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Biomedical subjects

G M Shaw

Publications and source records attributed to G M Shaw.

At least 91 records · Page 5Linked to original sources
PubMed1998

Characterization of CFTR expression and chloride channel activity in human endothelia.

The cystic fibrosis transmembrane conductance regulator (CFTR) functions as a low-conductance, cAMP-regulated chloride (Cl-) channel in a variety of cell types, such as exocrine epithelial cells. Our results demonstrate that human primary endothelial cells isolated from umbilical vein (HUVEC) and lung microvasculature (HLMVEC) also express CFTR as determined via RT-PCR and immunohistochemical and immunoprecipitation analyses. Moreover, Cl- efflux and whole cell patch-clamp analyses reveal that HUVEC (n = 6 samples, P < 0.05) and HLMVEC (n = 5 samples, P < 0.05) display cyclic nucleotide-stimulated Cl- transport that is inhibited by the CFTR selective Cl- channel blocker glibenclamide but not by the blocker DIDS, indicative of CFTR Cl- channel activity. Taken together, these findings demonstrate that human endothelial cells derived from multiple organ systems express CFTR and that CFTR functions as a cyclic nucleotide-regulated Cl- channel in human endothelia.

Base Sequence↗
PubMed1998

Infant TGF-alpha genotype, orofacial clefts, and maternal periconceptional multivitamin use.

OBJECTIVE: We previously demonstrated a strong association between periconceptional maternal cigarette smoking, infant transforming growth factor-alpha (TGFa) genotype, and risk of orofacial clefts. Because serum folate may be decreased by cigarette smoking and because maternal periconceptional use of multivitamins containing folic acid has been associated with a reduced risk of clefting, we explored whether a potential relation existed between infant TGFa genotype, maternal multivitamin use, and risk of orofacial cleft phenotypes. DESIGN: Data were derived from a population-based case-control study of fetuses and live-born infants among a cohort of 1987 to 1989 California births (n = 548,844). Information concerning periconceptional multivitamin use was obtained via telephone interviews with mothers of 731 (84.7% of eligible) orofacial cleft case infants, and of 734 (78.2%) nonmalformed control infants. DNA was obtained from newborn screening bloodspots and genotyped for the Taql polymorphism of TGFa. Among infants of interviewed mothers, genotypes were available for 571 (78.1%) case infants and 640 (87.2%) control infants. SETTING: The study encompassed all hospitals in selected California counties. MAIN OUTCOME MEASURE: The main outcome measures were the risks of specific cleft phenotypes among infants with uncommon TGFa genotypes and whose mothers did not use multivitamins periconceptionally. RESULTS: Compared with infants homozygous for the common TGFa genotype and whose mothers used multivitamins, increased clefting risks were observed for infants with the A2 genotype (homozygous or heterozygous) and whose mothers did not use multivitamins. Risk estimates were 3.0 (1.4-6.6 [95% confidence interval]) for isolated cleft lip with or without cleft palate (CLP), 2.4 (0.69-11.6) for multiple CLP, 2.6 (0.97-7.7) for isolated cleft palate (CP), 4.2 (1.3-16.2) for multiple CP, and 8.1 (2.6-27.7) for "known-syndrome" clefts. Clefting risks for infants with the A2 genotype and whose mothers used multivitamins were substantially smaller, as were the risks for infants with the A1 genotype whose mothers did not use multivitamins. CONCLUSION: These data provide preliminary evidence for a gene-nutrient interaction in risk of clefting.

Adult↗
PubMed1998

Socioeconomic status, neighborhood social conditions, and neural tube defects.

OBJECTIVES: This study evaluated the contributions of lower socioeconomic status (SES) and neighborhood socioeconomic characteristics to neural tube defect etiology. The influence of additional factors, including periconceptional multivitamin use and race/ethnicity, was also explored. METHODS: Data derived from a case-control study of California pregnancies from 1989 to 1991. Mothers of 538 (87.8% of eligible) case infants/fetuses with neural tube defects and mothers of 539 (88.2%) nonmalformed infants were interviewed about their SES. Reported addresses were linked to 1990 US census information to characterize neighborhoods. RESULTS: Twofold elevated risks were observed for several SES indicators. Risks were somewhat confounded by vitamin use, race/ethnicity, age, body mass index, and fever but remained elevated after adjustment. A risk gradient was seen with increasing number of lower SES indicators. Women with 1 to 3 and 4 to 6 lower SES indicators had adjusted odds ratios of 1.6 (1.1-2.2) and 3.2 (1.9-5.4), respectively, compared with women with no lower SES indicators. CONCLUSIONS: Both lower SES and residence in a SES-lower neighborhood increased the risk of an neural tube defect-affected pregnancy, with risks increasing across a gradient of SES indicators.

Adult↗
PubMed1997

Effects of tapering doses of oral prednisone on viral load among HIV-infected patients with unexplained weight loss.

In an exploratory study of virologic and immunomodulatory effects of corticosteroid therapy for wasting syndrome, four HIV-infected adults with recent unexplained weight loss were given tapering doses of prednisone over a 2-month period. Serum neopterin and TNF receptor II levels decreased from baseline after 7 days. An antiretroviral effect was observed initially, peaking on days 14-21 (mean change in HIV-1 branched chain DNA assay on day 21 of -0.52 log10; mean change, from baseline to nadir for each individual, of -0.63 log10); subsequent bDNA levels returned toward baseline as prednisone was tapered. No patient lost weight and there was a mean weight gain of 3.5 kg. Anecdotal reports of corticosteroid benefits in the wasting syndrome may result in part from decreased T cell activation leading to decreased HIV replication, an effect that may be self-limited or that may occur only at higher prednisone doses. Studies involving more targeted immunomodulatory agents for wasting syndrome are warranted.

Adult↗
PubMed1997

Complementation of integrase function in HIV-1 virions.

Proviral integration is essential for HIV-1 replication and represents an important potential target for antiviral drug design. Although much is known about the integration process from studies of purified integrase (IN) protein and synthetic target DNA, provirus formation in virally infected cells remains incompletely understood since reconstituted in vitro assays do not fully reproduce in vivo integration events. We have developed a novel experimental system in which IN-mutant HIV-1 molecular clones are complemented in trans by Vpr-IN fusion proteins, thereby enabling the study of IN function in replicating viruses. Using this approach we found that (i) Vpr-linked IN is efficiently packaged into virions independent of the Gag-Pol polyprotein, (ii) fusion proteins containing a natural RT/IN processing site are cleaved by the viral protease and (iii) only the cleaved IN protein complements IN-defective HIV-1 efficiently. Vpr-mediated packaging restored IN function to a wide variety of IN-deficient HIV-1 strains including zinc finger, catalytic core and C-terminal domain mutants as well as viruses from which IN was completely deleted. Furthermore, trans complemented IN protein mediated a bona fide integration reaction, as demonstrated by the precise processing of proviral ends (5'-TG...CA-3') and the generation of an HIV-1-specific (5 bp) duplication of adjoining host sequences. Intragenic complementation between IN mutants defective in different protein domains was also observed, thereby providing the first evidence for IN multimerization in vivo.

Amino Acid Sequence↗
PubMed1997

Multivitamin supplementation and multiple births.

It is well established that maternal multivitamin supplementation reduces the risk of neural tube defects and evidence suggests that it may be associated with other reproductive outcomes. The present study was prompted by a report from a randomized trial in Hungary which showed a 40% increase in multiple births among periconceptional vitamin users. Retrospectively collected data on multivitamin supplementation were obtained on multiple and singleton births from three separate studies: Atlanta Birth Defects Case-Control Study (ABDCCS) malformed and nonmalformed infants born 1968-1980, California Birth Defects Monitoring Program (CBDMP) malformed and nonmalformed infants born 1987-1989, and Boston University Slone Epidemiology Unit Birth Defects Study (SEU-BDS) malformed infants born 1987-1994. Supplementation was divided into three mutually exclusive categories based on timing: "periconceptional" use--before through at least the third month after conception; "early" use--beginning in the first month and continuing through at least the third month after conception; and "later" use--beginning in the second or third month after conception. For periconceptional use, four of five datasets showed a 30 to 60% greater prevalence of supplementation among mothers of multiple births. In contrast, this pattern was not evident for "early" and "later" use. Overall, the study findings are tentative, due to a lack of consistency across all five datasets and they should not alter recent recommendations related to folate supplementation for the prevention of neural tube defects.

Congenital Abnormalities↗
PubMed1997

Virus dynamics and drug therapy.

The recent development of potent antiviral drugs not only has raised hopes for effective treatment of infections with HIV or the hepatitis B virus, but also has led to important quantitative insights into viral dynamics in vivo. Interpretation of the experimental data depends upon mathematical models that describe the nonlinear interaction between virus and host cell populations. Here we discuss the emerging understanding of virus population dynamics, the role of the immune system in limiting virus abundance, the dynamics of viral drug resistance, and the question of whether virus infection can be eliminated from individual patients by drug treatment.

Animals↗
PubMed1997

A full-length and replication-competent proviral clone of SIVAGM from tantalus monkeys.

African green monkeys (AGM) are classified into four distinct species (commonly termed vervet, grivet, sabaeus, and tantalus monkeys), all of which are known to be infected with simian immunodeficiency virus (SIVAGM) in the wild. Sequence analysis of partial gag and env regions has indicated that each of the four species harbors a phylogenetically distinct SIVAGM subtype. This species-specific diversity suggests that African green monkeys have been infected with SIVAGM for an extended period of time, possibly even before their speciation from a common ancestor. However, our understanding of the evolutionary history of this group of viruses is still incomplete, in part because sequence information for most isolates is limited to small subgenomic regions. There are only six SIVAGM proviruses which have been sequenced in their entirety, and these represent only three of the four SIVAGM lineages (i.e., SIVAGMgri, SIVAGMver, and SIVAGMsab). In this paper, we have generated the first full-length proviral clone for SIVAGM infecting tantalus monkeys (SIVAGMtan). Lambda phage techniques were employed to clone this provirus (TAN) as a single genomic unit from productively infected Molt 4 (clone 8) cells, and sequence analysis confirmed the integrity of all major open reading frames, except vpr which contained an in-frame stop codon. The proviral clone was also biologically active since transfection yielded replication-competent virions. Amino acid sequence comparisons of all major viral proteins indicated that TAN was roughly equidistant from previously characterized sabaeus, grivet, and vervet strains, thus confirming that it represents a fourth independent SIVAGM lineage. Given the need for well-characterized reference reagents, this full-length tantalus provirus should facilitate future studies of SIVAGM molecular biology and evolution.

Animals↗
PubMed1997

Anti-viral drug treatment: dynamics of resistance in free virus and infected cell populations.

Anti-viral drug treatment of infections with the human immunodeficiency virus type I (HIV-1) usually leads to a rapid decline in the abundance of plasma virus. The effect of single drug therapy, however, is often only short-lived as the virus readily develops drug-resistant mutants. In this paper we provide analytic approximations for the rate of emergence of resistant virus. We study the decline of wildtype virus and the rise of resistant mutant virus in different compartments of the virus population such as free plasma virus, cells infected with actively replicating virus, long-lived infected cells and cells carrying defective provirus. The model results are compared with data on the rise of drug-resistant virus in three HIV-1 infected patients treated with neverapine (NVP). We find that the half-life of latently infected cells is between 10 and 20 days, whereas the half-life of cells with defective provirus is about 80 days. We also provide a crude estimate for the basic reproductive ratio of HIV-1 during NVP therapy.

Antiviral Agents↗
PubMed1997

The qualitative nature of the primary immune response to HIV infection is a prognosticator of disease progression independent of the initial level of plasma viremia.

Following infection of the host with a virus, the delicate balance between virus replication/spread and the immune response to the virus determines the outcome of infection, i.e., persistence versus elimination of the virus. It is unclear, however, what relative roles immunologic and virologic factors play during primary viral infection in determining the subsequent clinical outcome. By studying a cohort of subjects with primary HIV infection, it has been demonstrated that qualitative differences in the primary immune response to HIV, but not quantitative differences in the initial levels of viremia are associated with different clinical outcomes.

CD4 Lymphocyte Count↗
PubMed1997

Is dietary intake of methionine associated with a reduction in risk for neural tube defect-affected pregnancies?

Results from experimental animals and other laboratory data have suggested a role for methionine, an essential amino acid, in normal closure of the neural tube. We hypothesized that women who had higher dietary intakes of methionine would be at lower risk for neural tube defect (NTD)-affected pregnancies. Data were derived from a population-based case-control study of fetuses and liveborn infants with NTDs among a 1989-1991 California birth cohort. Interviews, which included a 100-item food frequency questionnaire, were conducted with mothers of 424 NTD cases and 440 nonmalformed controls. Risk for having an NTD-affected pregnancy was estimated according to quartiles (established from intakes among control mothers) of average daily maternal dietary intake of methionine in the 3 months before conception. We observed an approximately 30-40% reduction in NTD-affected pregnancies among women whose average daily dietary intake of methionine was above the lowest quartile of intake (> 1,341.86 mg/ day). These reductions in NTD risk were observed for both anencephaly and spina bifida; remained after adjustment for maternal race/ethnicity and education; and were observed irrespective of maternal level of folate intake. Although we were unable to establish whether the observed reductions in NTD risk were attributable to maternal periconceptional methionine intake or to another highly correlated nutrient, these data add to the growing body of evidence that maternal diet plays a role in neural tube closure.

Adult↗
PubMed1997

Infection of gastrointestinal tract macrophages by HIV-1.

As the largest lymphoid organ and the largest reservoir of macrophages in the body, the gastrointestinal tract mucosa is probably the largest organ reservoir of macrophages infected with HIV-1. To elucidate the biology of HIV-1 infection of intestinal macrophages, we isolated lamina propria macrophages from normal human jejunum by neutral protease digestion, purified the cells by counterflow centrifugal elutriation, and then infected the cells with HIV-1. The lamina propria macrophages were permissive to macrophagetropic isolates of HIV-1 and substantially less permissive to lymphocyte-tropic isolates. Compared with blood monocytes, mucosal macrophages produced 2-3 logs less p24 antigen at peak infection. The reduced level of infection was not due to impaired macrophage viability, reduced CD4 expression, or the isolation procedure. These results confirm that macrophages isolated from the gastrointestinal tract mucosa can support HIV-1 production, albeit at a lower level than blood monocytes. The reduced level of virus production may reflect the unique biology of intestinal lamina propria macrophages.

Antigens, CD↗
PubMed1997

Antiviral pressure exerted by HIV-1-specific cytotoxic T lymphocytes (CTLs) during primary infection demonstrated by rapid selection of CTL escape virus.

The HIV-1-specific cytotoxic T lymphocyte (CTL) response is temporally associated with the decline in viremia during primary HIV-1 infection, but definitive evidence that it is of importance in virus containment has been lacking. Here we show that in a patient whose early CTL response was focused on a highly immunodominant epitope in gp 160, there was rapid elimination of the transmitted virus strain and selection for a virus population bearing amino acid changes at a single residue within this epitope, which conferred escape from recognition by epitope-specific CTL. The magnitude (> 100-fold), kinetics (30-72 days from onset of symptoms) and genetic pathways of virus escape from CTL pressure were comparable to virus escape from antiretroviral therapy, indicating the biological significance of the CTL response in vivo. One aim of HIV-1 vaccines should thus be to elicit strong CTL responses against multiple codominant viral epitopes.

Acquired Immunodeficiency Syndrome↗
PubMed1997

Maternal residential proximity to hazardous waste sites and risk for selected congenital malformations.

Using data from two population-based case-control studies, we investigated whether maternal residential proximity to hazardous waste sites increased the risk for neural tube defects, conotruncal heart defects, and oral cleft defects in California. We obtained a residential history by interview for mothers of 507 neural tube defect cases (82.7% of eligible) and their 517 controls (84.6%); and 201 heart cases (84.4%), 439 cleft cases (82.2%), and their 455 controls (72.1%). We identified the locations of 764 inactive hazardous waste sites and systematically collected information on site-related contamination for the subset of 105 National Priority List sites. After controlling for several potential confounders, we found little or no increased risk for maternal residence in a census tract containing a site [odds ratio (OR) = 0.9, 95% confidence interval (CI) = 0.7-1.3 for neural tube defects; OR = 1.3, 95% CI = 0.8-2.1 for heart cases; OR = 1.2, 95% CI = 0.8-1.8 for clefts], but elevated risks for neural tube defects (OR = 2.1, 95% CI = 0.6-7.6) and heart defects (OR = 4.2, 95% CI = 0.7-26.5) for maternal residence within 1/4 mile of a National Priority List site. Furthermore, we observed elevated ORs (> or = 2.0) for neural tube defects and heart defects in association with maternal residence within 1 mile of National Priority List sites containing selected chemical contaminants. Among controls, only 0.6% and 4.4% lived within 1/4 mile and 1 mile of a National Priority List site, respectively, resulting in imprecision in risk estimation.

Adult↗
PubMed1997

Risk for neural tube defect-affected pregnancies among women of Mexican descent and white women in California.

OBJECTIVES: This study investigated a previously reported 50% or more increased risk for neural tube defect-affected pregnancies among Latina women compared with White women. METHODS: Data were derived from a population-based case-control study of fetuses and live-born infants with neural tube defects in a 1989-through-1991 California birth cohort. Interviews were conducted with mothers of 538 (88% of eligible) infants/fetuses with neural tube defects and mothers of 539 (88%) nonmalformed control infants. RESULTS: The risk for a neural tube defect-affected pregnancy was approximately twice as high among women of Mexican descent than among White women (odds ratio = 1.9, 95% confidence interval [CI] = 1.5, 2.8). The odds ratio for Mexico-born Mexican women compared with White women was 2.4 (95% CI = 1.7, 3.2), whereas the risk for US-born women of Mexican and other racial/ethnic descent was not substantially higher than that for Whites. The higher risk among Mexico-born Mexican women was not attributable to differences in numerous studied parental characteristics and exposures. CONCLUSIONS: Given that nearly 20% of all California births are to Mexico-born Mexican women, the increased risks observed are relevant to the population burden of neural tube defects.

Adult↗