PubMed Health⌕ Search

Biomedical subjects

J Workman

Publications and source records attributed to J Workman.

17 recordsLinked to original sources
PubMed2001

Antiretroviral drug concentrations in semen of HIV-infected men: differential penetration of indinavir, ritonavir and saquinavir.

Variable drug penetration of antiretroviral drugs into the genital tract may contribute to the differential evolution of HIV and the emergence of drug resistance. This, in turn, may have an impact on the sexual transmission of resistant HIV in patients treated with antiretroviral drugs. We have measured concentrations of the HIV-1 protease inhibitors indinavir, ritonavir and saquinavir in the blood plasma (BP) and seminal plasma (SP) of 23 HIV-1-positive men. Forty-five time-matched blood and semen samples were obtained. SP concentrations of indinavir exceeded the EC95 of indinavir, corrected for protein binding, of 42 ng/mL at all time intervals. In contrast, the median ritonavir and saquinavir SP concentrations were below the relevant EC95 at all times post drug ingestion. The median SP:BP concentration ratios for indinavir were 0.6, 0.8 and 1.4, respectively, at 0-2, 2-6 and 6-8 h post-drug ingestion. In contrast, the median SP:BP concentration ratios at 0-3, 3-9 and 9-12 h post-drug ingestion were <0.02, <0.04 and <0.04, respectively, for both ritonavir and saquinavir. These differences justify further study of HIV-1 evolution and development of resistance in the genital tract of men taking these anti-HIV drugs.

Adult↗
PubMed2000

Concentrations of nevirapine, lamivudine and stavudine in semen of HIV-1-infected men.

OBJECTIVE: To determine the concentrations of nevirapine (NVP), lamivudine (3TC) and stavudine (D4T) in seminal and blood plasma in HIV-1-infected men. METHODS: Twelve HIV-1-infected men on NVP-containing regimens including 3TC (n = 8) or D4T (n = 11) provided 23 blood plasma and 22 seminal plasma samples for drug concentration and viral load quantitation. Concentrations of all drugs were assessed by sensitive validated high performance liquid chromatography (HPLC) assays. Blood plasma and seminal plasma viral loads were measured using nucleic acid sequence-based amplification (NASBA). Samples were grouped according to time after drug ingestion, 0-2, 2-4, 4-8 and 8-12 h. For matched seminal and blood plasma samples, obtained within 1 h of each other, a seminal:blood plasma ratio was calculated. RESULTS: The concentration of NVP in seminal plasma appeared to mirror the concentrations in blood plasma. Absolute median seminal plasma NVP concentrations at 0-2, 2-4, 4-8 and 8-12 h were 3.1 microg/ml (range 1.7-4.89), 2.68 microg/ml (2.5-3.9), 2.5 microg/ml (2.3-2.7) and 3.09 microg/ml (1.3-9.1). The median seminal:blood plasma ratios for the four time periods were 0.54 (range 0.34-0.85), 0.83 (range 0.43-1.08), 0.53 (0.48-0.59), and 0.61 (0.59-0.78). 3TC and D4T appeared to reach concentrations in seminal plasma of a similar magnitude or higher than concentrations in blood plasma. The median seminal plasma viral load for all patients was less than 800 copies/ml (range < 800-11000). The median blood plasma viral load was less than 400 copies/ml (< 400-1100). CONCLUSION: NVP reaches concentrations in the semen approximately 60% of those in the blood plasma throughout the 12 h dosing period. In a smaller dataset, 3TC and D4T concentrations in blood plasma and seminal plasma were similar. These data may well have implications for the evolution of drug-resistant virus within the genital tract.

Adult↗
PubMed2000

Mitochondrial dysfunction and free radical damage in the Huntington R6/2 transgenic mouse.

Huntington's disease is a progressive neurodegenerative disease caused by an abnormally expanded (>36) CAG repeat within the ITI5 gene encoding a widely expressed 349-kd protein, huntingtin. The medium spiny neurons of the caudate preferentially degenerate in Huntington's disease, with the presence of neuronal intranuclear inclusions. Excitotoxicity is thought to be important in the pathogenesis of Huntington's disease; the recently described mitochondrial respiratory chain and aconitase defects in Huntington's disease brain are consistent with this hypothesis. A transgenic mouse model (R6/2) of Huntington's disease develops a movement disorder, muscle wasting, and premature death at about 14 to 16 weeks. Selective neuronal death in these mice is not seen until 14 weeks. Biochemical analysis of R6/2 mouse brain at 12 weeks demonstrated a significant reduction in aconitase and mitochondrial complex IV activities in the striatum and a decrease in complex IV activity in the cerebral cortex. Increased immunostaining for inducible nitric oxide synthase and nitrotyrosine was seen in the transgenic mouse model but not control mouse brains. These results extend the parallels between Huntington's disease and the transgenic mouse model to biochemical events and suggest complex IV deficiency and elevated nitric oxide and superoxide radical generation precede neuronal death in the R6/2 mouse and contribute to pathogenesis.

Animals↗
PubMed2000

Tryptophan hydroxylase polymorphisms in suicide victims.

Both environmental and genetic factors appear to contribute to the risk for suicide. The serotonergic system has been implicated in depression, impulsivity and suicidality. Tryptophan hydroxylase (TPH) is the rate-limiting enzyme in the synthesis of serotonin. Suicide has been associated with polymorphisms in intron 7 of the TPH gene. These alleles were studied in samples from 47 deceased Caucasian males as part of the Utah Youth Suicide Study. A 918 base pair fragment spanning the region of interest was amplified. The A218C polymorphism was visualized by restriction fragment length polymorphism (RFLP) and the A779C was sequenced. Neither A218C nor A779C appeared to be associated with suicide in this population. These results did not change when the sample was stratified by age (10-21 years, 22-31 years) or when violent suicides were selected. The complexity of the phenotype of suicide may reflect multiple biological and social etiologic factors, and poses a worthy challenge for genetic studies.

Adolescent↗
PubMed1999

Peripheral nerve abnormalities in the congenital cataracts facial dysmorphism neuropathy (CCFDN) syndrome.

Observations have been made on the peripheral nerve changes in four patients, ranging in age from 4 to 32 years, with the congenital cataracts facial dysmorphism neuropathy syndrome. Myelinated fibre density was within normal limits. The salient abnormality was diffuse hypomyelination which, in the older patients, was associated with demyelination and then axonal degeneration. These findings could be correlated with the relative preservation of sensory action potential amplitude despite markedly reduced nerve conduction velocity. Unmyelinated axon density was preserved. The morphological observations suggest the operation of a developmental process affecting myelination with a later superimposed degenerative disorder.

Adult↗
PubMed1999

Evaluating and selecting video equipment for the OR.

Purchasing video equipment for minimally invasive procedures can present a huge challenge. Standardization offers obvious advantages; however, it often is dismissed as an unattainable goal when dealing with physicians of multiple specialties. Standardization of video equipment throughout all specialties, however, is attainable. The keys to evaluating and selecting one product or vendor are clearly defined goals, the proper tools, and education. Although it might seem like an overwhelming task, it is possible to stay in control throughout this process and achieve the facility's goals.

Decision Making, Organizational↗
PubMed1999

Asymptomatic urethritis and detection of HIV-1 RNA in seminal plasma.

OBJECTIVE: To define risk factors for detection of HIV-1 RNA in semen in men attending the two largest HIV clinics in the West Midlands. METHODS: 94 HIV-1 seropositive men at any stage of infection donated matched semen and blood samples. 36 subjects (38%) were on no antiretroviral treatment, 12 (13%) were on dual therapy, and 46 (49%) were on three or more drugs. Median CD4 count was 291 cells x 10(6)/l. 87 subjects underwent a urethritis screen (Gram stained urethral smear and culture for gonococcus, and LCR for Chlamydia trachomatis on first pass urine). Quantitative cell free HIV-1 RNA was determined by commercial nucleic acid sequence based assay with a lower detection limit of 800 copies/ml for semen and 400 copies/ml for blood. Independent risk factors for seminal HIV RNA detection were defined by logistic regression. RESULTS: In univariate analysis, subjects not taking antiretrovirals were 11 times more likely to shed HIV RNA (21/36 (58%) v 6/58 (10%); p < 0.0001). Seven subjects (8%) had urethritis (including one C trachomatis infection). Urethritis was significantly associated with detection of seminal HIV RNA (adjusted OR, 80.2; p = 0.006), as was blood plasma viral load (adj OR, 19.3 per factor 10 increase; p < 0.001) and age (adj OR, 1.16 per 1 year older; p = 0.001). Antiviral treatment status, absolute CD4 and CD8 count, clinical stage, treatment centre, ethnicity, and risk factor were not independent predictors. No subject with undetectable blood viral load had detectable seminal HIV RNA. CONCLUSION: Asymptomatic urethritis is independently associated with seminal HIV RNA shedding.

Adult↗
PubMed1998

Persistent interactions of core histone tails with nucleosomal DNA following acetylation and transcription factor binding.

In this study, we examined the effect of acetylation of the NH2 tails of core histones on their binding to nucleosomal DNA in the absence or presence of bound transcription factors. To do this, we used a novel UV laser-induced protein-DNA cross-linking technique, combined with immunochemical and molecular biology approaches. Nucleosomes containing one or five GAL4 binding sites were reconstituted with hypoacetylated or hyperacetylated core histones. Within these reconstituted particles, UV laser-induced histone-DNA cross-linking was found to occur only via the nonstructured histone tails and thus presented a unique tool for studying histone tail interactions with nucleosomal DNA. Importantly, these studies demonstrated that the NH2 tails were not released from nucleosomal DNA upon histone acetylation, although some weakening of their interactions was observed at elevated ionic strengths. Moreover, the binding of up to five GAL4-AH dimers to nucleosomes occupying the central 90 bp occurred without displacement of the histone NH2 tails from DNA. GAL4-AH binding perturbed the interaction of each histone tail with nucleosomal DNA to different degrees. However, in all cases, greater than 50% of the interactions between the histone tails and DNA was retained upon GAL4-AH binding, even if the tails were highly acetylated. These data illustrate an interaction of acetylated or nonacetylated histone tails with DNA that persists in the presence of simultaneously bound transcription factors.

Acetylation↗
PubMed1996

The TAF(II)250 subunit of TFIID has histone acetyltransferase activity.

The transcription initiation factor TFIID is a multimeric protein complex composed of TATA box-binding protein (TBP) and many TBP-associated factors (TAF(II)s). TAF(II)s are important cofactors that mediate activated transcription by providing interaction sites for distinct activators. Here, we present evidence that human TAF(II)250 and its homologs in Drosophila and yeast have histone acetyltransferase (HAT) activity in vitro. HAT activity maps to the central, most conserved portion of dTAF(II)230 and yTAF(II)130. The HAT activity of dTAF(II)230 resembles that of yeast and human GCN5 in that it is specific for histones H3 and H4 in vitro. Our findings suggest that targeted histone acetylation at specific promoters by TAF(II)250 may be involved in mechanisms by which TFIID gains access to transcriptionally repressed chromatin.

Acetyltransferases↗
PubMed1986

Morphometric analysis of in vivo development of porcine ovarian granulosa cells in preovulatory antral follicles.

Granulosa cells (GC) from immature (1-2 mm), developing (3-5 mm), and preovulatory (6-12 mm) antral porcine follicles were examined by stereological, ultrastructural techniques. Partial cell volumes occupied by nuclei or mitochondria did not differ significantly as follicles enlarged. Whorled smooth endoplasmic reticulum (ER) increased significantly in large follicles compared to either small or medium sized follicles. Whorled rough ER elements were present in similar amounts in small and medium sized follicles and absent in large follicles. The GC of large follicles contained significantly more lipid and Golgi complexes than that of small follicles, but the lipid and Golgi complex content of GC from medium follicles was not significantly different from that of either small or large follicles. Proportions of total cell volumes occupied by lysosomes and multivesicular bodies increased as follicular size increased. This confirms earlier qualitative studies, and provides a quantitative in situ basis for future in vitro studies.

Animals↗
PubMed1980

Accuracy of radionuclide imaging in distinguishing renal masses from normal variants.

To determine the accuracy of scintigraphy in distinguishing true renal masses from normal variants, 40 patients with excretory urographic findings indicating a possible, but not definite, mass lesion were studied. Scintigraphy correctly identified 17 true masses and 17 normal variants. Four false positive and two false negative results were obtained.

Abscess↗