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Biomedical subjects

G Gray

Publications and source records attributed to G Gray.

At least 19 recordsLinked to original sources
PubMed2006

Persistence of nevirapine-resistant HIV-1 in women after single-dose nevirapine therapy for prevention of maternal-to-fetal HIV-1 transmission.

Single-dose nevirapine (sdNVP) for prevention of mother-to-child transmission of HIV-1 can select nevirapine (NVP)-resistant variants, but the frequency, duration, and clinical significance of this resistance is not well defined. We used a sensitive allele-specific PCR assay to assess the emergence and persistence of NVP-resistant variants in plasma samples from 22 women with HIV-1 subtype C infection who participated in a study of sdNVP for prevention of mother-to-child transmission of HIV-1. The women were categorized into three groups on the basis of detection of NVP resistance by standard genotype analysis. Group 1 (n = 6) had NVP resistance detected at 2 and 6 mo after sdNVP, but not at 12 mo. Group 2 (n = 9) had NVP resistance detected at 2 mo, but not 6 mo. Group 3 (n = 7) had no NVP resistance detected at any time point. Allele-specific PCR analysis for the two most common NVP resistance mutations (K103N and Y181C) detected NVP-resistant variants in most (16 of 21) samples that were negative for NVP resistance by standard genotype, at levels ranging from 0.1% to 20% 1 yr after treatment. The frequency of NVP-resistant mutations decreased over time, but persisted above predose levels for more than 1 yr in > or = 23% of the women. These findings highlight the urgent need for studies assessing the impact of sdNVP on the efficacy of subsequent antiretroviral therapy containing NVP or other nonnucleoside reverse transcriptase inhibitors.

Adult↗
PubMed2006

A survey of pregnant women on the use of graduated elastic compression stockings on the antenatal ward.

Pulmonary thromboembolism is the leading direct cause of maternal death in the UK. This direct approach structured questionnaire survey was carried out on 100 randomly chosen pregnant in-patients in a London teaching hospital: (a) to assess the quality and frequency of advice given to them by the healthcare professionals on the use of graduated elastic compression stockings (GECS) as a primary physical prophylaxis against venous thromboembolism (VTE) and (b) to find out the rate of compliance and the possible reasons for non-compliance of their use. The information and advice given to pregnant patients by healthcare professionals are generally of good-to-excellent quality, but not universally offered. A total of 40% of mothers wore the GECS all the time, while 38% did not wear them at all. Among the non-wearers, the two major groups were those who did not receive any advice (28%) and those who found them uncomfortable (18%). All healthcare professionals should be aware of the potential risks of VTE, and routinely educate and advise the pregnant women-at-risk on the use of GECS.

Adolescent↗
PubMed2005

Is there a difference in the efficacy of peripartum antiretroviral regimens in reducing mother-to-child transmission of HIV in Africa?

BACKGROUND: Peripartum antiretroviral regimens have been shown to prevent mother-to-child transmission of HIV (MTCT) in randomized clinical trials; however, direct comparison of published results is impossible given methodological and population differences. OBJECTIVE: To directly compare the efficacy of different antiretroviral regimens in reducing the risk of 6-week MTCT rate in African breastfeeding populations. METHODS: Pooled analysis including all mother-infant pairs from any relevant trial: West African ZDV-placebo trials, Petra ZDV+3TC [two regimens A (pre/intra/post-partum) and B (intra/post-partum), placebo from Uganda and Tanzania], SAINT (NVP and Petra arm B), HIVNET012 (NVP, ultra short ZDV pp) and the Vitamin A trial (as placebo arm in South Africa). Peripartum HIV infection was any positive RNA or DNA polymerase chain reaction test < day 60. The MTCT risk was estimated at 6 weeks for each treatment arm and compared with placebo or single-dose NVP using logistic regression adjusting for maternal CD4 cell count, breastfeeding and birthweight. RESULTS: Overall, 4125 singleton live-births were included; 3629 (88%) were assessed for HIV status at 6 weeks of age. In comparison with placebo, zidovudine + lamivudine (ZDV+3TC) arm A [adjusted odds ratio (AOR), 0.23; P < 0.0001], ZDV+3TC arm B (AOR, 0.49; P < 0.001), antenatal ZDV short (AOR, 0.55; P = 0.006) and nevirapine (NVP) (AOR, 0.60; P = 0.0007) significantly reduced MTCT. In comparison with NVP, only the longest regimen of ZDV+3TC (AOR, 0.39, P < 0.0005) was significantly more effective. CONCLUSION: These results are in line with current World Health Organisation guidelines suggesting equivalence of choice between single-dose NVP and short-course ZDV, and confirm the greater efficacy of ZDV+3TC than with any single antiretroviral drug.

Adult↗
PubMed2005

POLG mutations in Alpers syndrome.

Described are six patients with Alpers syndrome from four unrelated families. Affected individuals harbored the following combinations of POLG mutations: 1) A467T/W1020X, 2) W748S-E1143G/G848S, 3) A467T/A467T, and 4) A467T/G848S. Homozygosity for the A467T allele in one patient was associated with a later age at onset. Mitochondrial respiratory chain studies in skeletal muscle were normal in each case. Nine combinations of mutant POLG alleles that cause Alpers syndrome are summarized.

Age of Onset↗
PubMed2004

Detection of Aspergillus fumigatus mycotoxins: immunogen synthesis and immunoassay development.

Immunological detection of secreted low molecular weight toxins represents a potentially novel means of diagnosing infection by the fungus Aspergillus fumigatus. Two such metabolites, gliotoxin and helvolic acid, were selected and conjugated to thyroglobulin for antisera generation in rabbits. Gliotoxin was initially activated using N-[p-maleimidophenyl] isocyanate (PMPI) and subsequently conjugated to S-acetyl thioglycolic acid N-hydroxysuccinimide-activated thyroglobulin, whereas helvolic acid was activated with N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide (EDC) in the presence of thyroglobulin prior to immunisation. To facilitate subsequent antisera evaluation, both toxins were similarly conjugated to bovine serum albumin (BSA). Matrix-Assisted Laser Desorption Ionisation-Time Of Flight (MALDI-TOF) mass spectrometry and SDS-PAGE analysis confirmed covalent attachment of toxins to BSA in the ratios of 15 and 2.4 mol per mol BSA for gliotoxin and helvolic acid, respectively. Resultant high titer antisera were capable of detecting both BSA-conjugated toxins (inhibitory concentration (IC)(50): 4-5 microg/ml). Free toxins were also detectable by competitive immunoassay, whereby 10 microg/ml free gliotoxin (30 microM) and helvolic acid (17 microM), respectively, inhibited antibody binding to cognate toxin-BSA previously immobilised on microwells. This work confirms that sensitive and specific antisera can be raised against fungal toxins and may have an application in diagnosing fungal infection.

Animals↗
PubMed2003

Poor specificity and recovery of urinary free cortisol as determined by the Bayer ADVIA Centaur extraction method.

BACKGROUND: Immunoassay methods for urinary free cortisol (UFC) lack specificity, and many procedures have not been fully evaluated for routine use. In the current study we evaluated the Bayer ADVIA Centaur extraction UFC immunoassay and compared results to those obtained by a specific gas chromatography-mass spectrometry (GC-MS) method. RESULTS: The Bayer ADVIA Centaur cortisol assay lacked specificity. Cortisone, a steroid present in urine at concentrations similar to those of cortisol, demonstrated a cross-reactivity of 44%. In addition, the choice of matrix used to resuspend steroids after solvent extraction from urine affected recovery. Recovery was improved if the recommended urine reconstruction buffer was replaced by steroid-free serum. CONCLUSION: Irrespective of the sample matrix used, the Centaur method overestimates UFC, giving results up to twice those obtained by a specific GC-MS method.

Cross Reactions↗
PubMed2003

Mother-to-child transmission of HIV: developing integration of healthcare programmes with clinical, social and basic research studies. Report of the International Workshop held at Chobe Marina Lodge, Kasane, Botswana, 21-25 January 2003.

Considerable efforts are still needed in the public health sector, as well as in clinical, social and basic research, to improve programmes for HIV-1 MTCT (mother-to-child transmission) prevention and care. Advantage should be taken of the remarkable amount of expertise and resources that have accumulated over the past few years to accelerate the process of integration. Future initiatives should include integrating specialists and people with diverse backgrounds and targeting their scientific and programmatic ideas to address real-world problems in the area of MTCT of HIV-1.

Female↗
PubMed2001

Prednisolone does not prevent hypersensitivity reactions in antiretroviral drug regimens containing abacavir with or without nevirapine.

OBJECTIVES: To determine the effect of adjuvant prednisolone use on the development of abacavir (ABC)- and nevirapine (NVP)-associated hypersensitivity reactions (HSR). METHODS: Randomized open-label study in antiretroviral-naive adult HIV-1 infected patients using a factorial design in which NVP and/or hydroxyurea (HU) and/or prednisolone are added to a regimen of ABC, zidovudine and lamivudine. Prednisolone (40 mg once daily) was added for the first 2 weeks of treatment. As it was difficult to distinguish ABC-associated HSR from NVP-associated HSR, these events were treated as a composite endpoint. The odds ratio (OR) of developing HSR for prednisolone-use was calculated with and without stratification by NVP and/or HU. Logistic regression was performed to identify risk factors for developing HSR. RESULTS: Of the 229 patients 115 were randomized to prednisolone and 114 to no-prednisolone; 19 (17%) and 11 (10%) patients, respectively, developed HSR. The expected prevention of HSR by prednisolone use was not observed. In fact use of prednisolone showed an increased risk for HSR although this did not reach statistical significance [OR, 1.82; 95% confidence interval (CI), 0.82-4.03]. There was a higher incidence of HSR in the NVP group than in the non-NVP group (20% versus 6%; P = 0.002). An additional risk factor identified in a multivariate logistic model was a high baseline CD4 cell count (OR, 1.26 per 100 x 10(6) cells/l increase; 95% CI, 1.06-1.51). CONCLUSIONS: The simultaneous start of ABC and NVP in first-line antiretroviral regimens should be avoided because of a high (20%) incidence of HSR. Short-term therapy with prednisolone did not prevent HSR in patients using ABC with or without NVP.

Adult↗
PubMed2001

Metabolic and cardiopulmonary responses to acute progressive resistive exercise in a person with C4 spinal cord injury.

STUDY DESIGN: Single-subject (female, 38 years of age) case. OBJECTIVES: To describe metabolic and cardiopulmonary responses to progressive resistive exercise in an individual with C4 ASIA A tetraplegia, and to review the relationship between level of spinal cord injury (SCI) and exercise responses. SETTING: Large, urban mid-western city rehabilitation hospital in United States of America. METHODS: Bilateral shoulder elevation/depression (shoulder shrug) exercise with two different resistances (0.7 kg/shoulder, 1.4 kg/shoulder) at two different frequencies (20 min., 40 min.), for 2 min per bout, deployed in a discontinuous protocol. RESULTS: Compared to rest heart rate (HR), exercise HR increased the greatest (13 bpm) for the 1.4 kg resistance at 40 min. and the least (6 bpm) during the 0.7 kg at 20 min. Blood pressure (BP) response was lower than resting BP for all four exercise conditions with the lowest (74/56 mmHg) at 1.4 kg at 40 min. Oxygen uptake was highest (4.6 ml.kg(-1) min(-1)) during 1.4 kg at 20 min and V(E) was greatest (18.2 L/min) during 1.4 kg at 40 min. Rate of perceived exertion (RPE) was the highest (17) during the 1.4 kg at 40 min. CONCLUSIONS: Progressive resistance exercise provoked intense perceived physical effort, but only small metabolic and cardiopulmonary increases in a person with C4 SCI. Exercise recommended at a 'somewhat hard' intensity should avoid significant hypotension and still impressively increase oxygen uptake and ventilation compared to rest. An inverse relation between level of injury and aerobic responses may extend rostrally to the C4 level.

Adult↗
PubMed2001

Reduced HIV-stimulated T-helper cell reactivity in cord blood with short-course antiretroviral treatment for prevention of maternal-infant transmission.

T-helper cell responses to HIV have been associated with protection against maternal-infant HIV transmission in the absence of antiretroviral treatment, but the effects of antiretroviral treatment, now widely used for prevention, on development of these cell-mediated responses is unknown. We tested whether development of T-helper cell responses to HIV and other antigens would be affected by exposure to short-course regimens of zidovudine-lamivudine (ZDV-3TC) given to prevent maternal-infant HIV transmission. Cord blood samples were collected from 41 infants of HIV-infected mothers enrolled in a clinical trial in which they were treated with regimens of ZDV-3TC and from 29 infants whose HIV-infected mothers were not treated with any antiretroviral drugs. T-helper cell reactivity to HIV envelope peptides and other antigens was measured in vitro using a sensitive culture supernatant titration assay based on IL-2-dependent proliferation. Infants in the clinical trial were followed to 18 months to determine their HIV infection status, and venous blood samples were re-tested at 4.5 and 9 months for T-cell reactivity to HIV. HIV-stimulated T-helper cell reactivity in cord blood was detected 10-fold less frequently among those exposed to antiretroviral prophylaxis (2.4%) than among those unexposed (24.1%) (P = 0.007). Reductions in HIV-stimulated responses in cord blood occurred despite detectable HIV RNA (mean 3.38 standard deviation 0.76 log(10) copies per ml) at delivery among treated women and occurred independent of treatment duration. Our results suggest that short-course antiretroviral treatment given to prevent maternal-infant HIV transmission may attenuate HIV-stimulated T-cell memory responses in the neonate.

Amino Acid Sequence↗
PubMed2001

Mitochondrial cytopathy presenting with focal segmental glomerulosclerosis, hypoparathyroidism, sensorineural deafness, and progressive neurological disease.

A 6 year old boy who presented with steroid unresponsive nephrotic syndrome is reported. He was found to have focal segmental glomerulosclerosis and associated hypoparathyroidism and sensorineural deafness. The child progressed to end stage renal failure and was successfully managed by dialysis and cadaveric renal transplantation. He later developed progressive neurological deterioration and mitochondrial myopathy and neuropathy was diagnosed.

Blotting, Southern↗
PubMed2001

Viral hepatitis in the U.S. military: a study of hospitalization records from 1974 to 1999.

Viral hepatitis remains a health threat for military forces. Most recently, there has been concern about hepatitis C virus transmission during military service because a high prevalence of hepatitis C virus infection has been found in some U.S. veteran populations. In this study, hospitalizations of active duty U.S. military personnel for hepatitis were evaluated using standardized computer records. Only the first hospitalization was assessed during the period January 1, 1989, to December 31, 1999. Among active duty forces, the rate of hospitalization for all types of acute hepatitis declined from 13 to 1.1 per 100,000 personnel from 1989 to 1999. Males, nonwhite racial/ethnic groups, and older troops were more likely to be hospitalized for acute hepatitis. This study's finding of declining rates of acute hepatitis is a continuation of a trend observed since 1974. The decreasing risk of viral hepatitis in the U.S. military is attributable to several factors, including reduced levels of injection drug use because of routine, randomized drug testing.

Acute Disease↗
PubMed2001

Melatonin and zopiclone as pharmacologic aids to facilitate crew rest.

PURPOSE: In response to mission imperatives, transport aircrews must often sleep at inappropriate circadian times resulting in inadequate sleep. This study was undertaken to determine whether either melatonin or zopiclone could facilitate early circadian sleep, and to assess whether either of these medications would result in a psychomotor performance decrement which would preclude their use in aircrew. METHOD: Thirteen subjects from DCIEM completed a double-blind cross-over protocol. All subjects were assessed for psychomotor performance during 3 drug conditions (placebo, 10 mg melatonin, and 7.5 mg zopiclone), which were separated by one week. Each of these conditions involved 2 nights of sleep, back-to-back, with the first night being a normal circadian control sleep (23:00 h bedtime, arising at 06:45 h), and the second night being an early circadian drug sleep (drugs at 16:45 h, 17:00 h bedtime, arising at 23:45 h). All subjects were tested for psychomotor performance, on both nights of each of the 3 drug conditions, pre- and post-sleep. Further, during the early circadian drug night, all subjects were tested every hour after arising at 23:45 h (24:00 h until 07:00 h. At the beginning of each psychomotor test session, subjects were asked for their subjective levels of sleepiness and fatigue. RESULTS: Relative to placebo (339.5 min) the subjects slept more on melatonin (370.2 min, p < 0.01), and zopiclone (373.3 min, p < 0.01). Performance in serial reaction time (SRT) task (p < 0.001), logical reasoning task (LRT) (p < 0.001), serial subtraction task (SST) (p < 0.02), and Multitask (MT) (p < 0.03) were impaired for all 3 drug conditions immediately on awakening, compared with pre-sleep performance, as a result of a sleep-inertia effect. With respect to the subjective data, sleep inertia effects were evident for sleepiness (p < 0.001), mental fatigue (p < 0.002), and physical fatigue (p < 0.05). For SRT, LRT, and SST, performance recovered to pre-sleep levels within 1.25 h of awakening, and for MT recovery occurred 2.25 h after awakening. There were no differences in performance or subjective measures between placebo, melatonin and zopiclone. CONCLUSIONS: Both zopiclone and melatonin improved sleep relative to placebo. After sleep inertia, performance recovered to pre-sleep levels for all tasks and was sustained at that level throughout the balance of the testing period. There was no impact of melatonin or zopiclone on performance measures compared with placebo.

Adult↗
PubMed2001

HIV-1 drug resistance and mother-to-child transmission.

The use of antiretroviral drug therapies in HIV-1 infected pregnant women and their infants has resulted in significant reductions in the rates of mother-to-child transmission of HIV-1. A number of drugs that target the reverse transcriptase enzyme have been tested either alone or in combination in short-course regimens tailored for use in developing countries. The drug of choice is nevirapine, which is cheap, easy to administer and highly effective even following a single dose to mother and child. However, this regimen is associated with the selection of mutations associated with drug resistance. While these mutations do not compromise the ability of nevirapine to prevent mother-to-child transmission there is some concern that they may compromise future treatment options. Here we review the current data on HIV-1 drug resistance mutations and what they might mean in terms of efficacy of antiretroviral therapies to prevent mother-to-child transmission.

Anti-HIV Agents↗
PubMed2000

cDNA cloning, chromosomal localization, and expression analysis of human BEHAB/brevican, a brain specific proteoglycan regulated during cortical development and in glioma.

BEHAB (Brain Enriched HyAluronan Binding)/brevican, a brain-specific member of the lectican family of chondroitin sulfate proteoglycans (CSPGs), may play a role in both brain development and human glioma. BEHAB/brevican has been cloned from bovine, mouse and rat. Two isoforms have been reported: a full-length isoform that is secreted into the extracellular matrix (ECM) and a shorter isoform with a sequence that predicts a glycophosphatidylinositol (GPI) anchor. Here, we report the characterization of BEHAB/brevican isoforms in human brain. First, BEHAB/brevican maps to human chromosome 1q31. Second, we report the sequence of both isoforms of human BEHAB/brevican. The deduced protein sequence of full-length, secreted human BEHAB/brevican is 89.7, 83.3 and 83.2% identical to bovine, mouse and rat homologues, respectively. Third, by RNase protection analysis (RPA) we show the developmental regulation of BEHAB/brevican isoforms in normal human cortex. The secreted isoform is highly expressed from birth through 8years of age and is downregulated by 20years of age to low levels that are maintained in the normal adult cortex. The GPI isoform is expressed at uniformly low levels throughout development. Fourth, we confirm and extend previous studies from our laboratory, here demonstrating the upregulation of BEHAB/brevican mRNA in human glioma quantitatively. RPA analysis shows that both isoforms are upregulated in glioma, showing an approximately sevenfold increase in expression over normal levels. In contrast to the developmental regulation of BEHAB/brevican, where only the secreted isoform is regulated, both isoforms are increased in parallel in human glioma. The distinct patterns of regulation of expression of the two isoforms suggest distinct mechanisms of regulation of BEHAB/brevican during development and in glioma.

Amino Acid Sequence↗