Viral dynamics of primary viremia and antiretroviral therapy in simian immunodeficiency virus infection

Mathematical modeling of viral replication dynamics, based on sequential measurements of levels of virion-associated RNA in plasma during antiretroviral treatment, has led to fundamental new insights into human immunodeficiency virus type 1 pathogenesis. We took advantage of the simian immunodeficiency virus (SIV)-infected macaque model to perform detailed measurements and mathematical modeling during primary infection and during treatment of established infection with the antiretroviral drug (R)-9-(2-phosphonylmethoxypropyl)adenine (PMPA). The calculated clearance half-life for productively infected cells during resolution of the peak viremia of primary infection was on the order of 1 day, with slightly shorter clearance half-lives calculated during PMPA treatment. Viral reproduction rates upon discontinuation of PMPA treatment after 2 weeks were approximately twofold greater than those obtained just prior to initiation of treatment in the same animals, likely reflecting accumulation of susceptible target cells during treatment. The basic reproductive ratio (R0) for the spread of SIV infection in vivo, which represents the number of productively infected cells derived from each productively infected cell at the beginning of infection, was also estimated. This parameter quantifies the extent to which antiviral therapy or vaccination must limit the initial spread of virus to prevent establishment of chronic disseminated infection. The results thus provide an important guide for efforts to develop vaccines against SIV and, by extension, human immunodeficiency virus.     

Coronary bypass in vascular patients: a relatively high-risk procedure

A premise of cardiac risk stratification is that the added risk of coronary artery bypass grafting (CABG) is offset by the improved safety of subsequent vascular reconstruction (VR). We questioned if elective CABG is patients with severe peripheral vascular disease (PVD) is a relatively high-risk procedure. A cohort study of 680 elective CABG patients from January 1993 to December 1994 was performed using three mutually exclusive outcomes of complication-free survival, morbidity, and mortality. Patient characteristic, operative, and outcome data were prospectively collected. Retrospective review determined that 58 patients had either a standard indication for or a history of VR. Overall CABG mortality was 2.5%, with statistically similar but relatively higher rates for PVD as compared to non-PVD patients. In contrast, major morbidity occurred at rates 3.6-fold higher in PVD patients (39.7%) than in disease-free patients (16.7%) after adjustment for the effects of patient and operative variables (odds ratio [OR] 3.67, 95% confidence interval [CI] 1.93-6.99). CABG morbidity in the PVD patient was most likely in those patients with aortoiliac (OR 9.51, CI 3.20-28.27) and aortic aneurysmal (OR 5.24, CI 1.28-21.41) disease types. CABG in PVD patients is associated with significant major morbidity. Such morbidity may preclude or alter the timing of subsequent VR.     

Proteolytic cleavage of MHC class I by complement C1-esterases--an overlooked mechanism?

This paper reviews recent changes in morbidity and mortality of respiratory syncytial virus (RSV) infection in infants with congenital heart disease. Mortality since the late 1970s has declined substantially, from approximately 37% to 3%. Although the frequency of admission to intensive care units has declined from approximately 60% to 30%, the frequency for mechanical ventilatory support has not changed significantly. Because mortality dropped prior to the widespread use of ribavirin, it is difficult to ascribe the improvement to this therapy. In infants with congenital heart disease (CHD), nosocomial infection remains a significant problem, accounting for approximately 33% of the RSV cases. Some authors report significant reductions in hospital-acquired RSV by use of gloves and gowns for contacts with infectious cases. Efforts at primary prevention have encountered problems with development of an RSV vaccine. Preliminary data from studies of passive immunization using immune globulins with high RSV antibody titers suggest that this therapy may reduce the severity of RSV infection in infants with serious heart disease.     

Treatment of essential arterial hypertension with hypercholesterolemia. Effects of an alpha-adrenergic blocker and an inhibitor of the angiotensin converting enzyme

BACKGROUND: Hypertension and hypercholesterolemia are frequently associated with this leading to considerable cardiovascular risk. METHODS: An open parallel randomized study was performed in which the effects of doxazosin, an alpha-adrenergic blocker and enalapril, an inhibitor of the angiotensin converting enzyme were compared in 70 patients with essential high blood pressure and plasma cholesterol levels greater than 240 mg/dl. Following 2-4 weeks of placebo administration the patients were randomly treated with one of the two drugs. When required doses were increased and hydrochlorothiazide added until blood pressure lower than 160/95 mmHg was achieved. After this period the patients were observed for a minimum of 8 weeks. The mean length of the study was of 22 weeks. RESULTS: Both drugs significantly reduced blood pressure without modifying cardiac frequency. Doxazosin tended to favorably modify the lipid profile of the plasma while enalapril significantly reduced the levels of cholesterol, lipids and high density lipoproteins (HDL). Upon termination of the study the total HDL/cholesterol index increased 8.6% in those treated with doxazosin and decreased 5.5% in those receiving enalapril (p < 0.05). CONCLUSIONS: Although doxazosin and enalapril are potent antihypertensive drugs, the effects on plasma lipid obtained with doxazosin indicate that a reduction in cardiovascular risk was achieved with this drug in the patients included in this study.     

Fibrinolytic variables and cardiovascular prognosis in patients with stable angina pectoris treated with verapamil or metoprolol. Results from the Angina Prognosis study in Stockholm

BACKGROUND: Disturbed fibrinolytic function may influence the progression of coronary atherosclerosis and contribute to thrombotic cardiovascular (CV) events. METHODS AND RESULTS: In the Angina Prognosis Study in Stockholm (APSIS), patients with stable angina pectoris were studied prospectively during double-blind treatment with metoprolol or verapamil. Various measures of fibrinolytic function were studied in 631 (of 809) patients. During a median follow-up time of 3.2 years (2132 patient-years), 32 patients suffered a CV death, 21 had a nonfatal myocardial infarction (MI), and 77 underwent revascularization. Plasma levels of tissue plasminogen activator (TPA) activity and antigen (ag), plasminogen activator inhibitor (PAI-1) activity at test, and TPA responses to exercise were determined at baseline and after 1 month's treatment and were related to subsequent fatal and nonfatal CV events. Univariate Cox regression analysis revealed that elevated levels of TPA-ag at rest (P < .05), high PAI-1 activity (P < .05), and low TPA-ag responses to exercise (P < .05) were associated with increased risk of subsequent CV death. After adjustment for baseline risk factors, TPA-ag independently predicted CV death or MI. In addition, PAI-1 activity independently predicted CV death or MI in male patients. Verapamil treatment was associated with a 10% decrease of TPA-ag levels and metoprolol treatment with a 2% increase (P < .001 for treatment difference). CONCLUSIONS: Plasma TPA-ag levels at rest, and among male patients PAI-1 activity as well, independently predict subsequent CV death or MI in patients with stable angina pectoris.     

Nitric oxide synthase-immunoreactive neurons in human and porcine respiratory tract

The presence of nitric oxide synthase (NO-synthase), the enzyme responsible for the production of nitric oxide (NO) from L-arginine, is shown immunocytochemically in the intrinsic neurons of the human and porcine respiratory tract. NO-synthase immunoreactivity is demonstrated in a subpopulation of neurons of the microganglia present in the wall of the extra- and intrapulmonary bronchi as well as in the hilar region of the lung in relation to blood vessels. The immunostaining was also found in some nerve fibers of the respiratory nervous system. Human and porcine lung gave similar results. The possible involvement of NO in the nonadrenergic noncholinergic (NANC) nervous regulation of the lung is discussed.     

Pharmacokinetics of hyperimmune anti-human immunodeficiency virus immunoglobulin in persons with AIDS

Hyperimmune anti-human immunodeficiency virus immunoglobulin (HIVIG) is an intravenous immunoglobulin prepared from HIV-infected asymptomatic donors with a CD4 cell count greater than 400 cells/microl and a high titer of antibody to HIV-1 p24 protein. Twelve persons with AIDS received four doses of HMG (two at 50 mg/kg of body weight and then two at 200 mg/kg) every 28 days. Pharmacokinetics were evaluated by measurement of anti-p24 antibody. HIVIG was well tolerated, and all participants completed the study. Three subjects who were not receiving Pneumocystis carinii pneumonia (PCP) prophylaxis developed PCP. The mean value for HIVIG clearance was 3.02 ml/kg/day at 50 mg/kg and 3.65 ml/kg/day at 200 mg/kg (P = 0.027); the mean trough antibody titers (reciprocal units) were 1,442 and 4,428, respectively. This study indicates that high titers of anti-p24 antibody can be maintained with a monthly administration schedule of HIVIG and that short-term safety is acceptable. Comparisons to evaluate the therapeutic potential of HIVIG are justified.