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Biomedical subjects

B D Walker

Publications and source records attributed to B D Walker.

155 records · Page 9Linked to original sources
PubMed1989

Synergistic inhibition of human immunodeficiency virus type 1 and type 2 replication in vitro by castanospermine and 3'-azido-3'-deoxythymidine.

Castanospermine and 3'-azido-3'-deoxythymidine (zidovudine) were evaluated in combination against human immunodeficiency virus (HIV) replication in vitro. Castanospermine and 3'-azido-3'-deoxythymidine inhibited HIV type 1 synergistically in acutely infected H9 cells. In addition, they synergistically inhibited both HIV type 1 and HIV type 2 in peripheral blood mononuclear cells. There were no additional toxic effects of these agents in combination. Drug interactions were evaluated by the median-effect principle and the isobologram technique. Combinations of a glycosylation inhibitor, such as castanospermine, with 3'-azido-3'-deoxythymidine deserve consideration for HIV-related chemotherapeutic intervention.

Alkaloids↗
PubMed1988

HIV-1 reverse transcriptase is a target for cytotoxic T lymphocytes in infected individuals.

Characterization of the host immune response to human immunodeficiency virus type 1 (HIV-1) is critical to the rational design of an effective AIDS vaccine. In this study, cytotoxic T lymphocytes (CTL) specific for HIV-1 reverse transcriptase (RNA-dependent DNA polymerase) were found in blood samples from HIV-1-infected individuals. CTL targets were prepared by immortalizing B cells from ten seropositive and six seronegative individuals, and then infecting these cells with recombinant vaccinia viruses containing HIV-1 genes. CTL directed against autologous B lymphoblasts expressing HIV-1 reverse transcriptase were detected in fresh blood samples from eight HIV-1 seropositive subjects, but in no seronegative controls. The effector cells were identified as major histocompatibility complex-restricted CD3+CD8+ lymphocytes. Because the HIV-1 pol gene is highly conserved among different isolates and generates both humoral and cellular immune responses, it bears consideration for inclusion in a candidate AIDS vaccine.

Acquired Immunodeficiency Syndrome↗
PubMed1988

HIV infection is blocked in vitro by recombinant soluble CD4.

The T-cell surface glycoprotein, CD4 (T4), acts as the cellular receptor for human immunodeficiency virus, type 1 (HIV-1), the first member of the family of viruses that cause acquired immunodeficiency syndrome. HIV recognition of CD4 is probably mediated through the virus envelope glycoprotein (gp120) as shown by co-immunoprecipitation of CD4 and gp120 (ref.5) and by experiments using recombinant gp120 as a binding probe. Here we demonstrate that recombinant soluble CD4(rsT4) purified from the conditioned medium of a stably transfected Chinese hamster ovary cell line is a potent inhibitor of both virus replication and virus-induced cell fusion (syncytium formation). These results suggest that rsT4 is sufficient to bind HIV, and that it represents a potential anti-viral therapy for HIV infection.

Animals↗
PubMed1987

Inhibition of human immunodeficiency virus syncytium formation and virus replication by castanospermine.

Castanospermine (1,6,7,8-tetrahydroxyoctahydroindolizine) is a plant alkaloid that modifies glycosylation by inhibiting alpha-glucosidase I. Castanospermine is shown to inhibit syncytium formation induced by the envelope glycoprotein of the human immunodeficiency virus and to inhibit viral replication. The decrease in syncytium formation in the presence of castanospermine can be attributed to inhibition of processing of the envelope precursor protein gp160, with resultant decreased cell surface expression of the mature envelope glycoprotein gp120. In addition, castanospermine may cause defects in steps involved in membrane fusion after binding of CD4 antigen. The antiviral effects of castanospermine may be due to modifications of the envelope glycoprotein that affect the ability of the virus to enter cells after attachment to the CD4 cell receptor.

Alkaloids↗
PubMed1976

A randomized, comparative study of tobramycin and gentamicin in treatment of acute urinary tract infections.

Eighty patients with urinary tract infections were randomly divided into two equal groups; one group received tobramycin, and the other received gentamicin. The daily dose of antibiotic for each group was 3 mg/kg. Mean levels in serum were 4.5 and 4.7 mug/ml, respectively, 1 hr after an intramuscular injection, and the mean duration of therapy was 6.5 days. Mean ages and sex ratios were similar in the two groups. Essentially equal numbers of patients with pyelonephritis and cystitis were assigned randomly to each group. Eradication of infection was similar in patients in the two treatment groups, and there was not a significant number of relapses or reinfections in either group. Renal function was abnormal in seven patients treated with gentamicin and in two patients treated with tobramycin. One patient in the gentamicin group developed a skin eruption. Our data suggest that tobramycin is as effective as gentamicin in the treatment of acute urinary tract infection and may be less nephrotoxic at similar doses.

Acute Disease↗
PubMed1976

Metabolism of a benzothiazine compound (SQ 11,579) by the intact rat, isolated perfused rat liver, and rat-liver microsomes.

1. The metabolic dispositions of a benzothiazine compound (SQ 11,579) by the intact rat, isolated perfused rat liver, and rat-liver microsomes have been investigated, and the results compared. 2. The drug was well absorbed after oral administration to rats and was widely distributed in all tissues, which, with the exception of brain, had higher concentrations of the drug, its metabolites, or both, than did plasma. 3. Metabolism by rat-liver microsomes included N-oxidation, N-demethylation, S-oxidation and aryl hydroxylation. Metabolites hydroxylated in the aromatic ring were excreted only in bile, both by the isolated perfused rat livers and by anaesthetized bile-duct-cannulated rats. 4. Liver perfusion of the benzothiazine or its monodesmethyl analogue (V) resulted in temporary cessation of the flow of perfusate through the organ. The benzothiazine sulphoxide (IV) had only a slight effect on the flow of liver perfusate, but IV followed by I caused the flow of perfusate to cease.

Administration, Oral↗
PubMedDate not supplied

Reduced antiretroviral drug susceptibility among patients with primary HIV infection.

CONTEXT: The transmission of drug-resistant human immunodeficiency virus (HIV) has been documented, but the prevalence of such transmission is unknown. OBJECTIVE: To assess the spectrum and frequency of antiretroviral susceptibility among subjects with primary HIV infection. DESIGN, SETTING, AND PATIENTS: Retrospective analysis of 141 subjects identified from clinical research centers in 5 major metropolitan areas, enrolled from 1989 to 1998, with HIV seroconversion within the preceding 12 months and no more than 7 days' prior antiretroviral (ARV) therapy. MAIN OUTCOME MEASURES: Phenotypic and genotypic ARV susceptibility of HIV from plasma samples. RESULTS: The transmission of drug-resistant HIV as assessed by a greater than 10-fold reduction in ARV susceptibility to 1 or more drugs was observed in 3 (2%) of 141 subjects, including to a nonnucleoside reverse transcriptase inhibitor in 1 patient and to a nucleoside reverse transcriptase inhibitor and a protease inhibitor in 2 patients. Population-based sequence analysis of these 3 samples identified multidrug-resistance mutations in reverse transcriptase (M184V, T215Y, K219K/R) and protease (L101/V, K20R, M361, M46I, G48V, L63P, A71T, V771, V82T, 184V, L90M) in the 2 latter patient samples, along with numerous polymorphisms. A reduction in susceptibility of greater than 2.5- to 10-fold to 1 or more drugs was observed in viral isolates from 36 patients (26%). Sequence analysis of these 36 samples identified well-characterized drug resistance mutation in reverse transcriptase and protease in only 1 of these patients. CONCLUSIONS: Reductions in drug susceptibility of more than 10-fold were rare among this cohort of recently HIV-infected subjects and were distributed among each of the 3 major classes of ARV drugs tested. Reductions in susceptibility of more than 2.5- to 10-fold to certain ARV drugs of unknown clinical significance were highly prevalent among newly infected patients. Resistance testing may be warranted to monitor the frequency of drug resistance over time and to assess the potential for geographic variability.

Adolescent↗
PubMedDate not supplied

HIV-specific cytotoxic T lymphocytes in seropositive individuals.

Virus-specific cytotoxic T lymphocytes (CTL) which kill virus-infected cells are thought to be a major host defence against viral infections. Here we report the existence of human immunodeficiency virus (HIV)-specific CTL in persons infected with this virus, the aetiological agent of AIDS (acquired immunodeficiency syndrome). Recombinant HIV-vaccinia viruses were used to express HIV antigens in B-cell lines established from subjects seropositive for HIV and seronegative controls. Circulating lymphocytes capable of killing HIV env-expressing autologous B cells were detected in eight of eight seropositive subjects; in addition, at least three seropositive subjects demonstrated gag-specific cytotoxic responses. No HIV-specific cytotoxicity was observed in seronegative subjects. Selective inhibition of the env-specific cytotoxicity by a CD3-specific monoclonal antibody indicates that the effectors are T cells. This demonstration of a cytotoxic T-cell immune response to HIV in infected individuals should prove useful in investigating the immunopathogenesis of HIV infection further and in evaluating AIDS vaccine strategies.

Acquired Immunodeficiency Syndrome↗
PubMedDate not supplied

Role of smooth muscle activation in conduction of vasodilation along isolated hamster feed arteries.

Vasodilation originating within a muscle is conducted into feed arteries, but the determinants of conduction along feed arteries are undefined. We have investigated the effect of vasomotor tone on conducted vasodilation in feed arteries of the hamster retractor muscle. Unbranched segments (length, 2-3 mm) were isolated, cannulated, and studied in vitro at 37 degreesC while pressurized to 25 mm Hg, 75 mm Hg (in vivo pressure), or 120 mm Hg in the absence and presence of norepinephrine (NE, 10(-7) M + 10(-6) M propanolol). Internal diameter decreased (p < 0.05) as pressure increased (85 +/- 7, 73 +/- 4, 66 +/- 6 microm, respectively), confirming myogenic reactivity. Acetylcholine (ACh, 0.1 M) was delivered (1 microA, 500 ms) from a micropipette; vasomotor responses were recorded at the site of release ('local') and at distances up to 1,500 microm ('conducted') along the vessel. There were no responses to ACh at 25 mm Hg. However, dilations (diameter change, microm) were pronounced at 75 mm Hg (local: 22 +/- 3; conducted: 18 +/- 2, respectively), without further change at 120 mm Hg. NE constricted vessels (p < 0. 05) at each pressure (to 65 +/- 9, 57 +/- 6, and 56 +/- 8 microm, respectively); this enabled both local (14 +/- 2 microm) and conducted (10 +/- 1 microm) vasodilation at 25 mm Hg but was without effect on conduction at 75 or 120 mm Hg. Our findings indicate that conducted responses plateau at a physiological level of myogenic tone. Whereas NE had no effect on conduction under normal or hypertensive conditions, it enabled conduction during hypotension. We conclude that pressure and NE influence the ability of conducted vasodilation to govern muscle blood flow.

Acetylcholine↗