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Biomedical subjects

A Phillips

Publications and source records attributed to A Phillips.

At least 55 records · Page 3Linked to original sources
PubMed1999

Progression of diabetic nephropathy. Insights from cell culture studies and animal models.

Nephropathy in patients with type I and II diabetes mellitus is a rapidly increasing problem worldwide. Studies using both glomerular and tubular cells have delineated some of the consequences induced by acute hyperglycemia. In vitro studies have clearly demonstrated that exposure of cultured renal cells, such as glomerular mesangial cells and proximal tubular epithelial cells, to elevated glucose concentrations, may alter cell proliferation and/or extracellular matrix turnover. The latter is effected both directly and indirectly by the alteration of cytokine generation. Furthermore, these in vitro studies have allowed detailed examination of the mechanisms by which exposure of these cells to high ambient glucose concentrations may alter cell function. Extension of these studies to the experimental in vivo situation has confirmed most of the in vitro findings. Important insights gained from models of type I diabetes (i.e. streptocotocin-induced diabetes) as well as type II diabetes (i.e. Goto-Kakizaki (GK) rats and obese Zucker rats) include: (1) The demonstration that increased glomerular cell proliferation and renal matrix accumulation, driven by TGF-beta and/or PDGF, occur in streptocotocin-induced diabetes, yet that nephropathy in these rats does not progress to renal failure. (2) The demonstration that prolonged mild type II diabetes does induce morphological changes characteristic of pre-clinical diabetic nephropathy in GK-rats but does not result in albuminuria or progressive renal disease. (3) The demonstration that the association of type II diabetes with hyperlipidemia in obese Zucker rats results in early podocyte damage and subsequent progression to glomerulosclerosis, tubulointerstitial damage, and renal insufficiency. Identification of the mediators involved in the above processes and in particular of the conditions that will determine progression of subclinical morphological changes to overt nephropathy and renal failure will likely result in future novel therapeutic approaches to diabetic nephropathy.

Animals↗
PubMed1999

Cellular expression of a leech netrin suggests roles in the formation of longitudinal nerve tracts and in regional innervation of peripheral targets.

Netrins are secreted, diffusible proteins that direct axonal growth. To study the functions of netrins in the relatively simple and easily accessible nervous system of the leech Hirudo medicinalis, we have cloned a leech netrin and have characterized its expression during embryogenesis. By probing a leech cDNA library at low stringency with chick netrin probes, we have identified a complete cDNA clone that bears significant sequence similarity to netrins of other species. In situ hybridization and dye filling of individual neurons show that this leech netrin is expressed by several identifiable central neurons in every segmental ganglionic primordium during early stages of embryogenesis. Some of these neurons, including the bipolar cells which are thought to be involved in setting up longitudinal tracts, express this gene only transiently during embryogenesis, while others continue to express it in the adult. In addition, leech netrin is expressed by ventral but not dorsal longitudinal muscle cells in each segment before central neurons project their axons to the periphery. These highly specific expression patterns are consistent with the hypothesis that leech netrin plays a role in forming the major interganglionic neuronal tracts and in defining ventral versus dorsal domains of peripheral innervation.

Amino Acid Sequence↗
PubMed1998

Disease progression and survival in HIV-1-infected Africans in London.

OBJECTIVE: To examine differences in progression to AIDS and death between HIV-1-positive Africans (most infected in sub-Saharan Africa and therefore with non-B subtypes) and HIV-1-positive non-Africans in London. DESIGN: Retrospective cohort study of 2048 HIV-1-positive individuals. SETTING: HIV-1-infected individuals attending 11 of the largest HIV/AIDS units in London. PATIENTS: Subjects were 1056 Africans and 992 non-Africans seen between 1982-1995. RESULTS: There were no differences in crude survival from presentation to death between Africans and non-Africans (median 82 and 78 months, respectively; P = 0.22). Africans progressed more rapidly to AIDS [hazard ratio (HR), 1.21; 95% confidence interval (CI), 1.02-1.45] but after adjustment for age, sex, Centers for Disease Control and Prevention category B symptoms and CD4+ lymphocyte count at presentation, year of HIV diagnosis and hospital attended, this difference was no longer significant (adjusted HR, 1.15; 95% CI, 0.93-1.43). Africans with AIDS had a reduced risk of death compared with non-Africans (HR, 0.78; 95% CI, 0.63-0.96) but not after adjustment for age, CD4+ lymphocyte count at AIDS, initial AIDS-defining conditions (ADC) and hospital attended (HR, 0.98; 95% CI, 0.76-1.27). Tuberculosis as the first ADC was associated with a 64% reduction in the risk of death. CD4+ lymphocyte decline was not significantly different between Africans and non-Africans (P = 0.18). CONCLUSIONS: Differences in progression to AIDS and death and CD4+ lymphocyte decline between HIV-1-infected Africans and non-Africans in London could not be attributed to ethnicity or different viral subtypes. Age and the clinical and immunological stage at presentation, or AIDS, were the major determinants of outcome. Compared with other diagnoses, tuberculosis as the initial ADC was associated with increased survival. Lack of access to health care and exposure to environmental pathogens are the most likely causes of reduced survival with AIDS in Africa, rather than inherently different rates of progression of immune deficiency due to racial differences or viral subtypes.

Acquired Immunodeficiency Syndrome↗
PubMed1998

Dual resistance to zidovudine and lamivudine in patients treated with zidovudine-lamivudine combination therapy: association with therapy failure.

Human immunodeficiency virus type 1 (HIV-1) strains dually resistant to zidovudine and lamivudine (3TC) may arise during zidovudine-3TC combination therapy. The objective of this cross-sectional study (n = 43 patients) was to test the association between therapy response (clinical and immunologic) to zidovudine-3TC and the level of phenotypic zidovudine resistance and zidovudine resistance-associated genotype of 3TC-resistant isolates. Other variables included were baseline CD4+ cell count, baseline Centers for Disease Control and Prevention (CDC) classification, virus load, and time receiving zidovudine. Phenotypic resistance was assessed using a recombinant virus assay. Genotypic analysis was based on population sequencing of plasma HIV-1. In a univariate analysis using a logistic regression model, it was found that therapy response was significantly associated with phenotypic and genotypic zidovudine resistance, baseline CD4+ cell count, and virus load. After adjustment for all variables, phenotypic resistance to zidovudine remained the only significantly associated factor, independent of baseline CD4+ cell count, baseline CDC classification, and virus load.

Anti-HIV Agents↗
PubMed1998

Bombs away.

Explore the source record for details and available documents.

Child Psychiatry↗
PubMed1997

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.

ADP-ribosyl Cyclase↗
PubMed1997

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.

Adult↗
PubMed1997

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.

Adult↗
PubMed1997

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.

Androstane-3,17-diol↗
PubMed1997

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.

Animals↗
PubMed1997

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.

Clinical Trials as Topic↗
PubMed1997

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.

AIDS-Related Opportunistic Infections↗
PubMed1997

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.

Adult↗
PubMed1997

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.

Base Sequence↗