Cardiovascular pharmacology of SKP-450, a new potassium channel activator, and its major metabolites SKP-818 and SKP-310

The cardiovascular effects of SKP-450, a newly synthesized potassium channel activator, and its two major metabolites SKP-818 and SKP-310 were evaluated on isolated rat aorta and in freely moving rats and anesthetized beagle dogs. The rank order of potency in relaxing rat aorta precontracted with norepinephrine was SKP-450 > SKP-818 > Lemakalim > SKP-310 (EC50: 0.12, 0.55, 0.71 and 5.89 mumol/l, respectively). In rats, SKP-450, SKP-818 and lemakalim (3-100 micrograms/kg, i.v.) induced a dose-dependent decrease in mean arterial pressure (MAP; ED20: 9.8, 11.7 and 22.4 micrograms/kg, respectively) followed by reflex tachycardia. In dogs, SKP-818 and SKP-310 (0.3-1,000 micrograms/kg, i.v.) had quite similar hemodynamic profiles to SKP-450 but with a smaller potency. SKP-450, SKP-818 and SKP-310 dose-relatedly decreased MAP (ED20: 2.6, 4.2 and 588.8 micrograms/kg, respectively). They slightly increased left ventricular positive dP/dtmax with a transient decrease at the highest dose, while inducing a dose-related decrease in rate-pressure product, tension time index and systolic time. SKP-450, SKP-818 and SKP-310 induced a marked dose-dependent increase in coronary blood flow (Emax: 172.8, 257.9 and 178.7%, respectively) with less effects on blood flow through other arteries. Glybenclamide antagonized all the hemodynamic effects of SKP-450 in rats and dogs, whereas propranolol antagonized its reflex tachycardia in rats. These results indicate that SKP-450 is a potent coronary and peripheral vasodilator in rats and dogs activating ATP-sensitive potassium channels and that SKP-818 and SKP-310 exert a similar hemodynamic profile to the parent compound with equi- and weaker potency, respectively.     

The SOCS proteins: a new family of negative regulators of signal transduction

An asymptomatic tumor in the pelvis was incidentally found by ultrasonography in a 67-year-old woman while being examined after presenting with a common cold. Further examinations revealed a presacral cystic tumor, which measured 10 x 12cm in size. The cyst was thus removed in the normal manner for such cases. The pathological diagnosis was an epidermoid cyst. An analysis of 15 other cases previously reported in the literature indicated that large epidermoid cysts should normally be excised through an abdominal approach alone, provided that the tumor is benign.     

Measurement of cerebral blood flow during cardiopulmonary bypass with near-infrared spectroscopy

OBJECTIVES: We sought to assess the incidence and clinical relevance of examination data to recurrent ischemia within an international randomized trial. BACKGROUND: Ischemic symptoms commonly recur after thrombolysis for acute myocardial infarction. METHODS: Patients (n = 40,848) were prospectively evaluated for recurrent angina and transient electrocardiographic (ECG) or hemodynamic changes. Five groups were developed: Group 1, patients with no signs or symptoms of recurrent ischemia; Group 2, patients with angina only; Group 3, patients with angina and ST segment changes; Group 4, patients with angina and hemodynamic abnormalities; and Group 5, patients with angina, ST segment changes and hemodynamic abnormalities. Baseline clinical and outcome variables were compared among the five groups. RESULTS: Group 1 comprised 32,717 patients, and Groups 2 to 5 comprised 20% of patients (4,488 in Group 2; 3,021 in Group 3; 337 in Group 4; and 285 in Group 5). Patients with recurrent ischemia were more often female, had more cardiovascular risk factors and less often received intravenous heparin. Significantly more extensive and more severe coronary disease, antianginal treatment, angioplasty and coronary bypass surgery were observed as a function of ischemic severity. The 30-day reinfarction rate was 1.6% in Group 1, 6.5% in Group 2, 21.7% in Group 3, 13.1% in Group 4 and 36.5% in Group 5 (p < 0.0001); in contrast, the 30-day mortality rate was significantly lower (p < 0.0001) in Groups 1, 2 and 3 (6.6%, 5.4% and 7.7%, respectively) than in Groups 4 and 5 (21.8% and 29.1%). CONCLUSIONS: Postinfarction angina greatly increases the risk of reinfarction, especially when accompanied by transient ECG changes. However, mortality is markedly increased only in the presence of concomitant hemodynamic abnormalities.     

Videolaparoscopic access in the surgical treatment of colorectal cancer: critical analysis]

Clozapine was approved by the U.S. Food and Drug Administration in 1989 for treatment of severely ill schizophrenic patients. It has activity against both the positive and negative symptoms of schizophrenia, which has made it an alternative to traditional antipsychotic medications such as haloperidol. However, clozapine must be used cautiously due to its side effect profile. These side effects include agranulocytosis, seizures, and cardiorespiratory symptoms. We report the case of a patient who developed polyserositis (pericardial effusion, pleural effusion, and pericarditis) after being started on clozapine, and whose symptoms remitted upon discontinuation of clozapine. The literature is reviewed and the treatment implications are discussed.     

SAMSON: a software package for the biopolymer primary structure analysis

One hundred and twenty seven patients belonging to Neurosurgery (49), Neuromedicine (48), Cardiac medicine (30) wards and Blood donors (30) as healthy controls were investigated for the prevalence of Toxoplasmosis by means of detecting specific IgM antibody against Toxoplasma gondii (T. gondii) employing Enzyme Immuno Assay (EIA). The detection rate of specific IgM antibody against T.gondii was found to be 32.7% (16/49) among Neurosurgery patients, 20.8% (10/48) among Neuromedical patients and 20% (6/30) among Cardiac medical patients. None of the voluntary blood donors tested was found to have T. gondii IgM antibody. Maximum prevalence rate was found among female patients undergoing Neurosurgery (42.3%) followed by Neuromedical patients (40%). There is an increasing rate of prevalence of Toxoplasmosis from the lower age group upto thirty years and a declining prevalence rate among the higher age groups. The present study revealed high prevalence rate of Toxoplasmosis in Neurosurgery patients (32.7%) and in particular among female (35.2%) than male (17.8%) patients.     

Carcinoma of the esophagus and esophagogastric junction: sensitivity of radiographic diagnosis

OBJECTIVE: The purpose of this study was to determine the sensitivity of barium studies in revealing carcinoma of the esophagus and esophagogastric junction. MATERIALS AND METHODS: We retrospectively reviewed 50 cases of squamous cell carcinoma of the esophagus (n = 25) and adenocarcinoma of the esophagus (n = 14) or esophagogastric junction (n = 11) in which double-contrast (n = 46) or single-contrast (n = 4) barium studies had been done. The original radiology reports were reviewed to determine whether the lesions had been seen on barium studies and whether cancer had been diagnosed. Records were also reviewed to determine the number of patients who underwent esophageal endoscopy because of findings suggestive of cancer on barium studies at some point from January 1992 through December 1992. Pathology records were then reviewed to determine the number of true- and false-positive barium studies during this same period. RESULTS: Lesions were shown on barium studies in 49 (98%) of 50 patients, and carcinoma of the esophagus or esophagogastric junction was diagnosed or suspected in 48 patients (96%). In a separate part of the study, we found that endoscopy had been recommended to rule out malignant tumor in only 26 (1%) of 2484 patients who underwent barium studies at some point from January 1992 through December 1992. Endoscopy revealed cancer in 11 of those 26 patients; the remaining 15 were assumed to have false-positive radiologic examinations. Barium studies therefore had a positive predictive value of 42%. CONCLUSION: The double-contrast barium study is a sensitive technique for the diagnosis of carcinoma of the esophagus and esophagogastric junction. This high sensitivity can be achieved while recommending endoscopy in only about 1% of all patients who undergo barium studies.     

Endothelium-medicated control of the coronary circulation. Exercise training-induced vascular adaptations

This review discusses the role of the endothelium in the regulation of coronary vascular function. The role of endothelium-mediated mechanisms at rest, during exercise, in exercise training-induced adaptations of coronary function and in the presence of coronary heart disease (CHD) are examined. Mechanisms of control of coronary blood flow are briefly discussed with emphasis on endothelium-mediated control of vascular resistance. The concept that the relative importance of vascular control mechanisms differs as a function of position along the coronary arterial tree is developed and discussed. Metabolic, myogenic and endothelium-mediated control systems contribute in parallel to regulating coronary blood flow. The relative importance of these mechanisms varies throughout the coronary arterial tree. Endothelium-dependent vasodilation contributes to maintenance of resting coronary blood flow but the endothelium's role in dilation of small resistance arteries, thereby increasing coronary blood flow during exercise, remains in question. In contrast, the endothelium plays an essential role in dilation of the conduit coronary arteries during exercise. Atherosclerosis and CHD convert this exercise-induced dilation to a vasoconstriction, apparently due to endothelium dysfunction. Long term increases in physical activity and exercise training alter the control of coronary blood flow. Adaptations in endothelium-mediated control play a role in these changes. However, the effects of the mode, frequency, and intensity of exercise training bouts and duration of training on adaptive changes in endothelial function have not been established. The role of the endothelium in control of the permeability characteristics of the exchange vessels in the coronary circulation is discussed. Current evidence indicates that vascular permeability is a dynamic characteristic of the vessel wall that is controlled, at least in part, by endothelium-dependent phenomena. Also, preliminary results indicate that exercise training alters microvessel permeability and the control of permeability in the coronary circulation. Further research is needed to provide clarification of the effects of exercise training on coronary endothelial control of vascular resistance and vascular permeability in atherosclerosis and CHD.     

Increased nitric oxide deactivation by polymorphonuclear leukocytes in patients with intermittent claudication

PURPOSE: Local activation of polymorphonuclear leukocytes (PMNLs) is considered an important aspect of the pathogenesis of intermittent claudication, although concrete mechanisms of their effects on circulatory homeostasis in peripheral atherosclerotic disease remain unclear. This study evaluated the ability of PMNLs to deactivate nitric oxide (NO), a key regulator of regional circulation, as a possible factor determining PMNL involvement into ischemic disorders in patients who have intermittent claudication before and after vascular reconstruction. METHODS: A total of 57 patients who had peripheral occlusive disease in an aortofemoral segment before surgical treatment (group 1) and 65 patients who had similar occlusive lesions and other clinical and demographic data 6 to 12 months after undergoing inflow vascular reconstruction (group 2) were examined. All patients from group 2 had anatomically patent grafts; their satisfaction and level of function after surgical treatment were assessed by a five-point questionnaire. The sex- and age-matched control group included 35 subjects. NO activity was bioassayed by measuring its ability to increase cyclic guanosine monophosphate (cGMP) accumulation in rat fetal lung-cultured fibroblasts (RFL-6 cells). The ability of PMNLs to deactivate NO was characterized as the percent decrease in NO-induced cGMP accumulation in RFL-6 cells. RESULTS: Stimulated PMNLs caused inhibition of the activity of authentic NO; accumulation of cGMP induced by sodium nitroprusside was not affected. PMNLs from patients with peripheral atherosclerotic disease either before or after vascular reconstruction had a more marked capacity of NO inactivating than the cells from healthy subjects. For both groups of patients, levels of PMNL-induced NO deactivation were higher for patients with diabetes, and especially both diabetes and arterial hypertension. For both groups of patients, there was no correlation between levels of PMNL-induced NO deactivation and resting ankle-brachial indexes (ABIs). In contrast, close correlation was revealed between levels of PMNL-induced NO deactivation and postexercise ABIs and percent decrease in resting ABIs after exercise in patients evaluated either before or after surgical treatment. CONCLUSIONS: The ability of stimulated PMNLs to deactivate NO is elevated in peripheral occlusive disease and may be implicated in the pathogenesis of intermittent claudication. In patients who underwent successful recanalization of magistral arteries, levels of PMNL-induced NO deactivation remained higher than in control subjects. The increase in the ability of PMNL to deactivate NO positively correlated to ABI decreases after exercise in patients with peripheral occlusive disease either before or after surgical treatment.     

Magnesium transport across the basolateral plasma membrane of the fish enterocyte

The aim of the study was to assess the influence of aortic valve replacement on left ventricular size and muscle hypertrophy according to the type of preexisting valve disease (aortic stenosis, insufficiency or combined disease). The study group consisted of 143 consecutive patients (pts) after aortic valve replacement (109 men, 34 women, mean age 48.1 +/- 10.9 years). Reason for the operation was aortic stenosis in 35 pts, aortic insufficiency in 64 pts and combined disease in 44 pts. Echocardiography was performed before surgery, 1 month and 1 year after operation, and yearly during 5-year follow-up. Transvalvular aortic pressure gradients decreased significantly after valve replacement in all subsets without further changes during follow-up (Pmax (mmHg): from 54.2 +/- 20.7 to 17.9 +/- 9.6 in combined disease pts, from 72.3 +/- 19.9 to 21.6 +/- 14.6 in aortic stenosis and from 34.5 +/- 24.2 to 15.6 +/- 11.3 in aortic insufficiency pts, respectively, P < 0.0005). One year after surgery the diastolic dimension of the left ventricle decreased significantly in all subjects, whereas the systolic dimension only in aortic insufficiency and combined disease pts (from 44 +/- 11.8 to 31.6 +/- 5.4 mm, P < 0.001 and from 41.9 +/- 11.5 to 33 +/- 6.7 mm, P < 0.05, respectively). Further decrease of both diastolic and systolic dimensions was observed only in the aortic insufficiency group. Ejection fraction of left ventricle increased only in combined disease pts (from 51.6 +/- 10% to 56.8 +/- 8.2%, P < 0.05). Wall thickness of the left ventricle decreased 1 year after valve replacement only in the aortic stenosis group and in further follow-up in the aortic stenosis and combined disease group. Normalization of left ventricular size is observed in more than 90% of patients during 5-year follow-up as opposed to left ventricular muscle hypertrophy, regressed only in less than a half of the study population. In patients with aortic valve disease the greatest hemodynamic improvement is observed 1 year after valve replacement. This is expressed by marked reduction of the left ventricular dimensions and wall thickness, without significant improvement of the ejection fraction. Further regression of left ventricle dimensions occurs in patients operated on due to predominant valve insufficiency, whereas regression of left ventricular hypertrophy is observed in patients with preexisting valvular stenosis.