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Biomedical subjects

I McGowan

Publications and source records attributed to I McGowan.

17 recordsLinked to original sources
PubMed2001

Hydroxyurea does not enhance the anti-HIV activity of low-dose tenofovir disoproxil fumarate.

Tenofovir disoproxil fumarate (DF) is an adenosine analogue with significant activity against HIV-1. Hydroxyurea decreases the intracellular concentrations of deoxyadenosine triphosphate, the active metabolite of adenosine. We therefore tested the hypothesis that hydroxyurea could enhance the anti-HIV activity of low-dose tenofovir in vivo. Eight patients received tenofovir DF, 75 mg, plus hydroxyurea, 500 mg bid, for 28 days. Changes in plasma HIV RNA levels were compared with a previously studied cohort of patients treated with tenofovir DF, 75 mg once daily ( n = 8), or tenofovir placebo ( n = 12). The median change in HIV RNA levels after 28 days of continuous treatment was -0.01 log(10) copies/ml for tenofovir placebo, -0.33 log(10) copies/ml for tenofovir 75 mg once daily, and -0.22 log(10) copies RNA/ml for tenofovir plus hydroxyurea. The difference between placebo and tenofovir-treated groups was significant ( p <.05); however, the difference between the tenofovir and tenofovir plus hydroxyurea groups was not significant ( p =.90). We conclude that hydroxyurea does not significantly enhance the antiviral activity of low-dose tenofovir.

Adenine↗
PubMed2001

Sensitive and reproducible quantitation of mucosal HIV-1 RNA and DNA viral burden in patients with detectable and undetectable plasma viral HIV-1 RNA using endoscopic biopsies.

Mucosal tissue is the main portal of entry for HIV-1 infection and, in macaques, has been demonstrated to be a significant compartment for viral replication and CD4+ T lymphocyte depletion. Quantitating tissue viral burden in addition to plasma viral load provides insights into HIV-1 pathogenesis and an additional means to gauge antiretroviral response. The aim of this study was to develop reliable, reproducible, and sensitive assays to quantitate tissue viral burden of HIV-1 RNA and DNA using 1-3 endoscopically acquired, rectosigmoid biopsies. Total DNA and RNA were simultaneously extracted following homogenization from the same tissue samples. Quantitative polymerase chain reaction (PCR) assay in the HIV-1 LTR region was used to detect viral DNA and RT-PCR for viral RNA. It was determined that HIV-1 RNA and DNA can be reproducibly quantified from a single rectosigmoid biopsy with minimal intra-assay or intra-patient variability. These results reflect high recovery of extracted nucleic acids with calculated results accurately reflecting in vivo levels. The techniques outlined differ from currently available approaches by incorporating control standards to identify loss or degradation of RNA and DNA from acquisition through the in vitro assay and permit extraction with high yields of RNA and DNA from the same tissue sample.

Colonoscopy↗
PubMed2001

HIV-related diarrhea is multifactorial and fat malabsorption is commonly present, independent of HAART.

OBJECTIVE: Highly active antiretroviral therapy (HAART) has significantly decreased the incidence of infectious diarrhea affecting HIV-infected patients. Still, diarrhea remains a common symptom in HIV. We sought to determine the incidence of fat malabsorption as a cause of diarrhea in HIV patients receiving non-HAART (nucleoside analog only) and HAART (protease inhibitor-containing) antiretroviral regimens. METHODS: From June, 1995, to April, 1999, 88 HlV-infected patients underwent evaluation for diarrhea, which included endoscopy. We examined the incidence of fat malabsorption with a 24-h stool collection for fecal fat in a cohort of these patients (N = 33). Patients were divided into two groups, those receiving protease inhibitor-containing HAART and those receiving less intensive, nucleoside analog-only, non-HAART regimens. RESULTS: Thirty of 33 patients (90.9%) had fat malabsorption. Twenty of 21 patients not receiving HAART (95.2%) had fat malabsorption with a mean of 34 +/- 38 g of stool fat and a mean stool weight of 797 +/- 454 g. Ten of 12 patients receiving HAART (83.3%) had fat malabsorption with a mean of 46 +/- 86 g of stool fat and a mean stool weight of 800 +/- 647 g. Stool weight correlated with the degree of fat malabsorption (R = 0.77). CONCLUSION: Fat malabsorption represents a commonly undiagnosed entity in HIV-infected patients with diarrhea, whether or not they are receiving HAART therapy. Fecal fat determination should be considered a routine part of the diagnostic workup of HIV-infected patients experiencing diarrhea.

AIDS-Related Opportunistic Infections↗
PubMed2001

Phase i/ii trial of the pharmacokinetics, safety, and antiretroviral activity of tenofovir disoproxil fumarate in human immunodeficiency virus-infected adults.

Tenofovir DF is an antiviral nucleotide with activity against human immunodeficiency virus type 1 (HIV-1). The pharmacokinetics, safety, and activity of oral tenofovir DF in HIV-1-infected adults were evaluated in a randomized, double-blind, placebo-controlled, escalating-dose study of four doses (75, 150, 300, and 600 mg given once daily). Subjects received a single dose of tenofovir DF or a placebo, followed by a 7-day washout period. Thereafter, subjects received their assigned study drug once daily for 28 days. Pharmacokinetic parameters were dose proportional and demonstrated no change with repeated dosing. Reductions in plasma HIV-1 RNA were dose related at tenofovir DF doses of 75 to 300 mg, but there was no increase in virus suppression between the 300- and 600-mg dose cohorts, despite dose-proportional increases in drug exposure. Grade III or IV adverse events were limited to laboratory abnormalities, including elevated creatine phosphokinase and liver function tests, which resolved with or without drug discontinuation and without sequelae. No patients developed detectable sequence changes in the reverse transcriptase gene.

Adenine↗
PubMed1997

Advances in mucosal immunology.

HIV infection is likely to remain a significant medical and scientific problem well into the twenty-first century. During the first 15 years of the epidemic, much has been learned about the biology of HIV infection, but the majority of biomedical research has focused on the peripheral circulation. It is likely that the behavior of the virus within the unique immunologic environment of the intestinal mucosa differs from that which is observed in the periphery. Many clinical and epidemiologic features of HIV infection offer compelling reasons to encourage further examination of the mucosal immune system's role in AIDS pathogenesis. This article has touched on most of the significant observations concerning the mucosal immune system and HIV infection, and it is clear that much remains to be done. As mentioned earlier, the mucosal abnormalities observed in HIV infection are likely to have many causes. Careful evaluation of patients with early disease and fewer confounding variables may provide fresh insight into AIDS pathogenesis. Similarly, prospective evaluation of selected patient populations may be more informative in characterizing the progressive alterations in mucosal immune function than random cross-sectional studies of poorly defined groups. It is equally important for immunologic assessment to be correlated with nutritional and symptomatic evaluation. Finally, the success or failure of future antiretroviral therapies will be critically related to the impact of such agents on lymphoid reservoirs of HIV infection such as the gastrointestinal tract, which are at present refractory to treatment.

Antigen-Presenting Cells↗
PubMed1997

Intestinal microsporidiosis.

Intestinal microsporidiosis is caused by the protozoan parasites Enterocytozoon bieneusi and Encephalitozoon intestinalis. The disease has been described within the past decade and is found predominantly in acquired immunodeficiency syndrome (AIDS) patients in association with diarrhea. There have been rare reports of infections in immunocompetent patients. Both species of microsporidia invade and multiply within the enterocytes of the small intestine; Encephalitozoon intestinalis also causes a disseminated infection. Electron microscopy has been the mainstay of diagnosis, but improved noninvasive methods of detecting spores in feces are in development. The biology and pathogenicity of the parasites and the pathology and treatment of the disease are poorly understood.

AIDS-Related Opportunistic Infections↗
PubMed1996

Cytokine gene transcription of human colonic intraepithelial lymphocytes costimulated with epithelial cells bearing HLA-DR and its inhibition by 5-aminosalicylic acid.

The objectives of this study were to activate human colonic intraepithelial lymphocytes at the transcriptional level with HLA-DR+ human colonic epithelial cell line (HT29) in synergy with CD3 monoclonal antibody and to investigate the molecular mechanism for the therapeutic effects of 5-aminosalicylic acid. Lymphocytes were isolated by a mechanical method from resected colon of 22 cases and then cocultured on 10 ng/ml CD3mAb immobilized plates with HT29 which had been induced to express MHC class II molecules by interferon gamma. Flow cytometry analysis suggested that the lymphocyte population had a CD4/CD8 ratio similar to that observed in intact tissue sections and that there was no HT29 contamination of the lymphocytes isolated again from cocultured cells. The activation of intraepithelial lymphocytes showed the gene transcription of interferon gamma and tumor necrosis factor alpha, as measured by means of the reverse-transcriptase polymerase chain reaction, and this activation was antagonized by 5-aminosalicylic acid. Thus, epithelial cells bearing HLA-DR are capable of enhancing CD3-induced activation of human colonic intraepithelial lymphocytes and subject to inhibition by 5-aminosalicylic acid, the active moiety of salicylates used in inflammatory bowel disease.

Actins↗
PubMed1994

Cytokine gene expression in HIV-infected intestinal mucosa.

OBJECTIVE: Cytokine dysregulation has been implicated in AIDS pathogenesis and the gastrointestinal tract, containing approximately 40% of the body's lymphoid tissue, is likely to act both as a reservoir of viral infection and a site for immune dysregulation. In this study evidence of cytokine dysregulation in intestinal mucosa has been sought using the reverse transcriptase polymerase chain reaction (RT-PCR) to amplify cytokine mRNA. METHODS: RT-PCR was performed on intestinal biopsies obtained from 50 HIV-infected patients and 31 controls. Tissue was obtained at diagnostic endoscopy and total RNA extracted using an RNAzol technique. Following RT, cDNA was amplified using primers specific for beta-actin, interleukin (IL)-1 beta, tumour necrosis factor (TNF)-alpha, interferon (IFN)-gamma, IL-2, IL-4, IL-10 and IL-13. RESULTS: There was a significant increase in the expression of the proinflammatory cytokines IL-1 beta and IFN-gamma in the HIV-infected compared with the control small intestinal samples (P < 0.01). IL-10 was significantly reduced in the respective groups' large intestine (P < 0.02). The expression of IL-2 was also reduced in both the small and large intestinal HIV samples although this was not significant. IL-13 mRNA was only detected in one control patient. CONCLUSIONS: Dysregulation of cytokine gene expression occurs in the intestinal mucosa of patients with HIV infection and is characterized by increased expression of proinflammatory cytokine mRNA. Further studies are needed to localize the cellular origin of such dysregulation and to quantify the degree of abnormality.

Base Sequence↗
PubMed1994

Symptomatic management of HIV associated gastrointestinal disease.

This chapter describes the differential diagnosis and management of gastrointestinal symptoms associated with HIV infection. There is no clear point when management moves from intervention to palliation, and as with other manifestations of HIV disease, clinical decisions have to be guided by the wishes of the patient. In general, early diagnosis and treatment of HIV associated opportunistic infection are likely to keep patients symptom free, but when specific therapy is unavailable, unsuccessful or unwanted, then there is a clear indication to strive for symptom control using conventional palliative care.

Abdominal Pain↗
PubMed1993

The natural history of cryptosporidial diarrhoea in HIV-infected patients.

OBJECTIVE: To determine the natural history of cryptosporidial infection in HIV-infected individuals. DESIGN: Retrospective study. SETTING: University teaching hospital HIV inpatient and outpatient unit. PATIENTS: Thirty-eight HIV-infected patients presenting with cryptosporidial diarrhoea between April 1986 and July 1991 were identified retrospectively from laboratory records. RESULTS: Eleven of the 38 patients had a clinical remission of their diarrhoea. Median lymphocyte count of the remission group was significantly higher than that of the non-remission group (1100 and 550 x 10(6)/l, respectively; P = 0.003). Median survival times were 66 and 11.5 weeks for the remission and non-remission groups, respectively (P = 0.001). Liver function tests performed at the initial diagnosis of cryptosporidial diarrhoea were available for 28 patients. Aspartate transaminase was raised in 16 and alkaline phosphatase in 10 of these 28 patients. Ten patients showed evidence of AIDS-associated sclerosing cholangitis, one patient had an episode of acute pancreatitis and another presented with acute cholecystitis. CONCLUSIONS: This study suggests that HIV-associated cryptosporidial diarrhoea does not have a uniformly poor prognosis. Eleven out of 38 patients had a spontaneous clinical remission, which appears to be predicted by the absolute lymphocyte count. Abnormal liver function tests and hepatobiliary disease were common.

AIDS-Related Opportunistic Infections↗
PubMed1991

High definition computed tomography in rheumatoid arthritis associated pulmonary disease.

Eighteen patients with rheumatoid arthritis (American Rheumatism Association definition) were selected consecutively from a rheumatology clinic. All patients were examined with plain chest radiographs, thin slice computed tomography, and pulmonary function tests. Four patients with normal chest radiographs, and normal pulmonary function tests were found to have normal CT scans. In ten patients, abnormalities consistent with rheumatoid associated lung disease were demonstrated, including changes of interstitial fibrosis in seven cases. This fibrosis had a predominantly peripheral pattern on CT scan. Computed tomography was found to be more sensitive than plain radiographs in detecting abnormalities; however, all the patients in this series with CT lung changes had abnormalities on pulmonary function testing.

Adult↗
PubMed1989

Palliative laser therapy for inoperable rectal cancer--does it work? A prospective study of quality of life.

Endoscopic neodymium yttrium aluminium garnet (Nd YAG) laser therapy, is a new and simple method for the palliative treatment of inoperable colorectal cancer. To date the authors have treated 70 patients and the value of this method was assessed prospectively in 14 patients. Quality of life was measured before, during, and after treatment. The quality of life (QL) index, a physician's assessment and a linear analogue self-assessment (LASA) were used. A close correlation was found between the two assessment methods (r = 0.79). Overall there was a significant improvement from the mean pretreatment score and the best score achieved posttreatment (QL: P = 0.002; LASA: P = 0.002). Patients with diarrhea, rectal bleeding, mucus discharge, or pain secondary to tumor bulk, will benefit most from this treatment. Malignant cachexia, pain secondary to sacral plexus involvement, tumor encroachment on the anal canal and/or sphincter dysfunction resulting from tumor invasion should be viewed as relative contraindications to laser therapy. The authors conclude that in selected patients endoscopic laser therapy can provide effective palliation in patients with malignant tumors of the rectum and descending colon.

Aged↗
PubMed1986

A longitudinal psycho-physiological study of active and inactive men.

After an interval of ten years, physically active and inactive male university teachers were re-examined across four measures; predicted maximum oxygen uptake, percentage body fat, personality and attitudes towards physical activity. Both groups showed a decrease in predicted oxygen uptake and an increase in body fat although the active subjects continued to possess higher predicted maximum oxygen uptake values and have a lower percentage body fat than the inactive subjects. In general the psychological assessments revealed no major changes but minor shifts in attitudes towards physical activity were noted.

Adult↗