Biomedical subjects

Bryan E Shepherd

Publications and source records attributed to Bryan E Shepherd.

9 recordsLinked to original sources

PubMed2006

Evidence for preferential Ig gene usage and differential TdT and exonuclease activities in human naïve and memory B cells.

Memory B cells and the antibodies they encode are important for protective immunity against infectious pathogens. Characterization of naïve and memory B cell antibody repertoires will elucidate the molecular basis for the generation of antibody diversity in human B cells and the optimization of antibody structures that bind microbial antigens. In this study we aimed to investigate the influence of antigenic selection on the antibody genes of the two CD27+ memory B cell subsets, comparing them with the naïve repertoire in CD27- cells. We analyzed and compared the Ig heavy chain gene transcripts in three recently defined circulating naïve and memory B cell subsets (CD19+IgD+CD27- [naïve], CD19+IgD+CD27+ [un-class-switched memory] or CD19+IgD- CD27+ [class-switched memory]) at the single cell level. We found similar biased patterns of variable, diversity and joining heavy chain gene usages in all three groups of cells. CD19+IgD+CD27+ memory B cells harbored as diverse an antibody gene repertoire as CD19+IgD-CD27+ memory B cells. Interestingly, CD19+IgD+CD27+ memory B cells possessed a lower frequency of somatic mutations, a higher incidence of exonuclease activity at the 3' end of D regions, and a lower frequency of N and P nucleotide additions at both VH-D and D-JH junctions of CDR3 regions compared to CD19+IgD-CD27+ memory B cells. These data suggest distinct functional mechanisms underlying selection of this unique subset of un-class-switched memory B cells.

Adult↗

PubMed2006

Absolute count and percentage of CD4+ lymphocytes are independent predictors of disease progression in HIV-infected persons initiating highly active antiretroviral therapy.

BACKGROUND: Highly active antiretroviral therapy (HAART) is recommended when the absolute CD4(+) T lymphocyte count is <200 cells/mm(3), and it should be considered when that count is > or =200, although the optimal timing when it is > or =200 is unclear. Because preliminary data had suggested that a low CD4(+) T lymphocyte percentage (%CD4) is associated with disease progression in persons initiating HAART who have a higher absolute CD4, we sought to further characterize the predictive utility of %CD4. METHODS: We conducted an observational study of persons in Collaborations in HIV Outcomes Research/US cohort who initiated their first HAART regimen between 1997 and 2004, received > or =30 days of therapy, and had baseline values of absolute CD4, %CD4, and HIV-1 RNA. Cox proportional-hazards models determined associations between %CD4 and disease progression (to either a new AIDS-defining event [ADE] or death). RESULTS: Of 1891 persons, 11% were female and 18% were African American; the median age was 38 years. Median follow-up was 55 months (interquartile range, 23-83 months), and 468 (25%) had disease progression. Multivariable analysis including age, race, sex, HIV-1 RNA, prior antiretroviral therapy, probable route of infection, prior ADE, absolute CD4, and %CD4 was performed; prior ART (P<.0001), injection-drug use (P=.04), lower absolute CD4 (P=.002), and lower %CD4 (P=.002) predicted disease progression. CONCLUSIONS: %CD4 at initiation of the first HAART regimen predicted disease progression independent of absolute CD4; %CD4 may be used to determine the timing of HAART.

Adolescent↗

PubMed2006

Cellular recognition of Mycobacterium tuberculosis ESAT-6 and KatG peptides in systemic sarcoidosis.

Sarcoidosis is an enigmatic disease with a pathology similar to that of tuberculosis. We detected Th-1 immune responses to Mycobacterium tuberculosis ESAT-6 and KatG peptides from peripheral blood mononuclear cells from 15/26 sarcoidosis, 1/24 purified-protein-derivative-negative (PPD-) (P < 0.0001, Fisher's exact test), and 7/8 PPD-positive (PPD+) subjects (P = 0.21). This finding provides immunologic links between mycobacteria and systemic sarcoidosis.

Adult↗

PubMed2006

Prevalence and predictors of squamous intraepithelial lesions of the cervix in HIV-infected women in Lusaka, Zambia.

OBJECTIVES: HIV-infected women living in resource-constrained nations like Zambia are now accessing antiretroviral therapy and thus may live long enough for HPV-induced cervical cancer to manifest and progress. We evaluated the prevalence and predictors of cervical squamous intraepithelial lesions (SIL) among HIV-infected women in Zambia. METHODS: We screened 150 consecutive, non-pregnant HIV-infected women accessing HIV/AIDS care services in Lusaka, Zambia. We collected cervical specimens for cytological analysis by liquid-based monolayer cytology (ThinPrep Pap Test) and HPV typing using the Roche Linear Array PCR assay. RESULTS: The median age of study participants was 36 years (range 23-49 years) and their median CD4+ count was 165/microL (range 7-942). The prevalence of SIL on cytology was 76% (114/150), of which 23.3% (35/150) women had low-grade SIL, 32.6% (49/150) had high-grade SIL, and 20% (30/150) had lesions suspicious for squamous cell carcinoma (SCC). High-risk HPV types were present in 85.3% (128/150) women. On univariate analyses, age of the participant, CD4+ cell count, and presence of any high-risk HPV type were significantly associated with the presence of severely abnormal cytological lesions (i.e., high-grade SIL and lesions suspicious for SCC). Multivariable logistic regression modeling suggested the presence of any high-risk HPV type as an independent predictor of severely abnormal cytology (adjusted OR: 12.4, 95% CI 2.62-58.1, p=0.02). CONCLUSIONS: The high prevalence of abnormal squamous cytology in our study is one of the highest reported in any population worldwide. Screening of HIV-infected women in resource-constrained settings like Zambia should be implemented to prevent development of HPV-induced SCC.

Adult↗

PubMed2006

Sensitivity analyses comparing outcomes only existing in a subset selected post-randomization, conditional on covariates, with application to HIV vaccine trials.

In many experiments, researchers would like to compare between treatments and outcome that only exists in a subset of participants selected after randomization. For example, in preventive HIV vaccine efficacy trials it is of interest to determine whether randomization to vaccine causes lower HIV viral load, a quantity that only exists in participants who acquire HIV. To make a causal comparison and account for potential selection bias we propose a sensitivity analysis following the principal stratification framework set forth by Frangakis and Rubin (2002, Biometrics58, 21-29). Our goal is to assess the average causal effect of treatment assignment on viral load at a given baseline covariate level in the always infected principal stratum (those who would have been infected whether they had been assigned to vaccine or placebo). We assume stable unit treatment values (SUTVA), randomization, and that subjects randomized to the vaccine arm who became infected would also have become infected if randomized to the placebo arm (monotonicity). It is not known which of those subjects infected in the placebo arm are in the always infected principal stratum, but this can be modeled conditional on covariates, the observed viral load, and a specified sensitivity parameter. Under parametric regression models for viral load, we obtain maximum likelihood estimates of the average causal effect conditional on covariates and the sensitivity parameter. We apply our methods to the world's first phase III HIV vaccine trial.

AIDS Vaccines↗

PubMed2005

HIV-1 virologic and immunologic progression and initiation of antiretroviral therapy among HIV-1-infected subjects in a trial of the efficacy of recombinant glycoprotein 120 vaccine.

The first trial of the efficacy of a human immunodeficiency virus (HIV)-1 vaccine was conducted in North America and The Netherlands between 1998 and 2003. This multicenter, randomized, placebo-controlled trial of a recombinant glycoprotein 120 vaccine included 5403 initially HIV-negative volunteers who were monitored for 3 years. The 368 subjects who acquired HIV-1 infection were monitored for 2 years by use of the following postinfection end points: plasma HIV-1 RNA level (viral load), CD4+ lymphocyte count, initiation of antiretroviral therapy (ART), and HIV-1-related clinical outcomes. This article reports the study results that pertain to the effect of vaccination on the postinfection end points. The time until initiation of ART and the time until virologic failure or initiation of ART were similar in the vaccine arm and the placebo arm. The pre-ART viral load and CD4+ lymphocyte count trajectories were also comparable between the groups. Evidently, the vaccine did not affect HIV-1 disease progression.

AIDS Vaccines↗

PubMed2005

Sampling designs for HIV molecular epidemiology with application to Honduras.

Proper sampling is essential to characterize the molecular epidemiology of human immunodeficiency virus (HIV). HIV sampling frames are difficult to identify, so most studies use convenience samples. We discuss statistically valid and feasible sampling techniques that overcome some of the potential for bias due to convenience sampling and ensure better representation of the study population. We employ a sampling design called stratified cluster sampling. This first divides the population into geographical and/or social strata. Within each stratum, a population of clusters is chosen from groups, locations, or facilities where HIV-positive individuals might be found. Some clusters are randomly selected within strata and individuals are randomly selected within clusters. Variation and cost help determine the number of clusters and the number of individuals within clusters that are to be sampled. We illustrate the approach through a study designed to survey the heterogeneity of subtype B strains in Honduras.

Adolescent↗

PubMed2004

Estimating human hematopoietic stem cell kinetics using granulocyte telomere lengths.

OBJECTIVE: To study in vivo behavior of hematopoietic stem cells (HSC). MATERIALS AND METHODS: Behavior of HSC is difficult to study because one cannot observe and track cells within the marrow microenvironment. Therefore, information must be obtained from indirect means, such as competitive repopulation assays or surrogate studies, such as observations of telomere shortening in granulocytes. In this article, we use granulocyte telomere length data and a novel approach, stochastic simulation, to derive replication rates of HSC. The approach is first applied to cats and then to humans. RESULTS: Human HSC replicate infrequently, on average once per 45 weeks (range: once per 23 to once per 67 weeks). CONCLUSIONS: This rate is substantially slower than the average replication rates estimated for murine (once per 2.5 weeks) and feline (once per 8.3-10 weeks) HSC in vivo.

Age Factors↗

PubMed2004

Mortality and burden of disease in a cohort of HIV-seropositive adults in Nairobi, Kenya.

The purposes of this study were to measure incidence and determine risk factors associated with opportunistic infections (OIs) and mortality among an HIV-infected cohort in Nairobi, Kenya. Three hundred and eighty-one seropositive ambulatory adults in Nairobi, Kenya were followed from 1997 to 2000 with participants visiting the clinic every two months and when acutely ill. Acute bronchitis was the most frequent diagnosis, followed by sexually transmitted infections, candida vaginitis (among women), fever, diarrhoea, pneumonia, HIV-associated skin rash, oral candidiasis and urinary tract infection. Associations between the frequency of these diagnoses including survival and sociodemographic factors and initial CD4 count were assessed. A CD4 count <200 cells/mL at recruitment was strongly associated with decreased survival (adjusted odds ratio=3.0, 95% confidence interval 1.7-5.1). These findings may help to target high-risk populations and guide OI prevention and treatment strategies including decisions regarding initiation of antiretroviral therapy in sub-Saharan Africa.

AIDS-Related Opportunistic Infections↗