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G M Shaw

Publications and source records attributed to G M Shaw.

At least 19 recordsLinked to original sources
PubMed2001

Near full-length clones and reference sequences for subtype C isolates of HIV type 1 from three different continents.

Among the major circulating HIV-1 subtypes, subtype C is the most prevalent. To generate full-length subtype C clones and sequences, we selected 13 primary (PBMC-derived) isolates from Zambia, India, Tanzania, South Africa, Brazil, and China, which were identified as subtype C by partial sequence analysis. Near full-length viral genomes were amplified by using a long PCR technique, sequenced in their entirety, and phylogenetically analyzed. Amino acid sequence analysis revealed 10.2, 6.3, and 17.3% diversity in predicted Gag, Pol, and Env protein sequences. Ten of 13 viruses were nonmosaic subtype C genomes, while all three isolates from China represented B/C recombinants. One of them was composed primarily of subtype C sequences with three small subtype B portions in gag, pol, and nef genes. Two others exhibited these same mosaic regions, but contained two additional subtype B portions at the gag/pol overlap and in the accessory gene region, suggesting ongoing B/C recombination in China. All subtype C genomes contained a prematurely truncated second exon of rev, but other previously proposed subtype C signatures, including three potential NF-kappa B-binding sites in the viral promoter-enhancer regions, were found in only a subset of these genomes.

Adult↗
PubMed2001

Adverse human reproductive outcomes and electromagnetic fields: a brief summary of the epidemiologic literature.

Power frequency fields are of concern as risk factors for adverse reproductive outcomes. This report briefly summarizes the epidemiologic evidence of potential associations between a number of adverse reproductive outcomes and parental exposures to electric and magnetic fields (EMFs). Over the last decade numerous reviews of the human literature regarding these potential associations have been published. These reviews, in general, have concluded that: (1) evidence is lacking for a strong association between a woman's use of a video display terminal (VDT) and fetal loss, (2) evidence is lacking for a strong association between a woman's use of a VDT and adverse reproductive outcomes other than fetal loss, primarily a result of too few available data, and (3) the paucity of data on other parental EMF exposures and subsequent adverse outcomes of pregnancy limits drawing a valid scientific conclusion. Since those earlier reviews appeared, the number of new investigations have been relatively small. These new studies do not substantially alter the above summary conclusions. The lack of epidemiologic data in this area, coupled with some speculations about potential biological effects associated with EMFs, raises the importance of researching this area further.

Abortion, Spontaneous↗
PubMed2001

Lowered weight gain during pregnancy and risk of neural tube defects among offspring.

BACKGROUND: Maternal nutritional factors have been implicated in the complex aetiology of neural tube defects (NTD). We investigated whether the amount of weight a woman gained during pregnancy was associated with her risk of delivering an infant with an NTD. METHODS: We conducted a population-based case-control study within the cohort of 708 129 live births and fetal deaths occurring in selected California counties in 1989-1991. Face-to-face interviews were conducted with mothers of 538 (88% of eligible) NTD cases (including those electively terminated, stillborn, or liveborn) and with mothers of 539 (88%) non-malformed liveborn controls within an average of 5 months from the term delivery date. Respondent-reported weight gain during pregnancy (kg) was analysed. Risks of infants having NTD were estimated among women who gained <10 kg compared to those who gained > or =10 kg during > or =38 week gestations. RESULTS: Compared to women who gained > or =10 kg, an increased risk for NTD offspring was observed among women who gained <10 kg (odds ratio [OR] = 3.2, 95% CI : 2.3-4.6). The OR was 5.0 (95% CI : 2.6-9.7) among those women who gained <5 kg during pregnancy. The increased risk was not attributable to maternal non-use of a multivitamin containing folic acid, diabetes, NTD-pregnancy history, age, race/ethnicity, education, gravidity, alcohol use, cigarette use, prepregnant obesity, low socioeconomic status, dieting, nausea, nor to lower dietary intakes of folate, zinc, energy, protein, fat, carbohydrates, and methionine. An increased risk was observed even after simultaneous adjustment for most of these factors (OR = 2.2, 95% CI : 1.2-3.8). The risk associated with gaining <10 kg was greater for anencephaly, but still elevated for spina bifida. CONCLUSIONS: We did not have information on weight gain during early pregnancy. Because weight gain during the relevant embryological period for NTD (first month post-conception) is relatively small and often variable, it seems less likely that elevated NTD risks indicate a causal association between lowered weight gain throughout pregnancy and abnormal development of the neural tube. It seems more likely that lowered weight gain is a consequence of carrying an NTD-affected fetus. However, what this consequence is and why risk was substantially larger for anencephaly is unknown.

Adult↗
PubMed2001

Functional analysis of the simian immunodeficiency virus Vpx protein: identification of packaging determinants and a novel nuclear targeting domain.

The vpx gene products of human immunodeficiency virus type 2 (HIV-2) and of the closely related simian immunodeficiency viruses from sooty mangabeys (SIVsm) and macaques (SIVmac) comprise a 112-amino-acid virion-associated protein that is critical for efficient virus replication in nondividing cells such as macrophages. When expressed in the absence of other viral proteins, Vpx localizes to the nuclear membrane as well as to the nucleus; however, in the context of virus replication Vpx is packaged into virions via interaction with the p6 domain of the Gag precursor polyprotein (p55(gag)). To identify the domains essential for virion incorporation and nuclear localization, site-directed mutations were introduced into the vpx gene of SIVsmPBj1.9 and functionally analyzed. Our results show that (i) mutation of two highly conserved L74 and I75 residues impaired both virion incorporation and nuclear localization of Vpx; (ii) substitution of conserved H82, G86, C87, P103, and P106 residues impaired Vpx nuclear localization but not virion incorporation; (iii) mutations of conserved Y66, Y69, and Y71 residues impaired virion incorporation but not the translocation of Vpx to the nucleus; and (iv) a mutation at E30 (predicted to disrupt an N-terminal alpha-helix) had no effect on either virion incorporation or nuclear localization of Vpx. Importantly, mutations in Vpx which impaired nuclear localization also reduced virus replication in macaque macrophages, suggesting an important role of the carboxyl terminus of Vpx in nuclear translocation of the viral preintegration complex. Analyzing this domain in greater detail, we identified a 26-amino-acid (aa 60 to 85) fragment that was sufficient to mediate the transport of a heterologous protein (green fluorescent protein [GFP]) to the nucleus. Taken together, these results indicate that virion incorporation and nuclear localization are encoded by two partially overlapping domains in the C-terminus of Vpx (aa 60 to 112). The identification of a novel 26-amino-acid nuclear targeting domain provides a new tool to investigate the nuclear import of the HIV-2/SIV preintegration complex.

Amino Acid Sequence↗
PubMed2000

Lamina propria lymphocytes, not macrophages, express CCR5 and CXCR4 and are the likely target cell for human immunodeficiency virus type 1 in the intestinal mucosa.

Most human immunodeficiency virus type 1 (HIV-1) infections are acquired via mucosal surfaces, and transmitted viruses are nearly always macrophage-tropic, suggesting that mucosal macrophages participate in early HIV-1 infection. Mucosal lymphocytes isolated from normal human intestine expressed CD4 (14,530+/-7970 antibody-binding sites [ABSs]/cell), CCR5 (2730+/-1524 ABSs/cell), and CXCR4 (2507+/-1840 ABSs/cell), but intestinal macrophages, which also expressed CD4 (2959+/-2695 ABSs/cell), displayed no detectable CCR5 or CXCR4 ABS. The absence of CCR5 on intestinal macrophages was not due to expression of the Delta32 deletion allele because matched-blood monocytes expressed CCR5. CCR5(+)CXCR4(+) intestinal lymphocytes supported both R5 (BaL) and X4 (IIIB) HIV-1 replication, whereas the CCR5(-)CXCR4(-) macrophages were not permissive to either isolate or other laboratory isolates (ADA and DJV) and primary isolates (MDR 24 and JOEL). In the intestinal mucosa, lymphocytes, not macrophages, are the likely target cell for R5 (and X4) HIV-1 and are the major source of HIV-1 production during early infection.

CD4 Antigens↗
PubMed2000

Periconceptional intake of vitamin supplements and risk of multiple congenital anomalies.

Numerous studies have reported reduced risks for a variety of single congenital anomaly phenotypes associated with maternal periconceptional use of vitamin supplements containing folic acid. Here we investigated whether periconceptional use of vitamin supplements containing folic acid by women altered their risk for delivering infants with multiple congenital anomalies (MCAs). Data were derived from a case-control study representing deliveries (fetal deaths and infants) from 2 California counties between January 1993 and July 1996. MCAs were defined as 2 or more congenital anomalies affecting more than one organ system or a major anomaly in combination with 2 minor anomalies. Controls were randomly selected from nonmalformed live-born infants. Telephone interviews were conducted with 112 (73.7% of eligible) case and 195 (78.0% of eligible) control mothers. Compared to women who did not use multivitamin supplements containing folic acid in the period 3 months before through 3 months after conception, women who used in this time period were observed to have an elevated risk to deliver fetuses or infants with MCAs, odds ratio = 2.6 (95% confidence interval 1.1-6.2). This elevated risk was not substantially altered (adjusted odds ratio = 2.9 [0.8-10.3]) by adjusting for maternal race/ethnicity, education, gravidity, body mass index, alcohol consumption, and cigarette smoking. No particular organ system seemed to be uniquely represented among the MCA fetuses and infants whose mothers used vitamin supplements. The observed elevated risk associated with maternal vitamin use is considered to be preliminary and needs to be replicated in other populations.

Abnormalities, Multiple↗
PubMed2000

Effect of highly active antiretroviral therapy and thymic transplantation on immunoreconstitution in HIV infection.

The purpose of this study was to determine whether thymic transplantation in addition to highly active antiretroviral therapy (HAART) will restore T cell function in HIV infection. Eight treatment-naive HIV-infected patients with CD4+ T cell counts of 200-500/mm3 were randomized into thymic transplantation and control arms. All patients received HAART (zidovudine, lamivudine, and ritonavir) for 6 weeks prior to transplantation. Thymic transplantation was done without immunosuppression, using postnatal HLA-unmatched cultured allogeneic thymus tissue. Patients were immunized every 6 months with the neoantigen keyhole limpet hemocyanin (KLH) and the recall antigen tetanus toxoid (TT). T cell phenotype and function and T cell receptor rearrangement excision circles (TRECs) were assessed. Thymic allografts were biopsied at 2 months. Six HIV-infected patients completed the study. Four patients received cultured allogeneic postnatal thymic grafts, two others were controls. CD4+ T cell counts increased and T cell-proliferative responses to Candida antigen and TT normalized in all patients. Proliferative responses to KLH developed in three of four transplant recipients and one of two controls. Patients responding to KLH after secondary immunization had greater TREC increases compared with the patients who did not respond. All thymic allografts were rejected within 2 months. In summary, four of six patients developed T cell-proliferative responses to the neoantigen KLH over the first 2 years of HAART. The transplanted thymus tissue, however, was rejected. There was no clear difference in restoration of T cell function in the transplant recipients compared with the controls. Increases in TRECs after initiation of HAART may correlate with improved immune function.

Adult↗
PubMed2000

Prior spontaneous abortion, prior elective termination, interpregnancy interval, and risk of neural tube defects.

A woman with a history of spontaneous abortion in her immediately prior pregnancy may be at increased risk for a pregnancy affected by a neural tube defect (NTD). A short interpregnancy interval may further increase this risk. Using data from a population-based case-control study (1989-1991), the authors investigated NTD risk resulting from a prior spontaneous abortion or elective termination and a short interpregnancy interval. Of 538 interviewed case mothers and 539 interviewed control mothers, 408 case mothers and 433 control mothers reported having a prior pregnancy. Analysis showed a slightly decreased NTD risk among mothers whose immediately prior pregnancy had ended in a spontaneous abortion or elective termination in comparison with a live birth (odds ratio (OR) = 0.82; 95% confidence interval (CI): 0.61, 1.1). This decreased risk was consistent across strata of short or long interpregnancy intervals. Additional analysis revealed an increased NTD risk for mothers with an interpregnancy interval of < or =6 months compared with >12-< or =24 months (OR = 1.5; 95% CI: 0.93, 2.4). This latter risk was greatest among mothers whose immediately prior pregnancy had resulted in a live birth (OR = 2.0; 95% CI: 1.0, 3.8) rather than a spontaneous abortion or elective termination (OR = 0.96; 95% CI: 0.44, 2.1). Adjustment for potential covariates did not substantially alter observed risk estimates.

Abortion, Induced↗
PubMed2000

Risk factors for cytogenetically normal holoprosencephaly in California: a population-based case-control study.

Holoprosencephaly is a developmental field defect manifested by a spectrum of abnormalities of the forebrain and midface. Approximately 50% of holoprosencephaly cases are associated with a cytogenetic abnormality or a monogenic syndrome. Suggested risk factors for the remaining 50% of cases have been described in case reports, but have not been confirmed in systematically conducted studies. We report the results of a population-based case-control study of holoprosencephaly. Live births, fetal deaths, and terminations with a diagnosis of cytogenetically normal holoprosencephaly were identified by the California Birth Defects Monitoring Program. Telephone interviews were conducted with the mothers of 58 cases and 107 live born, nonmalformed controls. Women were questioned about their health and reproductive histories, family demographics, and exposures occurring during their pregnancies. Among nonsyndromic cases, increased risks were observed for females (OR=1.8, 95% C.I. 0.9-3.9), foreign-born vs. U.S. or Mexico-born women (OR=3.1, 95% C.I. 1.1-8.6), and women with early menarche (OR=2.3, 95% C.I. 0.9-5.7). Maternal periconceptional exposures associated with increased risks for nonsyndromic holoprosencephaly included alcohol consumption (OR=2.0, 95% C.I. 0.9-4.5), cigarette smoking (OR=4.1, 95% C.I. 1.4-12.0), and combined alcohol and smoking (OR=5.4, 95% C.I. 1.4-20.0), insulin-dependent diabetes (OR=10.2, 95% C.I. 1.9-39.4), medications for respiratory illnesses (OR=2.3, 95% C.I. 0.9-6.0), and salicylate-containing medications (OR=2.5, 95% C.I. 0.8-7.9). These findings are consistent with risk factors identified in some previous reports, and identify several new potential risk factors that require confirmation in future studies.

California↗
PubMed2000

AIDS as a zoonosis: scientific and public health implications.

Evidence of simian immunodeficiency virus (SIV) infection has been reported for 26 different species of African nonhuman primates. Two of these viruses, SIVcpz from chimpanzees and SIVsm from sooty mangabeys, are the cause of acquired immunodeficiency syndrome (AIDS) in humans. Together, they have been transmitted to humans on at least seven occasions. The implications of human infection by a diverse set of SIVs and of exposure to a plethora of additional human immunodeficiency virus-related viruses are discussed.

Acquired Immunodeficiency Syndrome↗
PubMed2000

Microsatellites proximal to leptin and leptin receptor as risk factors for spina bifida.

Several recent studies have observed an association between neural tube defect risk and prepregnant obesity. This association was generally stronger for spina bifida and was observed irrespective of additional maternal factors, including periconceptional intake of vitamin supplements. Other studies have identified mutations within the genes that code for leptin (LEP) and its receptor (LEPR), which have been linked to obesity in mice and humans. We investigated the potential association between nucleotide variation at the LEP and LEPR loci, and increased risk of spina bifida. We searched specifically for allelic association at a pair of highly polymorphic microsatellites closely linked to either the LEP or LEPR gene. Data were derived from a population-based case-control study that had previously identified an association between a woman's prepregnant obesity and her risk of delivering an infant with spina bifida. A total of 56 spina bifida case infants and 126 nonmalformed control infants were genotyped for 10 microsatellite alleles closely linked to the LEP gene, and 49 cases and 125 controls were genotyped for 10 microsatellite alleles closely linked to the LEPR gene. In general, alleles were not observed to be exclusively associated with substantially greater spina bifida risk in the body mass index (BMI) category (obese) of >29 kg/m(2) compared with the BMI category (nonobese) of </=29 kg/m(2). Thus, these particular infant allelic variants did not appear to explain the previously reported elevated risk observed for women whose prepregnant BMI exceeded 29 kg/m(2). A modest elevated spina bifida risk, irrespective of maternal BMI, was observed for two LEP microsatellite alleles (257 and 271). These estimates, however, were imprecise. Compared with those infants who did not have either of these alleles and whose mother's prepregnant BMI was </=29 kg/m(2), we computed odds ratios for (1) having either the 257 or 271 allele and maternal BMI >29 kg/m; (2) having either allele and BMI </=29 kg/m(2); and (3) not having either allele but BMI >29 kg/m(2). The odds ratios (95% confidence interval) for these comparisons were: for allele 257, 4.5 (1.1-19.4), 1.9 (0.5-6.3), and 2.9 (1.3-6.4), respectively, and for allele 271, 6.7 (1.6-30.4), 2.7 (0.7-10.9), and 2.7 (1.2-5.9), respectively. Owing to the exploratory nature of this investigation, the significance of these latter results is unclear.

Alleles↗
PubMed2000

Spina bifida phenotypes in infants or fetuses of obese mothers.

BACKGROUND: A twofold or greater risk of neural tube defect (NTD)-affected pregnancy has been associated with prepregnant obesity, where obesity was defined as body mass index (BMI) of >29 kg/m(2). Risks have been more elevated for spina bifida than for anencephaly. METHODS: We investigated whether finer phenotypic classifications of spina bifida, in combination with other factors, were associated with a BMI of >29 kg/m(2). Data were derived from a case-control study of fetuses and infants with NTDs among 1989-1991 California births. Interviews were conducted with mothers of 277 spina bifida cases and 517 nonmalformed controls. RESULTS: Women with a BMI of >29 kg/m(2) compared with those </=29 kg/m(2) revealed an odds ratio (OR) of 2.2 (95% confidence interval [95% CI] = 1.4-3. 3) for spina bifida in their infants and fetuses. Elevated risks were observed for each spina bifida subphenotype, and risks varied by subphenotype: open spina bifida, OR = 2.0 (1.2-3.1); closed (skin-covered), 3.3 (1.4-7.5); isolated, 2.2 (1.4-3.4); nonisolated, 1.9 (0.9-4.2); high, 4.5 (2.1-9.6); low, 1.9 (1.2-2.9); open/isolated/high, 7.1 (2.8-18.1); and open/isolated/low, 1.8 (1. 1-3.1). Risks were higher among female infants/fetuses and foreign-born Latinas, and for some phenotypes the risks were quite large, e.g., OR = 8.3 (2.9-23.6) for "closed" spina bifida among female infants/fetuses whose mothers were >29 kg/m(2) compared with males whose mothers were </=29 kg/m(2). Maternal periconceptional vitamin use was not observed to influence risk as greatly across phenotypes. CONCLUSIONS: The observed pathogenetic heterogeneity of prepregnant obesity and spina bifida risks suggests that there are likely to be several biologic mechanisms underlying the association.

Body Mass Index↗
PubMed2000

Maternal height and prepregnancy body mass index as risk factors for selected congenital anomalies.

Previous studies have observed an increased risk of approximately twofold or more for neural tube defects (NTD) associated with maternal obesity before pregnancy based on a body mass index (BMI) of > 29 kg/m2. No additional maternal factor appeared substantially to influence this association. Here, we explore further the association between BMI and NTD risk by considering the separate contributions of maternal prepregnant BMI and height. We also explore whether selected congenital anomalies, in addition to NTDs, were associated with maternal height or prepregnant BMI. Data were derived from two California population-based case-control studies. One study comprised 538 NTD cases and 539 non-malformed control infants. The other study included an additional 265 NTD cases, as well as 207 conotruncal cases, 165 limb anomaly cases, 662 orofacial cleft cases and 734 non-malformed controls. Maternal interviews in both studies elicited information on maternal height and prepregnant weight. Anomaly risk was described using additive linear logistic regression models. Results revealed increasing NTD risk with increasing maternal prepregnant BMI, controlling for maternal height. These patterns were observed overall as well as for most race/ethnic groups. Increasing NTD risk for decreasing height controlling for maternal BMI was also observed in one NTD study, but was not as evident in the other. Elevated risks for increasing maternal BMI and decreasing maternal height were not observed consistently for the other studied anomalies. The mechanisms underlying the association between maternal weight, or possibly maternal height, and NTD-affected pregnancy risk are unknown. Exploration of other data sets will be needed to determine whether similar patterns of NTD risk or lack of risk for other anomalies are associated with the two maternal anthropometric variables, height and prepregnant weight.

Body Height↗
PubMed2000

Maternal life event stress and congenital anomalies.

We used data from a population-based case-control study to explore the relation between certain life events during the periconceptional period and several types of congenital anomalies. We ascertained cases from pregnancies ending in 1987-1989 and randomly selected controls from eligible liveborn infants. In telephone interviews, women reported deaths of anyone close to them. They also reported job losses or separations/divorces, for themselves or anyone close to them. Experiencing at least one stressful event during the periconceptional period was associated with a prevalence odds ratio of 1.4-1.5 for the delivery of infants with conotruncal heart defects, neural tube defects, and isolated cleft lip with or without palate. These associations tended to be restricted to women who were not obese and women with less than or equal to a high school education. This study suggests that women who experience stressful life events around the time of conception or early gestation may be at increased risk of delivering infants with certain congenital anomalies.

Congenital Abnormalities↗
PubMed2000

Genetic basis of susceptibility to environmentally induced neural tube defects.

Neural tube defects (NTDs) are among the most common of all human congenital defects, with multifactorial etiologies comprising both environmental and genetic components. Several murine model systems have been developed in an effort to elucidate genetic factors regulating expression of NTDs. Strain-dependent differences in susceptibility to teratogenic insults and altered patterns of gene expression observed within the neuroepithelium of affected embryos support the hypothesis that subtle genetic changes can result in NTDs. Since several affected genes are folate-regulated, transgenic knockout mice lacking a functional folate receptor were developed. Nullizygous embryos died in utero with significant morphological defects, supporting the critical role of folic acid in early embryogenesis. While epidemiological studies have not established an association between polymorphisms in the human folate receptor gene and NTDs, it is known that folate supplementation reduces infant NTD risk. Continued efforts are therefore necessary to reveal the mechanism by which folate works and the nature of the gene(s) responsible for human NTDs.

Animals↗
PubMed2000

Sensitivity of human immunodeficiency virus type 1 to the fusion inhibitor T-20 is modulated by coreceptor specificity defined by the V3 loop of gp120.

T-20 is a synthetic peptide that potently inhibits replication of human immunodeficiency virus type 1 by interfering with the transition of the transmembrane protein, gp41, to a fusion active state following interactions of the surface glycoprotein, gp120, with CD4 and coreceptor molecules displayed on the target cell surface. Although T-20 is postulated to interact with an N-terminal heptad repeat within gp41 in a trans-dominant manner, we show here that sensitivity to T-20 is strongly influenced by coreceptor specificity. When 14 T-20-naive primary isolates were analyzed for sensitivity to T-20, the mean 50% inhibitory concentration (IC(50)) for isolates that utilize CCR5 for entry (R5 viruses) was 0.8 log(10) higher than the mean IC(50) for CXCR4 (X4) isolates (P = 0. 0055). Using NL4.3-based envelope chimeras that contain combinations of envelope sequences derived from R5 and X4 viruses, we found that determinants of coreceptor specificity contained within the gp120 V3 loop modulate this sensitivity to T-20. The IC(50) for all chimeric envelope viruses containing R5 V3 sequences was 0.6 to 0.8 log(10) higher than that for viruses containing X4 V3 sequences. In addition, we confirmed that the N-terminal heptad repeat of gp41 determines the baseline sensitivity to T-20 and that the IC(50) for viruses containing GIV at amino acid residues 36 to 38 was 1.0 log(10) lower than the IC(50) for viruses containing a G-to-D substitution. The results of this study show that gp120-coreceptor interactions and the gp41 N-terminal heptad repeat independently contribute to sensitivity to T-20. These results have important implications for the therapeutic uses of T-20 as well as for unraveling the complex mechanisms of virus fusion and entry.

Anti-HIV Agents↗