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Family Practitioner, Primary Care Doctor
43 years of experience

Credentials

Education ?

Medical School Score Rankings
University of Minnesota, Twin Cities (1968)
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Top 25%

Publications & Research

Dr. Wallace has contributed to 50 publications.
Title The Dopamine Agonist Bromocriptine Differentially Affects Fronto-striatal Functional Connectivity During Working Memory.
Date July 2011
Journal Frontiers in Human Neuroscience
Excerpt

We investigated the effect of bromocriptine, a dopamine agonist, on individual differences in behavior as well as frontal-striatal connectivity during a working memory task. After dopaminergic augmentation, frontal-striatal connectivity in low working memory capacity individuals increases, corresponding with behavioral improvement whereas decreases in connectivity in high working memory capacity individuals are associated with poorer behavioral performance. These findings corroborate an inverted U-shape response of dopamine function in behavioral performance and provide insight on the corresponding neural mechanisms.

Title Human Cytomegalovirus-specific Cd8(+) T-cell Expansions Contain Long-lived Cells That Retain Functional Capacity in Both Young and Elderly Subjects.
Date January 2011
Journal Immunology
Excerpt

The immune response to human cytomegalovirus (HCMV) infection is characterized by the accumulation of HCMV-specific CD8(+) T cells, particularly in the elderly; such expansions may impair immune responses to other pathogens. We investigated mechanisms underlying HCMV-specific expansions in 12 young and 21 old healthy subjects (although not all analyses were performed on all subjects). Phenotypically, HCMV-pentamer(+) CD8(+) T cells were characterized by marked Vβ restriction, advanced differentiation (being predominantly CD27(-) CD28(-) ), and variable CD45RO/RA expression. Although more common and larger in older subjects, expansions had similar phenotypic characteristics in the young. In one old subject, repeated studies demonstrated stability in size and Vβ distribution of pentamer(+) populations over 6 years. We tested whether HCMV-specific CD8(+) T-cell expansions arose from accelerated proliferation or extended lifespan by in vivo labelling with deuterated glucose and ex vivo Ki-67 expression. Uptake of deuterated glucose was lower in pentamer(+) cells than in pentamer(-) CD8(+) CD45RO(+) or CD8(+) CD45RA(+) cells in three old subjects, consistent with reduced proliferation and extended lifespan. Similarly Ki-67 labelling showed no evidence for increased proliferation in HCMV-specific CD8(+) expansions in older subjects, although pentamer(-) CD45RA(+) cells from young donors expressed very little Ki-67. We investigated Bcl-2 and CD95 as possible anti-apoptotic mediators, but neither was associated with pentamer-positivity. To investigate whether expansion represents a compensatory response to impaired functionality, we performed two tests of functionality, peptide-stimulated proliferation and CD107 expression; both were intact in pentamer(+) cells. Our data suggest that HCMV-specific CD8(+) expansions in older subjects accumulate by extended lifespan, rather than accelerated proliferation.

Title Deltafosb in Brain Reward Circuits Mediates Resilience to Stress and Antidepressant Responses.
Date June 2010
Journal Nature Neuroscience
Excerpt

In contrast with the many studies of stress effects on the brain, relatively little is known about the molecular mechanisms of resilience, the ability of some individuals to escape the deleterious effects of stress. We found that the transcription factor DeltaFosB mediates an essential mechanism of resilience in mice. Induction of DeltaFosB in the nucleus accumbens, an important brain reward-associated region, in response to chronic social defeat stress was both necessary and sufficient for resilience. DeltaFosB induction was also required for the standard antidepressant fluoxetine to reverse behavioral pathology induced by social defeat. DeltaFosB produced these effects through induction of the GluR2 AMPA glutamate receptor subunit, which decreased the responsiveness of nucleus accumbens neurons to glutamate, and through other synaptic proteins. Together, these findings establish a previously unknown molecular pathway underlying both resilience and antidepressant action.

Title Oral Microbial and Respiratory Status of Persons with Mental Retardation/intellectual and Developmental Disability: an Observational Cohort Study.
Date January 2010
Journal Oral Surgery, Oral Medicine, Oral Pathology, Oral Radiology, and Endodontics
Excerpt

The objective of this study was to determine the prevalence of select microorganisms in oral biofilms and to investigate relationships between oral and respiratory status in persons with mental retardation/intellectual and developmental disabilities (IDD).

Title Mastectomy Scars Following Breast Reconstruction: Should Routine Histologic Analysis Be Performed?
Date May 2009
Journal Plastic and Reconstructive Surgery
Excerpt

There is some debate in the recent literature regarding the routine submission of mastectomy scars for histologic analysis when performing delayed breast reconstructions. The aim of this study was to review the relevant publications and evaluate the practice of routine histologic examination of mastectomy scars.

Title Creb Regulation of Nucleus Accumbens Excitability Mediates Social Isolation-induced Behavioral Deficits.
Date February 2009
Journal Nature Neuroscience
Excerpt

Here, we characterized behavioral abnormalities induced by prolonged social isolation in adult rodents. Social isolation induced both anxiety- and anhedonia-like symptoms and decreased cAMP response element-binding protein (CREB) activity in the nucleus accumbens shell (NAcSh). All of these abnormalities were reversed by chronic, but not acute, antidepressant treatment. However, although the anxiety phenotype and its reversal by antidepressant treatment were CREB-dependent, the anhedonia-like symptoms were not mediated by CREB in NAcSh. We found that decreased CREB activity in NAcSh correlated with increased expression of certain K(+) channels and reduced electrical excitability of NAcSh neurons, which was sufficient to induce anxiety-like behaviors and was reversed by chronic antidepressant treatment. Together, our results describe a model that distinguishes anxiety- and depression-like behavioral phenotypes, establish a selective role of decreased CREB activity in NAcSh in anxiety-like behavior, and provide a mechanism by which antidepressant treatment alleviates anxiety symptoms after social isolation.

Title The Influence of Deltafosb in the Nucleus Accumbens on Natural Reward-related Behavior.
Date November 2008
Journal The Journal of Neuroscience : the Official Journal of the Society for Neuroscience
Excerpt

The transcription factor deltaFosB (DeltaFosB), induced in nucleus accumbens (NAc) by chronic exposure to drugs of abuse, has been shown to mediate sensitized responses to these drugs. However, less is known about a role for DeltaFosB in regulating responses to natural rewards. Here, we demonstrate that two powerful natural reward behaviors, sucrose drinking and sexual behavior, increase levels of DeltaFosB in the NAc. We then use viral-mediated gene transfer to study how such DeltaFosB induction influences behavioral responses to these natural rewards. We demonstrate that overexpression of DeltaFosB in the NAc increases sucrose intake and promotes aspects of sexual behavior. In addition, we show that animals with previous sexual experience, which exhibit increased DeltaFosB levels, also show an increase in sucrose consumption. This work suggests that DeltaFosB is not only induced in the NAc by drugs of abuse, but also by natural rewarding stimuli. Additionally, our findings show that chronic exposure to stimuli that induce DeltaFosB in the NAc can increase consumption of other natural rewards.

Title Telemedicine for Acute Plastic Surgical Trauma and Burns.
Date April 2008
Journal Journal of Plastic, Reconstructive & Aesthetic Surgery : Jpras
Excerpt

Visual images can enhance communication over a distance. In the UK, plastic surgery provides services over large distances by a 'hub and spoke' model. Telemedicine could help to increase the efficiency of service for plastic surgery patients. Telemedicine, along with the impending Electronic Patient Record system could combine to improve communication, patient triage, record keeping, audit and could lead to a better quality of clinical care. Another benefit could be significant cost savings. We report our experience of the introduction of telemedicine to a Regional Plastic Surgery Service. Our first study compared assessments from images and patient examinations, which gave us confidence in the use of images [Jones SM, Milroy C, Pickford MA. Telemedicine in acute plastic surgical trauma and burns. Ann R Coll Surg Engl 2004;86:239-42]. We proceeded to a 10-week evaluation of all 973 referrals to our unit. We found that the system was used for a wide variety of injuries and for 42% of the 452 patients where the system was available. Initial resistance was overcome by the ease of use of the system, with both receiving and referring clinicians reporting benefits. The third phase was a 12-week prospective cohort study of 996 patients comparing the referrals with and without the telemedicine system. The system was available for 389 patients, and used for 243 patients (63%). The groups were analysed by a chi squared test and confidence interval calculation. We demonstrated a significant difference in the initial management of patients, with 10% more being booked directly to our Day Surgery Unit. There was a decrease in number of occasions when we were unable to accept a patient due to a lack of capacity. We found no change in the patients being managed with telephone only advice. We found that telemedicine is a valuable method of providing useful preliminary information in the referral process for injured patients and often significantly modifies their treatment and/or management plan. This has implications for the use of Information Technology resources and potentially the delivery of healthcare in relation to the management of injured patients.

Title A Cohort Study of Acute Plastic Surgery Trauma and Burn Referrals Using Telemedicine.
Date March 2008
Journal Journal of Telemedicine and Telecare
Excerpt

A store-and-forward telemedicine system was used to supplement normal telephone referrals to the plastic surgery unit at the Queen Victoria Hospital (QVH). During a 12-week prospective study, 11 units (8 hospitals and 3 minor injury units) with the telemedicine system and 10 units (8 hospitals and 2 minor injury units) without it regularly made referrals (at least 10) to the QVH. There were 389 referrals from the telemedicine-equipped units and 607 telephone referrals from the non-telemedicine units. The telemedicine system was used for 246 of the 389 referrals (63%) made from telemedicine-equipped units. There was a significant difference in the management of patients when the telemedicine system was available, with more patients booked directly into day surgery and fewer attending for assessment. The burns unit and the day surgery unit demonstrated a significantly improved accuracy of triage. Telemedicine could have a valuable role to play in the triage and planning of acute plastic surgery referrals.

Title In Vivo Kinetics of Human Natural Killer Cells: the Effects of Ageing and Acute and Chronic Viral Infection.
Date June 2007
Journal Immunology
Excerpt

Human natural killer (NK) cells form a circulating population in a state of dynamic homeostasis. We investigated NK cell homeostasis by labelling dividing cells in vivo using deuterium-enriched glucose in young and elderly healthy subjects and patients with viral infection. Following a 24-hr intravenous infusion of 6,6-D(2)-glucose, CD3(-) CD16(+) NK cells sorted from peripheral blood mononuclear cells (PBMC) by fluorescence-activated cell sorter (FACS) were analysed for DNA deuterium content by gas chromatography mass spectrometry to yield minimum estimates for proliferation rate (p). In healthy young adults (n=5), deuterium enrichment was maximal approximately 10 days after labelling, consistent with postmitotic maturation preceding circulation. The mean (+/- standard deviation) proliferation rate was 4 x 3 +/- 2 x 4%/day (equivalent to a doubling time of 16 days) and the total production rate was 15 +/- (7 x 6) x 10(6) cells/l/day. Labelled cells disappeared from the circulation at a similar rate [6 x 9 +/- 4 x 0%/day; half-life (T((1/2))) < 10 days]. Healthy elderly subjects (n=8) had lower proliferation and production rates (P=2 x 5 +/- 1 x 0%/day and 7 x 3 +/- (3 x 7) x 10(6) cells/l/day, respectively; P=0 x 04). Similar rates were seen in patients chronically infected with human T-cell lymphotropic virus type I (HTLV-I) (P=3 x 2 +/- 1 x 9%/day). In acute infectious mononucleosis (n=5), NK cell numbers were increased but kinetics were unaffected (P=2 x 8 +/- 1 x 0%/day) a mean of 12 days after symptom onset. Human NK cells have a turnover time in blood of about 2 weeks. Proliferation rates appear to fall with ageing, remain unperturbed by chronic HTLV-I infection and normalize rapidly following acute Epstein-Barr virus infection.

Title In Vivo T Lymphocyte Dynamics in Humans and the Impact of Human T-lymphotropic Virus 1 Infection.
Date June 2007
Journal Proceedings of the National Academy of Sciences of the United States of America
Excerpt

Human T-lymphotropic virus type 1 (HTLV-1) is a persistent CD4+ T-lymphotropic retrovirus. Most HTLV-1-infected individuals remain asymptomatic, but a proportion develop adult T cell leukemia or inflammatory disease. It is not fully understood how HTLV-1 persists despite a strong immune response or what determines the risk of HTLV-1-associated diseases. Until recently, it has been difficult to quantify lymphocyte kinetics in humans in vivo. Here, we used deuterated glucose labeling to quantify in vivo lymphocyte dynamics in HTLV-1-infected individuals. We then used these results to address four questions. (i) What is the impact of HTLV-1 infection on lymphocyte dynamics? (ii) How does HTLV-1 persist? (iii) What is the extent of HTLV-1 expression in vivo? (iv) What features of lymphocyte kinetics are associated with HTLV-1-associated myelopathy/tropical spastic paraparesis? We found that CD4+CD45RO+ and CD8+CD45RO+ T lymphocyte proliferation was elevated in HTLV-1-infected subjects compared with controls, with an extra 10(12) lymphocytes produced per year in an HTLV-1-infected subject. The in vivo proliferation rate of CD4+CD45RO+ cells also correlated with ex vivo viral expression. Finally, the inflammatory disease HTLV-1-associated myelopathy/tropical spastic paraparesis was associated with significantly increased CD4+CD45RO+ cell proliferation. We suggest that there is persistent viral gene expression in vivo, which is necessary for the maintenance of the proviral load and determines HTLV-1-associated myelopathy/tropical spastic paraparesis risk.

Title Fatal Injuries Among Children by Race and Ethnicity--united States, 1999-2002.
Date May 2007
Journal Mmwr. Surveillance Summaries : Morbidity and Mortality Weekly Report. Surveillance Summaries / Cdc
Excerpt

PROBLEM/CONDITION: In the United States, unintentional injury, homicide, and suicide are the first, second, and fourth leading causes of death among persons aged 1-19 years, respectively; the highest rates have occurred among minority populations. The effects of age on the difference in rates between white and minority children and the mechanisms of injury that contribute most to that difference have not been previously reported. REPORTING PERIOD COVERED: Data are presented for fatal injuries among children in the United States by race/ethnicity and mechanism of injury during 1999-2002. Trends in injury mortality by race/ethnicity are provided for 1982-2002. DESCRIPTION OF SYSTEM: Fatal injury data were derived from death certificates reported through CDC's National Vital Statistics System. RESULTS: During 1999-2002, among infants aged <1 year, American Indian/Alaska Natives (AI/ANs) and blacks had consistently higher total injury death rates than other racial/ethnic populations. Both populations had more than twice the rate of injury death compared with white infants. Black infants had the highest rates of unintentional suffocation and homicide, whereas AI/AN infants had the highest rate of motor-vehicle (MV)-traffic death. Among children aged 1-9 years, AI/ANs and blacks had the highest injury death rates. AI/ANs aged 1-9 years had the highest rates of MV-traffic death and drowning; in contrast, blacks aged 1-9 years had the highest rates of homicide and fire/burn death. Among children aged 10-19 years, AI/ANs and blacks consistently had higher total injury death rates than whites. AI/ANs aged 10-19 years had the highest rates of suicide and MV-traffic death, and blacks aged 10-19 years had the highest rates of homicide. The disparity in injury mortality rates by race/ethnicity during 1982-1985 had not declined by 1999-2002. INTERPRETATION: Significant disparities in injury rates still exist between white and minority children. Disparities varied by age and mechanism of injury. Hispanics and Asian/Pacific Islanders consistently had lower risk, whereas AI/ANs and blacks consistently had higher risk for fatal injuries than other racial/ethnic populations. PUBLIC HEALTH ACTIONS: Educational, regulatory, and environmental modification strategies (e.g., home visitation programs, safety-belt laws, and swimming pool fencing) have been developed for each type of injury for use by health-care providers and government agencies.

Title Long-term Effects of Perinatal Nutrition on T Lymphocyte Kinetics in Young Gambian Men.
Date March 2007
Journal The American Journal of Clinical Nutrition
Excerpt

BACKGROUND: Nutritional status is highly dependent on season in countries such as The Gambia. In a rural Gambian setting, individuals born during periods of seasonal nutritional deprivation ("hungry seasons") are susceptible to mortality from infectious diseases in adult life. OBJECTIVE: We investigated the hypothesis that impaired immunocompetence in those born in the hungry season results from an underlying defect in immunologic memory, similar to the immunosenescence of old age, which is likely to be reflected in the phenotype and kinetics of T lymphocytes in young adults. DESIGN: T cell phenotype in terms of CD3, CD4, CD8, CD45RA, and CD45R0 expression and in vivo dynamics measured by stable isotope labeling of T cell subsets combined with gas chromatography-mass spectrometry and frequency of T cell receptor excision circles were measured in 25 young (18-24-y-old) Gambian men. Thirteen of these 25 men were exposed to perinatal malnutrition as defined by birth season and birth weight. RESULTS: In persons born in the hungry season with low birth weight, no differences in the proportions of memory or naive T cells were found. Kinetic analysis showed higher proliferation rates in memory (CD45R0(+)) subsets of T cells than in naïve (CD45R0(-)) cells, which is consistent with previous studies, but no evidence was found for an effect of birth weight or season on T lymphocyte proliferation and disappearance rates. No significant correlations were found between in vivo T cell kinetics and frequency of T cell receptor excision circles. Only absolute numbers of granulocytes were elevated in those born in the nutritionally deprived season. CONCLUSION: In healthy young Gambian men, T lymphocyte homeostasis is extremely robust regardless of perinatal nutritional compromise.

Title Prolonged Exposure of Naïve Cd8+ T Cells to Interleukin-7 or Interleukin-15 Stimulates Proliferation Without Differentiation or Loss of Telomere Length.
Date November 2006
Journal Immunology
Excerpt

Interleukin (IL)-7 and IL-15 are cytokines implicated in homeostatic control of the peripheral CD8 T-cell pool. We compared the effects of IL-7 and IL-15 on survival and proliferation of purified human CD8+ T-cell subsets. Low concentrations of either cytokine reduced the spontaneous apoptosis of all subsets, and enhancement of survival corresponded to the extent of Bcl-2 up-regulation. Surprisingly, although minimal proliferation of naïve CD8+ T cells was observed during the first week of culture with cytokines, a marked expansion of these cells occurred at later time points, particularly in response to IL-15. This occurred largely without phenotypic change or acquisition of effector function, indicating a dissociation of differentiation from proliferation. Notably, progression of naïve CD8+ T cells through several cell divisions resulted in up-regulation of telomerase and the maintenance of telomere length. These data show that IL-7 and IL-15 induce cell proliferation and rescue from apoptosis in a concentration, time and subset-dependent manner, and have implications for the homeostatic expansion of the naïve CD8+ T-cell pool.

Title Measuring Lymphocyte Kinetics in Tropical Field Settings.
Date October 2005
Journal Transactions of the Royal Society of Tropical Medicine and Hygiene
Excerpt

Studies involving in-vivo labelling of lymphocyte DNA with 6,6-2H2-glucose to track T-cell turnover have contributed to understanding lymphocyte homeostasis in health and disease. Applying such studies in tropical settings (where diseases that affect T-cells are prevalent) requires protocol modifications including non-intravenous label administration, applicability in outpatient facilities, and T-cell sorting methods independent of a fluorescence activated cell sorter (FACS). Such protocols were validated in UK pilot studies and applied in The Gambia. Healthy adult subjects (n=12) were recruited from three Gambian villages. 6,6-2H2-glucose was administered orally in an outpatient clinic and T-cell subpopulations isolated from peripheral blood using plastic adherence, and Multisorttrade mark magnetic cell sorting (MACStrade mark) to obtain CD8+CD45R0+, CD8-CD45R0+, CD8+CD45R0- and CD8-CD45R0- subsets. To achieve high cell purity and yield, CD45R0- cells were reincubated with CD45R0 beads. T-cell proliferation and disappearance were quantified using gas chromatography mass spectrometry. Results were consistent with those of other studies showing higher turnover in memory (CD45R0+) than in naïve (CD45R0-) T-cell subsets, and an association between recent cell proliferation and susceptibility to cell death. Cell kinetics research is applicable in tropical settings, and can contribute to further understanding the regulation of adaptive immunity in response to infections and other insults.

Title Deltafosb Accumulates in a Gabaergic Cell Population in the Posterior Tail of the Ventral Tegmental Area After Psychostimulant Treatment.
Date August 2005
Journal The European Journal of Neuroscience
Excerpt

The transcription factor deltaFosB is induced in the nucleus accumbens and dorsal striatum by chronic exposure to several drugs of abuse, and increasing evidence supports the possibility that this induction is involved in the addiction process. However, to date there has been no report of deltaFosB induction by drugs of abuse in the ventral tegmental area (VTA), which is also a critical brain reward region. In the present study, we used immunohistochemistry to demonstrate that chronic forced administration of cocaine induces deltaFosB in the rat VTA. This induction occurs selectively in a gamma-aminobutyric acid (GABA) cell population within the posterior tail of the VTA. A similar effect is seen after chronic cocaine self-administration. Induction of deltaFosB in the VTA occurs after psychostimulant treatment only: it is seen with both chronic cocaine and amphetamine, but not with chronic opiates or stress. The expression of deltaFosB appears to be mediated by dopamine systems, as repeated administration of a dopamine uptake inhibitor induced deltaFosB in the VTA, while administration of serotonin or norepinephrine uptake inhibitors failed to produce this effect. Time course analysis showed that, following 14 days of cocaine administration, deltaFosB persists in the VTA for almost 2 weeks after cocaine withdrawal. This accumulation and persistence may account for some of the long-lasting changes in the brain associated with chronic drug use. These results provide the first evidence of deltaFosB induction in a discrete population of GABA cells in the VTA, which may regulate the functioning of the brain's reward mechanisms.

Title Regulation of Anxiety and Initiation of Sexual Behavior by Creb in the Nucleus Accumbens.
Date July 2005
Journal Proceedings of the National Academy of Sciences of the United States of America
Excerpt

Sexual deficits and other behavioral disturbances such as anxiety-like behaviors can be observed in animals that have undergone social isolation, especially in species having important social interactions. Using a model of protracted social isolation in adult rats, we observed increased anxiety-like behavior and deficits in both the latency to initiate sexual behavior and the latency to ejaculate. We show, using transgenic cAMP response element (CRE)-LacZ reporter mice, that protracted social isolation also reduces CRE-dependent transcription within the nucleus accumbens. This decrease in CRE-dependent transcription can be mimicked in nonisolated animals by local viral gene transfer of a dominant negative mutant of CRE-binding protein (CREB). We previously showed that this manipulation increases anxiety-like behavior. We show here that it also impairs initiation of sexual behavior in nonisolated animals, a deficit that can be corrected by anxiolytic drug treatment. This local reduction in CREB activity, however, has no influence on ejaculation parameters. Reciprocally, we used the viral transgenic approach to overexpress CREB in the nucleus accumbens of isolated animals. We show that this local increase in CREB activity completely rescued the anxiety phenotype of the isolated animals, as well as their deficit in initiating sexual behavior, but failed to rescue the deficit in ejaculation. Our data suggest a role for the nucleus accumbens in anxiety responses and in specific aspects of sexual behavior. The results also provide insight into the molecular mechanisms by which social interactions affect brain plasticity and behavior.

Title B-cell Kinetics in Humans: Rapid Turnover of Peripheral Blood Memory Cells.
Date June 2005
Journal Blood
Excerpt

Information about the kinetic behavior and lifespan of lymphocytes is crucial to understanding the mechanisms that regulate processes such as immunologic memory. We have used in vivo labeling of dividing cells with 6,6-(2)H(2)-glucose, combined with cell sorting and gas-chromatography-mass spectrometry for deuterium enrichment, in order to analyze the kinetics of human total, naive, or memory B lymphocytes, separated from peripheral blood using monoclonal antibodies. We show that total blood B cells of young adults divide at an average rate of 1.9% (+/-1.0%) per day and at a similar though slightly slower rate, 1.5% (+/-1.3%) per day, in the elderly. Separation of naive and memory B cells according to expression of CD27 indicates that naive peripheral blood B cells divide slowly (0.46% per day), while memory cells proliferate more rapidly (2.66% per day). These data are compatible with the view that B-cell memory may be maintained by clones of proliferating B cells.

Title Direct Measurement of T Cell Subset Kinetics in Vivo in Elderly Men and Women.
Date November 2004
Journal Journal of Immunology (baltimore, Md. : 1950)
Excerpt

The age-associated decline in immunocompetence is paralleled by changes in the proportions of PBL subpopulations. In turn, the size and composition of the peripheral lymphocyte pool is determined by input from the thymus and bone marrow and by the balance of proliferation and death in each lymphocyte subpopulation. We compared the kinetics of lymphocyte subtypes in young (seven of eight CMV seronegative) and healthy elderly human subjects (six of seven CMV seropositive), using deuterated glucose DNA labeling in vivo to measure rates of T cell proliferation and disappearance. For CD45RO(+) cells of both CD4(+) and CD8(+) subtypes and for CD4(+)CD45RA(+) cells the kinetics of proliferation and disappearance were remarkably similar between elderly and young subjects. In the young, the kinetics of CD8(+)CD45RA(+) cells with a naive phenotype resembled those of CD4(+)CD45RA(+) cells. However, CD8(+)CD45RA(+) T cells from the elderly exhibited a predominantly primed phenotype, and for this subset, although the proliferation rate was similar to that of other CD45RA(+) cells, the disappearance rate of labeled cells was greatly decreased compared with that of all other T cell subsets. Our data provide a direct demonstration that there are no substantial changes in in vivo kinetics for most T cell populations in healthy elderly compared with young subjects. However, primed CD8(+)CD45RA(+) cells show unusual kinetic properties, indicating the persistence of these cells in the blood and dissociation of proliferation from disappearance.

Title Rapid Turnover of T Cells in Acute Infectious Mononucleosis.
Date November 2003
Journal European Journal of Immunology
Excerpt

During acute infectious mononucleosis (AIM), large clones of Epstein-Barr virus-specific T lymphocytes are produced. To investigate the dynamics of clonal expansion, we measured cell proliferation during AIM using deuterated glucose to label DNA of dividing cells in vivo, analyzing cells according to CD4, CD8 and CD45 phenotype. The proportion of labeled CD8(+)CD45R0(+) T lymphocytes was dramatically increased in AIM subjects compared to controls (mean 17.5 versus 2.8%/day; p<0.005), indicating very rapid proliferation. Labeling was also increased in CD4(+)CD45R0(+) cells (7.1 versus 2.1%/day; p<0.01), but less so in CD45RA(+) cells. Mathematical modeling, accounting for death of labeled cells and changing pool sizes, gave estimated proliferation rates in CD8(+)CD45R0(+) cells of 11-130% of cells proliferating per day (mean 47%/day), equivalent to a doubling time of 1.5 days and an appearance rate in blood of about 5 x 10(9) cells/day (versus 7 x 10(7) cells/day in controls). Very rapid death rates were also observed amongst labeled cells (range 28-124, mean 57%/day),indicating very short survival times in the circulation. Thus, we have shown direct evidence for massive proliferation of CD8(+)CD45R0(+) T lymphocytes in AIM and demonstrated that rapid cell division continues concurrently with greatly accelerated rates of cell disappearance.

Title Measurement and Modeling of Human T Cell Kinetics.
Date September 2003
Journal European Journal of Immunology
Excerpt

The ability to measure, describe and interpret T cell kinetics is pivotal in understanding normal lymphocyte homeostasis and diseases that affect T cell numbers. Following in vivo labeling of dividing cells with 6,6-D(2)-glucose in eight healthy volunteers, peripheral blood T cells were sorted by CD4, CD8 and CD45 phenotype. Enrichment of deuterium in DNA was measured by gas chromatography-mass spectrometry. A novel model of T cell kinetics, allowing for heterogeneity within T cell pools, was used to analyze data on acquisition and loss of label and calculate proliferation and disappearance rates for each subpopulation. Proliferation rates for CD45RO(+)CD8(+) cells and CD45RO(+)CD4(+) cells were 5.1% and 2.7% /day, respectively (equivalent doubling times: 14 and 26 days). CD45RA(+)CD8(+) lymphocytes and CD45RA(+)CD4(+) lymphocytes had slower proliferation rates, 0.5% and 0.6% / day, respectively (doubling time about 4 months). Disappearance rates of labeled cells were similar for all cell types (7%-12% / day) and exceeded corresponding proliferation rates. This disparity may be understood conceptually in terms of either phenotypic heterogeneity (rapid versus slow turnover pools), or history (recently divided cells are more likely to die). The new kinetic model fits the data closely and avoids the need to postulate a large external source of lymphocytes to maintain equilibrium.

Title Novel Perforin Mutation in a Patient with Hemophagocytic Lymphohistiocytosis and Cd45 Abnormal Splicing.
Date August 2003
Journal American Journal of Medical Genetics. Part A
Excerpt

Hemophagocytic lymphohistiocytosis (HLH) composes a group of rare heterogenous disorders characterized by uncontrolled accumulation and infiltration of activated T lymphocytes and macrophages. Cytotoxic T and natural killer cell activity is significantly reduced or absent in these patients. Mutations in the important mediator of lymphocyte cytotoxicity perforin were identified in a number of HLH individuals. Here we report a novel missense mutation thr435met in the conserved Ca(2+) binding domain of perforin in a patient with HLH. Prediction of the 3-dimensional structure of the thr435met perforin mutant using comparative molecular modeling indicates that the protein's ability to bind Ca(2+), and therefore its cytolytic function, would be strongly compromised. In addition, this patient exhibited abnormal CD45 splicing caused by a C77G mutation in the gene encoding CD45 (PTPRC). Our findings suggest a combined role for perforin mutation and abnormal CD45 splicing as significant contributory factors in the pathogenesis of HLH.

Title A Point Mutation in Cd45 May Be Associated with an Increased Risk of Hiv-1 Infection.
Date December 2001
Journal Aids (london, England)
Excerpt

The CD45 antigen is essential for normal antigen receptor-mediated signalling in lymphocytes, and different patterns of splicing of CD45 are associated with distinct functions in lymphocytes. Here we show that abnormal CD45 splicing caused by a C77G transversion in exon A of the gene encoding CD45 (PTPRC) is associated with increased susceptibility to HIV-1 infection.

Title The Exon A (c77g) Mutation is a Common Cause of Abnormal Cd45 Splicing in Humans.
Date August 2001
Journal Journal of Immunology (baltimore, Md. : 1950)
Excerpt

The leukocyte common (CD45) Ag is essential for normal T lymphocyte function and alternative splicing at the N terminus of the gene is associated with changes in T cell maturation and differentiation. Recently, a statistically significant association was reported in a large series of human thymus samples between phenotypically abnormal CD45 splicing and the presence of the CC chemokine receptor 5 deletion 32 (CCR5del32) allele, which confers resistance to HIV infection in homozygotes. We show here that abnormal splicing in these thymus samples is associated with the presence of the only established cause of CD45 abnormal splicing, a C77G transversion in exon A. In addition we have examined 227 DNA samples from peripheral blood of healthy donors and find no association between the exon A (C77G) and CCR5del32 mutations. Among 135 PBMC samples, tested by flow cytometric analysis, all those exhibiting abnormal splicing of CD45 also showed the exon A C77G transversion. We conclude that the exon A (C77G) mutation is a common cause of abnormal CD45 splicing and that further disease association studies of this mutation are warranted.

Title A Deletion in the Gene Encoding the Cd45 Antigen in a Patient with Scid.
Date March 2001
Journal Journal of Immunology (baltimore, Md. : 1950)
Excerpt

SCID is a heterogeneous group of hereditary diseases. Mutations in the common gamma-chain (gamma(c)) of cytokine receptors, including those for IL-2, IL-4, IL-7, IL-9, and IL-15, are responsible for an X-linked form of the disease, while mutations of several other genes, including Janus-associated kinase-3, may cause autosomal recessive forms of SCID. We investigated the first SCID patient to be described with minimal cell surface expression of the leukocyte common (CD45) Ag. CD45 is an abundant transmembrane tyrosine phosphatase, expressed on all leukocytes, and is required for efficient lymphocyte signaling. CD45-deficient mice are severely immunodeficient and have very few peripheral T lymphocytes. We report here that a homozygous 6-bp deletion in the gene encoding CD45 (PTPRC, gene map locus 1q31-32), which results in a loss of glutamic acid 339 and tyrosine 340 in the first fibronectin type III module of the extracellular domain of CD45, is associated with failure of surface expression of CD45 and SCID. Molecular modeling suggests that tyrosine 340 is crucial for the structural integrity of CD45 protein. This is the second description of a clinically relevant CD45 mutation, provides direct evidence for the importance of CD45 in immune function in humans, and suggests that abnormalities in CD45 expression are a possible cause of SCID in humans.

Title Fibroblasts Prevent Apoptosis of Il-2-deprived T Cells Without Inducing Proliferation: a Selective Effect on Bcl-xl Expression.
Date January 1997
Journal Immunology
Excerpt

The apoptosis of human cytokine-deprived activated T cells can be prevented by a soluble mediator secreted by fibroblasts, epithelial and endothelial cells, and this rescue occurs with fibroblasts from different species. Fractionation of W138 fibroblast-conditioned medium indicated that the survival-promoting agent(s) were > 30,000 MW. The continuous presence of the survival factor was required for prevention of apoptosis, which did not involve the induction of proliferation. Nevertheless, the co-cultured T cells remained in a primed state. The expression of the apoptosis-inducing proteins Bax and CD95 (Fas/Apo-1) was either unchanged or slightly increased in fibroblast-rescued T cells, suggesting that constraints on survival still existed after co-culture. A fundamental observation in the present study was that although Bcl-2 was reduced, the levels of Bcl-XL was maintained in cytokine-deprived T cells by fibroblast co-culture. This suggests that fibroblasts and/or other stromal cells may promote activated T-cell survival by a selective effect on Bcl-XL expression, which is consistent with histological examination of activated T cells within lymphoid tissue in vivo. The rescued T cell could be re-activated by CD3 antibody, but only in the presence of CD28 co-stimulation, which induced both Bcl-2 and Bcl-XL expression and also proliferation. Thus, survival signals from stromal cells in tissue microenvironments may enable activated T-cell persistence in a primed but quiescent state, and our data suggest that the regulation of Bcl-XL expression may be central in this process. The further characterization of this process is essential to clarify how signals from stromal cells can influence the resolution and/or chronicity of immune responses in different tissues in vivo.

Title Intraperitoneal Mitoxantrone or Floxuridine: Effects on Time-to-failure and Survival in Patients with Minimal Residual Ovarian Cancer After Second-look Laparotomy--a Randomized Phase Ii Study by Thesouthwest Oncology Group.
Date July 1996
Journal Gynecologic Oncology
Excerpt

A randomized phase II study of intraperitoneal (ip) mitoxantrone or floxuridine (FUDR) was performed for the treatment of minimal residual epithelial ovarian cancer found at second-look laparotomy after initial platinum-based chemotherapy. Entry was to take place within 30 days of reassessment laparotomies, with documentation of peritoneal metastases either microscopic or gross with cytoreduction to less than or equal to 1 cm in largest diameter. Patients were stratified by the site of the largest disease present (microscopic to 0.5 cm maximum diameter versus greater than 0.5 to 1 cm maximum diameter), by time of registration (< 14 days versus up to 30), and by serum CA-125 (< or = 35 versus >35 units/ml) prior to randomization to either ip mitoxantrone 10 mg/m2 every 2 weeks X 9 or ip floxuridine (FUDR) 3 g (total dose)/ day X 3 days every 3 weeks X 6 cycles. Implantable ip systems and 1.5-2 liters of normal saline were used to deliver the drugs of 83 patients registered between December 1988 and January 1994; there were 6 pathology exclusions and 9 surgical exclusions, and 1 nonevaluable patient for a total of 39 evaluable on mitoxantrone and 28 on FUDR being evaluable. FUDR is the choice for further study because of a progression-free survival exceeding 15% at 1 year over mitoxantrone and a median overall survival of 38 months. It should be emphasized again that the goal of a randomized phase II selection design is to select a winner for phase III testing should there be a substantial difference between the treatments with respect to the primary endpoint. Comparative conclusions between the treatment arms should not be attempted due to the inherently much smaller sample sizes. This should reemphasize the limitations in a comparison of efficacy; however, the toxicologic differences still emerge quite clearly.

Title Gonadotropin Releasing Hormone (gnrh) Agonist Therapy for Reduction of Leiomyoma Volume.
Date July 1993
Journal Gynecologic Oncology
Excerpt

A patient with menorrhagia, dysmenorrhea, and an enlarged uterus was treated with a GnRH agonist for leiomyoma volume reduction. A laser-assisted myomectomy yielded five tumors that did not appear to be well demarcated and had a combined weight of only 30 g. Postoperative pathologic evaluation revealed leiomyosarcoma with 22 mitoses per 10 high-power fields. The 8-month delay in therapy was associated with Stage IV, grade 3 disease at diagnosis. In rare cases GnRH agonist therapy may palliate symptoms and delay definitive surgical therapy of leiomyosarcoma, resulting in more advanced disease at diagnosis.

Title Characterization of a Novel Subset of T Cells from Human Spleen That Lacks L-selectin.
Date June 1993
Journal Immunology
Excerpt

Human L-selection (LAM-1, Leu-8, TQ1, DREG 56) is a member of the 'selection' family of adhesion molecules. Antibodies to L-selectin have been shown to block the binding of T cells to peripheral lymph node high endothelial venules (HEV). Most unstimulated peripheral blood T cells express high levels of L-selectin whilst it is only weakly expressed on the majority of T cells from secondary lymphoid organs. We show here (a) that T cells from tonsil and lymph node up-regulate L-selectin when released from their microenvironment, (b) that in contrast, spleen contains a stable L-selectin negative subset, (c) that this subset remains surface L-selection negative after stimulation even though the T cells can respond by proliferation, (d) that this subset expresses minimal levels of LAM-1 mRNA and (e) that mucosal lymphocyte antigen (MLA) positive and T-cell receptor (TcR) gamma delta positive T cells found within the L-selectin negative population are similar to subsets of T cells found amongst lamina propria (LP) and intraepithelial lymphocytes (IEL) of the gut.

Title Menometrorrhagia in an Oral Contraceptive User.
Date March 1993
Journal The Journal of Family Practice
Excerpt

Endometrial carcinoma is the most frequent malignancy of the female reproductive tract, and irregular vaginal bleeding is the most common presenting symptom. Endometrial carcinoma is found most commonly among postmenopausal women and is associated with obesity, nulliparity, and anovulation. Oral contraceptive (OC) use and tobacco smoking have been reported to protect against endometrial carcinoma. Irregular vaginal bleeding is a common side effect of OC therapy. We report the case of an obese, premenopausal nulliparous woman with normal menses who developed menometrorrhagia and was then found to have endometrial carcinoma despite her youth and her use of both tobacco and combination OC.

Title Functional Subsets of T Cells Defined by Isoforms of Cd45.
Date August 1992
Journal Biochemical Society Transactions
Title Esorubicin in Advanced Endometrial Cancer: an Ineffective and Potentially Toxic Therapy. A Southwest Oncology Group Study.
Date September 1991
Journal Investigational New Drugs
Excerpt

The Southwest Oncology Group conducted a phase II study of esorubicin treatment in patients with advanced endometrial cancer who had received no prior chemotherapy. Twenty of 31 patients were fully evaluable for response and toxicity. There were no clinical responses to treatment and 60% (12/20) of the patients developed severe or life threatening leukopenia on therapy. One evaluable patient was removed from study after a cumulative dose of 150 mg/M2 due to a reduction in left ventricular ejection fraction on MUGA scan and another developed congestive heart failure several months after discontinuation of treatment. Esorubicin has significant toxicity and limited clinical activity in patients with advanced endometrial cancer.

Title A Phase Ii Trial of Carboplatin for Recurrent or Metastatic Squamous Carcinoma of the Uterine Cervix: a Southwest Oncology Group Study.
Date January 1991
Journal Gynecologic Oncology
Excerpt

Forty-one eligible patients with metastatic or recurrent carcinoma of the uterine cervix received 149 courses of carboplatin. The drug was administered at a starting dosage of 400 mg/m2 IV every 28 days. The overall response rate was 15% (two complete responses, four partial responses; 95% confidence interval 6-29%) and response durations were 2.0, 2.0, 2.5 +, 2.5+, 5.25 +, and 6.75 months. The major toxic effects included nausea and vomiting in 48% of courses, anemia in 47%, leukopenia in 38%, and thrombocytopenia in 22%. The activity of carboplatin against advanced cervical cancer is modest and similar to the activity of cisplatin alone. However, the toxicity profile of carboplatin is substantially better than that of cisplatin and warrants exploration of this agent against cervix cancer in more aggressive regimens or in combination with other agents.

Title A Phase Ii Trial of Cisplatin and 5-fluorouracil with Allopurinol for Recurrent or Metastatic Carcinoma of the Uterine Cervix: a Southwest Oncology Group Trial.
Date July 1990
Journal Gynecologic Oncology
Excerpt

On the strength of recent evidence of the activity of the combination of cisplatin and 5-fluorouracil against squamous malignancies of the esophagus and head and neck, this regimen was evaluated in a phase II trial against metastatic or recurrent squamous carcinoma of the uterine cervix. Cisplatin was administered at a dosage of 100 mg/m2 iv bolus and 5-fluorouracil was continuously infused iv at a dosage of 1000 mg/m2/day for 4 days. In an effort to determine whether the toxicities of 5-fluorouracil could be ameliorated by coadministration of allopurinol, patients were randomized to receive allopurinol, 900 mg orally, an odd or even courses of therapy beginning 5 days before 5-fluorouracil administration and continuing until conclusion of the infusion. Fifty-two eligible patients received 177 evaluable courses of treatment. The overall response rate was 28% (8 complete responses and 6 partial responses). Toxicity was confined to nausea and vomiting (81% of courses), anemia (47%), leukopenia (37%), oral mucositis (15%), diarrhea (6%), and thrombocytopenia (4%). Allopurinol produced no improvement in treatment-related toxicities. Allopurinol did not permit substantial increases in 5-fluorouracil dosage.

Title Phenotypic Changes Associated with Activation of Cd45ra+ and Cd45ro+ T Cells.
Date April 1990
Journal Immunology
Excerpt

Resting CD45RO+, mature/memory, T cells are phenotypically distinct from intermediate CD45RO+/CD45RA+ and CD45RA+, immature/virgin, T cells, and are characterized by high levels of expression of a number of adhesion molecules, such as CD2, CD18, CD58 and CD29. The kinetics of up-regulation of molecules, like CD25 and CD54 associated with activation, were similar in both subsets and suggested that their high level expression was associated with later events rather than initial recognition and signal transduction. CD45RA+ T cells, unlike CD45RO+ T cells, were unable to proliferate in response to mitogenic combinations of CD2 monoclonal antibodies (mAb), although in combination with submitogenic doses of PMA both up-regulation of cell-surface molecules and proliferation occurred. In addition, recruitment of CD45RA+ T cells by CD2 mAb-activated CD45RO+ T cells can occur.

Title Early Events in Lymphocyte Activation Triggered Via Cd3/ti or Cd2.
Date October 1987
Journal Advances in Experimental Medicine and Biology
Title Signal Transduction in Human T Lymphocytes.
Date May 1987
Journal Immunological Reviews
Title Different Pathways of Human T-cell Activation Revealed by Pha-p and Pha-m.
Date March 1986
Journal Immunology
Excerpt

Antigen-specific T-cell activation is mediated via the CD3-Ti (antigen receptor) complex, and monoclonal antibodies to both CD3 and Ti cause a rapid rise in intracellular Ca2+. This calcium mobilization is not inhibited by monoclonal antibodies to CD2. The rise in calcium mobilization induced by purified PHA (PHA-P) does not occur in a cell line which lacks CD2 expression, and can be blocked in other T cells by anti-CD2 antibodies. A combination of monoclonal antibodies to different epitopes of CD2 causes calcium mobilization and mitogenesis. Reagent grade PHA (PHA-M) induces calcium moblization in cells that lack CD2, and its effects in other T cells cannot be blocked by anti-CD2 antibodies. The effects of PHA-P and PHA-M are thus mediated predominantly through different activation pathways.

Title Investigation of Early T Cell Activation: Analysis of the Effect of Specific Antigen, Interleukin 2 and Monoclonal Antibodies on Intracellular Free Calcium Concentration.
Date March 1985
Journal European Journal of Immunology
Excerpt

The three mitogenic anti-T3 antibodies, UCHT1, anti-Leu-4 and WT-32, all produce a rapid increase in T cell intracellular Ca2+ ( [Ca2+]i) in all individuals, as measured by quin 2 tetra-acetoxymethyl ester fluorescence. This indicates that the lack of responsiveness of approximately 30% of individuals to UCHT1 in proliferation assays is not due to failure of the antibody to elicit Ca2+ mobilization and that a rise in [Ca2+]i is per se not adequate to induce cell division. Another mitogenic antibody, WT-31, which is directed against the constant portion of the T cell receptor, did not, however, produce a rapid calcium rise in peripheral blood T cells. The clone HA1.7 gave a similar Ca2+ response to UCHT1. WT-31 did not induce a rise in [Ca2+]i, nor did the specific antigen to which the clone responded. Accessory cells may be required to induce Ca2+ mobilization with these ligands. There was no response to IL2, or an antibody (anti-Tac) to the IL2 receptor. In contrast to peripheral blood T cells treatment of HA1.7 with WT-31 led to an enhancement of the calcium response to subsequent UCHT1 addition. Furthermore, cross-linking of WT-31 on the surface of HA1.7 cells did produce a small rise in [Ca2+]i. The IL2-independent malignant T cell line, HUT78, exhibited a calcium response to both UCHT1 and WT-32. Both of these responses occurred without cross-linking. The T cell receptor is closely associated with cell-surface proteins, including the T3 antigen and these studies confirm the importance of the T3 antigen in T cell activation. They also suggest that the relationship between the T cell receptor and the T3 antigen may vary in T cells in different proliferative states.

Title Congress Examines Ethical Issues Given Birth by Genetic Engineering.
Date November 1984
Journal Modern Healthcare
Title Drug Therapy Update for the Long-term-care Nurse--assessment of Need and Evaluation of Method.
Date February 1979
Journal American Journal of Hospital Pharmacy
Title Hematopoietic Studies in Vitamin A Deficiency.
Date June 1978
Journal The American Journal of Clinical Nutrition
Excerpt

Recent studies of experimental vitamin A deficiency in man led the authors to conclude that anemia may result from lack of vitamin A. A review of numerous nutrition surveys in underdeveloped countries enhanced the suspicion that deficiency of vitamin A does contribute to the prevalence of anemia. Preliminary studies of vitamin A-deficient rats confirmed previous observations that anemia may result from lack of this vitamin. The livers of these animals had very low concentrations of vitamin A but normal or increased concentrations of iron. The finding of anemia is in contrast with other reports that vitamin A deficiency may cause elevated values for hemoglobin and hematocrit. The authors suggest that loss of taste and smell as a result of deficiency may account for refusal of experimental animals to eat and drink enough to prevent inanitation and dehydration. The resulting hemoconcentration may mask the true hematological picture, which is one of anemia.

Title Autoradiographic Localization of Vitamin A in the Kidney of Rats.
Date June 1977
Journal Proceedings of the Society for Experimental Biology and Medicine. Society for Experimental Biology and Medicine (new York, N.y.)
Title Autoradiographic Localization of Vitamin A in the Adrenal Gland of Rats.
Date March 1976
Journal Life Sciences
Title Extraction of [14c] Vitamin A from Rat Liver and Kidney During Processing for Transmission Electron Microscopy.
Date March 1976
Journal Stain Technology
Excerpt

The retention of radioisotope-labeled vitamin A during processing for electron microscopy was investigated using the livers and kidneys of vitamin A deficient rats. [15-14C]Retinol (3muCi/animal) was administered by esophageal intubation to male rats which had been maintained on a vitamin A deficient diet for five or six weeks postweaning. Glutaraldehyde- or osmium-fixed tissue was processed by three methods: a) routine (a graded series of ethanols, propylene oxide and epoxy), b) rapid (75% and 95% ethanol with three changes of epoxy), or c) water-soluble embedding (70% and 80% hydroxypropyl methacrylate). Water-soluble embedding retained the highest percentage of label in the tissue (liver: 96.31%; kidney: 98.68%). Inclusion of osmium tetroxide in the processing sequence and minimal exposure of tissue to lipid solvents were necessary for good retention of labeled vitamin A in tissues.

Title Teenage Cervical Carcinoma in Situ.
Date June 1973
Journal Obstetrics and Gynecology
Title Correlation of Ranges of Correlated Deviates.
Date June 1967
Journal Biometrika
Title Comparison of Methods of Extracting Intracellular Proteases from Bacteria.
Date June 1966
Journal Applied Microbiology
Excerpt

Five commonly used methods of disintegrating bacterial cells were compared by use of Bacillus subtilis, Pseudomonas putrefaciens, and Streptococcus durans as the test organisms. These methods were: (i) sonic treatment, (ii) grinding, (iii) freezing and thawing, (iv) acetone-powder, and (v) toluene. Sonic treatment and grinding yielded more protein in the cell-free extracts than did the other methods. Likewise, the protease activities (micrograms of tyrosine liberated per milliliter of extract) of sonically disrupted and ground cell extracts on casein substrates were far greater than those in extracts from cells disintegrated by the other methods. When the specific activity was based on the amount of tyrosine liberated per milligram of protein in the extract, the acetone-powder method yielded the most active protease extract, whereas the extract obtained by sonic treatment was least active. Other methods yielded extracts with intermediate specific activity.

Title Short-cut Multiple Comparisons for Balanced Single and Double Classifications. 2. Derivations and Approximations.
Date April 1966
Journal Biometrika
Title Modulation of Inhibition of Return by the Dopamine D2 Receptor Agonist Bromocriptine Depends on Individual Dat1 Genotype.
Date
Journal Cerebral Cortex (new York, N.y. : 1991)
Excerpt

Involuntary visual spatial attention is captured when a salient cue appears in the visual field. If a target appears soon after the cue, response times to targets at the cue location are faster relative to other locations. However, after longer cue-target intervals, responses to targets at the cue location are slower, due to inhibition of return (IOR). IOR depends on striatal dopamine (DA) levels: It varies with different alleles of the DA transporter gene DAT1 and is reduced in patients with Parkinson's disease, a disease characterized by reduced striatal dopaminergic transmission. We examined the role of DA in involuntary attention and IOR by administering the DA D2 receptor-specific agonist bromocriptine to healthy human subjects. There was no effect of either DAT1 genotype or bromocriptine on involuntary attention, but participants with DAT1 alleles predicting higher striatal DA had a larger IOR. Furthermore, bromocriptine increased the magnitude of IOR in participants with low striatal DA but abolished the IOR in subjects with high striatal DA. This inverted U-shaped pattern resembles previously described relationships between DA levels and performance on cognitive tasks and suggests an involvement of striatal DA in IOR that does not include a role in involuntary attention.

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