Hemodynamic effects of KRN2391 (potassium channel opener) in halothane-anesthetized dogs

The cardiovascular responses to an infusion of KRN2391, a potassium channel opener, was studied in halothane-anesthetized dogs. Intravenous administration of KRN2391 at 1.0 and 5.0 μg·kg⁻¹·min⁻¹ for 60 min produced dose-dependent decreases in mean arterial pressure (MAP) and systemic vascular resistance (SVR) associated with dose-dependent increases in the cardiac index (CI) and stroke volume index (SVI) but was not accompanied by an increase in heart rate (HR). The maximum decrease in MAP during the infusion of KRN2391 at 1.0 and 5.0 μg·kg⁻¹·min⁻¹ was −13±7% (P<0.01) and −37±10% (P<0.01), respectively. The maximum reduction in SVR after 1.0 and 5.0 μg·kg⁻¹·min⁻¹ was −20±11% (P<0.01) and −60±16% (P<0.01), respectively. A KRN2391 infusion of 1.0 and 5.0 μg·kg⁻¹·min⁻¹ increased Cl a maximum of 11±13% (P<0.05) and 65±33% (P<0.01), respectively. KRN2391 1.0 μg·kg⁻¹·min⁻¹ showed a tendency to increase SVI but this change was not significant, KRN2391 5.0 μg·kg⁻¹·min⁻¹, however, produced a significant increase in SVI. The present results demonstrate that the decrease in MAP and the increases in CI and SVI caused by KRN2391 are due to a reduction in the afterload. Therefore, we conclude that these cardiovascular profiles of KRN2391 may be benificial in perioperative uses including the control of systemic blood pressure and the treatment of hypertension during halothane anesthesia in clinical practice.     

A study of five cases of traumatic diaphragmatic rupture

During the last 5 years, 5 cases of traumatic diaphragmatic rupture were surgically treated. These cases were reported and the literature concerning traumatic diaphragmatic hernia in the last one decade in Japan, including 80 cases was studied. The purpose of this study is to discuss the most important early diagnostic tools and to consider the choice of incision and approach. The following two results were gotten. (1) Plain chest X-ray, computed tomography and ultrasonography were the most valuable diagnostic tools. (2) The choice of incision and approach depends on the stage at which the rupture is recognized (early or late), the site of rupture and associate injuries.     

Ascorbic acid prevents ischemia-reperfusion injury in the rat small intestine

Ischemia-reperfusion injury by free radicals and lipid peroxides is observed in various organs. Ascorbic acid (AsA) or glutathione (GSH) in various doses (AsA:2, 0.5, 0.1 mmol/kg, GSH:2 mmol/kg) was intraperitoneally administered to male Wistar rats. The entire small intestines were resected just before ischemia, after ischemia, and after 20 min of reperfusion (n = 7–10 at each time point). At each time point, the specimens were subjected to assays of lipid peroxides, GSH, and glutaminase activity of the tissues; they were also examined histologically. In the AsA group, the production of lipid peroxides after reperfusion was significantly suppressed in a dose-dependent manner, and the ratio of oxidized GSH to total GSH was also significantly low. Tissue glutaminase activity decreased to a lesser extent, and the degree of injury was apparently less marked in the AsA group. This study indicates that AsA acts as an antioxidant against peroxidative tissue injury, possibly by scavenging radicals, preserving reduced GSH, and reducing the peroxidative reaction. Received: 21 June 1996 Received after revision: 8 October 1996 Accepted: 12 November 1996     

Beta-blockers and primary prevention of coronary heart disease in patients with high blood pressure

We conducted a population-based, case-control study to determine whether beta-blockers, used for the treatment of hypertension, prevent first events of coronary heart disease. Cases were patients who had high blood pressure treated with medicines and who presented in 1982 to 1984 with angina or fatal or nonfatal myocardial infarction. Controls were a probability sample of health maintenance organization patients with pharmacologically treated hypertension and free of coronary heart disease. Blinded to case-control status, we reviewed the medical records of the 248 cases and 737 controls. The health maintenance organization's computerized pharmacy database was used to ascertain the use of beta-blockers. Fewer cases than controls were taking beta-blockers. This difference was confined to those with nonfatal infarctions. After adjustment for confounding, the estimated relative risk was 0.62 (95% confidence interval, 0.39 to 0.99). Higher doses of beta-blockers conferred greater protection. We conclude that beta-blockers may prevent first events of nonfatal myocardial infarction in patients with high blood pressure.     

A case of autoimmune hepatitis needed to be differentiated from EBV hepatitis, in that the histology of liver biopsy specimen was useful for diagnosis]

A 10-year-old girl with autoimmune hepatitis (AIH) was reported. She was admitted to our hospital because of cholestasis and elevation of liver enzymes for 2 months. Laboratory examination revealed that EBV-DNA copy number in the PBMNC (peripheral mononuclear cells) was 1.2 x 10(3) copies/microg of DNA, hypergammaglobulinemia, and positive antinuclear antibody, positive anti-smooth muscle antibody. The histology of her liver biopsy specimen revealed interface hepatitis, dense mononuclear cell infiltrates, mild fibrosis, and negative for EBV in situ hybridization assay indicating AIH and not EBV-associated hepatitis. She was treated firstly with methylprednisolone pulses, then will prednisolone p.o.+azathioprine p.o.. Intravenous cyclophosphamide pulse therapy was introduced because of her abnormal immune pathology. All abnormal laboratory parameters improved to normal levels within 2 months, and EBV-DNA copy number in the PBMNC became negative after 4 months. The histology of liver biopsy specimen was useful for the diagnosis of AIH in such a difficult case needed to be differentiated from EBV hepatitis.     

A clinical study of cerebral perfusion during pulsatile and nonpulsatile cardiopulmonary bypass

The purpose of this study was to determine the effect of pulsatile flow on cerebral perfusion under cardiopulmonary bypass (CPB). Twenty-three patients who underwent cardiac operations were divided into two comparable groups: Group A (N = 11) had standard nonpulsatile flow, while in Group B (N = 12), a pulsatile pump was used. The blood flow of left common carotid artery and radial arterial pressure were continuously monitored during cardiac operation in both groups and cerebral vascular resistance was calculated. In Group B, the perfusion pressure of left common carotid artery was monitored and compared with that of radial artery. Arterial and internal jugular venous blood were sampled and the difference of cerebral A.V O2 contents and cerebral oxygen consumption was calculated. Cerebral vascular resistance in Group B (54.0 +/- 11.2% of the value of before-CPB) significantly decreased compared to that in Group A (72.2 +/- 11%) at the end of CPB (p less than 0.05). Pulse pressure following pulsatile CPB flow was 15.1 +/- 5.8 mmHg monitored in radial artery and it reduced to 8.5 +/- 5 mmHg in left common carotid artery. Although there was no significant difference in cerebral oxygen consumption of both groups during and just after CPB, the difference of cerebral A-V O2 contents of Group B was greater than Group A just after CPB. These data suggest that pulsatile flow may minimize the cerebral microcirculatory shunt during CPB, resulting from the reduction of cerebral vascular resistance.     

Participation of rat liver cytochrome P450 2E1 in the activation of N-nitrosodimethylamine and N-nitrosodiethylamine to products genotoxic in an acetyltransferase-overexpressing Salmonella typhimurium strain (NM2009).

The possible roles of cytochrome P450 (P450) enzymes in the metabolic activation of N-nitrosodimethylamine (NDMA) and N-nitrosodiethylamine (NDEA) by rat liver microsomes have been examined in a system containing the bacterial tester strain Salmonella typhimurium NM2009, a newly developed strain showing high O-acetyltransfer activities. The DNA-damaging activity could be determined by measuring expression of the umu gene in a plasmid containing the fused umuC-lacZ gene construct in the bacteria. The following lines of evidence support the view that both NDMA and NDEA are principally oxidized to reactive products by P450 2E1 in rat liver microsomes. First, NDMA and NDEA were activated by rat liver microsomes in a protein- and substrate-dependent manner and the former chemical was more active than the latter; both activities were induced in rats treated with P450 2E1 inducers such as ethanol, acetone and isoniazid and by starvation. Second, activation of NDMA and NDEA were both inhibited significantly by antibodies raised against rat P450 2E1 and by P450 2E1 inhibitors such as diethyldithiocarbamate and 4-methylpyrazole in rat liver microsomes. Finally, in reconstituted monooxygenase systems containing purified rat P450 enzymes, P450 2E1 gave the highest rates of the activation of both NDMA and NDEA; the addition of rabbit cytochrome b5 to the system caused about a 1.5-fold increase in both reactions. In separate experiments we also found that N-nitrosomethylacethoxymethylamine, a compound that reacts with DNA after ester cleavage, is more genotoxic in S.typhimurium NM2009 than in S.typhimurium NM2000, a strain that is defective in O-acetyltransferase activity. Part of the pathway involved in the activation of nitrosamines is suggested to be acetylation of alkyldiazohydroxides formed by P450 or acetylesterase, because the genotoxic activity of N-nitrosomethylacethoxymethylamine in S.typhimurium NM2009 could be inhibited by the O-acetyltransferase inhibitor pentachlorophenol. These results indicate that NDMA and NDEA are oxidized to gentoxoic products by rat liver microsomes and that a P450 2E1 enzyme plays a major role in the activation of these two potent carcinogens. The activation pathway of N-nitrosodialkylamines through acetylation by O-acetyltransferase has been proposed. This simple bacterial system for measuring genotoxicity should facilitate studies on the activation of N-nitroso alkylamines.     

Preoperative evaluation of endometrial carcinoma by selective hysterography: a preliminary report

Using a new instrument designed by the Authors having two cannulas to allow filling of a contrast medium exclusively in the cervical canal and uterine cavity, selective hysterography was performed for 22 cases of endometrial carcinoma. This method was useful not only for evaluation of the size, location and growth patterns but also for estimation of the cervical involvement of endometrial carcinoma.     

Predictive validity of certification by the American Board of Internal Medicine

STUDY OBJECTIVE: To determine the predictive validity of the American Board of Internal Medicine (ABIM) certification process. DESIGN: Prospective measurement of the knowledge, skills, and attitudes of 185 ABIM-certified and 74 noncertified internists by a written examination; evaluation by professional associates; a patient questionnaire assessing satisfaction with care, physician's counseling role, and preventive care; and review of records of patients with common illnesses. SUBJECTS: Practicing internists who completed training or received ABIM certification 5 to 10 years previously. SETTING: Office-based practices in six western states. RESULTS OF DATA ANALYSIS: Physicians certified by the ABIM had significantly higher scores on the written examination than the noncertified physicians, and scores on our examination correlated highly with the ABIM certification examination (r = 0.73). Ratings of clinical skills by professional associates were significantly higher for certified internists and also correlated highly with ABIM examination scores (r = 0.53 to 0.59). Regression analysis showed that ABIM certification status was the major variable affecting performance on these measures of clinical competence. Results from other measures did not show many differences between certified and noncertified physicians in the care of patients with common illnesses, but modest differences in preventive care and a few differences in outcome favored the certified physicians. CONCLUSIONS: Comparison of findings from the written examination and the professional associate ratings with certification status and original ABIM certification examination scores shows predictive validity of ABIM certification. Further studies are needed to determine if certification status predicts important differences in the care of patients with complex illnesses.     

Moment analysis of drug disposition in kidney. II: Urine pH-dependent tubular secretion of tetraethylammonium in the isolated perfused rat kidney

Effects of urine pH on the renal tubular secretion of an organic cation (tetraethylammonium, TEA) and an organic anion (p-aminohippurate, PAH) were investigated using the isolated erythrocyte-perfused rat kidney. The method was based on a multiple indicator dilution experiment and noncompartmental moment analysis. Treatment with sodium bicarbonate and sodium dihydrogen phosphate increased and decreased urine pH, respectively, but affected neither the condition of the perfused kidney nor the renal handling of albumin and inulin. In TEA studies, the increase of urine pH prolonged the mean residence time in renal epithelial cells (T cell) and reduced the apparent secretion intrinsic clearance, but did not influence the volume of distribution in the kidney (Vd drug). The decrease of urine pH did not affect these kinetic parameters. By contrast, PAH secretion was constant against the change of urine pH. Since any change in the basolateral membrane transport is reflected in Vd drug, the net transport from blood to cells can be regarded as similar under these treatments. On the other hand, the prolonged T cell of TEA with the increased urine pH suggested a slow transport from cells to lumen across the brush-border membranes. The present results coincide with the hypothetical mechanism that organic cations are secreted via an active transport system, coupled to the countertransport of H+ into cells. In conclusion, the present method is useful to separately evaluate the transmembrane transport across both sides of the renal epithelial cells in a morphologically intact kidney.