Biomedical subjects
A Phillips
Publications and source records attributed to A Phillips.
Trial design in the era of highly effective antiviral drug combinations for HIV infection.
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The Fracture Intervention Trial.
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CD8+,CD38+ lymphocyte percent: a useful immunological marker for monitoring HIV-1-infected patients.
We investigated the relationship between three prognostic markers, CD4 lymphocyte count, serum beta2-microglobulin (beta2M) levels, and CD8+,CD38+ lymphocyte percent, and the association with the rate of development of AIDS. The markers were measured regularly throughout follow-up in 224 patients. The risk of developing AIDS during follow-up was investigated using Cox proportional hazards models. Time-updated values of the prognostic markers were used, which modelled the risk of AIDS according to the latest measurement of the marker rather than using a single value of the marker at baseline. During a median follow-up period of 13.6 months (range 0.5-31.9 months), 34 cases of AIDS occurred. In a univariate analysis, all three markers predicted the development of AIDS; a 10% increase in the percentage of CD8+ T cells expressing CD38+ resulted in an 88% increase in the risk of AIDS (95% confidence interval: 53-130%; p < 0.0001). After adjustment for the current CD4 count and beta2M, a 10% increase in the CD8+,CD38+ population was associated with a 37% increase in the risk of AIDS (95% confidence interval: 4-81%; p = 0.02). Thus, the percentage CD8+,CD38+ level predicts the development of AIDS independently of the latest CD4 count and beta2M. This assay is therefore potentially useful in conjunction with blood CD4 counts and serum beta2M levels in patient management and clinical trial design.
Cervical abnormality and sexually transmitted disease screening in human immunodeficiency virus-positive women.
OBJECTIVE: To determine the incidence of genital tract infections and cervical abnormalities in 185 human immunodeficiency virus (HIV)-positive outpatients with a view toward establishing an effective policy for gynecology screening. METHODS: Gynecology results were reviewed for 185 HIV-positive women seen as outpatients at the Royal Free Hospital in London. All subjects underwent screening for cervical abnormalities (smear and colposcopy) and sexually transmitted disease (STD) at 6-month intervals for 6 years. The STD prevalence was calculated, and the relationship between the occurrence of STDs and the demography and sexual lifestyle of the women was examined to determine whether these factors were predictive for women at risk for STDs. The incidence of cervical intraepithelial neoplasia (CIN) was determined. We reviewed the use of colposcopy in addition to cytology as a primary screening test to see whether it improved the detection rate of CIN. RESULTS: Sixty-five (35.1%) women had a history of previous STDs, and new STDs were detected in 18 women at their first visits. None were detected at subsequent visits. Sexual lifestyle details did not predict women at risk for STDs. Ninety-eight (53%) cervical smears were reported as normal at the first visit, but there was a 3.1% (95% confidence interval 0, 6.6) false-negative rate when compared with colposcopy and directed biopsy. Five of fifty women (10%) with CIN I had progressed to higher-grade lesions by 6-month follow-up. CONCLUSIONS: Given the low prevalence of STDs detected, except for initial screening at presentation, regular, repeat STD screening of HIV-positive women appears to be unnecessary. Because of the high incidence of cervical abnormalities, screening for cervical biopsy improved the detection rate of cervical abnormalities.
Confirming testosterone administration by isotope ratio mass spectrometric analysis of urinary androstanediols.
A gas chromatographic combustion isotope ratio mass spectrometric (GC/C/IRMS) method was used for studying the incorporation of exogenous testosterone enanthate into excreted urinary 5 alpha- and 5 beta-androstane-3 alpha, 17 beta-diols. A multistep but straightforward work-up procedure produced a simple GC chromatogram of urinary steroid acetates composed principally of two androstanediols and pregnanediol. It is anticipated that such a method may form the basis of a doping control test for testosterone that could be used as a primary method during major sporting events or alternatively as a verification technique. Urine samples from five individuals were collected before and after administration of testosterone enanthate (250 mg). The delta 13C0/1000 value of andro-stanediols was around -26 to -28 during the baseline period and decreased to about -29 to -30 in the days following synthetic testosterone administration. One of the other major steroids in the chromatogram, pregnanediol, was utilized as the "internal standard," because its delta 13C0/1000 values did not markedly change following testosterone administration, remaining at -25 to -27. In all subjects studied, the delta 13C0/1000 values for androstanediols were reduced sufficiently over 8 days to confirm administration of synthetic testosterone. Although steroids isolated from urine of normal individuals from 12 different countries gave values between -24 and -28, this seemed not to be related to nationality or region. The most likely variable is the proportion of plants with low and high carbon 13 content in the diet. This variable is likely to be more affected by individual food preferences than broad ethnic food divisions. In this paper, we propose a ratio of delta 13C0/1000 for androstanediols to pregnanediol as a useful discriminant of testosterone misuse, a value above 1.1:1.0 being indicative of such misuse. The work-up procedure was designed for batch analysis and to use only simple techniques, rather than employ further instrumentation, such as high-performance liquid chromatography (HPLC), in purifying steroids for GC/C/IRMS.
Androstanediol and 5-androstenediol profiling for detecting exogenously administered dihydrotestosterone, epitestosterone, and dehydroepiandrosterone: potential use in gas chromatography isotope ratio mass spectrometry.
The basis of a potential method for confirming intake of four natural androgens (testosterone, epitestosterone, dihydrotestosterone, and dehydroepiandrosterone is presented. The method relies on isolating from urine a steroid fraction containing androstenediol and androstanediol metabolites of these natural steroids and analyzing their 13C content by gas chromatography, combustion, isotope ratio mass spectrometry. The steroids were recovered from urine by conjugate hydrolysis with a Helix pomatia preparation (sulfatase and beta-glucuronidase), Girard T reagent separation to obtain a nonketonic fraction, and Sephadex LH-20 chromatography for purification. Metabolites appropriate for all of the natural steroids could be separated (as diacetates) by gas chromatography on a DB-17 capillary column viz.: 5 alpha (and beta)-androstane-3 alpha,17 alpha-diol (epitestosterone as precursor); 5 alpha (and beta)-androstane-3 alpha,17 beta-diol (testosterone as precursor); 5-androstene-3 beta,17 beta-diol (dehydroepiandrosterone precursor); and 5 alpha-androstane-3 alpha,17 beta- (and 17 alpha-) diol (dihydrotestosterone precursor). Measurement of the 13C content of the specific analytes after ingestion of the androgen precursors demonstrated a lowering of delta 13C/1000 value compared to normal values. Typically, in the male individual studied, delta 13C/1000 values for all components were -26 to -27 before drug administration and -29 to -30 at 6 h after, the latter values reflecting those obtaining for commercial synthetic steroid compared to in vivo synthesized steroid. While generally the metabolism of the steroids was as expected, this was not the case for 5 alpha-dihydrotestosterone. A major metabolite was 5 alpha-androstane-3 alpha,17 alpha-diol, which had presumably been formed by 17 beta/17 alpha isomerization, a process previously known for unnatural anabolics but not for natural hormones. The isolation, purification, and isotope ratio mass spectrometry techniques described may form the basis of a general method for confirming natural steroid misuse by sports participants.
Variation in cuticular hydrocarbons among strains of Anopheles (Cellia) stephensi Liston possibly related to prior insecticide exposure.
Cuticular lipids were extracted in hexane from the females of four strains of Anopheles stephensi and separated by capillary gas chromatography. When the chromatograms produced were quantified and compared by discriminant analysis, compositional variations in the hydrocarbons indicated that two of the strains, 'Russ' (originally isolated in the former (U.S.S.R.) and 'Iraq' (from Iraq), both of which were susceptible to DDT and malathion, could be confidently separated from 'Beech' from India and 'St Mal' from Pakistan, both of which were resistant to DDT and malathion. A high degree of hydrocarbon segregation between each of the four strains might be associated with geographical variation. It appears that there are significant and real differences in the hydrocarbons of these strains and these may be at least partially related to genetic alterations resulting from prior insecticide exposure. However, far more analysis is required if any relationship with prior exposure is to be confirmed.
Hydrocarbon variations/discrimination between two strains of Anopheles albimanus Wied from El Salvador.
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Using aspects of study design in sample size estimation.
The basis of sample size calculations is usually needed in protocols for clinical trials and when publishing results in respected journals. Although a large amount of research has been undertaken on sample size estimation for different trial designs, in practice the methods are rarely used. This paper describes some useful theory that has practical relevance.
Mycobacterium xenopi infection in patients with human immunodeficiency virus infection.
Mycobacterium xenopi is one of the most frequently isolated nontuberculous mycobacteria in Ontario, Canada. We reviewed the records of 28 human immunodeficiency virus (HIV)-infected patients from whom M. xenopi was isolated between 1982 and 1995. M. xenopi was recovered from respiratory specimens from 24 patients, most of whom had clinical and radiographic evidence of pulmonary disease. However, coexistent pulmonary infection due to other pathogens was found in 17 patients: Pneumocystis carinii (9 patients), cytomegalovirus (5), Haemophilus influenzae (2), Mycobacterium avium complex (2), Streptococcus pneumoniae (1), Staphylococcus aureus (1), Aspergillus species (1), and Histoplasma capsulatum (1). Three patients had bacteremia with M. xenopi, including two patients with pulmonary infection. Two of the bacteremic patients had chronic fever and a wasting syndrome. Twenty-one (75%) of the 28 patients were thought to be colonized, and seven patients (25%; of whom four had CD4 cell counts of < or = 50/mm3) were thought to have significant infection due to M. xenopi. Sixteen patients died, but in no case was death attributable to M. xenopi infection. In a region where M. xenopi is a relatively common mycobacterial isolate, the organism frequently colonizes HIV-infected patients. Significant disease occurs in those patients with more advanced HIV infection.
Access to medical care one year prior to diagnosis in 100 HIV-positive women.
BACKGROUND: Anonymous antenatal testing for HIV antibodies suggests that the majority of HIV-positive women in the UK remain undiagnosed. Primary care reaches the majority of the population and women present more often than men. Sexual health matters are frequently raised, so there is an opportunity to discuss concerns with respect to HIV. Women often present with advanced HIV disease and with antiviral treatments proving to be more effective, there is now an even greater incentive to diagnose HIV early. OBJECTIVE: We aimed to look at access to medical care 1 year prior to HIV diagnosis in 100 HIV-positive women and to establish whether a discussion regarding HIV was recalled. METHOD: The setting was an established clinic for HIV-positive women in the Royal Free Hospital, London. In a 6-month period a questionnaire was completed by 100 women with their clinic doctor. RESULTS: Women were young (mean age 31). Most (84%) were infected by heterosexual sex. Forty-six per cent of the women presented with symptomatic HIV or AIDS and 50% were black Africans, hence there is a large ethnic bias in this sample. General practice was accessed by 65% of the women 1 year prior to HIV diagnosis. Few (14%) women recalled a discussion concerning HIV. Secondary care settings such as gynaecology and general outpatients were also frequently attended, but again HIV was apparently rarely discussed. There was no significant difference when variables such as time since diagnosis, health care setting, or ethnic group were concerned with respect to recall of a discussion concerning HIV. CONCLUSIONS: Despite coming from 'high risk' groups or presenting with symptomatic disease in the year prior to HIV diagnosis, few women recalled discussing HIV in either primary or secondary care settings. As these sites were commonly accessed, we feel that doctors and other health care workers should be encouraged and trained to raise HIV more routinely in their consultations.
A putative human male infertility gene DAZLA: genomic structure and methylation status.
The DAZLA (DAZ Like Autosomal) gene on human chromosome 3 shares a high degree of homology with the DAZ (Deleted in AZoospermia) gene family on the Y chromosome, a gene family frequently deleted in males with azoospermia or severe oligospermia. The involvement of both DAZ and DAZLA in spermatogenesis is suggested by their testis-specific expression and their homology with a Drosophila male infertility gene, boule. Whereas male infertility resulting from deletion of the DAZ genes on the Y chromosome occurs sporadically, that due to a defective DAZLA gene is expected to be inheritable. The fraction of males with idiopathic azoospermia or oligospermia that harbour mutations in the DAZLA gene remains unknown. As a prerequisite for mutation screening, the genomic structure of the DAZLA gene was elucidated and found to consist of 11 exons spanning 19 kh. The exon/intron boundaries are conserved between DAZ and DAZLA. The 5' end of both genes are hypomethylated in spermatozoa but not in leukocytes or placenta, consistent with the expression pattern of the genes. The genomic structure of DAZLA paves the way for mutation detection in families with autosomal recessive male infertility.
Aggregative adherence fimbria II, a second fimbrial antigen mediating aggregative adherence in enteroaggregative Escherichia coli.
Enteroaggregative Escherichia coli (EAEC) has been implicated as an agent of pediatric diarrhea in the developing world. We have shown previously that EAEC adheres to HEp-2 cells by virtue of a plasmid-encoded fimbrial adhesin designated aggregative adherence fimbria I (AAF/I), the genes for which have been cloned and sequenced. However, not all EAEC strains express AAF/I. Using TnphoA mutagenesis, we have characterized a novel fimbria (designated AAF/II) which mediates HEp-2 adherence of the human-pathogenic strain 042. AAF/II is 5 nm in diameter and does not bind AAF/I antiserum, as determined by immunogold transmission electron microscopy. TnphoA identified a gene (designated aafA) which bears significant homology to aggA, the fimbrial subunit of AAF/I (25% identity and 47% similarity at the amino acid level). When hyperexpressed and purified by polyhistidine tagging, the AafA protein assembled into 5-nm-diameter filaments which bound anti-AAF/II antiserum. The cloned aafA gene complemented a mutation in the aggA gene to confer fimbrial expression from the AAF/I gene cluster, manifesting phenotypes characteristic of AAF/II but not AAF/I. The aafA mutant did not adhere to human intestinal tissue in culture, suggesting a role for AAF/II in intestinal colonization. By using DNA probes for AAF/I and AAF/II derived from fimbrial biosynthesis genes, we show that AAF/I and AAF/II are each found in only a minority of EAEC strains, suggesting that still more EAEC adhesins exist. Our data suggest that AAF adhesins represent a new family of fimbrial adhesins which mediate aggregative adherence in EAEC.
Influence of age on rates of new AIDS-defining diseases and survival in 6546 AIDS patients.
It has consistently been reported that older AIDS patients have a shortened survival compared with younger patients. The aim of the present study was to investigate whether this difference in survival is caused by differences in the pattern of the complicating diseases. Information on patient follow-up after the AIDS diagnosis was obtained by retrospective case note review. The 6,546 patients were followed from the time of AIDS diagnosis as part of the multicentre AIDS in Europe study, which examined AIDS cases diagnosed at 52 centres in 17 European countries between 1979 and 1989. Occurrence of AIDS-defining events and demographic variables were recorded for all patients, and CD4 lymphocyte count at the time of AIDS diagnosis for approximately half the patients. After adjusting for imbalances in other variables, persons > or = 50 years of age had a significantly higher risk of contracting AIDS wasting syndrome, AIDS dementia complex and oesophageal candidiasis after the initial AIDS diagnosis, compared with age group 30-39 years [relative risk (RR) 95% confidence interval (CI)], 3.23 (2.70-3.75 CI); 2.48 (2.16-2.80 CI); 1.55 (1.26-1.83 CI), respectively]. Shortened survival after the time of AIDS diagnosis was associated with older age. After adjusting for pattern of complicating diseases, the age effect remained unchanged. Older age predisposes to AIDS-related wasting syndrome, AIDS dementia complex and oesophageal candidiasis. Independent of these differences, older age is significantly associated with shortened survival, suggesting that factors such as severity of complicating diseases or the capability of handling serious infections, rather than disease pattern, are responsible for the shortened survival.
Characterisation of a human homologue of a yeast cell division cycle gene, MCM6, located adjacent to the 5' end of the lactase gene on chromosome 2q21.
Four exons of a human homologue of a yeast cell division cycle gene (MCM6/mis5, which is thought to encode a DNA replication licensing factor) have been identified 3.3 kb upstream from the start of transcription of the intestinal lactase gene on human chromosome 2q21, initially by similarity to a rat 'intestinal crypt-cell replication factor'. RT-PCR analysis shows, that unlike lactase, MCM6 is not restricted in its tissue distribution and does not show person-to-person variation in the level of expression in adult intestine.
Re: "Height and the risk of cardiovascular disease in women".
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Impact on blood lead in children and adults following relocation from their source of exposure and contribution of skeletal tissue to blood lead.
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