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Biomedical subjects

P Shields

Publications and source records attributed to P Shields.

16 recordsLinked to original sources
PubMed2001

Memory T cells constitute a subset of the human CD8+CD45RA+ pool with distinct phenotypic and migratory characteristics.

Using HLA class I-viral epitope tetramers to monitor herpes virus-specific CD8(+) T cell responses in humans, we have shown that a significant fraction of responding cells revert from a CD45RO(+) to a CD45RA(+) state after priming. All tetramer-binding CD45RA(+) cells, regardless of epitope specificity, expressed a phenotype LFA-1(high)CCR7(low) that was stable for at least 10 years in infectious mononucleosis patients and indefinitely in asymptomatic carriers. CD8(+)CD45RA(+)LFA-1(high) cells were not present in cord blood but in adults account for up to 50% of CD8(+)CD45RA(+) cells. These CD45RA(+)LFA-1(high) cells have significantly shorter telomeres than CD45RA(+)LFA-1(low) cells, suggesting that the latter represent a naive population, while the former are memory cells. CD45RA(+) memory cells are a stable population of noncycling cells, but on stimulation they are potent producers of IFN-gamma, while naive CD8(+) cells produce only IL-2. The chemokine receptor profile and migratory potential of CD45RA(+) memory cells is very similar to CD45RO(+) cells but different to naive CD8 cells. In accord with this, CD45RA(+) memory cells were significantly underrepresented in lymph nodes, but account for virtually all CD8(+)CD45RA(+) T cells in peripheral tissues of the same individuals.

Apoptosis↗
PubMed2001

Cytokines and chemokines in the immune response to hepatitis C infection.

Over 170 million people are infected with the hepatitis C virus worldwide, resulting in a large disease burden and significant mortality. Hepatitis C virus is rarely cleared in the acute phase of the infection and most patients become chronically infected; a proportion of these patients develop progressive liver disease and fibrosis. The outcome of infection depends on the immune responses of both the innate and cognate immune systems, and these in turn are orchestrated by networks of cytokines and chemokines. There is evidence that a vigorous type 1 immune response to viral proteins is required for viral elimination, and the recruitment of such effector cells to the liver is dependent on the local activity of specific inducible chemokines. Multiple factors determine the ability of the hepatitis C virus to survive host immune responses, including an ability to alter the cytokine profile secreted by T cells and to cause resistance to the effects of antiviral cytokines such as interferon. In the present review, we briefly cover the important advances made in this area over the past 12 months.

Chemokines↗
PubMed2001

Nicotine metabolism and CYP2D6 phenotype in smokers.

We tested the hypothesis that the polymorphic enzyme CYP2D6 is related to nicotine metabolism in 261 healthy subjects enrolling in a smoking cessation clinic. Subjects completed a questionnaire, were given dextromethorphan, and contributed a urine and blood sample. The CYP2D6 phenotype (based on a determination of dextromethorphan and metabolites in an aliquot of overnight urine) and genotype (based on characterization of CYP2D6 variant alleles by a PCR-based method on a subset) were determined. Seventeen poor metabolizers (6.5%) were observed among 261 phenotyped smokers. Nicotine and it chief metabolites, cotinine and trans-3'-hydroxycotinine were measured in the urine and adjusted for pH. All of the nicotine metabolite levels were significantly related to usual and recent smoking. Neither levels of smoking nor nicotine metabolites overall exhibited a relationship to the CYP2D6-deficient metabolizer phenotype. The ratio of nicotine:cotinine + trans-3'-hydroxycotinine, stratified by time since the last cigarette, was unrelated to gender, age, education, race (white/African American), recent alcohol or caffeine consumption, or smoking practices. Subjects in either the lowest quintile or decile metabolic ratio (ultrametabolizers) exhibited a significantly lower nicotine:cotinine + trans-3'-hydroxycotinine ratio after adjustment for recent smoking, pH, and other factors. These data suggest that the polymorphic CYP2D6 gene is not a major contributor to nicotine metabolism in tobacco smokers but may influence the disposition of nicotine in the small subset of the population who are CYP2D6 ultrametabolizers.

Adult↗
PubMed2000

Outcome of lamivudine resistant hepatitis B virus infection in the liver transplant recipient.

BACKGROUND: In many transplant centres lamivudine is an important component of prophylaxis against, and treatment of, hepatitis B virus (HBV) graft infection. Drug resistant HBV species with specific polymerase mutations may emerge during lamivudine treatment. AIMS: To examine the clinical consequences of graft infection by lamivudine resistant virus. METHODS: The clinical course of four liver transplant patients who developed graft infection with lamivudine resistant virus was reviewed. The response of HBV infection to reduction of immunosuppression and to manipulation of antiviral therapy was assessed. For each patient, serum viral titre was measured and the viral polymerase gene was sequenced at multiple time points. RESULTS: High serum titres were observed following emergence of the lamivudine resistant species. Wild type HBV re-emerged as the dominant serum species after lamivudine withdrawal. All patients developed liver failure, and onset of liver dysfunction was observed when resistant virus was the dominant serum species. In three patients, liver recovery was observed when immunosuppression was stopped and when alternative antivirals were given. Wild type virus appeared to respond to ganciclovir, and to reintroduction of lamivudine. For one patient, introduction of famciclovir was associated with clinical, virological, and histological response. CONCLUSIONS: Failure of lamivudine prophylaxis may identify patients at special risk for the development of severe graft infection. Treatment of graft reinfection should include reduction of immunosuppression, and systematic exposure to alternative antivirals. Viral quantitation and genetic sequencing are essential components of therapeutic monitoring.

Adult↗
PubMed1997

The impact of nonacademic variables on performance at two medical schools.

Recent research shows that nonacademic variables must be taken into account when analyzing the indicators of medical student success. However, most previous studies have been limited to a single institution or population. This study investigated the relationship between nonacademic variables and performance at two very different medical schools. The Noncognitive Questionnaire was administered to 104 students at School A (predominantly white and historically oriented toward women) and 102 at School B (predominantly black). Correlation and multiple regression analyses were conducted to determine the relationship among nonacademic variables, undergraduate academic variables (Medical College Admission Test, undergraduate grade point average, and college quality), basic science grades, and US Medical Licensure Exam Step I (USMLE 1) scores. At School A, leadership/decisiveness, expected difficulty, and motivation predicted higher USMLE I scores and higher basic science grades each semester. At School B, expected difficulty was correlated with higher first semester grades only. For School A women, initiative/commitment was positively associated with both higher grades and higher USMLE scores. For black students of School B, expected difficulty was positively associated with higher grades. Identifying school-specific nonacademic variables of performance is critical to developing improved student support services.

Achievement↗
PubMed1996

Ultrafast computed tomography as a diagnostic modality in the detection of coronary artery disease: a multicenter study.

BACKGROUND: Ultrafast computed tomography (CT), by acquiring images of the proximal coronary arteries, detects coronary calcifications and has been demonstrated to be highly sensitive for the detection of coronary artery disease in many small studies. The aim of this study was to determine the relationship between ultrafast CT scanning and coronary angiography in a large number of symptomatic patients. METHODS AND RESULTS: The study population consisted of 710 patients from six participating centers. A multivariate logistic regression model was used to evaluate the individual contributions of age, number of calcified vessels, and the calcium score for the probability of angiographically significant disease. Of the 710 patients enrolled, 427 patients had significant angiographic disease, and coronary calcification was detected in 404, yielding a sensitivity of 95%. Of the 23 patients without calcifications, 19 (83%) had single-vessel disease at angiography. Of the 283 patients without angiographically significant disease, 124 had negative ultrafast CT coronary studies, for a specificity of 44%. An increasing number of vessels with calcification present on ultrafast CT was found to increase specificity for the presence of obstructive coronary artery disease in at least one vessel (P < .0001). As the log of the calcium score increases, the probability of multivessel obstructive disease increases (P < .0001). CONCLUSIONS: Ultrafast CT scanning is an noninvasive, non-exercise-dependent test with an excellent sensitivity for the detection of coronary artery disease. The presence of calcifications in multiple vessels and in younger populations correlates with higher specificities for obstructive disease, making ultrafast CT coronary scanning a very useful diagnostic test.

Adult↗
PubMed1996

Prognostic value of coronary calcification and angiographic stenoses in patients undergoing coronary angiography.

OBJECTIVES: This investigation sought to determine the relative prognostic value of coronary calcific deposits and coronary angiographic findings for predicting coronary heart disease-related events in patients referred for angiography. BACKGROUND: The relation among coronary calcification, coronary stenoses and coronary heart disease-related events is of interest on a clinical as well as a pathophysiologic basis. METHODS: Four hundred ninety-one symptomatic patients underwent coronary angiography and electron beam computed tomography at five different centers between April 1989 and December 1993. The electron beam computed tomograms were interpreted by a cardiologist with no knowledge of the coronary angiographic and clinical data. Receiver operating characteristic (ROC) curves were constructed to determine the relation between electron beam computed tomographic and coronary angiographic findings. A follow-up telephone survey was completed in 86% of patients. The records for all patients who died or were admitted to the hospital for chest pain or suspected myocardial infarction were reviewed by three other cardiologists with no knowledge of the coronary angiographic and electron beam computed tomographic study results. RESULTS: The mean (+/- SE) area under the ROC curve was 0.75 +/- 0.02 for the coronary calcium score, indicating moderate discriminatory power for this score for predicting angiographic findings. Thirteen coronary heart disease-related deaths and eight nonfatal acute infarctions occurred over 30 +/- 13 months. Scores were sorted in ascending order and divided into quartiles of equal size. One patient in the first quartile had a fatal myocardial infarction (coronary calcium score range 0 to 2.1); 2 in the second quartile (range 2.1 to 75.3), 8 in the third quartile (range 75.3 to 397.1) and 10 in the fourth quartile (> 397.1) had a coronary heart disease-related event. Application of bivariate logistic regression showed that log score but not number of angiographically diseased vessels significantly predicted the probability of a coronary heart disease-related event occurring during follow-up. CONCLUSIONS: Electron beam computed tomographic calcium scores correlate moderately well with angiographic findings. These scores predict coronary heart disease-related events in patients undergoing angiography as well as do the number of angiographically affected arteries.

Calcinosis↗
PubMed1996

Recruitment and retention of homeless mentally ill participants in research.

Are the unstable residential and personal lives of homeless mentally ill (HMI) individuals so difficult as to preclude their inclusion in rigorous, longitudinal research protocols? The continued presence of HMI individuals in U.S. society has prompted the mental health research community to reconsider the question of whether clinical trial and demonstration research protocols are feasible with this population. This article briefly examines the existing research literature on recruitment and retention rates in recent studies of this population and, in more detail, the specific strategies used by researchers to recruit and retain HMI individuals as research participants. In general, with sufficient resources and the persistent use of existing strategies for recruitment and retention, HMI individuals can be successfully studied over time. Finally, to demonstrate this potential, the recruitment and retention strategies of the San Diego McKinney Homeless Mentally Ill Demonstration Research Program are described.

Adult↗
PubMed1996

Cytochrome P4501A2: enzyme induction and genetic control in determining 4-aminobiphenyl-hemoglobin adduct levels.

Cytochrome P4501A2 (CYP1A2) activity may be related to bladder cancer risk through metabolic activation of aromatic amines, such as 4-aminobiphenyl (ABP), to reactive intermediates that can form DNA and hemoglobin (Hb) adducts. In the context of a study on smoking and bladder cancer risk, 97 healthy male volunteers were investigated. CYP1A2-dependent N-oxidation activity was measured using a molar ratio of urinary caffeine metabolites [(paraxanthine + 1,7-dimethyluric acid)/caffeine] obtained between the fourth and fifth h after drinking a standardized cup of coffee. N-Oxidation activity was induced by blond tobacco smoke, meat consumption the dinner before the test, or more than four cups of coffee a day. The regular use of medication appeared associated with a decrease in N-oxidation levels. Age and alcohol consumption were not related with CYP1A2 activity. A polymorphic distribution of the CYP1A2 and N-acetyltransferase-2 (determined by the caffeine metabolite ratio 5-acetylamino-6-formylamino-3-methyluracil:1-methylxanthine) phenotypes was examined in relation to susceptibility to ABP-Hb adduct formation. Rapid oxidizers and subjects with the combined slow acetylator-rapid oxidizer phenotype showed the highest ABP-Hb adduct levels at a low smoking dose. Blond tobacco smokers exhibited higher adduct levels compared with black tobacco smokers, after adjustment for the quantity of cigarettes smoked. At the highest levels of smoking exposure, no major difference in ABP-Hb adduct levels was found among the different combinations of CYP1A2 and N-acetyltransferase-2 phenotypes. In a subset of only 45 available samples, no association was seen between the ABP-Hb adduct levels and the glutathione S-transferase M1 genotype.

Age Factors↗
PubMed1981

Subchronic administration of caffeine and theophylline in drinking water: effects on rat liver RNA polymerase I activity.

Administration of caffeine or theophylline, 0.2 mg/ml (an average of 20 mg/kg/d) of drinking water, to male CD rats, 2 months of age, over a 15 week period resulted in the elevation of liver RNA polymerase I activity by 2-3 fold as assayed in isolated nuclei. This increase in activity was already apparent by the fourth week of exposure. The changes in RNA polymerase I activity were accompanied by moderate liver hypertrophy.

Animals↗