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Biomedical subjects

R Mohr

Publications and source records attributed to R Mohr.

At least 37 records · Page 2Linked to original sources

Cultural variations in the understanding of traumatic brain injury and brain injury rehabilitation.

Little is known about how people from different cultures experience and understand traumatic brain injury (TBI) and the process of brain injury rehabilitation. The Brain Injury Rehabilitation Unit (BIRU) undertook a qualitative project to research cultural variations in the understanding of TBI and the rehabilitation process, interviewing 39 people with TBI and family members from Italian, Lebanese and Vietnamese backgrounds. The focus was on the reporting of sequelae of the TBI; valued qualities of service providers; barriers to effective communication; the role of the families in the rehabilitation process; and the experience of social stigma. Findings suggest there is a universal experience of TBI that transcends individual cultures. Study participants valued attentiveness, friendliness and guidance from rehabilitation staff. Family support was not always available to the person with TBI due to family conflict. Generally, people with TBI and family members valued the assistance of health interpreters facilitating their communication with rehabilitation staff. People with TBI from all three cultures experienced problems of stigma and social isolation. The findings have a number of implications for how brain injury rehabilitation staff can approach service provision to people from diverse cultural backgrounds.

Adaptation, Psychological↗

Urticaria following varicella vaccine associated with gelatin allergy.

An uncommon reaction to varicella vaccine has been urticaria. Based on two reports of urticaria believed to be due to gelatin in recipients of measles-mumps-rubella vaccine, we suspected gelatin as the cause of generalized urticaria in two children after varicella vaccination. Intradermal testing with gelatin yielded a wheal and flare reaction in both children. We conclude that children known to be allergic to gelatin should not receive Oka/Merck varicella vaccine (VARIVAX).

Allergens↗

Routine use of bilateral skeletonized internal mammary arteries for myocardial revascularization.

BACKGROUND: Complete arterial myocardial revascularization without the use of saphenous veins grafts was primarily performed on selected patient populations such as the young and nondiabetic. In a recently developed surgical technique, the internal mammary artery is dissected gently as a longer skeletonized artery, providing greater versatility for complete arterial revascularization, without saphenous veins grafts. METHODS: We prospectively evaluated the impact of the routine use of double skeletonized internal mammary artery in 472 patients who underwent coronary artery bypass grafting between April 1996 and June 1997. Their average age was 65 years (30 to 87 years), 383 (83%) were men, and 89 (17%) women. One hundred sixty-nine (36%) of the patients were older than 70 years, and 145 (31%) were diabetic. The average number of grafts was 3.2 per patient (two to six grafts). RESULTS: Operative mortality was 1.7% (n = 8). The mortality of urgent and elective patients was 0.7% (3 of 410 patients), and that of emergency operations was 8.1% (5 of 62 patients; p < 0.01). There were three (0.6%) perioperative infarcts, and 6 patients (1.3%) sustained strokes. Sternal wound infection occurred in 8 patients (1.7%). Postoperative follow-up (1 to 25 months) was available in 462 patients (99%). Two-year actuarial survival was 96.8%, and 92% of the surviving patients are well and free of angina. Neither diabetes mellitus nor old age (>70 years) were significant independent predictors of any early or late untoward events. None of the 70 diabetic patients more than 65 years of age developed sternal wound infection. Chronic lung disease was found to be the only independent predictor for sternal infections. CONCLUSIONS: Routine use of bilateral skeletonized internal mammary artery is a safe replacement for the current myocardial revascularization technique even in the old and diabetic patients.

Adult↗

Coronary artery bypass without cardiopulmonary bypass for patients with acute myocardial infarction.

OBJECTIVE: Between January 1992 and December 1994, 57 patients having an acute myocardial infarction with coronary anatomy suitable for coronary artery bypass grafting without cardiopulmonary bypass underwent this procedure within 1 week of the infarction. We describe the surgical results of these high-risk patients. METHODS: The study population included 43 male patients (75%) and 14 female patients (25%) whose mean age was 58.5 +/- 10.4 years. Thirty-two patients (56%) underwent emergency bypass grafting within 48 hours of an acute myocardial infarction, 4 of them (12.5%) as a bailout procedure after complicated percutaneous transluminal coronary angioplasty. Of these 32 patients, 7 patients (22%) were in cardiogenic shock, and 10 patients (31%) required preoperative intra-aortic balloon pump. Twenty-five patients (44%) underwent coronary bypass grafting 2 to 7 days after an acute myocardial infarction. The mean number of grafts per patient was 1.8 (range, 1-4), and the internal thoracic artery was used in 47 patients (82%). Only 7 patients (12%) received grafts to a circumflex marginal branch. RESULTS: Operative mortality was 1.7% (1 patient), and the mean postoperative hospital stay was 6.8 +/- 3 days. One- and 5-year actuarial survivals were 94.7% and 82.3%, respectively. Angina returned in 7 patients (12%), 1 of whom underwent reoperation. Multivariate analysis revealed renal failure and preoperative cardiogenic shock to be independent predictors of overall mortality. Old myocardial infarction and operation within the first 48 hours were independent predictors of overall unfavorable outcome events. CONCLUSIONS: These results suggest that coronary artery bypass grafting without cardiopulmonary bypass is a relatively low-risk procedure for patients having an infarction with coronary anatomy suitable for this technique.

Actuarial Analysis↗

Sternal wound infections in patients after coronary artery bypass grafting using bilateral skeletonized internal mammary arteries.

OBJECTIVES: This study evaluated the risks of sternal wound infections in patients undergoing myocardial revascularization using bilateral skeletonized internal mammary arteries (IMAs). BACKGROUND: The skeletonized IMA is longer than the pedicled one, thus providing the cardiac surgeon with increased versatility for arterial myocardial revascularization without the use of vein grafts. It is isolated from the chest wall gently with scissors and silver clips, and no cauterization is employed. Preservation of collateral blood supply to the sternum and avoidance of thermal injury enable more rapid healing and decrease the risk of sternal wound infection. METHODS: From April 1996 to August 1997, 545 patients underwent arterial myocardial revascularization using bilateral skeletonized IMAs. The right gastroepiploic artery was used in 100 patients (18%). The average age of the patients was 65 years; 431 (79%) were men and 114 (21%) were women; 179 (33%) were older than 70 years of age; 166 (30%) were diabetics. The average number of grafts was 3.2 per patient. RESULTS: The 30-day operative mortality rate was 2% (n = 11). There were six perioperative infarcts (1.1%) and six strokes (1.1%); 9 patients had sternal infection (1.7%) and 15 (2.8%) had superficial infection. Risk factors for sternal infection were chronic obstructive pulmonary disease and emergency operation. Superficial sternal wound infections were more common in women and in patients with chronic obstructive pulmonary disease, renal failure, or peripheral vascular disease. The 1-year actuarial survival rate was 97%. Two of the six late deaths were not cardiac-related. Late dehiscence occurred in three patients (0.6%). The death rate (early and late) of patients with any sternal complication was higher than that of patients without those complications (33% vs. 2.7%). CONCLUSIONS: Routine arterial myocardial revascularization using bilateral skeletonized IMAs is safe, and postoperative morbidity and mortality rates are low, even in elderly patients and those with diabetes. Chronic obstructive pulmonary disease and emergency operations were found to be associated with an increased risk of sternal infections, and the authors recommend avoiding the use of bilateral skeletonized IMAs in patients with these preoperative risk factors.

Aged↗

[Routine use of of two internal mammary arteries for coronary bypass grafting--one year experience at the Tel Aviv Medical Center].

The skeletonized internal mammary artery (IMA) is longer, and its immediate spontaneous blood flow is greater than that of the pedicled IMA, thus providing increased versatility for complete, arterial myocardial revascularization without the use of saphenous vein grafts. From April 1996 to May 1997, 583 patients underwent coronary artery bypass grafting here and in 415 (71%) complete arterial revascularization was achieved using bilateral skeletonized IMA. The right gastroepiploic artery was used in 57 (13%); there were 329 males (79%) and 86 women (21%); average age was 64 (30-87) and 175 (36%) were older than 70; 131 (32%) were diabetics. Average number of grafts was 3.2 (range 2-6 grafts). At 30 days, 5 (1.2%) had died and there had been 6 perioperative infarcts (1.4%), 5 CVA's (1.2%), and 6 had sternal wound infections (1.4%). Up to 1-12 months of follow-up was achieved in 409 (99%). Late mortality was 1.4% (of which 3 were noncardiac). 394 (97%) were angina-free at latest follow-up. We conclude that arterial revascularization using bilateral skeletonized IMA is safe, as postoperative morbidity and mortality are low, even in old and diabetic patients.

Adult↗

Effects of an angiotensin II antagonist on ischemic and nonischemic isolated rat hearts.

BACKGROUND: Increasing evidence suggests that a locally integrated or intramyocardial renin-angiotensin system plays a significant role in ischemia-reperfusion injury. We evaluated the effects of losartan, an angiotensin II type 1 receptor blocking agent, on ischemic and nonischemic isolated rat hearts. METHODS: Using the modified Langendorff model, hearts were perfused with either low or high doses of losartan (18.2 mmol/L or 182.2 mmol/L, respectively) or with saline added to Krebs-Henseleit solution during phase I of the study. During phase II, hearts were exposed to a 60-minute period of global ischemia. Ischemic arrest was induced with warm cardioplegic solution (KCl, 16 mEq/L) containing either high-dose losartan (182.2 mmol/L) or Krebs-Henseleit solution only. RESULTS: During phase I of the study, no statistically significant differences were observed between the low-dose losartan group and the control group. However, hearts treated with high-dose losartan demonstrated an increase in peak systolic pressure, maximum first derivative of pressure, pressure-time integral, coronary flow, and oxygen consumption (p < 0.0001). During phase II, hearts treated with losartan showed a significantly better recovery on reperfusion, as reflected by better contractility (p < 0.001), higher oxygen consumption (p < 0.001), higher coronary flow (p < 0.0001), and lower creatine phosphokinase levels (41.1 +/- 1.7 versus 73.3 +/- 5.6 U/L; p < 0.001). CONCLUSIONS: High doses of losartan have a positive inotropic effect on normally perfused hearts. Given in cardioplegic solution, the drug has a significant protective effect on ischemic isolated rat hearts.

Angiotensin II↗

Dissection of signaling pathways and cloning of new signal transducers in tyrosine kinase-induced pathways by genetic selection.

We used genetic strategies which have been proven valuable to decipher signaling pathways in comparatively simple organisms such as Drosophila and Caenorhabditis elegans, to dissect signaling network activated by tyrosine kinases in mammals. The strategy was developed further towards a generally applicable expression cloning system to identify signal transducers in tyrosine kinase pathways. This system is based on the ability of downstream acting genes to rescue the transformation phenotype of partial loss-of-function mutants of BCR-ABL which still retain tyrosine kinase activity. Using this strategy we have previously shown that overexpression of c-Myc and Cyclin D1 can rescue a signaling defective SH2 mutant of BCR-ABL for transformation. In an unbiased approach to identify new compensating genes, a cDNA library was introduced by retroviral infection into fibroblasts which express the BCR-ABL SH2 mutant. CDNA clones, capable of rescuing the SH2 mutant for transformation should result in colony formation in soft agar. A PCR approach was used to recover these compensating genes from the genomic DNA of the transformed fibroblasts. Sequencing analysis of the initial cDNAs identified three known genes, the adapter molecule Shc, the kinases SPRK and p38 MAPK. These genes have been found to interact functionally with BCR-ABL for fibroblast and hematopoietic cell transformation. Currently, we are constructing and screening new libraries to identify novel genes which complement the BCR-ABL SH2 mutant. Our results demonstrate that this cloning approach is an effective means of identifying and characterizing signaling molecules that function in specific signaling pathways. This in turn may identify specific targets for mechanism-based therapeutic intervention to block altered signaling.

Adaptor Proteins, Signal Transducing↗

Anti-tumor necrosis factor-alpha improves myocardial recovery after ischemia and reperfusion.

OBJECTIVES: This study sought to assess the importance of locally released or paracrine myocardial tumor necrosis factor-alpha (TNF-alpha) in the evolution of postischemic myocardial dysfunction and to use immunohistochemical studies to localize TNF-alpha within the myocardium. BACKGROUND: TNF-alpha is implicated as a systemic mediator in the development of myocardial ischemia-reperfusion injury by promoting leukocyte myocardial infiltration, and it has been shown to originate from noncardiac peripheral mononuclear cells. We have recently documented in a blood-free environment the release of TNF-alpha from the ischemic-reperfused myocardium. METHODS: Isolated rat hearts undergoing 1 h of global cardioplegia-induced ischemia and 30 min of reperfusion were investigated with use of the modified Langendorff model. Hearts were randomly divided into three subgroups: group A, control group; and groups B and C, isolated hearts receiving cardioplegic solution containing monoclonal hamster antimurine TNF-alpha antibodies (group B) or hamster IgG (group C). RESULTS: Significant amounts of TNF-alpha were detected in group A and group C effluent on 1 min of reperfusion (752 +/- 212 and 958 +/- 409 pmol/ml, respectively). However, in group B, TNF-alpha was below detectable levels. In this group, postischemic left ventricular peak systolic pressures, first derivative of the rise in left ventricular pressure (dP/dtmax), pressure-time integral, coronary flow and O2 consumption improved (analysis of variance [ANOVA] p < 0.0001 for all variables) compared with values in groups A and C; creatine kinase levels decreased (p < 0.005); and myocardial structure was preserved. Immunohistochemical staining localized TNF-alpha to cardiac myocytes and to endothelial cells. CONCLUSIONS: Anti-TNF-alpha neutralizes local TNF-alpha release from cardiac myocytes after ischemia and improves myocardial recovery during reperfusion, indicating that postischemic paracrine TNF-alpha release plays an active role in myocardial dysfunction.

Animals↗

High-dose isosorbide dinitrate for myocardial revascularization with composite arterial grafts.

BACKGROUND: Composite arterial grafting for myocardial revascularization is a surgical technique in which free arterial conduits are proximally attached to an in situ internal mammary artery. METHODS: Composite arterial grafting was performed in 78 patients with internal mammary artery (n = 24), inferior epigastric artery (n = 21), or radial artery (n = 33) connected to the internal mammary artery. Overall, 254 distal anastomoses were performed (average number, 3.3 per patient), 225 of which were arterial. All patients were treated postoperatively with high-dose isosorbide dinitrate (4 to 20 mg/h for 24 hours). RESULTS: The in-hospital mortality rate was 2.6% (2 patients). Early recatheterization studies performed 3 weeks (range, 1 to 20 weeks) after operation in 30 patients demonstrated patency rates of 100%, 93%, and 100% for the composite internal mammary artery, inferior epigastric artery, and radial artery groups, respectively. In addition, two inferior epigastric artery conduits had major intraluminal constriction. At a mean follow-up of 20 months (range, 1 to 42 months) all patients are alive, and all but 2 in the inferior epigastric group (97%) are angina free. CONCLUSIONS: This surgical technique can be safely used. On the basis of our experience, the right internal mammary artery and the radial artery are the most suitable conduits for this procedure. High-dose nitrates given perioperatively prevent spasm and ensure early patency rates.

Adult↗

Captopril in cardioplegia and reperfusion: protective effects on the ischemic heart.

BACKGROUND: Previous studies have shown that long-term treatment with the angiotensin-converting enzyme inhibitor captopril attenuates left ventricular dilatation and improves survival after extensive myocardial infarction. However, there is only sparse evidence of the immediate effects of the drug on hearts undergoing global ischemia and reperfusion. The purpose of this study was to investigate the direct effect of captopril, given in cardioplegia or after ischemia, on the functional recovery of the reperfused myocardium. METHODS: Isolated rat hearts undergoing warm cardioplegic arrest followed by 1 hour of global ischemia and 30 minutes of reperfusion were studied using the modified Langendorff model. RESULTS: After ischemia, hearts receiving captopril (360 mumol/L) either in the cardioplegic solution (n = 9) or during reperfusion (n = 9) developed higher pressure (p < 0.001), greater first derivative of the rise in left ventricular pressure (p < 0.01 and p < 0.001, respectively), greater first derivative of the fall in left ventricular pressure (p < 0.001 and p < 0.002), higher pressure-time integral (p < 0.001), greater coronary flow (p < 0.001), and higher oxygen consumption values (p < 0.001 and p < 0.003) compared with the control group (n = 9). Hearts receiving captopril both in the cardioplegia and during reperfusion (n = 9) had the best recovery of all three groups and lower levels of creatine kinase (47.8 +/- 5.9 U/L versus 73.3 +/- 5.6 U/L; p < 0.01) compared with the control group. CONCLUSIONS: Captopril given in cardioplegia and in reperfusion has a favorable, protective, and additive effect on the recovery of isolated rat hearts undergoing global ischemia and reperfusion; hemodynamic performance improves, coronary flow and oxygen consumption increase, and myocardial damage decreases.

Angiotensin-Converting Enzyme Inhibitors↗

Reoperative coronary artery bypass without cardiopulmonary bypass.

BACKGROUND: Conventional reoperative coronary artery bypass grafting using cardiopulmonary bypass carries relatively high mortality and morbidity. METHODS: Seventy-seven patients underwent coronary artery bypass grafting without cardiopulmonary bypass in two centers between 1988 and 1994. Mean age was 65 +/- 8 years (mean +/- SD). Twenty-three (30%) were operated on urgently and 7 (9%) emergently. Nine (12%) were referred for operation up to 2 weeks after acute myocardial infarction. Fifteen patients (19%) had an ejection fraction less than or equal to 0.35. The mean number of grafts per patient was 1.7 (range, 1 to 3), and the internal mammary artery was used in 66 patients (86%). Only 18 patients (23%) received at least one graft to the circumflex artery. Hospital stay was 7.4 +/- 6.5 days. RESULTS: Early events included operative death in 4 patients (5.2%), nonfatal myocardial infarction in 3 (3.9%), sternal infection in 2 (2.6%), and stroke in 0 (0%). Follow-up (30 +/- 15 months) showed 11 deaths (5 cardiac, 6 noncardiac), 2 (2.8%) nonfatal myocardial infarctions, and return of angina in 9 patients (12.8%). One- and 4-year actuarial survival rates were 90% and 69%, respectively. CONCLUSIONS: Reoperative coronary artery bypass grafting without cardiopulmonary bypass has acceptable early and midterm outcome, and should be considered a viable alternative for properly selected patients.

Aged↗

Primary coronary artery bypass grafting without cardiopulmonary bypass in impaired left ventricular function.

BACKGROUND: Conventional coronary artery bypass grafting using cardiopulmonary bypass carries relatively high mortality and morbidity for patients with left ventricular dysfunction. METHODS: Seventy-five patients with ejection fraction less than or equal to 0.35 underwent primary coronary artery bypass grafting without cardiopulmonary bypass between December 1991 and December 1994. Thirty-two patients (43%) had congestive heart failure, 11 (15%) were referred for operation within the first 24 hours of evolving myocardial infarction, and 21 (28%) up to 1 week after acute myocardial infarction. Eighteen patients (24%), 6 of whom were in cardiogenic shock, underwent emergency operations. RESULTS: Mean number of grafts/patient was 1.9 (range, 1 to 4), and internal mammary artery was used in 66 patients (85%). Only 17 patients (23%) received a graft to a circumflex marginal artery. Two patients (2.7%) died perioperatively, and 1 (1.3%) sustained stroke. At mean follow-up of 28 months, 13 patients had died, and angina had returned in 7 (10.5%). One- and four-year actuarial survival was 96% and 73%, respectively. CONCLUSIONS: Coronary artery bypass grafting without cardiopulmonary bypass is a viable alternative to conventional coronary artery bypass grafting particularly for patients with extreme left ventricular dysfunction or those with coexisting risk factors, such as acute myocardial infarction and cardiogenic shock.

Adult↗

Comparison of myocardial revascularization without cardiopulmonary bypass to standard open heart technique in patients with left ventricular dysfunction.

OBJECTIVE: To compare myocardial revascularization without cardiopulmonary bypass to standard open heart technique in patients with left ventricular (LV) dysfunction. METHODS: 117 patients with LV dysfunction (ejection fraction (EF) < 35%) underwent coronary artery bypass surgery between January 1991 and July 1994. Sixty-four (group A) were operated on without a cardiopulmonary bypass, and 53 (group B) with one. Prevalence of EF < 20% (17 vs. 6%) and emergency operations (22 vs. 7%, P = 0.03) was higher in group A. The average number of grafts was 1.9 +/- 0.8/pt in group A and 3.5 +/- 0.9/pt in group B (P < 0.01), and the internal mammary artery was used in 54 (84%) and 42 (79%) patients, respectively. Only 16 patients (25%) in group A received a graft to a circumflex marginal artery compared to 51 (96%) in group B (P < 0.0001). RESULTS: Two patients (3.1%) died perioperatively in group A compared to 7 (13%) in group B (P = NS). In two patients from group A (3.1%) and in four (7.5%) from group B intra-aortic balloon pump was inserted postoperatively (P = NS). One year actuarial survival was 91 and 79% (P = 0.03) and 2-year survival was 86 and 65% (P = 0.04), respectively. Return of angina occurred in five (8%) and three (6%) patients (P = NS). CONCLUSIONS: These results show a trend for lower operative risk resulting in better overall survival in selected patients with LV dysfunction undergoing coronary artery bypass surgery without cardiopulmonary bypass.

Actuarial Analysis↗

Predictors of early and overall outcome in coronary artery bypass without cardiopulmonary bypass.

OBJECTIVE: Cardiopulmonary bypass in coronary artery bypass graft operations may adversely affect the outcome especially in high-risk patients. The purpose of this study is to evaluate results of coronary artery bypass performed without cardiopulmonary bypass, in a relatively high-risk cohort, and to identify predictors of unfavorable outcome. METHOD: Three hundred and thirteen (313) patients, 246 (79%) of whom had high-risk conditions, who have a coronary anatomy suitable for coronary artery bypass surgery without cardiopulmonary bypass, underwent this procedure between December 1991 and July 1995. Mean number of grafts/patient was 1.8 (1-5), and only 71 patients (23%) received a graft to the circumflex coronary system. RESULTS: Early unfavorable outcome events included operative mortality (12 patients, 3.8%), nonfatal perioperative myocardial infarction (eight patients, 2.6%), emergency reoperation (three patients, 0.9%), sternal infection (five patients, 1.6%), and nonfatal stroke (two patients, 0.6%). Multivariate analysis revealed angina pectoris class IV (odds ratio 5.4) and age > or = 70 years (odds ratio 5.0) as independent predictors of early mortality. Preoperative risk factors such as repeat coronary artery bypass grafting (50 patients, 16%), ejection fraction < or = 0.35 (85 patients, 27%), acute myocardial infarction (86 patients, 28%), cardiogenic shock (ten patients, 3.2%), chronic renal failure (25 patients, 8%), chronic obstructive pulmonary disease (20 patients, 6%), and peripheral vascular disease (51 patients, 16%) did not increase early mortality. During 33 months of follow-up (range 1-57 months), there were 42 deaths, at least 16 cardiac-related (one and four years actuarial survival of 90% and 76% respectively), and 39 patients (12.5%) in whom angina returned. Calcified aorta (odds ratio 2.6) and old myocardial infarction (odds ratio 1.8) were independent predictors of overall unfavorable events. CONCLUSIONS: Coronary artery bypass grafting without cardiopulmonary bypass can be performed with relatively low operative mortality in certain high-risk subgroups of patients; however, an increased risk of graft occlusion is a potential disadvantage. This procedure should therefore be considered only for patients with suitable coronary anatomy, in whom cardiopulmonary bypass poses a high risk. Although the risk of stroke is relatively low, the procedure is still hazardous for patients aged 70 years and over.

Adult↗

Tumor necrosis factor-alpha is released from the isolated heart undergoing ischemia and reperfusion.

OBJECTIVES: The purpose of this study was to examine whether tumor necrosis factor-alpha (TNF-alpha) is released directly from the ischemic myocardium undergoing reperfusion. BACKGROUND: Tumor necrosis factor-alpha is a protein hormone produced by systemic leukocytes (primarily by activated macrophages). It has been implicated as a systemic mediator in the development of septic shock and other pathologic conditions. Serum TNF-alpha has also been detected in a variety of cardiac disease states and after myocardial ischemia-reperfusion injury. METHODS: Nine isolated rat hearts undergoing 30 min of perfusion, followed by warm cardioplegic arrest, 1 h of global ischemia and 30 min of reperfusion, were investigated using the modified Langendorff model. RESULTS: Significant amounts of TNF-alpha (752 +/- 212 pmol/ml) were detected in the effluent during the first minute of reperfusion. Tumor necrosis factor-alpha levels correlated with postischemic deterioration in peak systolic pressures (r = 0.7882, p = 0.012), dP/dt max (r = 0.6795, p = 0.044), time-pressure integral (r = 0.7661, p = 0.0016) and postischemic creatine kinase levels (r = 0.8367, p = 0.005). The deterioration in coronary flow, however, was inversely correlated with TNF-alpha levels (r = -0.7581, p = 0.018). CONCLUSIONS: To our knowledge, this study is the first to suggest that the isolated rat myocardium synthesizes and releases TNF-alpha in response to ischemia and reperfusion, which directly correlates with the postischemic deterioration in myocardial mechanical performance and the amount of cellular necrosis.

Animals↗

Kir, a novel Ras-family G-protein, induces invasive pseudohyphal growth in Saccharomyces cerevisiae.

Kir belongs to a novel class of Ras-family G-proteins which includes Gem and Rad. These proteins are unique among Ras super-family G-proteins since their expression is under transcriptional regulation in mammalian cells. To gain insight into the function of Kir, we took advantage of the well-defined signal transduction pathways of yeast. When kir is expressed in Saccharomyces cerevisiae, the transformants form pseudohyphae and exhibit invasive properties characteristics of yeast cells undergoing a developmental transition induced by nitrogen starvation. Analysis of pseudohyphal signaling pathway mutants suggests that the Kir-induced pseudohyphae formation requires a MAP kinase cascade involving ste20, ste11, ste7 but not ste5 gene products. Furthermore, our results are consistent with the idea that Kir functions upstream of the STE20 kinase which plays a critical role in two distinct MAP kinase cascades.

Cloning, Molecular↗

Synthesis and histamine H2-receptor antagonist activity of 4-(1-pyrazolyl)butanamides, guanidinopyrazoles, and related compounds.

A series of 4-(1-pyrazolyl)butanamides, pyrazolylalkyl cyanoguanidines, and related compounds with diverse functional groups (e.g. nitro, amino, guanidino groups) in the 3-position of the pyrazole ring was prepared via 4-(3-nitro-1-pyrazolyl)butanenitrile (5) and the corresponding carboxylic acid 7 as central intermediates. The amides 9a-d were prepared from the primary amines 8a-d which represent partial structures of the H2-receptor antagonists roxatidine, cimetidine, ranitidine, and famotidine. The roxatidine-derived 4-(3-nitro-1-pyrazolyl)butanamide (9a) proved to be the compound with the highest H2-receptor antagonist activity of 23 compounds tested at the isolated guinea pig right atrium preparation, achieving about 6 times famotidine's or 160 times cimetidine's potency. By contrast, in Ghosh-Schild rats 9a did not inhibit histamine-stimulated gastric acid secretion at a dosage of 0.1 mumol/kg i.v. Compounds 20a (the 3-(trifluoroethyl-guanidino)pyrazole analogue of 9a, 12a (the cyanoguanidine analogue) and N-(4-[3-(trifluoroethylguanidino)-1-pyrazolyl]butyl)cyanogua nidine (29), which are about as active as famotidine in the atrium, turned out to be very potent inhibitors of gastric acid secretion as well (e.g., 29: 74% inhibition at 0.025 mumol/kg). These compounds are comparable to famotidine in the rat stomach and by far superior to cimetidine and ranitidine in this test system.

Amides↗