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Biomedical subjects

Nancy Wilson

Publications and source records attributed to Nancy Wilson.

At least 19 recordsLinked to original sources
PubMed2006

Polymorphisms in eight host genes associated with control of HIV replication do not mediate elite control of viral replication in SIV-infected Indian rhesus macaques.

Polymorphisms in several host genes in HIV-infected individuals facilitate slow progression to AIDS. We have identified several SIV-infected Indian rhesus macaques that naturally control viral replication. We investigated whether spontaneous control of SIV in any of these animals could be explained by mutations in host genes. Such variables could confound studies of associations between MHC class I alleles and control of viral replication. We searched for polymorphisms in CCR5, CXCR6, GPR15, RANTES, IL-10, APOBEC3G, TNF-alpha, and TSG101 and looked for associations with decreased viral replication. We did not detect any correlations between plasma viral concentration and polymorphisms in host genes examined in this study. In addition, we did not find the polymorphisms present in humans in any of our macaques.

Animals↗
PubMed2006

Creatinine for evaluation of glomerular filtration rate in children.

This report is to provide primary care physicians with a convenient method for identifying children with impaired kidney function. This is important because of the prevalence of chronic kidney disease in adults and because intervention may delay disease progression. The glomerular filtration rate (GFR) measured using cimetidine clearance and calculated using height and serum creatinine concentration were compared during 222 clearance studies in 32 pediatric patients over 8 years. A child 1 year or older with a calculated GFR<60 mL/min/1.73 m2 has a significantly reduced GFR and should be referred to a pediatric nephrologist for further evaluation.

Adolescent↗
PubMed2005

Timed-urine collections for renal clearance studies.

The purpose of this study was to describe the reproducibility of timed-urine collections for renal clearance studies and the effect variations in urine collection has on measurement of glomerular filtration rate (GFR). Data from 222 cimetidine clearance studies (GFR-Cim) were obtained from 32 pediatric renal patients over a period of 8 years. There were three to 18 studies per child aged 4.8 years to 21 years at the time of a study. The urinary creatinine excretion rate is measured during supervised urine collection periods. The creatinine excretion rates in each child were compared to obtain data on the reproducibility of the urine collections. The coefficient of variation (CV) of the creatinine excretion rate is approximately 10% in both children and adults. The variation in GFR to be expected during repeated renal clearance studies in subjects with stable GFR, using voided urine collections, was similar in children and adults, with a CV of 12% to 14%.

Adolescent↗
PubMed2005

CD8+ T-lymphocyte response to major immunodominant epitopes after vaginal exposure to simian immunodeficiency virus: too late and too little.

In the acute stage of infection following sexual transmission of human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV), virus-specific CD8+ T-lymphocyte responses partially control but do not eradicate infection from the lymphatic tissues (LTs) or prevent the particularly massive depletion of CD4+ T lymphocytes in gut-associated lymphatic tissue (GALT). We explored hypothetical explanations for this failure to clear infection and prevent CD4+ T-lymphocyte loss in the SIV/rhesus macaque model of intravaginal transmission. We examined the relationship between the timing and magnitude of the CD8+ T-lymphocyte response to immunodominant SIV epitopes and viral replication, and we show first that the failure to contain infection is not because the female reproductive tract is a poor inductive site. We documented robust responses in cervicovaginal tissues and uterus, but only several days after the peak of virus production. Second, while we also documented a modest response in the draining genital and peripheral lymph nodes, the response at these sites also lagged behind peak virus production in these LT compartments. Third, we found that the response in GALT was surprisingly low or undetectable, possibly contributing to the severe and sustained depletion of CD4+ T lymphocytes in the GALT. Thus, the virus-specific CD8+ T-lymphocyte response is "too late and too little" to clear infection and prevent CD4+ T-lymphocyte loss. However, the robust response in female reproductive tissues may be an encouraging sign that vaccines that rapidly induce high-frequency CD8+ T-lymphocyte responses might be able to prevent acquisition of HIV-1 infection by the most common route of transmission.

Animals↗
PubMed2004

Measurement of renal functional reserve in children.

Renal functional reserve was measured during 89 studies in 78 children as the difference between the baseline glomerular filtration rate (GFR) and that following a protein meal. GFR was measured using creatinine as the filtration marker in children pre-treated with cimetidine. The children had been on a diet free of meat, fish, and fowl for 24 h. The protein meal to stimulate GFR was derived from milk, cheese, eggs, and baked goods. The increase in GFR following the protein meal was due mainly to an increase in the glomerular filtration of creatinine, with a small contribution by decreased serum creatinine concentration. This study confirmed that renal functional reserve can be measured using a meat-free protein meal to stimulate GFR. The protocol employed is a relatively noninvasive and inexpensive procedure for identifying glomerular hyperfiltration in children.

Adolescent↗
PubMed2004

Comparison of two formulae for estimation of glomerular filtration rate in children.

Glomerular filtration rate (GFR) was measured in 216 studies in 151 children using the cimetidine protocol. This was compared with the GFR calculated using Léger's pharmacokinetic equation and with that calculated using k*L/[Cr](s )(constant x length in centimeters divided by serum creatinine concentration). The GFR calculated using the equation GFR=k*L/[Cr](s) yielded a closer approximation to the measured GFR than that using Léger's pharmacokinetic equation. Currently there is focus on screening children for decreased GFR to identify those with asymptomatic chronic kidney disease at a time when intervention may delay progression to chronic renal failure. This study showed close approximation of the calculated GFR with the measured GFR using the equation GFR=k*L/[Cr](s), when the values for k were determined in the laboratory in which creatinine was measured.

Adolescent↗
PubMed2004

The ratio of urinary cystatin C to urinary creatinine for detecting decreased GFR.

Glomerular filtration rate (GFR) and urine and serum concentrations of cystatin C and creatinine were measured in 40 boys and 42 girls. The fractional excretion of cystatin C (FE Cyst C) increased in proportion to the decrease in GFR. Since serum creatinine concentration (S-Creatinine) in the numerator of the fractional excretion equation and serum cystatin C concentration (S-Cystatin C) in the denominator have similar numerical values, they cancel out. The result is an equation in which the FE Cyst C is equal to the ratio of urinary cystatin C to urinary creatinine (u[cystatin-C/Cr]). The ratio of u[cystatin C/Cr] was compared with GFR. Using a receiving operating characteristic (ROC) plot, the data showed that a ratio of u[cystatin C/Cr]*100 that is > or =0.100 has a sensitivity of 90.0% for identification of children with GFR < or =60 ml/min per 1.73 m(2). The false-positive rate is 16.1%. The u[cystatin C/Cr] ratio is a reliable screening tool for detecting decreased GFR that does not require a serum sample.

Adolescent↗
PubMed2004

Reversion of CTL escape-variant immunodeficiency viruses in vivo.

Engendering cytotoxic T-lymphocyte (CTL) responses is likely to be an important goal of HIV vaccines. However, CTLs select for viral variants that escape immune detection. Maintenance of such escape variants in human populations could pose an obstacle to HIV vaccine development. We first observed that escape mutations in a heterogeneous simian immunodeficiency virus (SIV) isolate were lost upon passage to new animals. We therefore infected macaques with a cloned SIV bearing escape mutations in three immunodominant CTL epitopes, and followed viral evolution after infection. Here we show that each mutant epitope sequence continued to evolve in vivo, often re-establishing the original, CTL-susceptible sequence. We conclude that escape from CTL responses may exact a cost to viral fitness. In the absence of selective pressure upon transmission to new hosts, these original escape mutations can be lost. This suggests that some HIV CTL epitopes will be maintained in human populations.

AIDS Vaccines↗
PubMed2004

Consequences of cytotoxic T-lymphocyte escape: common escape mutations in simian immunodeficiency virus are poorly recognized in naive hosts.

Cytotoxic T lymphocytes (CTL) are associated with control of immunodeficiency virus infection but also select for variants that escape immune recognition. Declining frequencies of epitope-specific CTL frequencies have been correlated with viral escape in individual hosts. However, escape mutations may give rise to new epitopes that could be recognized by CTL expressing appropriate T-cell receptors and thus still be immunogenic when escape variants are passed to individuals expressing the appropriate major histocompatibility complex class I molecules. To determine whether peptide ligands that have been altered through escape can be immunogenic in new hosts, we challenged naïve, immunocompetent macaques with a molecularly cloned simian immunodeficiency virus (SIV) bearing common escape mutations in three immunodominant CTL epitopes. Responses to the altered peptides were barely detectable in fresh samples at any time after infection. Surprisingly, CTL specific for two of three escaped epitopes could be expanded by in vitro stimulation with synthetic peptides. Our results suggest that some escape variant epitopes evolving in infected individuals do not efficiently stimulate new populations of CTL, either in that individual or upon passage to new hosts. Nevertheless, escape variation may not completely abolish an epitope's immunogenicity. Moreover, since the mutant epitope sequences did not revert to wild type during the study period, it is possible that low-frequency CTL exerted enough selective pressure to preserve epitope mutations in viruses replicating in vivo.

Amino Acid Sequence↗
PubMed2004

A dominant role for CD8+-T-lymphocyte selection in simian immunodeficiency virus sequence variation.

CD8(+) T lymphocytes (CD8-TL) select viral escape variants in both human immunodeficiency virus and simian immunodeficiency virus (SIV) infections. The frequency of CD8-TL viral escape as well as the contribution of escape to overall virus diversification has not been assessed. We quantified CD8-TL selection in SIV infections by sequencing viral genomes from 35 SIVmac239-infected animals at the time of euthanasia. Here we show that positive selection for sequences encoding 46 known CD8-TL epitopes is comparable to the positive selection observed for the variable loops of env. We also found that >60% of viral variation outside of the viral envelope occurs within recognized CD8-TL epitopes. Therefore, we conclude that CD8-TL selection is the dominant cause of SIV diversification outside of the envelope.

Amino Acid Sequence↗
PubMed2004

Extraepitopic compensatory substitutions partially restore fitness to simian immunodeficiency virus variants that escape from an immunodominant cytotoxic-T-lymphocyte response.

Selection for escape mutant immunodeficiency viruses by cytotoxic T lymphocytes (CTL) has been well characterized and may be associated with disease progression. CTL epitopes accrue escape mutations at different rates in vivo. Interestingly, certain high-frequency CTL do not select for escape until the chronic phase of infection. Here we show that mutations conferring escape from immunodominant CTL directed against an epitope in the viral Gag protein are strongly associated with extraepitopic mutations in gag in vivo. The extraepitopic mutations partially restore in vitro replicative fitness of viruses bearing the escape mutations. Constraints on epitope sequences may therefore play a role in determining the rate of escape from CTL responses in vivo.

Amino Acid Sequence↗
PubMed2003

Multispecific vaccine-induced mucosal cytotoxic T lymphocytes reduce acute-phase viral replication but fail in long-term control of simian immunodeficiency virus SIVmac239.

Given the current difficulties generating vaccine-induced neutralizing antibodies to human immunodeficiency virus (HIV), the focus of the vaccine community has shifted toward creating cytotoxic-T-lymphocyte (CTL)-based vaccines. Recent reports of CTL-based vaccine trials in macaques challenged with simian/human immunodeficiency virus SHIV-89.6P have supported the notion that such vaccines can ameliorate the course of disease. However, almost all of these studies included Env as an immunogen and since SHIV-89.6P is sensitive to neutralizing antibodies it is difficult to determine the mechanism(s) of protection. Consequently, SHIV-89.6P challenge of macaques may be a poor model for determining vaccine efficacy in humans. To ascertain the effect of vaccine-induced multispecific mucosal CTL, in the absence of Env-specific antibody, on the control of an immunodeficiency virus challenge, we vaccinated Mamu-A*01(+) macaques with constructs encoding a combination of CTL epitopes and full-length proteins (Tat, Rev, and Nef) by using a DNA prime/recombinant modified vaccinia virus Ankara (rMVA) boost regimen. The vaccination induced virus-specific CTL and CD4(+) helper T lymphocytes with CTL frequencies as high as 20,000/million peripheral blood mononuclear cells. The final rMVA vaccination, delivered intravenously, engendered long-lived mucosal CTL. At 16 weeks after the final rMVA vaccination, the vaccinees and naive, Mamu-A*01(+) controls were challenged intrarectally with SIVmac239. Massive early anamnestic cellular immune responses controlled acute-phase viral replication; however, the three vaccinees were unable to control virus replication in the chronic phase. The present study suggests that multispecific mucosal CTL, in the absence of neutralizing antibodies, can achieve a modicum of control over early viral replication but are unable to control chronic-phase viral replication after a high-dose mucosal challenge with a pathogenic simian immunodeficiency virus.

Acute Disease↗
PubMed2003

Expression of the major histocompatibility complex class I molecule Mamu-A*01 is associated with control of simian immunodeficiency virus SIVmac239 replication.

Several HLA alleles are associated with attenuated human immunodeficiency virus disease progression. We explored the relationship between the expression of particular major histocompatibility complex (MHC) class I alleles and viremia in simian immunodeficiency virus SIV(mac)239-infected macaques. Of the common MHC class I alleles, animals that expressed Mamu-A*01 exhibited the best control of viral replication.

Alleles↗
PubMed2003

Using case studies to evaluate students' ability to develop a geriatric interdisciplinary care plan.

The Geriatric Interdisciplinary Team Training (GITT) program, an educational intervention funded by The John A. Hartford Foundation of New York City, has trained more than 1800 health care professions students and clinicians throughout the United States. Evaluating the effectiveness of this training intervention has proven to be quite a challenge. Core measures were collected pre- and post-GITT training to evaluate student development as a result of GITT. This paper focuses on one of these core measures, the Test of Geriatric Interdisciplinary Care Planning (TGICP). This instrument, developed for the GITT program, is one mechanism created to test trainees' ability to develop an interdisciplinary plan of care. Using a case study methodology, this two-part instrument provides an innovative approach to quantifying and correlating responses from an interdisciplinary cohort of students. This paper will describe the development of the TGICP, including the creation and validation of the case studies, the framework for the questionnaire, and the coding and scoring mechanism created to evaluate trainee responses.

Aged↗
PubMed2003

Using scripted video to assess interdisciplinary team effectiveness training outcomes.

As part of the Geriatric Interdisciplinary Team Training (GITT) Program funded by the John A. Hartford Foundation, the authors of this article worked to create an instrument, the Trainee Test of Team Dynamics, to assess health care trainees' understanding of team dynamics. The Trainee Test of Team Dynamics is a five-question written test designed to capture GITT trainees' knowledge of team process and skills in addressing conflict that is administered after watching a five-minute videotape of a simulated interdisciplinary health care team meeting. The test was created to measure health professions students' abilities to recognize effective geriatric health care teams, to respond to effective and ineffective team behaviors, and to determine whether or not the team meeting achieved its purpose: to meet the patient's needs for an interdisciplinary care plan. Scripts and test items developed and tested by practitioners in social work, medicine, public health, nursing and others assured a product that compensated for differences in educational level and occupation, yet captured accurate and appropriate responses. The results reported here include an analysis of 740 trainees' baseline responses from the multi-site educational programs to determine the construct validity of the new measure.

Adult↗
PubMed2002

Differences between T cell epitopes recognized after immunization and after infection.

Evidence suggests that cellular immune responses play a crucial role in the control of HIV and SIV replication in infected individuals. Several vaccine strategies have therefore targeted these CD8(+) and CD4(+) responses. Whether vaccination induces the same repertoire of responses seen after infection is, however, a key unanswered question in HIV vaccine development. We therefore compared the epitope specificity induced by vaccination to that present postchallenge in the peripheral blood. Intracellular cytokine staining of PBMC stimulated with overlapping 15/20-mer peptides spanning the proteins of SIV were measured after DNA/modified vaccinia Ankara vaccination of eight rhesus macaques. Lymphocytes from 8 animals recognized a total of 39 CD8 epitopes and 41 CD4 epitopes encoded by the vaccine. T cell responses were again monitored after challenge with SIVmac239 to investigate the evolution of these responses. Only 57% of all CD8(+) T cell responses and 19% of all CD4(+) T cell responses present after vaccination were recalled after infection as measured in the peripheral blood. Interestingly, 29 new CD8 epitopes and 5 new CD4 epitopes were recognized by PBMC in the acute phase. These new epitopes were not detected after vaccination, and only some of them were maintained in the chronic phase (33% of CD8 and no CD4 responses). Additionally, 24 new CD8 epitopes and 7 new CD4 epitopes were recognized by PBMC in the chronic phase of infection. The repertoire of the immune response detected in the peripheral blood after immunization substantially differed from the immune response detected in the peripheral blood after infection.

Administration, Rectal↗
PubMed2002

Acute phase cytotoxic T lymphocyte escape is a hallmark of simian immunodeficiency virus infection.

Cytotoxic T-lymphocyte (CTL) responses peak coincident with the decline in acute HIV viremia. Despite two reports of CTL-resistant HIV variants emerging during acute infection, the contribution of acute CTL escape to HIV pathogenesis remains unclear. Difficulties inherent in studying acute HIV infection can be overcome by modeling virus-host interactions in SIV-infected rhesus macaques. We sequenced 21 complete simian immunodeficiency virus (SIV)mac239 genomes at four weeks post-infection to determine the extent of acute CTL escape. Here we show that viruses from 19 of 21 macaques escaped from CTLs during acute infection and that these escape-selecting CTLs were responsive to lower concentrations of peptide than other SIV-specific CTLs. Interestingly, CTLs that require low peptide concentrations for stimulation (high 'functional avidity') are particularly effective at controlling other viral infections. Our results suggest that acute viral escape from CTLs is a hallmark of SIV infection and that CTLs with high functional avidity can rapidly select for escape variants.

Acute Disease↗