSTRACT TRUNCATED AT 250 WORDS)

    Title Influences of Dietary Sodium on Functional Taste Receptor Development: a Sensitive Period.
    Date November 1988
    Journal Science (new York, N.y.)
    Excerpt

    Restriction of maternal dietary sodium on or before embryonic day 8 reduced taste responses of the chorda tympani nerve to sodium chloride in the offspring. The response attenuation was substantial; responses to sodium chloride in the offspring of deprived rats were approximately 40 percent of those in control animals. Instituting the low sodium diet at embryonic day 10 or later did not produce functional changes. Thus, a sensitive period for the gustatory system exists, and the abrupt transition from maximal environmental susceptibility to no susceptibility occurs during a 2-day prenatal period. Moreover, events important in determining the developmental fate of taste membrane components occur before the initial formation of taste buds.

    Title Automatic External Defibrillators: Importance of Field Testing to Evaluate Performance.
    Date January 1988
    Journal Journal of the American College of Cardiology
    Excerpt

    A new automatic external defibrillator was tested first against a tape-recorded data base of rhythms and then during use by first-responding fire fighters in a tiered emergency system. The sensitivity for correctly classifying ventricular fibrillation and ventricular tachycardia was substantially less during clinical testing in 298 patients than would have been predicted from preclinical results: 52% of ventricular fibrillation analyses in patients were correctly classified versus 88% of episodes in the data base, and 22 versus 86%, respectively, for ventricular tachycardia (p less than 0.001). The detection algorithm was modified and evaluated further in another 322 patients. The modified detector performed substantially better than did the one that had been designed from prerecorded rhythms: with its use, 118 (94%) of 125 patients in ventricular fibrillation were counter-shocked compared with 91 (77%) of 118 similar patients with use of the initial algorithm (p less than 0.001). No inappropriate shocks were delivered. This improvement resulted in a shorter time to first shock (p less than 0.01) and more shocks being delivered for persistent or recurrent episodes of ventricular fibrillation (p less than 0.05). Of 620 patients treated with the automatic defibrillator, 243 (39%) had ventricular fibrillation; 57 (23%) of the 243 regained pulse and blood pressure before paramedics arrived, 141 (58%) were admitted to hospital and 71 (29%) were discharged.(ABSTRACT TRUNCATED AT 250 WORDS)

    Title Electromagnetically Induced Focused Heat in the Treatment of Surgically Created Aneurysm Models.
    Date October 1987
    Journal Investigative Radiology
    Excerpt

    A hand-held radiofrequency (rf) probe of a novel design based on the principle of the induced current convergence was used to treat aneurysm models using focused hyperthermia. Aneurysms were created surgically in rats by a side-to-side anastomosis between the inferior vena cava and the abdominal aorta or by grafting a donor abdominal aorta from one rat onto the abdominal aorta of another rat. Aneurysms were treated by inserting the 0.3-mm diameter probe tip into the fundus and applying the power for brief periods (0.5-1.5 sec) using a foot pedal. Collapse of the fundus was observed as the result of the heat-induced thrombosis. Thermal distribution in the immediate vicinity of the probe as well as the heating rate were measured in a uniformly dielectric phantom and in rat vessels. The aneurysms were histologically examined immediately, three days, and three weeks after the treatment. Complete obliteration of the aneurysms and patency of the parent arteries were confirmed. Partial integrity of the vessels around the lesion was also confirmed.

    Title Noninvasive Tumor Volume Measurement Using Magnetic Resonance (mr) Imaging and an Open Sided Saddle Coil.
    Date March 1987
    Journal Physiological Chemistry and Physics and Medical Nmr
    Excerpt

    A magnetic resonance (MR) imaging scanner operated at 0.5 T with a specially constructed receiving coil was used to measure volumes of primary spontaneous tumors in rats and guinea pigs. The coil was used to improve the signal to noise ratio (S/N) of the MR images of tumors in these small animals. The tumor volume was determined by the summation of the volume of contiguous slices or ellipsoid approximation. The accuracy of the volume measurement was better when the numerical integration was used in calculating the slice volume. The open sided saddle (OSS) coil used as the receiving coil gave better S/N than that of the standard head coil.

    Title Effects of Dietary Nacl Deprivation During Early Development on Behavioral and Neurophysiological Taste Responses.
    Date September 1986
    Journal Behavioral Neuroscience
    Excerpt

    In order to determine whether the gustatory system can be modified by restricting dietary NaCl during early development, neurophysiological taste responses were recorded in rats at various times after deprivation, and behavioral taste preferences were measured in adults. Rats deprived of dietary NaCl from the third day of gestation to 12 days postnatally and then placed on a NaCl-replete diet had chorda tympani nerve responses similar to those of nondeprived rats when recordings were made at 28 days of age and older; however, preferences for NaCl solutions over water were significantly less than those of controls when tested at adulthood. NaCl deprivation in pups from the third day of gestation to approximately 35 days postnatally resulted in altered chorda tympani nerve responses to NaCl but not to other stimuli such as NH4Cl and KCl. Therefore, restriction of dietary NaCl at a period in the rat's development when peripheral and central taste responses are changing results in short-term alterations in peripheral neural responses and in long-term changes in preference behaviors.

    Title Cardiac Arrest Treated with a New Automatic External Defibrillator by Out-of-hospital First Responders.
    Date June 1986
    Journal The American Journal of Cardiology
    Excerpt

    Two hundred sixty patients in cardiac arrest were treated with an automatic external defibrillator by first-responding firefighters before arrival of paramedics. On average, first responders arrived 5 minutes before paramedics. Of 118 patients with ventricular fibrillation, 91 (77%) were administered shocks, 21 (23%) of whom had return of pulse and blood pressure by the time paramedics arrived. Fifty-six (62%) were admitted to the hospital and 30 (33%) survived. The survival rate for all 118 victims discovered with ventricular fibrillation was 27%. The device correctly classified the initial and all subsequent rhythms in 92 patients with asystole, 46 with electromechanical dissociation, and 22 others with presumed respiratory arrest; it did not deliver any inappropriate shocks to patients or to the rescuers using the device. An automatic external defibrillator can be used by first responders as an adjunct to basic life support, and its use may improve survival by shortening the time to defibrillation.

    Title Pharmacokinetic and Metabolism Studies of Two Novel 1-deaza-7,8-dihydropteridines in Mice.
    Date March 1986
    Journal Drug Metabolism and Disposition: the Biological Fate of Chemicals
    Excerpt

    The disposition of two 1-deaza-7,8-dihydropteridines, NSC 269416 and NSC 350386, was studied in mice dosed iv. After dosing with 25 mg/kg of NSC 269416, serum levels fell in two phases with half-lives of 3.1 and 32 min. Highest levels were in liver, kidney, spleen, lungs, and small intestines; little compound was detected in brain, muscle, or fat. Although no metabolites were detected in serum or tissues, four metabolites, but no parent compound, were present in urine. After administration of 7 mg/kg of NSC 350386, serum levels fell with apparent half-lives of 4.3 (alpha-phase) and 49 min (beta-phase). At most times of analysis, liver, kidney, spleen, lung, brain, fat, and small intestines had similar concentrations of the compound. In 24 hr, less than 5% of the dose was excreted into urine unchanged. Analyses of collected urinary products indicated that, in vivo, NSC 350386 was metabolically hydroxylated and conjugated with glucuronic acid and also cleaved, a process involving removal of the ethoxycarbonyl group.

    Title Development of Taste Responses in Rat Nucleus of Solitary Tract.
    Date December 1983
    Journal Journal of Neurophysiology
    Excerpt

    Extracellular responses from neurons in the nucleus of the solitary tract (NST) were studied in rats aged 5 days to adulthood during chemical stimulation of the tongue with monochloride salts, citric and hydrochloric acids, sucrose, sodium saccharin, and quinine hydrochloride. Multiunit taste responses were recorded in rats at 5-7 days of age and single-unit responses were recorded from 111 neurons in four other age groups of 14-20 days, 25-35 days, 50-60 days, and adult. NST neurons in rats aged 5-7 days consistently responded to relatively high concentrations (0.5 M) of NH4Cl and KCl and to citric and hydrochloric acid. However, they often did not respond to 0.5 M NaCl or to 0.1 M NH4Cl. Single NST neurons in rats aged 14 days and older characteristically responded to all 0.1 and 0.5 M salts and to both acids. At least 75% of neurons also responded to sucrose and sodium saccharin, and 46% responded to all of these stimuli and quinine hydrochloride. After 14 days, no developmental changes occurred in the number of stimuli to which neurons responded. There were substantial developmental alterations in the response magnitudes to some chemical stimuli. Average response frequencies increased after 35 days of age for 0.1 and 0.5 M NaCl, LiCl, KCl, and for sucrose and sodium saccharin. Response frequencies for NH4Cl, citric and hydrochloric acid, and quinine hydrochloride, however, did not change throughout development. The proportion of single NST neurons that responded maximally to specific monochloride salts did not change during development. Most single neurons in all age groups responded equally well to NH4Cl, NaCl, and LiCl. No NST neuron responded maximally to KCl. There were also no developmental differences in response latencies in rats aged 14 days and older. Response frequencies of second-order NST neurons generally reflect changes in responses from the primary afferent, chorda tympani fibers, throughout development; however, the increases in salt response frequencies from NST neurons occur comparatively later in development. Furthermore, at all ages, the taste responses to monochloride salts include higher response frequencies and a general loss in response specificity in NST compared to chorda tympani neurons.(ABSTRACT TRUNCATED AT 400 WORDS)

    Title Ammonia and Urea in Corn Silage-based Complete Mixed Diets for Dairy Cows.
    Date June 1983
    Journal Journal of Animal Science
    Excerpt

    Source of supplemental N was evaluated in three corn silage-based complete mixed diets (CMD) fed to lactating dairy cows. Diets were formulated to be isonitrogenous and contained 60% corn silage and 40% concentrate on a dry matter basis. Diets were: CMD-A, ammoniated corn silage (ammonia provided 16% of total N) plus concentrate; CMD-U, untreated corn silage and concentrate (16% of total N from urea) and CMD-S, untreated corn silage plus concentrate with soybean meal. Ammoniation at 1.0% of dry weight increased crude protein content of silage from 8.5 to 12.7%. Daily means for cows fed CMD-A, CMD-U and CMD-S were: 24.2, 24.3 and 24.5 kg of fat-corrected milk; 3.17, 3.10 and 3.15% milk protein; 3.41, 3.67 and 3.63% milk fat and 3.02, 2.99 and 3.02 kg intake of total dry matter/100 kg body weight. Differences were not significant except for reduced milk fat percentage for cows fed the ammoniated corn silage diet. Both anhydrous ammonia and urea at 16% of total dietary N were found to be practical and economical substitutes for part of the supplemental soy protein. When compared to CMD with all soybean protein, greater savings in feed costs resulted from inclusion of ammoniated corn silage than with inclusion of urea.

    Title Control of Methicillin-resistant Staphylococcus Aureus in a Burn Unit: Role of Nurse Staffing.
    Date January 1983
    Journal The Journal of Trauma
    Excerpt

    We investigated retrospectively the spread of methicillin-resistant Staphylococcus aureus (MRS) in a burn unit. During 8 months, 34% of the patients acquired MRS, and transmission continued despite barrier isolation precautions and treatment of colonized personnel with topical intranasal antibiotics. Several findings suggested MRS was spread primarily by contact transmission involving personnel: case-control comparison showed burn size to be the major host risk factor for colonization; correlation analysis of environmental factors revealed a significant (p = 0.001) association of new cases with increased patient load and with staffing by overtime or temporary nurses; and environmental sampling yielded few colonies of MRS. The outbreak halted following implementation of control measures, among which assignment of separate nurses to colonized patients appeared to be essential. The association of different nurse staffing variables with persistence then eradication of MRS suggests nurse staffing may have been an important factor in staphylococcal transmission.

    Title Identification of Metabolites of 9-beta-d-arabinofuranosyl-2-fluoroadenine, an Antitumor and Antiviral Agent.
    Date October 1982
    Journal Biochemical Pharmacology
    Excerpt

    Analysis of blood from a dog given a 400 mg/m2 dose of 9-beta-D-arabinofuranosyl-2-fluoroadenine (2-F-araA) led to the identification of parent drug and a major metabolite, 9-beta-D-arabinofuranosyl-2-fluorohypoxanthine. 2-Fluoroadenine, a toxic derivative of 2-F-araA, was not detected in blood within the limits of detection, suggesting that parent drug was absorbed and distributed without systemic exposure to this toxic derivative. Parent drug, 2-fluoroadenine, and 9-beta-D-arabinofuranosyl-2-fluorohypoxanthine were identified in urine of dog, monkey, and mouse.

    Title Developmental Changes in Taste Response Characteristics of Rat Single Chorda Tympani Fibers.
    Date August 1982
    Journal The Journal of Neuroscience : the Official Journal of the Society for Neuroscience
    Title Selective Uptake and Retention of Anticancer Agents by Sensitive Cells.
    Date February 1981
    Journal Cancer Chemotherapy and Pharmacology
    Excerpt

    Considerable evidence has been accumulated to demonstrate that sensitive tumor cells in experimental animals take up and retain at least some effective anticancer drugs to a greater extent than normal tissues, thus providing a greater degree of exposure and accounting for the selective effect of the drugs. In sensitive cells, DNA synthesis is inhibited for prolonged periods, whereas in cells less sensitive the time of inhibition is shorter. In those cases examined where a metabolite, formed intracellularly, is the active form of the agent, the metabolite is produced and is retained to a greater extent than in normal tissues.

    Title Toxic-shock Syndrome in Menstruating Women: Association with Tampon Use and Staphylococcus Aureus and Clinical Features in 52 Cases.
    Date January 1981
    Journal The New England Journal of Medicine
    Excerpt

    To determine the risk factors associated with toxic-shock syndrome (TSS) in menstruating women, we conducted a retrospective telephone study of 52 cases and 52 age-matched and sex-matched controls. Fifty-two cases and 44 controls used tampons (P < 0.02). Moreover, in case-control pairs in which both women used tampons, cases were more likely than controls to use tampons throughout menstruation (42 of 44 vs. 34 of 44, respectively; P < 0.05). There were no significant differences in brand of tampon used, degree of absorbency specified on label, frequency of tampon change, type of contraceptive used, frequency of sexual intercourse, or sexual intercourse during menstruation. Fourteen of 44 cases had one or more definite or probable recurrences during a subsequent menstrual period. In a separate study, Staphylococcus aureus was isolated from 62 of 64 women with TSS and from seven of 71 vaginal cultures obtained from healthy controls (P < 0.001).

    Title Distribution and Elimination of Melphalan in Rats and Monkeys and Distribution in Tumors of Mice Bearing L1210 or P388 Leukemias Sensitive and Resistant to This Agent.
    Date January 1981
    Journal Cancer Treatment Reports
    Excerpt

    Following iv injection, melphalan was eliminated monophasically from rat serum (half-life = 0.87 hour) and monkey serum (half-life = 1.9 hours) and in rat bile (half-life = 2.4 hours) and monkey urine (half-life = 1.3 hours). In rat bile and monkey urine, 2% and 20% of the dose, respectively, was excreted in 12 hours as unchanged melphalan. At each time of tissue assay (0.5-4 hours after injection), rat spleen contained less melphalan than serum, liver, or kidneys. The kidneys and bile of monkeys contained more melphalan that serum, liver, or spleen. Only a small amount of radioactivity from labeled melphalan appeared in the feces of monkeys. Melphalan reached higher concentrations in implants of P388 and L1210 leukemia cells sensitive to melphalan than in cell lines resistant to this drug. Furthermore, the amounts of radioactivity bound to macromolecules of the sensitive tumors were higher.

    Title Disposition of 9-beta-d-arabinofuranosyl-2-fluoroadenine in Mice, Dogs, and Monkeys.
    Date August 1980
    Journal Drug Metabolism and Disposition: the Biological Fate of Chemicals
    Excerpt

    The metabolic disposition of 9-beta-D-arabinofuranosyl-2-fluoroadenine (2-F-AraA) has been studied in mice, dogs, and monkeys after iv administration. Following injection of 2-F-AraA (30 mg/m2) into mice, serum levels fell with apparent half-lives of 17 min for the alpha-phase and 72 min for the beta-phase. For dogs given the same dose, these values were less than 5 and 112 min, and, for monkeys, 26 and 125 min, respectively. A higher concentration of metabolites was present in the serum of dogs than in the serum of mice and monkeys. Phosphorylated derivatives of 2-F-AraA were present in each of several mouse tissues examined; liver contained the highest concentration. In 24 hr, mice excreted more than half of the administered compound in the urine as unchanged 2-F-AraA. For dogs given a dose of 400 mg/m2, a single phase of disappearance of the drug (t1/2 = 130 min) was observed. For a single monkey, there were two phases, with half-lives of 15 min and 6.7 hr. In the urine, monkeys excreted about half of either dose as parent compound; but dogs excreted only about one-fourth as unchanged drug. These data indicate that 2-F-AraA is extensively metabolized by dogs but less so by mice and monkeys.

    Title Prevalence of Antibody to Legionella Pneumophila in Middle-aged and Elderly Americans.
    Date April 1980
    Journal The Journal of Infectious Diseases
    Excerpt

    An indirect fluorescent antibody (IFA) test was used to establish the background prevalence of antibody to Legionella pneumophila in single serum specimens from 1,143 persons. The serum specimens had been obtained from volunteers 46 years of age and older who were not acutely ill and who resided in the areas of Atlanta, Georgia; Washington, D.C.; Houston, Texas; and Rochester, New York. The overall prevalence of seropositivity (reciprocal titer, greater than or equal to 64) was 1.7%. The prevalence of seropositivity did not vary with age, sex, or geographic location. Groups of persons in which the prevalence of reciprocal titers of greater than or equal to 64 is significantly higher than 1.7% may have unusually great exposure to L. pneumophila. In the population tested, a reciprocal IFA titer of greater than or equal to 64 would have a specificity of 98.3% in the diagnosis of an acute illness as Legonnnaires' disease.

    Title Nonpneumonic, Short-incubation-period Legionellosis (pontiac Fever) in Men Who Cleaned a Steam Turbine Condenser.
    Date September 1979
    Journal Science (new York, N.y.)
    Excerpt

    Pontiac fever affected ten men who had cleaned a steam turbine condenser with compressed air. Previous epidemics of Pontiac fever and Legionnaires' disease--both caused by Legionella Pneumophila (proposed sp. nov.)--involved "airborne spread" from air-conditioning cooling towers or evaporative condensers. Aerosols of contaminated water in heat-rejection systems appear to be important sources of epidemic legionellosis.

    Title Changing Phage Typing Patterns of Epidemic Gentamicin-resistant Staphylococcus Aureus. Evidence for Transmission of Gentamicin Resistance.
    Date May 1979
    Journal Lancet
    Excerpt

    In a 10-week period, infection with gentamicin resistant Staphylococcus aureus appeared in 24 adults and infants in one hospital. Medical staff were affected first, and subsequently 16 infants in the neonatal intensive-care unit. The gentamicin-resistant staphyloccal isolates showed three distinct phage susceptibility patterns in two distinct phage groups during the early, middle, and late phases of the outbreak. Although not confirmed with in-vitro or in-vivo laboratory data, this outbreak suggests that gentamicin resistance may be transferred between different strains of Staph. aureus in vivo.

    Title Comparison of the Properties of Metabolites of Ccnu.
    Date February 1978
    Journal Biochemical Pharmacology
    Title Nucleosides of 2-aza-purines--cytotoxicities and Activities As Substrates for Enzymes Metabolizing Purine Nucleosides.
    Date September 1976
    Journal Biochemical Pharmacology
    Title Metabolic Studies with an Alpha-nucleoside, 9-alpha-d-arabinofuranosyl-8-azaadenine.
    Date July 1976
    Journal Molecular Pharmacology
    Title The Purine and Pyrimidine Metabolism of Tetrahymena Pyriformis.
    Date June 1968
    Journal Journal of Cellular Physiology
    Title The Biosynthesis of Proline by Tetrahymena Pyriformis.
    Date February 1968
    Journal Biochimica Et Biophysica Acta
    Title Acoustick: An Optically Tracked A-mode Ultrasonography System for Registration in Image-guided Neurosurgery
    Date
    Journal Stereotactic and Functional Neurosurgery
    Title Validity and Reliability of Active Shape Models for the Estimation of Cobb Angle in Patients with Adolescent Idiopathic Scoliosis.
    Date
    Journal Journal of Digital Imaging : the Official Journal of the Society for Computer Applications in Radiology
    Excerpt

    Choosing the most suitable treatment for scoliosis relies heavily on accurate and reproducible Cobb angle measurement from successive radiographs. The objective is to reduce variability of Cobb angle measurement by reducing user intervention and bias. Custom software to increase automation of the Cobb angle measurement from posteroanterior radiographs was developed using active shape models. Validity and reliability of the automated system against a manual and semiautomated measurement method was conducted by two examiners each performing measurements on three occasions from a test set (N = 22). A training set (N = 47) of radiographs representative of curves seen in a scoliosis clinic was used to train the software to recognize vertebrae from T4 to L4. Images with a maximum Cobb angle between 20 degrees and 50 degrees , excluding surgical cases, were selected for training and test sets. Automated Cobb angles were calculated using best-fit slopes of the detected vertebrae endplates. Intraclass correlation coefficient (ICC) and standard error of measurement (SEM) showed high intraexaminer (ICC > 0.90, SEM 2 degrees -3 degrees ) and interexaminer (ICC > 0.82, SEM 2 degrees -4 degrees ), but poor intermethod reliability (ICC = 0.30, SEM 8 degrees -9 degrees ). The automated method underestimated large curves. The reliability improved (ICC = 0.70, SEM 4 degrees -5 degrees ) with exclusion of the four largest curves (>40 degrees ) in the test set. The automated method was reliable for moderate-sized curves, and did detect vertebrae in larger curves with a modified training set of larger curves.

    Title Parenting Practices and Adolescent Sexual Behavior: A Longitudinal Study.
    Date
    Journal Journal of Marriage and the Family
    Excerpt

    The effects of parental attitudes, practices, and television mediation on adolescent sexual behaviors were investigated in a study of adolescent sexuality and media (N=887). Confirmatory factor analyses supported an eight-factor parenting model with television mediation factors as constructs distinct from general parenting practices. Logistic regressions indicated that adolescents reporting greater parental disapproval and limits on viewing at Wave 1 were less likely to initiate oral sex between Waves 1 and 2. Adolescents who reported more sexual communication with parents were more likely to initiate oral sex. Results for vaginal intercourse were similar to those for oral sex. Co-viewing was a significant negative predictor of initiation of sexual behavior. Parental attitudes and television mediation can delay potentially risky adolescent sexual behaviors.

    Title Televised Sexual Content and Parental Mediation: Influences on Adolescent Sexuality.
    Date
    Journal Media Psychology
    Excerpt

    Little research has been conducted to examine the influence of exposure to televised sexual content on adolescent sexuality or how parental intervention may reduce negative effects of viewing such content. This study uses self-report data from 1,012 adolescents to investigate the relations among exposure to sexually suggestive programming, parental mediation strategies, and three types of adolescent sexuality outcomes: participation in oral sex and sexual intercourse, future intentions to engage in these behaviors, and sex expectancies. As predicted, exposure to sexual content was associated with an increased likelihood of engaging in sexual behaviors, increased intentions to do so in the future, and more positive sex expectancies. Often, parental mediation strategies were a significant factor in moderating these potential media influences.

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