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Biomedical subjects

A Babiker

Publications and source records attributed to A Babiker.

At least 37 records · Page 2Linked to original sources
PubMed2000

Zidovudine (AZT) versus AZT plus didanosine (ddI) versus AZT plus zalcitabine (ddC) in HIV infected adults.

BACKGROUND: Zidovudine (AZT) monotherapy was the first antiretroviral drug to be tested widely. The next two drugs to be developed were didanosine (ddI) and zalcitabine (ddC). OBJECTIVES: To assess the effects of zidovudine (AZT), zidovudine plus didanosine (ddI) and zidovudine plus zalcitabine (ddC) on HIV disease progression and survival. SEARCH STRATEGY: Investigators and pharmaceutical companies were contacted, and MEDLINE searches were supplemented by searching conference abstracts. SELECTION CRITERIA: Randomised controlled trials comparing any two of AZT plus ddI, AZT plus ddC or AZT alone in participants with or without AIDS which collected information on deaths and new AIDS events. DATA COLLECTION AND ANALYSIS: Individual patient data with, wherever possible, follow-up obtained beyond that previously published were obtained and checked for internal consistency and consistency with any published reports; any apparent discrepancies were resolved with the trialists. Time to death and to disease progression (defined as a new AIDS-defining event or prior death) were analysed on an intention to treat basis, stratified to avoid direct comparisons between participants in different trials. MAIN RESULTS: Six trials were included in the meta-analysis. During a median follow-up of 29 months, 2904 individuals progressed, of whom 1850 died. The addition of ddI to AZT delayed both progression (RR 0.74; 95% CI 0.67 to 0.82, P<0.0001) and death (RR 0.72; 95% CI 0.64 to 0.82, P<0.0001). Likewise, the addition of ddC to AZT also delayed progression (RR 0. 86; 95% CI 0.78 to 0.94, P=0.001) and death (RR 0.87; 95% CI 0.77 to 0.98, P=0.02). After 3 years the estimated percentages alive and without a new AIDS event were 53% for AZT+ddI, 49% for AZT+ddC and 44% for AZT alone; the percentages alive were 68%, 63% and 59% respectively. Five of the six trials involved randomised comparisons of AZT+ddI versus AZT+ddC: in these, the AZT+ddI regimen had greater effects on disease progression (P=0.004) and death (P=0.009). REVIEWER'S CONCLUSIONS: The use of ddI and, to a lesser extent, ddC delayed both HIV disease progression and death, at least when added to AZT.

Adult↗
PubMed2000

Immediate versus deferred zidovudine (AZT) in asymptomatic or mildly symptomatic HIV infected adults.

BACKGROUND: Zidovudine (AZT) monotherapy was the first antiretroviral drug to be tested widely. Subsequent trials in asymptomatic or early symptomatic HIV infection indicated short-term delays in disease progression with AZT, but not improved survival. OBJECTIVES: To assess the effects of immediate versus deferred zidovudine (AZT) on HIV disease progression and survival. SEARCH STRATEGY: Investigators and pharmaceutical companies were contacted, and MEDLINE searches were supplemented by searching conference abstracts. SELECTION CRITERIA: Randomised controlled trials comparing immediate versus deferred AZT in participants without AIDS which prospectively collected deaths and new AIDS events. DATA COLLECTION AND ANALYSIS: Individual patient data with, wherever possible, follow-up obtained beyond that previously published was obtained and checked for internal consistency and consistency with any published reports; any apparent discrepancies were resolved with the trialists. Time to death and to disease progression (defined as a new AIDS-defining event or prior death) were analysed on an intention to treat basis, stratified to avoid direct comparisons between participants in different trials. MAIN RESULTS: Nine trials were included in the meta-analysis. During a median follow-up of 50 months, 1908 individuals developed disease progression, of whom 1351 died. In the deferred group, 61% started antiretroviral therapy (median time to therapy 28 months, which was AZT monotherapy in 94%). During the first year of follow-up immediate AZT halved the rate of disease progression (P<0.0001), increasing the probability of AIDS-free survival at one year from 96% to 98%, but this early benefit did not persist: after 6 years AIDS-free survival was 54% in both groups, and at no time was there any difference in overall survival, which at 6 years was 64% with immediate and 65% with deferred AZT (rate ratio [RR] 1.04, 95% confidence interval [CI] 0. 94 to 1.15). REVIEWER'S CONCLUSIONS: Although immediate use of AZT halved disease progression during the first year, this effect was not sustained, and there was no improvement in survival in the short or long term.

Anti-HIV Agents↗
PubMed2000

Associations between ambient ozone, hydrocarbons, and childhood wheezy episodes: a prospective observational study in south east London.

OBJECTIVES: To explore the hypothesis that hydrocarbon species and other air pollutants which accumulate at low and high concentrations of ozone are more directly associated with childhood wheezy episodes than ozone. METHODS: Prospective observational study over 1 year set in the Lewisham district of south east London. The daily attendance rate of children with acute wheeze at the accident and emergency department of Lewisham Hospital was related to local measurements of ozone, hydrocarbon species, nitrogen dioxide (NO2), sulphur dioxide (SO2) and small particulate matter with diameter < 10 microns (PM10). RESULTS: An inverse relation was found between the air pollutants and ozone. After seasonal and meteorological adjustment a non-linear U shaped trend was found between incidence of wheeze and ozone. The trend was significant in children < 2 years of age but not in older children. In the younger age group, after adjustment for season, temperature, wind speed, and respiratory infection, the incidence relative to that at the mean daily ozone concentration of 32.7 micrograms/m3, was estimated to increase by 65% (95% confidence interval (95% CI) 22% to 122%) at an ozone concentration of 5 micrograms/m3 (1.5 SDs below the mean) and by 63% (95% CI -6% to 184%) at 80 micrograms/m3 (2.5 SDs above the mean). For several hydrocarbons there were significant positive linear relations found, again in children < 2 years of age but not older children. For benzene, the incidence increased by 8% (95% CI 2 to 13%) per SD (SD 2.8 micrograms/m3) increase in benzene concentration. A same day association between incidence and ozone was found to be the most significant but for other pollutants a lag of 2 days gave the most significant associations. No significant association was found for the non-hydrocarbon pollutants including SO2, NO2, and PM10. CONCLUSIONS: A U shaped relation was found between ozone and the incidence of wheezy episodes in young children. Certain hydrocarbon pollutants accumulate in the atmosphere when ozone concentrations are low, and are associated with childhood wheezy episodes. However, the U shaped association of ozone on incidence cannot be explained by these other pollutants. The finding supports an earlier finding that incidences of wheeze are at a minimum when ozone concentrations are 30-40 micrograms/m3.

Adolescent↗
PubMed1999

Elimination of cholesterol as cholestenoic acid in human lung by sterol 27-hydroxylase: evidence that most of this steroid in the circulation is of pulmonary origin.

Human alveolar macrophages have exceptionally high capacity to convert cholesterol into 27-hydroxycholesterol and cholestenoic acid by the sterol 27-hydroxylase mechanism. It is shown here that the human lung has a higher content of 27-hydroxycholesterol relative to cholesterol than any other organ. In order to evaluate the importance of the sterol 27-hydroxylase mechanism for cholesterol homeostasis in the lung, the production of cholestenoic acid by human lung was investigated. Removal of one lung reduced the level of cholestenoic acid in the circulation by 48 +/- 4% (P < 0.005). The levels of cholestenoic acid in the pulmonary artery and in the pulmonary vein showed significant differences (P < 0.002) with higher levels in the pulmonary vein (108 +/- 16 and 104 +/- 16 ng/mL, respectively). This corresponds to a net flux of cholestenoic acid from the lung of about 14 mg/day, which is more than 80% of the reported removal of this oxysterol and its metabolites from the circulation by the liver per day. Bypassing the lung for 60 min led to a reduction in circulating cholestenoic acid (30%) that fits with a pulmonary origin when taking into account the half-life of cholestenoic acid. The level of circulating cholestenoic acid was found to be less in patients with different lung diseases. It is evident that most of the cholestenoic acid in the circulation is of pulmonary origin. The present results suggest that the sterol 27-hydroxylase in the lung is responsible for at least half of the total flux of 27-oxygenated cholesterol metabolites to the liver and that this enzyme system may be of importance for cholesterol homeostasis in the lung.

Cardiopulmonary Bypass↗
PubMed1998

Activities of recombinant human cytochrome P450c27 (CYP27) which produce intermediates of alternative bile acid biosynthetic pathways.

The primary physiological significance of cytochrome P450c27 (CYP27) has been associated with its role in the degradation of the side chain of C27 steroids in the hepatic bile acid biosynthesis pathway, which begins with 7alpha-hydroxylation of cholesterol in liver. However, recognition that in humans P450c27 is a widely or ubiquitously expressed mitochondrial P450, and that there are alternative pathways of bile acid synthesis which begin with 27-hydroxylation of cholesterol catalyzed by P450c27, suggests the need to reevaluate the role of this enzyme and its catalytic properties. 27-Hydroxycholesterol was thought to be the only product formed upon reaction of P450c27 with cholesterol. However, the present study demonstrates that recombinant human P450c27 is also able to further oxidize 27-hydroxycholesterol giving first an aldehyde and then 3beta-hydroxy-5-cholestenoic acid. Kinetic data indicate that in a reconstituted system, after 27-hydroxycholesterol is formed from cholesterol, it is released from the P450 and then competes with cholesterol for reentry the enzyme active site for further oxidation. Under subsaturating substrate concentrations, the efficiencies of oxidation of 27-hydroxycholesterol and 3beta-hydroxy-5-cholestenal to the acid by human P450c27 are greater than the efficiency of hydroxylation of cholesterol to 27-hydroxycholesterol indicating that the first hydroxylation step in the overall conversion of cholesterol into 3beta-hydroxy-5-cholestenoic acid is rate-limiting. Interestingly, 3beta-hydroxy-5-cholestenoic acid was found to be further metabolized by the recombinant human P450c27, giving two monohydroxylated products with the hydroxyl group introduced at different positions on the steroid nucleus.

Bile Acids and Salts↗
PubMed1998

Transport of side-chain oxidized oxysterols in the human circulation.

To study the transport of 24-hydroxycholesterol, 27-hydroxycholesterol and 3beta-hydroxy-5-cholestenoic acid in the circulation, the distribution of these oxysterols was determined in plasma, very low density lipoprotein, low density lipoprotein, high density lipoprotein, and lipoprotein-free plasma. An accurate method based on isotope dilution-mass spectrometry with use of individual deuterium labeled internal standards was used. 24-Hydroxycholesterol and 27-hydroxycholesterol were found to be associated mainly with HDL and LDL, whereas 3beta-hydroxy-5-cholestenoic acid was found predominantly in the lipoprotein-free fraction. While both 24-hydroxycholesterol and 27-hydroxycholesterol are present mainly in esterified form in plasma, 3beta-hydroxy-5-cholestenoic acid was present as free acid only. For reasons of comparison, a number of other oxysterols were determined in plasma and in isolated lipoprotein fractions. Significant amounts of these oxysterols were formed by cholesterol autoxidation during fractionation of plasma. It was therefore not possible to calculate the distribution of these oxysterols in the different plasma fractions. The present results are consistent with our previous finding that the less polar cholesterol metabolite 27-hydroxycholesterol competes with cholesterol for transport out of cells using HDL as an acceptor molecule, whereas the transport of the more polar compound 3beta-hydroxy-5-cholestenoic acid is facilitated by albumin.

Adult↗
PubMed1998

Comparison of culture- and non-culture-based methods for quantification of viral load and resistance to antiretroviral drugs in patients given zidovudine monotherapy.

Virological assays for human immunodeficiency virus type 1 load and drug resistance can broadly be divided into culture-based and molecular biology-based methods. Culture-based methods give a direct measure of infectious virus load and phenotypic drug resistance, whereas molecular biology-based methods are indirect, assaying nucleic acid levels to determine virus load and point mutations associated with drug resistance. We have compared culture-based and non-culture-based methods for patients enrolled in a placebo-controlled trial of zidovudine (the Concorde Trial). Virus loads were assayed by culture of peripheral blood mononuclear cells (PBMCs) or quantitative PCR, and drug resistance was assayed in culture or in a quantitative, PCR-based point mutation assay. The rates of detection of viremia and drug resistance were higher by PCR than by culture for this population of subjects. Comparison of the virus loads by the two measures showed a good correlation for virus loads in PBMCs but a poor correlation for virus loads in plasma. The latter result probably reflected the inaccuracies of culture in assaying plasma with the low infectious virus titers seen in the study population. The concordance of phenotypic and genotypic drug resistance methods was high, with all phenotypically resistant isolates having at least one resistance-associated mutation and with no mutations being found in a drug-sensitive isolate. Genomic resistance scores (weighted sums of levels of resistance mutations) showed good correlations with the levels of phenotypic resistance, and both resistance measures were observed to increase as the duration of exposure to drug increased. Overall, non-culture-based methods were shown to correlate well with culture-based methods and offer a low-cost, high-throughput alternative. However, culture-based methods remain the final arbiters of infectious virus load and phenotypic drug resistance and are unlikely to be superseded entirely.

Acquired Immunodeficiency Syndrome↗
PubMed1997

Elimination of cholesterol in macrophages and endothelial cells by the sterol 27-hydroxylase mechanism. Comparison with high density lipoprotein-mediated reverse cholesterol transport.

Cultured macrophages and endothelial cells have been reported to secrete 27-oxygenated metabolites of cholesterol. This mechanism was compared with the classical high density lipoprotein (HDL)-dependent reverse cholesterol transport. Under standard conditions, macrophage preparations had considerably higher capacity to secrete 27-hydroxycholesterol and 3beta-hydroxy-5-cholestenoic acid than had endothelial cells and fibroblasts. Western blotting showed that lung macrophages contained the most sterol 27-hydroxylase protein of the cells tested. The relative amounts of 3beta-hydroxy-5-cholestenoic acid produced by the macrophages were also highest. Macrophages derived from monocytes of patients with sterol 27-hydroxylase deficiency did not secrete 27-oxygenated products, demonstrating that sterol 27-hydroxylase is the critical enzyme for the conversion of cholesterol into the 27-oxygenated steroids. That sterol 27-hydroxylase is responsible not only for 27-hydroxylation of cholesterol but also for the further oxidation of this steroid into 3beta-hydroxy-5-cholestenoic acid was shown with use of tritium-labeled 27-hydroxycholesterol and an inhibitor of sterol 27-hydroxylase. Secretion of 27-oxygenated products by the cultured macrophages as well as the ratio between the alcohol and the acid appeared to be dependent upon total 27-hydroxylase activity, the availability of substrate cholesterol, and the presence of an acceptor for 27-hydroxycholesterol in the medium. With albumin as extracellular acceptor, the major secreted product was 3beta-hydroxy-5-cholestenoic acid. Under such conditions, secretion of labeled 27-oxygenated products was higher than that of labeled cholesterol from lung alveolar macrophages preloaded with [4-14C]cholesterol. With HDL as acceptor, 27-hydroxycholesterol was the major secreted product, and the total secretion of labeled 27-oxygenated products was only about 10% of that of labeled cholesterol. Thus, 27-hydroxycholesterol and cholesterol may compete for HDL-mediated efflux from the cells. The results support the contention that the sterol 27-hydroxylase-mediated elimination of cholesterol is more important in macrophages than in endothelial cells. This mechanism may be an alternative and/or a complement to the classical HDL-mediated reverse cholesterol transport in macrophages, in particular when the concentration of HDL is low.

Albumins↗
PubMed1996

Association between air pollution and acute childhood wheezy episodes: prospective observational study.

OBJECTIVE: To examine the association between the air pollutants ozone, sulphur dioxide, and nitrogen dioxide and the incidence of acute childhood wheezy episodes. DESIGN: Prospective observational study over one year. SETTING: District general hospital. SUBJECTS: 1025 children attending the accident and emergency department with acute wheezy episodes; 4285 children with other conditions as the control group. MAIN OUTCOME MEASURES: Daily incidence of acute wheezy episodes. RESULTS: After seasonal adjustment, day to day variations in daily average concentrations of ozone and sulphur dioxide were found to have significant associations with the incidence of acute wheezy episodes. The strongest association was with ozone, for which a non-linear U shaped relation was seen. In terms of the incidence rate ratio (1 at a mean 24 hour ozone concentration of 40 microg/m3 (SD=19.1)), children were more likely to attend when the concentration was two standard deviations below the mean (incidence rate ratio=3.01; 95% confidence interval 2.17 to 4.18) or two standard deviations above the mean (1.34; 1.09 to 1.66). Sulphur dioxide had a weaker log-linear relation with incidence (1.12; 1.05 to 1.19 for each standard deviation (14.1) increase in sulphur dioxide concentration). Further adjustment for temperature and wind speed did not significantly alter these associations. CONCLUSIONS: Independent of season, temperature, and wind speed, fluctuations in concentrations of atmospheric ozone and sulphur dioxide are strongly associated with patterns of attendance at accident and emergency departments for acute childhood wheezy episodes. A critical ozone concentration seems to exist in the atmosphere above or below which children are more likely to develop symptoms.

Acute Disease↗
PubMed1996

Importance of a novel oxidative mechanism for elimination of intracellular cholesterol in humans.

We have recently demonstrated that cultured human alveolar macrophages efficiently convert cholesterol into excretable 27-oxygenated products. We show here that increasing the intracellular concentration of cholesterol by a factor of 10 leads to about a twofold increase in the excretion of 27-oxygenated products from cultured macrophages. Inhibition of the sterol 27-hydroxylase caused a significant intracellular accumulation of cholesterol. A direct comparison was made between flux of cholesterol and 27-oxygenated products from macrophages preloaded with [4-14C]cholesterol. Under the specific conditions employed with fetal calf serum in the culture medium, the flux of 27-oxygenated products was about 10% of that of cholesterol. Since the sterol 27-hydroxylase, which converts cholesterol to 27-oxygenated products, is present in many cell types, we suggest that 27-oxygenation is a general mechanism for removal of intracellular cholesterol. To evaluate this hypothesis, we measured the net uptake by the human liver of circulating 27-oxygenated products, which was found to be about 20 mg/24 h. This uptake corresponds to approximately 4% of the bile acid production, assuming quantitative conversion into bile acids. It is concluded that the 27-hydroxylase pathway is of significance for elimination of extrahepatic cholesterol.

Cells, Cultured↗
PubMed1995

Time course of oxysterol formation during in vitro oxidation of low density lipoprotein.

Cholesterol oxidation products (oxysterols) have been implicated in several aspects of atherogenesis; they affect key enzymes in cholesterol homeostasis, induce calcification in vascular cells and possess cytotoxic properties. Oxysterols are formed during oxidative modification of low density lipoprotein (LDL). Using a recently developed method based on isotope dilution-mass spectrometry, the kinetics of formation of oxysterols during oxidation of LDL by cupric ions or soybean lipoxygenase was studied. The same products, mainly 7- and 5-oxygenated cholesterol, were formed by the two oxidation methods. Virtually no side-chain oxidized oxysterols were formed. During the oxidations, preferentially esterified cholesterol was consumed and consumption of polyunsaturated fatty acids and formation of conjugated dienes preceded the appearance of oxysterols. Cholesterol 7-hydroperoxides potential cytotoxins, were present in LDL oxidized by copper or lipoxygenase.

Cholesterol↗
PubMed1994

A simple frailty model for family studies with covariates.

A simple, easily analysed frailty model based on logistic regression and employing only binary frailties is developed and analysed. Methods for testing for frailty and estimates of frailty parameters and covariate effects are presented. The effects of ignoring or mis-specifying frailty are examined in detail and shown to downwardly bias the estimates of covariate effects in a variety of situations, even when frailty is over-estimated. When the true frailty is large it can be difficult to estimate accurately because of the flatness of the likelihood. However, it is shown that this does not have a large influence on the estimates of the effects of the observed covariates. Methods for dealing with multiple frailties, for example, sibships and spouse pairs, are also developed. The results are illustrated on a large data set examining the risk factors associated with palmar keratoses.

Epidemiologic Methods↗
PubMed1990

Palmar keratoses in family members of individuals with bladder cancer.

A total of 270 bladder cancer cases, 178 first-degree relatives and 127 spouses of the bladder cancer cases and 329 hospital controls were studied to evaluate the association between palmar keratoses, bladder cancer and environmental and genetic factors. Crude prevalences of keratoses in the 4 groups were 67, 54, 42 and 23%, respectively. Logistic regression models showed that bladder cancer patients had a raised risk of having palmar keratoses relative to hospital controls (odds ratio = 6.95; 95% CI: 4.77-10.12) whereas blood-relatives and spouses had significantly increased odds ratios only if the case in their family (or some other blood-relative) possessed keratoses. Among several environmental and behaviour factors, only cigarette smoking was significantly associated with increased risk (odds ratio = 2.32; 95% CI: 1.63-3.29). The data suggest a genetic component may influence the occurrence of palmar keratoses, but some unknown environmental agent appears to be causing the association between spouses.

Adult↗
PubMed1989

Prognostic factors in a T3 bladder cancer trial. Co-operative Urological Cancer Group.

Information on primary tumour size, status of the pelvic lymph nodes, histological type and macroscopic tumour appearance, as well as age and sex, was available at presentation for 394 patients in the Co-operative Urological Cancer Group's prospective randomised trial for T3 cancer of the urinary bladder. An apparently significant prognostic effect of age and sex was shown to be entirely consistent with the effect of natural mortality. Primary tumour size was found to be the single most powerful prognostic factor (P = 0.002), followed by nodal status (P = 0.02). These factors do not act independently. Multivariate analysis showed that 75% of the effect of all the six variables and their first order interactions could be explained by a single prognostic grouping based on tumour size and nodal status only. Three levels for this grouping are proposed: node-negative small tumour, node-negative moderate tumour and either node-positive or large tumour. The 3-year survival probabilities for the three prognostic groups were 85.7% (95% CI 57.2 and 96.4%), 60.3% (48.0 and 71.5%) and 33.3% (23.5 and 44.8%) respectively.

Age Factors↗