Thrombomodulin Attenuates Inflammatory Damage Due to Liver Ischemia and Reperfusion Injury in Mice in Toll-Like Receptor 4-Dependent Manner.

Liver ischemia reperfusion injury (IRI) is an important problem in liver transplantation. Thrombomodulin (TM), an effective drug for disseminated intravascular coagulation, is also known to exhibit an anti-inflammatory effect through binding to the high-mobility group box 1 protein (HMGB-1) known as a proinflammatory mediator. We examined the effect of recombinant human TM (rTM) on a partial warm hepatic IRI model in wild-type (WT) and toll-like receptor 4 (TLR-4) KO mice focusing on the HMGB-1/TLR-4 axis. As in vitro experiments, peritoneal macrophages were stimulated with recombinant HMGB-1 protein. The rTM showed a protective effect on liver IRI. The rTM diminished the downstream signals of TLR-4 and also HMGB-1 expression in liver cells, as well as release of HMGB-1 from the liver. Interestingly, neither rTM treatment in vivo nor HMGB-1 treatment in vitro showed any effect on TLR-4 KO mice. Parallel in vitro studies have confirmed that rTM interfered with the interaction between HMGB-1 and TLR-4. Furthermore, the recombinant N-terminal lectin-like domain 1 (D1) subunit of TM (rTMD1) also ameliorated liver IRI to the same extent as whole rTM. Not only rTM but also rTMD1 might be a novel and useful medicine for liver transplantation. This is the first report clarifying that rTM ameliorates inflammation such as IRI in a TLR-4 pathway-dependent manner.

Impact of Subnormothermic Machine Perfusion Preservation in Severely Steatotic Rat Livers: A Detailed Assessment in an Isolated Setting.

The current drastic shortage of donor organs has led to acceptance of extended-criteria donors for transplantation, despite higher risk of primary nonfunction. Here, we report the impact of subnormothermic machine perfusion (SMP) preservation on the protection of >50% macrosteatotic livers. Dietary hepatic steatosis was induced in Wistar rats via 2-day fasting and subsequent 3-day re-feeding with a fat-free, carbohydrate-rich diet. This protocol induces 50-60% macrovesicular steatosis, which should be discarded when preserved via cold storage (CS). The fatty livers were retrieved and preserved for 4 h using either CS in histidine-tryptophan-ketoglutarate or SMP in polysol solution. Graft functional integrity was evaluated via oxygenated ex vivo reperfusion for 2 h at 37°C. SMP resulted in significant reductions in not only parenchymal alanine aminotransferase (p < 0.001), but also mitochondrial glutamate dehydrogenase (p < 0.001) enzyme release. Moreover, portal venous pressure (p = 0.047), tissue adenosine triphosphate (p = 0.001), bile production (p < 0.001), high-mobility group box protein-1 (p < 0.001), lipid peroxidation, and tissue glutathione were all significantly improved by SMP. Electron microscopy revealed that SMP alleviated deleterious alterations of sinusoidal microvasculature and hepatocellular mitochondria, both of which are characteristic disadvantages associated with steatosis. SMP could protect 50-60% macrosteatotic livers from preservation/reperfusion injury, and may thus represent a new means for expanding available donor pools.

Surgical management of a double-chambered right ventricle and chylothorax in a Labrador retriever.

A 22-month-old, male Labrador retriever was presented with anorexia, dyspnoea, and fainting. The dog was diagnosed with a double-chambered right ventricle and tricuspid valve dysplasia using echocardiography and cardiac catheterisation. A marked bilateral pleural effusion was also present and chemical analysis of the fluid confirmed the diagnosis of chylothorax. Using echocardiography, a pressure gradient of 87.1 mmHg was found between the proximal and distal chambers of the double-chambered right ventricle. Initiation of cardiopulmonary bypass allowed the anomalous muscle bundle that divided the right ventricle into two chambers to be resected via a right ventriculotomy. The fainting completely resolved postoperatively, and this treatment seemed quite effective in the reduction of pressure overload ascribable to ejection disturbance. Because the tricuspid dysplasia was not corrected in the first operation, the postoperative chyle effusion was reduced but did not cease. A combination of thoracic duct ligation and passive pleuroperitoneal shunting was effective in the resolution of the chyle effusion.

Surgical correction of ventricular septal defect with aortic regurgitation in a dog.

An 8-month-old entire Miniature Dachshund, weighing 4.2 kg, was presented for examination following delvelopment of a cough. Ventricular septal defect had been diagnosed tentatively in its infancy on the basis of a cardiac murmur detected by auscultation and echocardiography. Echocardiography using a B mode right parasternal long-axis view showed a defect at the atrioventricular junction and a thickened cusp of the aortic valve prolapsing into the defect. Colour-flow Doppler showed shunt blood flow across the defect at the level of the atrioventricular junction, from left to right. The sinus of Valsalva was dilated, with turbulent blood flow. Aortic regurgitation was also observed. Cardiac catheterisation studies confirmed the diagnosis of a supracristal ventricular septal defect with aortic regurgitation. Despite medication with digoxin, enalapril and aminophylin, started from the first admission, left ventricular internal dimensions gradually increased, and fractional shortening of the left ventricle gradually decreased. Surgery, with the aid of extracorporeal circulation, to close the ventricular septal defect, was performed 1 year after the initial examination. The aortic valve was left untreated. Postoperatively, the systolic murmur disappeared. Shunt flow from the left to the right ventricle was no longer observed on echocardiography, however there was still a small amount of aortic regurgitation during diastole visualised with colour-flow Doppler echocardiography. The prolapse of the cusp of the aortic valve on B-mode echocardiography was no longer observed and thickening of the cusp had not progressed. Left ventricular function measurement using M mode echocardiography showed a reduced left ventricular volume overload with reduced left ventricular internal dimensions and increased fractional shortening. The cough was relieved and no follow-up medication was scheduled. Early surgical closure of the ventricular septal defect improved the patient's condition and controlled prolapse and thickening of the aortic valve.

Surgical correction of cor triatriatum dexter in a dog under extracorporeal circulation.

A shiba inu dog with marked abdominal distension was diagnosed with cor triatriatum dexter and surgical correction was performed under extracorporeal circulation. The total duration of cardiac arrest was 11 minutes and total perfusion time was 34 minutes. The dog had an uneventful postoperative recovery. Postoperative contrast radiography of the caudal vena cava revealed normal flow into the right heart. Abdominal distension was no longer observed. Although several methods have been used to treat cor triatriatum dexter in dogs, the authors consider surgical correction under extracorporeal circulation to be a reliable approach.

Calorie restriction reduced blood pressure in obesity hypertensives by improvement of autonomic nerve activity and insulin sensitivity.

Association between obesity and hypertension has been well recognized. A reduction in the body weight of over-weight hypertensive patients is a recommended lifestyle modification. The purpose of our study is to examine the relationship of insulin sensitivity and autonomic nervous activity with reduction of blood pressure by the calorie restriction. We evaluated the heart rate variability, nocturnal change of blood pressure and insulin resistance before and after a short-term low-calorie diet in 12 overweight essential hypertensives. After a week of standard diet (2000 kcal), 2 weeks of low-calorie diet (800 kcal) with normal sodium content induced a significant reduction in body mass index, triglyceride, fasting immunoreactive protein, homeostasis model assessment as an index of insulin resistance, and urinary excretion of sodium and potassium. Systolic blood pressure was significantly reduced both in daytime and night-time after the low-calorie diet (daytime, 134.5+/-6.0 to 122.0+/-4.1 mmHg; night-time, 126.8+/-5.2 to 113.4+/-7.2 mmHg). In daytime, diastolic blood pressure was also reduced (90.3+/-2.1 to 88.1+/-4.8 mmHg). Although heart rate was not significantly reduced, a rise of high frequency in night-time (346+/-82 to 572+/-108 ms2) and a fall of low frequency/high frequency in day-time (3.5+/-0.4 to 2.6+/-0.1) was significant after a low-calorie diet. In conclusion, weight loss by low-calorie diet with a constant intake of sodium, reduced blood pressure in obese hypertensives by improvement of vagal nervous activity and insulin resistance.

Plasma digoxin concentration in dogs with mitral regurgitation.

Fifteen and eight mature beagles, without (normal group) and with experimental mitral regurgitation (MR group), respectively, were given 0.02 mg/kg/day digoxin powder for 10 days orally. The optimum time for sample collection after administration of digoxin was observed to be 8-18 hr and 10-22 hr in the normal and MR groups, respectively. In both groups, a stable concentration was reached after 3-5 days of treatment. No differences in plasma level were observed between sexes. The optimum concentration of digoxin was attained at an earlier stage than has been previously reported for both dogs and humans.

Comparison of properties of slow pathway potential between successful and unsuccessful radiofrequency applications in patients who underwent catheter ablation for atrioventricular nodal reentrant tachycardia.

Findings concerning selective slow pathway radiofrequency ablation for atrioventricular nodal reentrant tachycardia (AVNRT) using the slow pathway potential (SPP) guided method are reported. The electrogram at the SPP recording site showed double potentials consisting of the atrial potential (A) and SPP. However, SPP is usually recorded widely in the right atrial posteroseptal region. To examine whether there was any characteristic marker in the electrogram at the SPP recording site specific to successful RF application, the properties of SPP and its anatomical locations in both successful (S) (38 sites) and unsuccessful (UN) (28 sites) application sites were analyzed in 38 patients who underwent SPP-guided ablation. The distance between the upper margin of the coronary sinus ostium (UCSO) and the ablation catheter (ABL) (DUCSO-ABL) was shorter in S than in UN (2.3 +/- 6.3 mm vs. 9.0 +/- 5.2 mm below the level of UCSO, p < 0.001). The interval between A and SPP (A-SPP) was longer in S than in UN (44.2 +/- 9.9 msec vs. 24.0 +/- 7.0 msec, p < 0.001). RF applications at the more anterior sites with longer A-SPP were more successful than at other sites. The sensitivity and specificity of A-SPP (more than 40 msec) were superior to those of DUCSO-ABL (within 5 mm) as the marker for the successful application (sensitivity; 73.7% v.s. 68.4%, specificity; 100% v.s. 82.1%, respectively). In conclusion, the sites with longer A-SPP might be specific for successful ablation.

Vitamin D receptor gene polymorphism is associated with serum total and ionized calcium concentration.

Restriction fragment length polymorphisms of the vitamin D receptor gene have recently been reported to be associated with changes in bone mineral density. Alterations in systemic calcium balance and Ca-regulating hormones such as 1,25(OH)2 vitamin D3 and parathyroid hormone have been demonstrated in essential hypertension. We investigated the relationship between polymorphisms of the vitamin D receptor gene and systemic Ca metabolism in patients with essential hypertension and in normotensives. We compared 147 subjects with essential hypertension and 100 normotensive control subjects. The genotype distribution and derived allele frequencies for the vitamin D receptor gene were similar in the two groups (genotype bb/Bb/BB and allele B/b: 60.1/32.6/7.2 and 0.24/0.76 in hypertensives vs. 56.0/36.0/8.0 and 0.26/0.74 in normotensive subjects). Serum concentrations of total Ca in the bb, Bb, and BB groups were, respectively, 4.5+/-0.3 vs. 4.5+/-0.4 vs. 4.4+/-0.5 mmol/l in normotensives and 4.6+/-0.3 vs. 4.6+/-0.4 vs. 4.4+/-0.5 mmol/l in hypertensives. Ionized Ca levels were 1.17+/-0.04 vs. 1.16+/-0.04 vs. 1.15+/-0.04 mmol/l in normotensives and 1.16+/-0.04 vs. 1.16+/-0.04 vs. 1.14+/-0.05 mmol/l in hypertensives, respectively. These results indicate that the BB genotype of the vitamin D receptor gene is associated with lower serum Ca levels but is not a useful predictive marker for the development of essential hypertension in Japanese subjects.

The role of nitric oxide in bradykinin-induced dilation of coronary resistance vessels in patients with hypercholesterolemia.

OBJECT: In hypercholesterolemic patients, acetylcholine- and substance P-mediated endothelium-dependent dilation of the coronary resistance vessels is impaired due to decreased nitric oxide production. However, it is not clear if bradykinin-induced coronary vasodilation is impaired in these patients. We investigated whether the endothelium-dependent dilation of coronary resistance vessels mediated by bradykinin is impaired in patients with hypercholesterolemia and, if so, whether this impairment is caused by a decreased production of nitric oxide. METHODS: We examined the coronary vascular responses to acetylcholine and bradykinin. The vascular responses to bradykinin were also assessed after N(G)-monomethyl-L-arginine was infused to inhibit nitric oxide production. Drugs were infused into the left coronary ostium and coronary blood flow (CBF) and coronary vascular resistance were evaluated by quantitative angiography and Doppler flow velocity measurements. PATIENTS: Twelve hypercholesterolemic patients and 11 control patients with angiographically normal coronary arteries were studied. RESULTS: The vasodilator responses to acetylcholine and bradykinin were reduced in hypercholesterolemic patients compared with control patients (p<0.005 and p<0.04, respectively, by two-way analysis of variance (ANOVA)). The CBF responses to acetylcholine and bradykinin were significantly correlated (r=0.56; p<0.01). Bradykinin-induced dilation was similar in hypercholesterolemic patients and control patients after inhibition of nitric oxide. CONCLUSION: These results suggest that the bradykinin-mediated endothelium-dependent dilation of coronary resistance vessels may be impaired due to depressed nitric oxide production in patients with hypercholesterolemia.

Adenosine 5'-triphosphate induced dilation of human coronary microvessels in vivo.

OBJECT: This study was performed to compare the coronary microvascular response to adenosine 5'-triphosphate (ATP) with the response to adenosine in humans. METHODS: Coronary blood flow velocity was determined using a Doppler flow wire. After intracoronary nitroglycerin infusion, intracoronary bolus injections of adenosine (20 microg) and ATP (20 microg) were performed to induce reactive hyperemia. PATIENTS: Twenty-nine patients (23 men and 6 women, mean age: 63+/-9 years) with coronary artery disease and risk factors for coronary atherosclerosis were studied. RESULTS: Coronary flow reserve in response to ATP was similar to that for adenosine (2.7+/-0.7 vs. 2.7+/-0.7). However, the duration of ATP-induced vasodilation was longer than that of adenosine-induced dilation (39+/-25 seconds vs. 26+/-12 seconds, p<0.0001). The coronary flow reserve obtained with either ATP or adenosine was significantly reduced in the interventioned arteries compared with non-stenosed arteries. The coronary flow reserve obtained with ATP was similar to that obtained with adenosine in both artery groups. The duration of the vasodilator effect of ATP was significantly greater than that of adenosine in both artery groups. CONCLUSION: These results suggest that ATP induces maximal dilation of coronary microvessels, most likely through an endothelium-independent mechanism. The degradation of ATP to adenosine 5'-monophosphate (AMP) and adenosine, as well as the direct action of ATP on A2-adenosine receptors may be responsible for the dilation. We conclude that coronary flow reserve can be determined safely with intracoronary ATP administration.

Idiopathic verapamil-sensitive left ventricular tachycardia complicated by right ventricular outflow tract ventricular tachycardia and ventricular fibrillation.

Idiopathic ventricular tachycardias (VTs) are generally divided into those arising from the right ventricle and those arising from the left ventricle. There has been few reports of two morphologically distinct VT occurring in patients with no apparent structural heart disease. We report a patient with verapamil-sensitive left VT with a right bundle branch block pattern that spontaneously changed to VT with a left bundle branch block pattern. Ventricular fibrillation was induced by the application of programmed stimulation. Although it is unclear if our patient with pleomorphic VT has ventricular vulnerability, it is necessary to investigate further and follow him carefully.

Relation between QT dispersion and adenosine triphosphate stress thallium-201 single-photon emission computed tomographic imaging for detecting myocardial ischemia and scar.

It is not known if QT dispersion is useful for detecting coronary artery disease. We investigated whether QT dispersion at baseline and during adenosine triphosphate (ATP) infusion correlate with the imaging patterns obtained from ATP stress thallium-201 single-photon emission computed tomography (ATP-SPECT). QT dispersion was determined in 169 patients who underwent ATP-SPECT from 12-lead electrocardiograms obtained at baseline and 3 minutes after the beginning of ATP infusion. Based on the results of ATP-SPECT, patients were divided into 4 groups: normal (n = 55), ischemia (n = 38), ischemia and scar (n = 42), and scar (n = 34). Baseline QT dispersions (mean +/- SD) in the normal, ischemia, ischemia and scar, and scar groups were 48 +/- 15, 50 +/- 17, 69 +/- 25, and 70 +/- 24 ms, respectively. Baseline QT dispersion was significantly greater in the groups with myocardial scar. QT dispersions during ATP infusion were 43 +/- 16, 63 +/- 20, 76 +/- 20, and 62 +/- 25 ms in the normal, ischemia, ischemia and scar, and scar groups, respectively. QT dispersion increased with ATP infusion in patients with myocardial ischemia. QT dispersion at baseline and during ATP infusion correlated with the ATP-SPECT imaging pattern. These findings suggest that baseline QT dispersion and ATP-induced changes in QT dispersion may help detect the presence of myocardial ischemia and scar.

Vasomotility and nitric oxide bioactivity of the bridging segments of the left anterior descending coronary artery.

We compared bridging and nonbridging coronary artery segments with respect to the vasoconstrictor effect of acetylcholine. Bridging segments were hypersensitive to the constrictor effect of acetylcholine, and results suggest that the effect of nitric oxide on the acetylcholine-stimulated condition is decreased, or that the smooth muscle sensitivity to acetylcholine is increased.

Frequency-dependent electrophysiologic properties of ventricular repolarization in patients with congenital long QT syndrome.

OBJECTIVES: This study was performed to evaluate the frequency dependency of ventricular repolarization and the effect of epinephrine in patients with congenital long QT syndrome (LQTS). BACKGROUND: The efficacy of pacemakers in addition to antiadrenergic therapy in the treatment of congenital LQTS has been reported. METHODS: Monophasic action potentials were recorded from right and left ventricular endocardium during atrial pacing at heart rates from 70 to 140 beats/min at baseline and from 100 to 140 beats/min during epinephrine infusion (0.1 microgram/kg body weight per min) in 11 patients with congenital LQTS and 10 control patients. The response of monophasic action potential duration at 90% repolarization (MAPD90) and the dispersion of MAPD90 were examined. RESULTS: At baseline, both the MAPD90 and the dispersion of MAPD90 were significantly (p < 0.001) longer in the congenital LQTS group than the control group. The differences in these variables between the two groups significantly decreased (MAPD90: from 105 to 31 ms; dispersion of MAPD90: from 55 to 13 ms, p < 0.001) at heart rate was increased. Epinephrine prolonged the MAPD90 and increased the dispersion of MAPD90 significantly (p < 0.001) at all paced heart rates in the congenital LQTS group without frequency dependency but did not change in the control group. Thus, epinephrine increased the differences in these variables between the two groups. CONCLUSIONS: The repolarization abnormalities in congenital LQTS were attenuated by increasing the heart rate, which supported the efficacy of pacemaker therapy. However, during sympathetic stimulation, the effects of increased heart rate on these repolarization abnormalities were limited.

[Studies on anti-allergic agent. I. 1,2,3-trisubstituted-2-propen-1-one derivatives, 3,4-disubstituted-4-oxo-2-butenoic acids and the related compounds].

A new series of 1,2,3-trisubstituted-2-propen-1-one derivatives (9a-v, 10a-j, 13a-c, 14a-j) and 3,4-disubstituted-4-oxo-2-butenoic acids (6a-i, 7a-n) with azole compounds were synthesized. Inhibitory activities against rat passive cutaneous anaphylaxis (PCA) reaction and histamine release from rat mast cells were tested. The ester derivatives (7a-n, 14a-j) exhibited a more potent inhibitory activity against histamine release compared with alkylamine (9a-v), beta-hydroxyethoxy (10a-j) and carboxylic acid (6a-i, 13a-c) derivatives, but somewhat weaker in their anti-PCA activity. Structure-activity relationships were discussed.

[Clinical statistics of the patients with malignant disease of the urinary tract].

The patients with malignant diseases of the urinary tract in our department from February, 1983 to October, 1986 were statistically analyzed. The total number of cancer patients was 100; 14 had renal cell carcinoma, 13 had renal pelvic and ureteral tumors, and 73 had bladder tumors. They were between 37 and 86 years old (mean 67 years) and the male to female ratio was 2.3:1.

[Extracorporeal circulation for renal cell carcinoma with supradiaphragmatic caval thrombus].

Removal of the tumor thrombus extended into the intrapericardial vena cava, was accomplished under direct vision with minimal blood loss in a patient with renal cell carcinoma. The liver was mobilized to expose the retrohepatic vena cava by incision of the falciform, triangular and coronary ligaments, and cardiopulmonary bypass was used to create a bloodless field avoiding the migration of tumor thrombus and uncontrollable hemorrhage. Tumor thrombus was delivered intact with a 20 Fr. Foley catheter. Vena cava surgery was done for the tumor invasion, and an artificial vascular graft was then sutured to replace the caval wall. We believe that this technique can be effectively used in selected patients with extensive intracaval involvement of renal cancer.

[Clinical trial of HAPA-B in complicated urinary tract infections].

HAPA-B was administered intramuscularly to 20 patients with complicated urinary tract infections to evaluate its clinical effects and safety in conformity with the estimations of efficacy of antimicrobial agents standardized by the UTI Committee. The overall clinical efficacy was excellent in 5 patients, moderate in 8 patients and poor in 7 patients. The effectiveness rate was 65.0%. Overall clinical efficacy as classified by type of infection was 66.7% in 12 patients with a single infection, and 62.5% in 8 patients with mixed infection. Bacteriological studies showed that 29 of the 34 strains isolated from the urine of the 20 patients were completely eradicated, and that the bacteriological response was 85.3%. The following side effects were detected in both blood chemistry checks and clinical symptoms. Peripheral blood examinations showed an increase in eosinophil level in one patient. Kidney function tests revealed a slight elevation of s-creatinine in this patient, too. In another patient, eruptions developed on his body on the 2nd day, but it was not necessary to discontinue the administration of HAPA-B.