Infection of baboons with a simian immunodeficiency virus/HIV-1 chimeric virus constructed with an HIV-1 Thai subtype E envelope

OBJECTIVE: To construct an infectious chimeric simian immunodeficiency virus/HIV-1 (SHIV) with the envelope of a Thai subtype E HIV-1 strain for use in a non-human primate model. METHODS: A novel SHIV genome was derived using the sequences of the ectodomain of the envelope gene from the Thai subtype E strain, HIV-1(9466). This SHIV (SHIV9466.33) was recovered by cocultivation from human peripheral blood mononuclear cells (PBMC) after transfection of human rhabdosarcoma cells. Rhesus macaque and baboon PBMC were screened in vitro for susceptibility to infection with SHIV9466.33. After successful infection of baboon PBMC, four animals were inoculated intravenously with SHIV9466.33 and monitored for plasma viral RNA, virus isolation from the PBMC, seroconversion, T-cell subsets, and signs of disease. RESULTS: SHIV9466.33 was able to infect PBMC from 12 out of 14 baboons. All four of the baboons selected for in vivo inoculation became infected. Peak plasma viral RNA levels of 8000 to 700,000 RNA copies/ml were measured at 2 weeks post-inoculation. Virus was isolated from the PBMC of all four baboons during acute infection, and all seroconverted. Although transient declines in CD4+ T-cells were observed during early infection, CD4+ levels remained within normal ranges thereafter. In contrast, in vitro cultures of PBMC of four rhesus macaques were not susceptible to infection with SHIV9466.33. CONCLUSION: SHIV9466.33 containing an HIV-1 subtype E envelope displayed tropism for baboon PBMC but not for rhesus macaque PBMC. This chimeric virus established infection and induced antiviral antibodies in baboons inoculated by the intravenous route with cell-free virus. Thus, infection of baboons with SHIV9466.33 will serve as an important animal model for future studies of HIV-1 vaccine efficacy.     

Susceptibility to atrial fibrillation: a study in an ovine model of pacing-induced early heart failure

INTRODUCTION: The development of susceptibility to atrial fibrillation (AF) is a common consequence of many forms of cardiovascular disease, especially heart failure. In this study we used a sheep model of pacing-induced stable early heart failure to describe, quantify, and relate the level of susceptibility to AF to changes in structural and electrophysiologic parameters. METHODS AND RESULTS: Epicardial electrodes were implanted on the atria and right ventricles of nine sheep. The AF threshold, atrial vulnerability period, atrial effective refractory period (ERP), and interatrial conduction time were examined during control and over a 6-week period of ventricular pacing at 190 beats/min. Left atrial (LA) area and left ventricular (LV) fractional shortening were monitored using echocardiography. There were significant increases in LA susceptibility to AF (P < 0.0003), LA area (P < 0.0002), and LA ERP400 (P < 0.0002). Rate of increase in LA area was related positively to AF susceptibility (P = 0.02) and inversely to LA ERP400 (P = 0.002). LV fractional shortening decreased to approximately 50% of control value (P < 0.00001). No changes were observed in right atrial electrophysiology. CONCLUSION: In this study, susceptibility (the ability of an extrastimulus to induce AF) was rigorously measured within a predetermined format. Significant relationships were found to exist between susceptibility, certain of the observed changes in atrial electrophysiology and structure.     

Comparison of the plasma pharmacokinetics and renal clearance of didanosine during once and twice daily dosing in HIV-1 infected individuals

OBJECTIVE: To compare the plasma pharmacokinetics of didanosine during once daily (qd) and twice daily (bid) dosing. DESIGN: Open-label, randomized, cross-over study. METHODS: HIV-1 infected patients who used didanosine were randomized to either a qd or a bid dosing regimen of didanosine. The total daily dose of didanosine was identical in both regimens. Seven days after the start of the study, the pharmacokinetic profile of didanosine in plasma and urine was assessed during an 8-h period. The next day, the patient was switched to the opposite dosing regimen, and after another 7 days, the study was concluded by again assessing the plasma and urine pharmacokinetics of didanosine during 8 h. RESULTS: A total of 19 patients completed the study. The pharmacokinetics of didanosine in plasma (with maximum plasma concentration adjusted for dose) and urine were not significantly different in the qd and bid dosing regimen (P > 0.28 for all parameters). CONCLUSION: We conclude that qd dosing of didanosine leads to a similar exposure in plasma as bid dosing (using the same total daily dose). Since qd dosing may lead to improved compliance of patients to regimens containing didanosine, these results provide a rationale for prescribing didanosine in a qd regimen, and is reassuring when we realize that the drug is being administered in a qd dosing regimen on a large scale in clinical practice.     

A secondary prevention trial of antioxidant vitamins and cardiovascular disease in women. Rationale, design, and methods. The WACS Research Group

The evidence for a potential benefit of antioxidant vitamins in the prevention and therapy of atherosclerotic disease is derived from laboratory, clinical, and observational epidemiologic studies but remains inconclusive. Data from randomized clinical trials are sparse, particularly for women. Therefore, it is both timely and important to conduct large-scale primary and secondary prevention trials of antioxidants and cardiovascular disease (CVD). The Women's Antioxidant and Cardiovascular Study (WACS) is a randomized, double-blind, placebo-controlled secondary prevention trial of the balance of benefits and risks of antioxidant vitamins (vitamins E and C, and beta-carotene) among 8000 women with preexisting CVD. This secondary prevention trial will be conducted as a companion to the recently started Women's Health Study, a primary prevention trial of vitamin E and beta-carotene, as well as aspirin. In the WACS, US female health professionals aged 40 years and older with a history of myocardial infarction, angina pectoris, coronary revascularization, stroke, transient cerebral ischemia, carotid endarterectomy, or peripheral artery surgery will be randomly assigned, utilizing a 2 x 2 x 2 factorial design, to receive vitamin E, vitamin C, beta-carotene, and/or placebo. Cardiovascular end points include nonfatal myocardial infarction, nonfatal stroke, coronary revascularization procedures, and total CVD mortality. The present article describes the rationale, design, and methods of the trial.     

Glucose monitoring of patients with diabetes mellitus receiving general anesthesia: a study of the practices of anesthesia providers in a large community hospital

We investigated the late negative components of the contingent negative variations (CNVs) in the verbalization task. Six subjects were instructed to perform three different motor tasks, jaw opening, vocalization of a meaningless sound and that of a word, in response to a sound stimulus following a visual warning stimulus with interstimulus interval of 4.0 sec. The electroencephalograms (EEGs) were recorded from the midline-central (Cz), left and right temporal areas (T3 and T4) and frontal areas (F7 and F8). EEGs were averaged 16 times using the visual stimulus pulse as a trigger to obtain the CNVs in each motor task. There was no significant difference between the tasks of the jaw opening and vocalization of the sound in the CNV amplitudes at bilateral electrodes. However, the amplitudes of the CNVs at the left frontal and temporal areas were significantly larger in the case of vocalization of the word than in that of jaw opening (p < 0.05). On the other hand, there was no significant difference between these two tasks in the CNV amplitudes at the right frontal and temporal areas. Our results suggested that the CNVs generated over the left hemisphere might reflect the brain activities involved in language production.     

Cancer-related neuropathic pain

Infection by the human immunodeficiency virus (HIV) causes depletion of CD4-positive lymphocytes with consequent immunodeficiency. HIV infection also causes, by direct or indirect mechanisms, both reactive and neoplastic changes in lymphoid tissues. In primary infection reactive changes are a direct response to HIV. Later in the course of the disease there are reactive changes in lymph nodes and extranodal lymphoid tissues which are likely to be largely an indirect effect of HIV infection, being a response to opportunistic infection by other organisms. There is also an increased incidence of autoimmune phenomena in HIV-infected subjects which is likely to be consequent, at least in part, on impaired control of the proliferation of self-reactive B-cell clones. A second mechanism of immune damage of blood cells, probably operating in the case of HIV-related immune thrombocytopenic purpura, is that of cellular damage by immune complexes containing antiviral antibodies. Lymphoid neoplasms associated with HIV infection include non-Hodgkin's lymphoma, Hodgkin's disease and, uncommonly, plasma cell dyscrasias. HIV-associated lymphomas have distinct clinicopathological features and generally a poor prognosis. As for reactive lymphoid lesions, induction of neoplasia is likely, in the majority of cases, to be an indirect rather than a direct effect of the virus. The combination of chronic B-cell stimulation and impaired T-cell function is important, and interaction of lymphoid cells with virus-infected stromal cells may also play a role. Infection by oncogenic viruses such as the Epstein-Barr virus and human herpes virus 8 is also aetiologically important. In rare cases of T-cell lymphoma, HIV may be directly oncogenic.     

The early phase of engraftment after murine blood cell transplantation is mediated by hematopoietic stem cells

Blood cells transplantation is largely replacing bone marrow transplantation because engraftment is more rapid. This accelerated engraftment is thought to be mediated by relatively mature committed hematopoietic progenitor cells. Herein, we have used a modified rhodamine (Rho) staining procedure to identify and purify Rho+/++ (dull/bright) and Rho- (negative) subpopulations of hematopoietic progenitor cells in murine cytokine-mobilized blood. The Rho+/++ cell population contained > 99% of committed progenitor cells with in vitro colony-forming ability. The Rho- cell population contained the majority of hematopoietic stem cells with in vivo marrow repopulating ability. The rate of hematopoietic reconstitution was identical in recipients of grafts containing only purified Rho- stem cells or purified Rho- stem cells in combination with large numbers of Rho+/++ committed progenitor cells. In contrast, transplantation of 3-fold more hematopoietic stem cells resulted in accelerated reconstitution, indicating that the reconstitution rate was determined by the absolute numbers of Rho- stem cells in the graft. In addition, we observed a 5- to 8-fold reduced frequency of the subset of hematopoietic stem cells with long-term repopulating ability in cytokine-mobilized blood in comparison to steady-state bone marrow. Our results indicate that hematopoietic stem cells and not committed progenitor cells mediate early hematopoietic reconstitution after blood cell transplantation and that relative to bone marrow, the frequency of stem cells with long-term repopulating ability is reduced in mobilized blood.     

Prognostic factors and treatment of localized Hodgkin's disease]

Cure is warranted in most cases of localized Hodgkin's disease, the more frequent ones. However, after 10 years of follow-up, early and late mortality of iatrogenic origin exceed casualties related to tumor progression. Reductions in irradiation doses and fields, as well as wiser chemotherapy choices attempt to circumvent these complications. Nevertheless, as long as the mechanism of disease propagation and the prognostic factors are not better defined, only pragmatic approaches are being tested. Large cooperative trials are therefore needed to improve the outcome.