Effect of granulocyte colony-stimulating factor treatment at a low dose but for a long duration in patients with coronary heart disease.

BACKGROUND: In animal models, granulocyte colony-stimulating factor (G-CSF) improves post-infarct cardiac function. However, in pilot studies involving patients with angina and acute myocardial infarction (AMI), G-CSF at a high dose frequently induced coronary occlusion or restenosis, but those at a low dose showed no significant beneficial effect. We hypothesized that a low dose but long duration of G-CSF will have a beneficial effect without serious complications to patients with coronary heart disease. METHODS AND RESULTS: Forty-six patients with angina or AMI were randomly assigned into G-CSF and non-G-CSF control groups, respectively. Recombinant G-CSF was subcutaneously injected once a day for 10 days. The leukocyte counts in the peripheral blood were controlled at approximately 30,000/microl. One month later, a Thallium-201 single photon emission computed tomography revealed the increased percentage uptake and the reduced extent and severity scores in the G-CSF angina group. In the G-CSF AMI group, the curve between the ejection fraction and peak creatine kinase shifted significantly upward, compared with that of the non-G-CSF AMI group. Serious complications were not observed during the 6 months of observation. CONCLUSIONS: A low dose but long duration of G-CSF treatment may have a beneficial effect without any serious complications in patients with coronary heart disease.     

Purification and properties of a lethal,hemorrhagic protein, “Mucrotoxin A”, from the venom of the Chinese habu snake (Trimeresurus mucrosquamatus)

Mucrotoxin A was purified from the lyophilized venom of Trimeresurus mucrosquamatus using gel filtration on a Sephadex G-100 column, followed by chromatography on CM-Sephadex C-50 and DEAE-Sephadex A-50. By these procedures, 14 mg of purified preparation could be obtained from 1 g of crude venom. The purified preparation was homogeneous by disc electrophoresis on polyacrylamide gel at pH 8.3, isoelectric focusing and by the presence of one precipitin line on immunodiffusion. Mucrotoxin A possessed both lethal and hemorrhagic activities, but it did not show caseinolytic activity. Its molecular weight was approximately 94,000 and the isoelectric point was 4.3. Mucrotoxin A contains approximately 3 moles of Ca and 2 moles of Zn per mole of toxin. The amino acid composition of Mucrotoxin A was determined. No carbohydrate was present.     

Myocardial Inflammatory Cell Infiltrates in Cases of Dilated Cardiomyopathy: Light Microscopic, Immunohisto-chemical, and Virological Analyses of Myocardium Specimens obtained by Partial Left Ventriculectomy

Abstract Objective: Partial left ventriculectomy was introduced for the treatment of refractory dilated cardiomyopathy (DCM). To determine the presence and degree of inflammatory cell infiltrates in DCM and the correlation between the underlying myocardial injury and early clinical outcomes after the operation, we performed histopathological, immunohistochemical, and virological studies of the resected myocardium. Methods: Posterolateral walls of the left ventricle from 13 idio-pathic DCM patients (9 males and 4 females; mean age = 53 ± 14 years) were examined. Qualitative and quantitative analyses of the interstitial fibrosis and of the infiltrating inflammatory cells were conducted. For the immunohistochemistry, leukocyte surface markers and antibodies to adhesion molecules and cytokines were used. The histopathological findings were compared with the clinical results, including outcome within 1 year, and pre- and postoperative hemodynamic data. Genomic analysis of the myocardium with polymerase chain reaction was performed for en-terovirus, mumps, influenza A, cytomegalovirus, and hepatitis C virus. Results: (1) The three patients who died of cardiac insufficiency after surgery had a higher count of infiltrating inflammatory cells than the eight survivors (32.1 ± 10.4 vs 16.3 ± 11.9 cells/mm², p = 0.07). The severity of interstitial fibrosis (percent fibrosis) did not differ significantly between these two groups (28.3 f 15.0 vs 24.0 ± 11.7%). (2) In patients who died of myocardial dysfunction, focal accumulations of lymphocytes were common, in which cytotoxic/suppressor T cells and helper/inducer T cells were observed. (3) Enterovirus genome was detected in the myocardium of two patients, both of them died after surgery. Conclusions: Inflammatory cell infiltrates or active myocarditis appear in some cases to play an important role in the etiology and pathophysiology of clinically diagnosed DCM. There is a possibility that those patients with a more severe or ongoing inflammatory process might have poor outcomes after partial left ventriculectomy.     

Selected ventriculoplasty for idiopathic dilated cardiomyopathy with advanced congestive heart failure: midterm results and risk analysis

Background: To treat advanced heart failure due to idiopathic dilated cardiomyopathy, surgical ventricular restoration with mitral reconstruction was conducted and evaluated. Methods: In 95 patients (81 men, mean age: 54 years), New York Heart Association class III/IV was 44/51, and 33 patients (36%) were inotropic dependent preoperatively. Mitral regurgitation (≥2+) was noted in all patients. All patients underwent left ventriculoplasty (septal anterior ventricular exclusion in 38, partial left ventriculectomy in 57) and mitral reconstruction (repair 53, replacement 42). Fifty-two patients (55%) had concomitant tricuspid repair. Intra-aortic balloon pumping and left ventricular assist device was used in 24 patients and two patients, respectively. Results: Hospital mortality was 11.6% (11 of 95), with 6.6% (5 of 76) in elective and 31.6% (6 of 19) in emergency operations. The ejection fraction and cardiac index increased from 22.3 ± 6.3% to 27.2 ± 8.0% and from 2.3 ± 0.5 ml/m²/min to 2.8 ± 0.5 ml/m²/min, respectively (p < 0.001). The endodiastolic volume index, endosystolic volume index and diastolic dimension decreased from 232.9 ± 56.1 ml/m² to 160.0 ± 49.8 ml/m², from 178.9 ± 46.7 ml/m² to 113.8 ± 44.7 ml/m² and from 82.0 ± 9.0 mm to 68.9 ± 11.6 mm, respectively (p < 0.001). Late death occurred in 27 patients with 22 cardiac deaths. The mean NYHA class was 1.7 among the survivors. One-, 3- and 5-year survival rates were 72.8%, 61.4% and 50.5%, respectively. In the 62 patients who were non-inotropic dependent preoperatively, 1-, 3-, and 5-year survival rates (81.8%, 73.7% and 62.9%) were significantly better than the inotropic-dependent group (55.3%, 37.3% and 28.0%). Patients with mitral annuloplasty showed a significantly higher 5-year survival rate than patients with mitral valve replacement (59.6% vs 43.6%) in univariate analysis. By application of the exclusion site selection method, the two different ventriculoplasty procedures did not show significant difference in survival rates. Multivariate analysis showed that preoperative inotropes and old age were significant predictors for postoperative mortality. Conclusion: The selected ventriculoplasty in combination with mitral annuloplasty is a useful option for patients with an extremely dilated left ventricle in idiopathic dilated cardiomyopathy. Surgery should be considered before inotropic dependency occurs when prior medical treatment has failed.     

Behavioral significance of monkey hypothalamic glucose-sensitive neurons

Feeding-related neuronal activity of lateral hypothalamic glucose-sensitive and glucose-insensitive neurons was investigated in behaving monkeys. The behavioral paradigm was a high fixed ratio of bar pressing for food reward signaled by light and tone cues. Twenty-seven percent of the neurons tested were glucose-sensitive. The population of neurons which changed in firing rate during the feeding task was higher among glucose-sensitive cells than among glucose-insensitive cells. The activity of many glucose-sensitive neurons decreased during the bar pressing and reward periods. A small population of glucose-sensitive neurons responded to cue stimuli. The results suggest that glucose-sensitive neurons are mainly involved in the drive and/or reward mechanism of feeding behavior, and that these cells may have specific roles in neural control of hunger-motivated food acquisition.     

Physiological and biochemical properties of A kallikrein-like enzyme from the venom of Vipera aspis aspis (aspic viper)

and . Physiological and biochemical properties of a kallikrein-like enzyme from the venom of Vipera aspis aspis (aspic viper), Toxicon 26, 1193–1204, 1988.—A kallikrein-like enzyme was isolated from the venom of Vipera aspis aspis by Sephadex G-75, Q-Sepharose and Heparin-Sepharose CL-6B column chromatography. The purified enzyme is a glycoprotein with a mol.wt of 43,000 and an isoelectric point of 4.1. The enzyme possesses arginine ester hydrolase activity, but no proteolytic activity against either dimethylcasein or fibrinogen. The reaction mixture of the enzyme and bovine plasma induced contraction of the isolated rat uterus, suggesting that the enzyme releases kinin from the plasma constituent. The amount of enzyme, which releases an equal amount of kinin corresponding to 1 nmole of bradykinin per min, is 2.36 mg. Additionally, the kallikrein-like enzyme demonstrated capillary permeability-increasing activity and hypotensive activity. A synthetic kininogen analog, Ser-Leu-Met-Lys-Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg-Ser-Val-Gln-Val-Ser, was cleaved by the enzyme to release bradykinin and kallidin, also indicating that the enzyme has a kallikrein-like activity. Uterine contraction, capillary permeability-increasing activity and arginine ester hydrolase activity were inhibited by diisopropyl fluorophosphate, suggesting that the serine hydroxyl group is essential for enzymatic and biological activities. Antithrombin III and heparin, serine-protease inhibitors found in plasma had no inhibitory effect on these activities of the purified enzyme. The amino acid sequence of the NH₂ terminal region of the enzyme has similarities with kallikrein-like enzynes from other snake venoms and with porcine pancreatic kallikrein.     

Extremely highly isospecific polymerization of olefins using solvay-type TiCl3 and Cp2TiMe2 as catalyst

Polymerizations of various olefins (ethylene, propene, 1-butene, 4-methyl-1-pentene,1-hexene, and 1-octene) were carried out using the Solvay-type TiCl₃ catalyst combined with Cp₂TiMe₂. The polymers produced were characterized by DSC, solvent fractionation, GPC, and ¹³C NMR. It was found that the present catalyst gives linear polyethylene without ethyl branches and extremely highly isotactic poly(α-olefins) containing very few steric defects. The catalyst seems to be most isospecific among the Ziegler-Natta catalysts reported so far.     

Four new macrocyclic trichothecenes from two strains of marine-derived fungi of the genus Myrothecium

Three new macrocyclic trichothecenes, named 12'-hydroxyroridin E (1), roridin Q (2), and 2',3'deoxyroritoxin D (3), were isolated from the marine-derived fungus Myrothecium roridum TUF 98F42, and a new macrocyclic trichothecene, named roridin R (4), was isolated from Myrothecium sp. TUF 02F6 together with roridins A and H and isororidin E. The structures of new compounds were determined on the basis of their spectral data. Compound 2 possessed a unique ether moiety at the 13' position of 1. Compound 4 was a 2',3'-dihydro-2'-hydroxy derivative of roridin H. The IC50 values of compounds 1, 2, and 4 against the murine leukemia cell line L1210 were 0.19, 31.2, and 0.45 microM, respectively. Compound 3 showed antiyeast activity to Saccharomyces cerevisiae at 1 microg/disc (inhibition zone: 12.2 mm), which was about 10 time more active than roritoxin D (10.2 mm at 10 microg/disc).