Biomedical subjects

J M Grimes

Publications and source records attributed to J M Grimes.

24 records · Page 2Linked to original sources

PubMed1995

A comparison of immediate with deferred zidovudine therapy for asymptomatic HIV-infected adults with CD4 cell counts of 500 or more per cubic millimeter. AIDS Clinical Trials Group.

BACKGROUND: The clinical benefits of zidovudine remain unproved in patients with asymptomatic human immunodeficiency virus (HIV) infection when CD4 cell counts exceed 500 per cubic millimeter. We compared zidovudine therapy given immediately with deferred therapy in such subjects. METHODS: Beginning in 1987, subjects with asymptomatic HIV infection and 500 or more CD4 cells per cubic millimeter were randomly assigned to receive placebo or zidovudine (either 500 or 1500 mg per day, starting immediately). In 1989, the study was modified so that open-label treatment with 500 mg of zidovudine per day (deferred therapy) was offered when CD4 cell counts fell below 500 per cubic millimeter. The study end points included overall survival, survival free of the acquired immunodeficiency syndrome (AIDS), toxic effects, and changes in CD4 cell counts. RESULTS: There were 1637 subjects who could be evaluated: 547 in the deferred-therapy group, 549 in the group receiving 500 mg of zidovudine immediately, and 541 in the 1500-mg group. The subjects were followed for up to 6.5 years (group medians, 4.8, 4.8, and 4.9, respectively). There was no significant difference in AIDS-free survival in the deferred-therapy group as compared with the low-dose or high-dose groups (81 cases of progression to AIDS or death vs. 81 and 74, respectively; P = 0.95 and P = 0.13) or in overall survival (51 deaths vs. 47 and 46; P = 0.25 and P = 0.16). The decline in CD4 cells was slower in both immediate-therapy groups than in the deferred-therapy group (P < 0.001 for both). Adverse effects were uncommon, and before the study modification their incidence was similar among the treatment groups, but severe anemia and granulocytopenia were more frequent in the 1500-mg group than in the deferred-therapy group (P < 0.001). CONCLUSIONS: In asymptomatic, HIV-infected adults with 500 or more CD4 cells per cubic millimeter, treatment with zidovudine slows the decline in the CD4 cell count but does not significantly prolong either AIDS-free or overall survival. These results do not encourage the routine use of zidovudine monotherapy in this population.

Acquired Immunodeficiency Syndrome↗

PubMed1995

Crystallization and preliminary X-ray analysis of the core particle of bluetongue virus.

Core particles of bluetongue virus serotype 1 (South Africa) have been crystallized. The crystals, which grow up to 0.8 mm in diameter, belong to a primitive orthorhombic space group and have point group symmetry 222. The unit cell dimensions are 754 x 796 x 823 A3 and the crystallographic asymmetric unit contains one-half of a core particle. The best crystals diffract strongly to 4.8 A Bragg spacings, which is the maximum resolution to which we can measure data with the detectors available, suggesting that useful diffraction extends well beyond this. Core particles of serotype 10 have also been crystallized but the crystals have yet to be analyzed by X-ray diffraction.

Animals↗

PubMed1994

The duration of zidovudine benefit in persons with asymptomatic HIV infection. Prolonged evaluation of protocol 019 of the AIDS Clinical Trials Group.

OBJECTIVE: To determine the durability of zidovudine-induced delay in clinical progression of asymptomatic human immunodeficiency virus (HIV) disease and to assess the relationship between this effect and the entry CD4+ cell count. DESIGN AND INTERVENTIONS: Extended follow-up data from subjects participating in protocol 019 of the AIDS [acquired immunodeficiency syndrome] Clinical Trials Group were examined. Subjects were offered a total daily dose of 500 mg of open-label zidovudine after the unblinding of the original randomized trial in 1989. Original treatment groups included placebo, 500 mg of zidovudine, or 1500 mg of zidovudine daily in divided doses. Three distinct analyses were conducted to assess the duration of zidovudine's effect on progression to AIDS or death: (1) analysis of all follow-up information from all subjects, (2) analysis of all subjects but with follow-up of original placebo-assigned subjects censored at the time open-label zidovudine was initiated, and (3) analysis of the effect of initiating zidovudine in subjects initially assigned to receive placebo. SETTING: University-based and university-affiliated AIDS research clinics participating in AIDS Clinical Trials Group protocol 019. PATIENTS: A total of 1565 asymptomatic HIV-infected subjects with entry CD4+ cell counts less than 0.50 x 10(9)/L (500/microL). MAIN OUTCOME MEASURE: Time to progression to AIDS or death. RESULTS: During follow-up of up to 4.5 years (mean, 2.6 years), 232 subjects progressed to AIDS or died. In each of the three analyses described herein, zidovudine was associated with a significant (P = .008, .004, .007) decrease in the risk of such progression. However, each of these analyses also indicated a decreasing placebo:zidovudine relative risk with duration of use (P = .002, .08, .04), suggesting a nonpermanent effect. The duration of benefit appeared to be related to entry CD4+ cell count, with greater benefit in those with higher counts at entry. No significant differences in survival were found between those originally randomized to zidovudine or placebo. CONCLUSIONS: Zidovudine at 500 mg/d caused a significant delay in progression to AIDS or death, but its earlier use in asymptomatic disease was not associated with an additional prolongation of survival compared with delayed initiation. The delay in progression diminished over time especially in subjects with entry CD4+ cell counts less than 0.30 x 10(9)/L (300/microL). Treatment strategies that alter drug regimens before the loss of zidovudine benefit should be explored.

Acquired Immunodeficiency Syndrome↗

PubMed1991

Activity and specificity of human aldolases.

The structure of the type I fructose 1,6-bisphosphate aldolase from human muscle has been extended from 3 A to 2 A resolution. The improvement in the resulting electron density map is such that the 20 or so C-terminal residues, known to be associated with activity and isozyme specificity, have been located. The side-chain of the Schiff's base-forming lysine 229 is located towards the centre of an eight-stranded beta-barrel type structure. The C-terminal "tail" extends from the rim of the beta-barrel towards lysine 229, thus forming part of the active site of the enzyme. This structural arrangement appears to explain the difference in activity and specificity of the three tissue-specific human aldolases and helps with our understanding of the type I aldolase reaction mechanism.

Amino Acid Sequence↗

PubMed1990

Effect of stage of disease and drug dose on zidovudine susceptibilities of isolates of human immunodeficiency virus.

Ninety-seven isolates of human immunodeficiency virus (HIV) from 73 individuals were assayed for susceptibility to zidovudine (AZT). All isolates from 41 individuals with no known therapy with zidovudine were uniformly susceptible to the drug in vitro. In contrast to isolates from subjects with AIDS or AIDS-related complex, isolates from subjects with fewer signs and symptoms or high CD4 lymphocyte counts developed reduced susceptibility at slower rates and lower levels of resistance. Patients receiving lower doses of zidovudine at both early and late stages of disease did not develop resistance more readily than patients receiving higher doses of drug.

AIDS-Related Complex↗

PubMed1987

Blood volume restitution after hemorrhage in adult sheep.

Indirect experimental evidence suggested the possibility that the restoration of blood volume to normal hemorrhage in adult sheep may occur more quickly than in other species that have been studied. To test this hypothesis, we studied unanesthetized chronically catheterized adult female sheep 1-2 wk after splenectomy. An average of 19.6 +/- 1.4% (SE) of their initial blood volume was removed over 10 min. Blood volume restitution at 0.5, 1, 3, 5, 7, 24, and 48 h posthemorrhage averaged 12 +/- 3, 34 +/- 3, 41 +/- 3, 50 +/- 4, 62 +/- 10, 79 +/- 10, and 124 +/- 25%, respectively. Arterial pressure decreased during the hemorrhage and returned to normal within 2 h, whereas venous pressure did not change significantly. No change in blood osmolality occurred. There was a highly significant correlation between blood volume and plasma protein mass (r = 0.98, P less than 10(-6)) during and after the hemorrhage. Thus it appears that the posthemorrhage restoration of blood volume in adult sheep occurs over essentially the same time course as in other species and this appears to be mediated by a restoration of plasma protein mass.

Animals↗