Early administration of ramipril in acute myocardial infarction: neurohormonal and hemodynamic effects and tolerability

Although several large studies indicate a beneficial effect of angiotensin-converting enzyme (ACE) inhibitors after myocardial infarction, the optimal timing of therapy in terms of safety and the effects on neurohormones during myocardial infarction are less well known. In order to investigate the effect of ramipril, administered within 24 h after myocardial infarction, on hemodynamics and neurohormones and its safety, 20 patients with a myocardial infarction were studied. Nine patients had an anterior, 10 an inferior, and 1 a non-Q-wave infarction. Fourteen patients received thrombolytic therapy, whereas 6 did not. The initial dose of ramipril was 1.25 mg, but was gradually increased to 5 mg during the next 4 days. Side effects did not occur. The mean arterial pressure decreased 8 h after the first dose from 84 +/- 2 mm Hg (control) to 77 +/- 2 mm Hg (p < 0.05) and remained decreased thereafter. This was accompanied by a reduction in systemic resistance of 8% after 8 h and of 12% on day 2. Heart rate, cardiac and stroke indexes, and pulmonary artery and wedge pressures did not change. The ACE activity decreased within 1 h of ramipril administration with a maximum of 71% at 4 h after the second dose and remained at this level throughout the study. Angiotensin II decreased by 34% (day 2) and by 41% (day 5). The renin activity gradually increased from 33 +/- 7.5 to 75.4 +/- 11.5 microM/ml on day 5, whereas epinephrine was reduced from day 2 onwards, with a maximal reduction of 71% on day 5. Arginine vasopressin was significantly reduced 5 h after ramipril administration until the end of the study, with a maximum of 77% on day 3. Moreover, a late but significant decrease in norepinephrine occurred on day 5. Thus, oral ramipril results in early ACE inhibition, followed by progressive attenuation of the neuroendocrine activation and a reduction in afterload during the acute phase of myocardial infarction. It is well tolerated, also in combination with nitroglycerin and thrombolytic therapy.     

PCR-ribotyping and pyrolysis mass spectrometry fingerprinting of environmental and hospital isolates of Clostridium difficile

Pancreatic ischemia is a very rare etiology of clinical acute pancreatitis, complicating cardiac surgery, hemorrhagic shock, and transplantation of the pancreas. In this article, we present two patients with acute ischemic necrotizing pancreatitis, complicating a generalized atheromatous disease with extensive lesions in the splanchnic circulation (patient 1) and repair of a descending thoracic aortic aneurysm (patient 2). Diagnostic approach and management of ischemic necrotizing pancreatitis are discussed.     

Neuron discharges in the rat auditory cortex during electrical intracortical stimulation

Cocaine and cocaine-associated cues elicit craving in addicts and reinstate cocaine-seeking behavior in rats. Craving and cocaine-seeking behavior may be mediated by withdrawal-induced changes in dopamine (DA) neurotransmission in the amygdala. To examine whether there are concomittant changes in cocaine-seeking behavior and extracellular DA levels during withdrawal, experimental rats were trained to self-administer cocaine (0.75 mg/kg i.v.). After 14 daily 3-hour training sessions, animals underwent either a 1-day, 1-week, or 1-month withdrawal period. Extracellular DA levels were assessed during baseline, extinction, cue reinstatement, and cocaine (15 mg/kg i.p.) reinstatement of cocaine-seeking behavior (i.e., defined as the difference in nonreinforced lever presses on an active minus inactive lever). Cocaine-seeking behavior became more intense during the course of cocaine withdrawal. Additionally, basal and cocaine-induced extracellular DA levels were enhanced after the 1-month withdrawal period. We suggest that the former may reflect a persistent elevation in tonic extracellular DA levels in the amygdala, whereas the latter may reflect a persistent elevation in phasic extracellular DA levels.     

Biodegradation and biocompatibility of a guided tissue regeneration barrier membrane formed from a liquid polymer material

Biodegradable barrier films were made by coagulating a solution of poly(DL-lactide) in N-methyl-2-pyrrolidone on porous polyethylene pads wetted with saline solution. The semisolid films were cut into 10 x 10 mm barriers and implanted subcutaneously in rabbits. At monthly intervals, the polymer implant sites were compared histologically to those implanted with USP negative control plastic. The polymer films were retrieved from the surrounding tissue, dried, weighed, and the changes in molecular weight determined using gel permeation chromatography. The molecular weight of the polymer decreased at a relatively constant rate over 5 months; however, no significant mass loss occurred until 5 months postimplantation. Also, no distinct histological differences were noted between the polymer barrier and the control plastic sites until 6 months when histiocytes and multinucleated giant cells showed a modest increase around fragmented polymer films. Similar barrier films also were fitted over naturally occurring buccal dehiscence defects in beagle dogs and the tissue sites compared histologically at 6 months to sham-operated control sites. New bone and dense connective tissues closely approximated segments of the remaining polymer and demonstrated the biocompatibility of the biodegradable films. Histomorphometric analyses of treated sites compared to sham controls showed that the polymer barrier is effective in promoting bone and cementum regeneration in periodontal defects in dogs.     

Completion rates and feasibility of outcome measures: experience in a multicenter clinical trial of systemic hypothermia for severe head injury

The National Acute Brain Injury Study: Hypothermia (NABIS:H) is an ongoing multicenter trial of systemic hypothermia for the treatment of severe head injury. Follow-up rates for the study's 3-and 6-month outcome assessments have been maintained at high levels by establishing close contact with family members, by reimbursing cost of travel, and by sending examiners to the subject's location whenever necessary. Two years into the study, global disability data (e.g., Glasgow Outcome Scale) have been obtained on 86% of patients due for 3-month assessment (n = 131) and for all subjects due at 6 months (n = 100). Over half of the patients have completed neuropsychological testing with high reliability ratings. These preliminary findings suggest that the procedures used to document data quality and increase follow-up and completion rates are being successful.     

Retinoblastoma-related protein pRb2/p130 and suppression of tumor growth in vivo

BACKGROUND: The RB/p105 and p107 genes of the retinoblastoma family are tumor suppressor genes whose proteins are inactivated by interaction with T-antigen proteins encoded by polyomaviruses (e.g., simian virus 40 and human JC virus), which have been found to be highly tumorigenic in animals. A variety of indirect evidence suggests that another member of the retinoblastoma gene family, RB2/p130, is also a tumor suppressor gene. To investigate the putative tumor suppressor activity of RB2/p130 more directly, we utilized a tetracycline-regulated gene expression system to control expression of the encoded protein pRb2/p130 in JC virus-induced hamster brain tumor cells and to study the effects of pRb2/p130 on the growth of such tumor cells in nude mice. The ability of pRb2/p130 to interact with JC virus T antigen was also studied. METHODS: Northern blot hybridization analyses were performed on samples of total cellular RNA to measure RB2/p130 and beta-actin messenger RNA levels. Immunoprecipitation and western blot analyses were used to determine T-antigen and pRb2/p130 protein levels and to assess the phosphorylation status of these proteins. Tumor cells were injected subcutaneously into nude mice, and tumor growth, with or without induced expression of pRb2/p130, was monitored. RESULTS: Induction of pRb2/p130 expression brought about a 3.2-fold, or 69% (95% confidence interval = 64%-73%), reduction in final tumor mass in nude mice. We also demonstrated that JC virus T antigen binds hypophosphorylated pRb2/p130 and that stimulation of pRb2/p130 expression overcomes cellular transformation mediated by this antigen. CONCLUSION: Our findings support the hypothesis that RB2/p130 is a tumor suppressor gene.     

Ritodrine- and terbutaline-induced hypokalemia in preterm labor: mechanisms and consequences

The effects of ritodrine and terbutaline on potassium homeostasis, renal function, and cardiac rhythm were assessed in women treated with these drugs for preterm labor. Timed blood and urine samples were obtained for two hours before and during six hours of intravenous ritodrine (N = 5) and terbutaline (N = 5) administered in pharmacologically equivalent doses. No differences were found in any parameters affecting potassium homeostasis or renal function between these drugs. A decrease in mean plasma potassium of 0.9 mEq/liter occurred after 30 minutes of drug infusion (4.2 +/- 0.1 to 3.3 +/- 0.1 mEq/liter, P < 0.005) before any significant changes in plasma glucose (75.0 +/- 4.7 to 93.7 +/- 6.1 mg/dl, P = NS) or plasma insulin (12.4 +/- 6.0 to 28.4 +/- 5.1 mU/ml, P = NS). The mean plasma potassium after four hours of drug infusion was 2.5 +/- 0.1 mEq/liter. Plasma insulin rose to a level known to induce cellular potassium uptake (39.2 +/- 7.7 mU/ml) after 60 minutes of drug therapy and remained at this level for four hours. Hyperlactatemia occurred at four hours (4.7 +/- 0.8 mmol/liter) and the plasma lactate/pyruvate ratio increased in a 10:1 ratio. Both drugs significantly reduced glomerular filtration rate, sodium, potassium, and chloride excretion and urinary flow rate. Changes in acid-base homeostasis, plasma aldosterone, or renal potassium excretion did not contribute to ritodrine-or terbutaline-induced hypokalemia. In 83 women with preterm labor randomly assigned to ritodrine (N = 42) or terbutaline (N = 41), the maximum decrease in plasma potassium occurred after six hours of drug infusion. During Holter monitoring, 3 of 14 women treated with ritodrine or terbutaline developed symptomatic cardiac arrhythmias at the lowest plasma potassium while no women treated with saline and morphine (N = 12) developed cardiac arrhythmias (P = 0.14). We conclude that ritodrine and terbutaline induce profound hypokalemia by stimulating cellular potassium uptake and both drugs cause significant renal sodium and fluid retention and cardiac arrhythmias. Careful monitoring of electrolytes, fluid balance, and cardiac rhythm should occur during tocolytic therapy with ritodrine or terbutaline.     

Review: JC virus infection of lymphocytes--revisited

JC virus (JCV), the causative agent of the fatal human demyelinating disease progressive multifocal leukoencephalopathy (PML), is an opportunistic papovavirus that infects and destroys oligodendrocytes, the myelin-producing cells of the central nervous system. Since its isolation from the brain of a PML patient, JCV has long been classed as a neurotropic virus. Many studies, however, have demonstrated that JCV can infect various other cell types, including immune system cells. Moreover, several recent studies have focused specifically on lymphocytes as a target of JCV. This review chronicles the association of JCV with lymphocytes, including cell type localization, molecular regulation, and viral sequences, and discusses clinical implications of these findings.