Clopidogrel and warfarin: absence of interaction in patients receiving long-term anticoagulant therapy for non-valvular atrial fibrillation

The effect of concomitantly administered clopidogrel on anti-coagulation status was investigated in patients receiving long-term warfarin therapy. Forty-three patients with non-valvular atrial fibrillation who were receiving long-term warfarin and had a stable international normalized ratio (INR) between 2 and 3 were randomly assigned to clopidogrel 75 mg daily or placebo for 8 days (Days 1-8). INR (primary endpoint) and plasma levels of warfarin enantiomers (secondary endpoint) were evaluated at Days 3, 6, 9, 13 and 22. Mean INR remained extremely stable in the clopidogrel group, the maximum percentage change from baseline being 0.6% at Day 6. Plasma levels of R- and S-warfarin also remained very stable in those receiving clopidogrel. No serious adverse events, premature discontinuations of study drug or bleeding occurred with clopidogrel. In conclusion, the stable anticoagulation status of patients receiving long-term warfarin therapy is unaffected by concomitant administration of clopidogrel 75 mg daily.     

Role of superoxide anion in pancreatic islet blood flow regulation in anesthetized rats

The aim of the investigation was to study the influence of the superoxide anion on pancreatic islet blood flow in rats. For this purpose, blood flow measurements were conducted with a microsphere technique 10 min after intravenous administration of different doses of superoxide dismutase (5, 15, 50, 100 or 1000 kU/kg body weight). In separate experiments, diethyldithiodicarbamate, an inhibitor of endogenous superoxide dismutase, was given to nontreated control rats or to rats subjected to a bilateral abdominal vagotomy before the injection. Only the highest dose of superoxide dismutase increased both whole pancreatic and islet blood flow. A 50% augmentation of fractional islet blood flow was seen. Administration of diethyldithiocarbamate induced marked hyperglycemia, which was partly prevented by vagotomy. Diethyldithiocarbamate decreased the whole pancreatic blood flow, while islet blood flow was maintained in both control and vagotomized rats. Consequently, a pronounced increase in fractional islet blood flow was noted in both these groups. We conclude that administration of superoxide dismutase and its inhibitor diethyldithiocarbamate influences pancreatic blood perfusion. In particular, superoxide dismutase causes a general increase in the whole pancreatic and islet blood flow, and an augmented fractional islet blood flow, presumably by a decrease in the local concentration of O(2)(z.rad;-), leading to increased concentration of NO. Diethyldithiocarbamate, on the other hand, by increasing the levels of O(2)(z.rad;-), decreases the whole pancreatic blood flow, whereas islet blood flow remains unaffected.     

Anticonvulsant Activity in Mice of Diazepam in an Emulsion Formulation for Intravenous Administration

Abstract: The anticonvulsant activity of diazepam has been investigated in mice using an electrical low voltage square wave technique. Diazepam was administered intravenously using two injection formulations, valium® inj. (Roche) and diazepam emulsion. In the latter formulation the lipophilic drug was dissolved in soya bean oil which was then emulsified to an o/w emulsion. A great difference was found in acute intravenous toxicity (LD50) between the two diazepam formulations. The higher toxicity of valium® inj. could probably be due to the solvents used in this formulation. The anticonvulsant activity was about equal for the two preparations. Thus, no difference was found in duration of anticonvulsant activity at the two dose levels and the slopes of the log. dose-response curves did not differ.     

Influence of Body Position on the Anginal Threshold during Leg Exercise

Abstract. The circulatory adaptation to leg exercise in the supine and sitting positions with stepwise increased work loads was studied in twelve patients with signs of coronary heart disease. In four patients right heart catheterization was performed. Anginal pain appeared during exercise in both body positions in all patients, but at a lower work load and lower pulmonary oxygen uptake during supine exercise. Heart rate and systolic blood pressure were lower and the systolic ejection period was longer at the occurrence of angina during supine exercise. The calculated pressure-time per minute was significantly lower during exercise in the supine position. Catheterization data suggested a greater rise in left ventricular filling pressure with supine exercise. It is concluded that the differences in work tolerance for the two positions are partly due to a lower mechanical efficiency and may partly be secondary to the augmented venous return and increased left ventricular filling pressure observed during supine exercise. The augmented filling pressure will tend both to increase heart volume–and thereby augment myocardial oxygen requirements–and to compromise coronary perfusion and thus reduce myocardial oxygen supply during supine exercise.     

Wound infections after surgery in a modern operating suite: clinical, bacteriological and epidemiological findings

A prospective study of 2983 operations in general and orthopaedic surgery during 3 years performed in four operating theatres in a modern operating suite was carried out in order to evaluate the importance of airborne infection. Weekly nose-and-throat samples were taken from the surgical staff and pre-operative samples were taken from the nose, throat, skin and perineum of the patients. The air contamination was followed by using settle plates, which showed low mean counts of total bacteria of between 9 and 15 c.f.u./m²/min, with mean counts of Staph. aureus of between 0·03 and 0·06 c.f.u./m²/min. No correlation was found between the total number of bacteria and the incidence of post-operative infections or between the amount of Staph. aureus in the air and post-operative Staph. aureus infections. It was concluded that further increases in ventilation could, at best, only marginally affect the incidence of post-operative infection.     

Cross-linked hyaluronan used as augmentation substance for treatment of glottal insufficiency: safety aspects and vocal fold function

OBJECTIVE: To examine safety aspects and vocal fold function after vocal fold augmentation with a cross-linked hyaluronan derivative (hylan B gel) as compared with bovine collagen. STUDY DESIGN; A prospective, randomized trial. METHODS: Eighty-three patients with glottal insufficiency were treated with injection augmentation with hylan B gel and bovine collagen and were examined at 1, 6, and 12 months after treatment. Seventy patients with unilateral vocal fold paresis (n = 35) or atrophy (n = 35) were randomly assigned to receive either hylan B gel (n = 47) or collagen (n = 23) injections into one vocal fold. Thirteen patients with glottal insufficiency caused by scar defects or paresis resulting from malignant disease were included in a nonrandomized group and were treated only with hylan B gel. Evaluations were made from patients' subjective ratings (visual analogue scales), digitized videostroboscopic measurements, phonetograms, maximum phonation time, and phonation quotients. RESULTS: Twelve months after injections, the patients' self-ratings were significantly improved for both the hylan B gel and the collagen groups. In addition, the videostroboscopic measurements showed significantly improved glottal closure for both groups. However, for the hylan B gel group, vibration amplitude and glottal area variations were preserved, and this group showed significantly less resorption at the injected vocal fold edge. Furthermore, maximum phonation time had increased significantly for the hylan B gel patients (collagen, nonsignificant). No serious adverse events were observed; three patients injected with hylan B gel had temporary inflammation at the injection site, which resolved without sequelae. CONCLUSIONS: The results showed that both hylan B gel and collagen can be safely used for injection treatment of glottal insufficiency. Both treatments resulted in significantly improved voice as rated by the patients. However, the patients treated with hylan B gel showed better vocal fold status and longer maximum phonation time at 12 months after treatment as compared with patients treated with collagen.     

Long-term effects of exposure of pancreatic islets to nicotinamide in vitro on DNA synthesis,metabolism and B-cell function

Summary Using³H-thymidine labeling techniques, we found that rates of DNA synthesis in islet cells doubled when mouse pancreatic islets were cultured for 1 week with 10 mmol/1 nicotinamide, a potent poly(ADP-ribose) synthetase inhibitor. Culture with nicotinamide partially inhibited glucose-stimulated insulin release, whereas the islet insulin content and rate of (pro)insulin biosynthesis remained unchanged. Long-term exposure to nicotinamide decreased glucose oxidation and ATP content in the islets. The findings support the view that poly(ADP-ribose)synthetase inhibitors stimulate islet cell replication, but may be accompanied by significant inhibitory effects on islet cell function.     

Arrhythmogenic left ventricular apical aneurysm in hypertrophic cardiomyopathy

A 70-year old lady with prior myectomy for hypertrophic obstructive cardiomyopathy presented with sustained ventricular tachycardia. She was found to have a large left ventricular (LV) apical aneurysm. Surgical intervention was not advised, due to the risk of creating a small LV cavity after surgery and ICD was not advised based on the risk of injuring a very thin walled aneurysm. The patient's arrhythmia settled on medical therapy, but unfortunately she suffered an unwitnessed death three months later.This case represents a rare complication to a rare disease with limited management options. In such patients evidence based medicine is of little help, if any.     

Evidence for FHL1 as a novel disease gene for isolated hypertrophic cardiomyopathy

Hypertrophic cardiomyopathy (HCM) is characterized by asymmetric left ventricular hypertrophy, diastolic dysfunction and myocardial disarray. HCM is caused by mutations in sarcomeric genes, but in >40% of patients, the mutation is not yet identified. We hypothesized that FHL1, encoding four-and-a-half-LIM domains 1, could be another disease gene since it has been shown to cause distinct myopathies, sometimes associated with cardiomyopathy. We evaluated 121 HCM patients, devoid of a mutation in known disease genes. We identified three novel variants in FHL1 (c.134delA/K45Sfs, c.459C>A/C153X and c.827G>C/C276S). Whereas the c.459C>A variant was associated with muscle weakness in some patients, the c.134delA and c.827G>C variants were associated with isolated HCM. Gene transfer of the latter variants in C2C12 myoblasts and cardiac myocytes revealed reduced levels of FHL1 mutant proteins, which could be rescued by proteasome inhibition. Contractility measurements after adeno-associated virus transduction in rat-engineered heart tissue (EHT) showed: (i) higher and lower forces of contraction with K45Sfs and C276S, respectively, and (ii) prolonged contraction and relaxation with both mutants. All mutants except one activated the fetal hypertrophic gene program in EHT. In conclusion, this study provides evidence for FHL1 to be a novel gene for isolated HCM. These data, together with previous findings of proteasome impairment in HCM, suggest that FHL1 mutant proteins may act as poison peptides, leading to hypertrophy, diastolic dysfunction and/or altered contractility, all features of HCM.