The binding of [3H]4-diphenylacetoxy-N-methylpiperidine methiodide to longitudinal ileal smooth muscle muscarinic receptors

Muscarinic receptors present in longitudinal ileum were characterized using the non-selective radioligand [3H]N-methylscopolamine [( 3H]NMS) and the M3 selective radioligand [3H]4-diphenylacetoxy-N-methylpiperidine methiodide [( 3H]4DAMP). In saturation studies, [3H]4DAMP, but not [3H]NMS, identified two populations of binding sites with 17% of the sites (155 fmol/mg protein) displaying high affinity (Kd = 0.39 nM) for [3H]4DAMP and the remaining sites displaying low affinity for the radioligand (Kd = 4.43 nM). In competition studies gallamine and methoctramine, but not AF-DX 116, identified two populations of [3H]NMS binding sites. Affinity estimates for gallamine and methoctramine indicated that 80% of the [3H]NMS binding sites were of the M2 subtype. The minor population of [3H]NMS binding sites could not be readily characterized, due partly to the low selectivity of the competing ligands and also to the relatively low density of the sites. In studies using the M3 muscarinic receptor selective radioligand [3H]4DAMP, the minor population of sites could be preferentially labeled by using a low concentration (0.4 nM) of [3H]4DAMP. Under these conditions, [3H]4DAMP labeled approximately equal levels of the two muscarinic receptor binding sites present in the ileum. Competition studies with AF-DX 116, gallamine and methoctramine indicated that the two [3H]4DAMP binding sites displayed the pharmacology expected of the M2 and M3 receptors, respectively. These results provide additional evidence that longitudinal ileal smooth muscle membranes contain both M2 and M3 muscarinic receptors and indicate that [3H]4DAMP is a useful ligand for identifying heterogeneity of muscarinic receptor subtypes.     

Cocaine-induced Increase in Cortical Acetylcholine Release: Interaction with the Hypothalamo—Pituitary—Adrenal Axis

An influence on drug-taking behaviours of the stress-related hypothalamo-pituitary-adrenal (HPA) axis and its final hormonal mediator, corticosterone, has previously been demonstrated. A role for cortically projecting cholinergic neurons in these behaviours can also be proposed. The experiments presented here examine the effect of the drug of abuse cocaine (15 mg/kg) on the release of acetylcholine (ACh) in the cortex of freely moving rats, using the technique of in vivo microdialysis. To assess a possible modulatory influence of the HPA axis via its final hormonal mediator corticosterone, the cocaine-induced effect on cortical ACh release in intact rats was compared to that in adrenalectomized (ADX) rats, which thus lacked their endogenous source of corticosterone, and in ADX rats in which the cocaine-induced corticosterone peak and/or the basal circadian concentrations of serum corticosterone were simulated by replacement treatments. The results reported here demonstrate that cortical ACh release is greatly increased by cocaine in intact rats; ADX prolongs the return to basal levels of cortical ACh, and the chronic replacement of circadian levels of corticosterone normalizes this effect. In contrast, during the plateau period of cocaine-induced increased cortical ACh release, where no effect of ADX is evident, rats with chronic replacement of corticosterone show an attenuated cocaine-induced cortical ACh release, and the acute replacement of the cocaine-induced corticosterone secretion further attenuates this response. These results demonstrate that cocaine stimulates cortically projecting cholinergic neurons, and that the HPA hormone corticosterone modulates this interaction in a complex manner which merits further investigation.     

Action of iturin A, an antifungal antibiotic from Bacillus subtilis, on the yeast Saccharomyces cerevisiae: modifications of membrane permeability and lipid composition

The action of iturin A on non-growing cells of Saccharomyces cerevisiae was tested. This antibiotic gave important modifications in the membrane permeability which permitted nucleotides, proteins, polysaccharides and lipids to escape from cells. The lipid content of cells was strongly disturbed; the level of phospholipids, essentially phosphatidylcholine, decreased while the level of fatty acids increased. A part of these fatty acids were extruded from yeast cells. The role of iturin A in these modifications was discussed.     

Group A Streptococcus invasive infections: a review

The incidence of group A Streptococcus (GAS) invasive infections has been increasing worldwide, and there is no obvious explanation for this phenomenon. In 1993, a working group on severe GAS infections was established to define accurately what constitutes an invasive infection. Three types of infection are particularly feared: necrotizing fasciitis, myositis and a newly defined entity, named streptococcal toxic shock syndrome (STSS) because of a certain analogy with its staphylococcal counterpart. GAS produces many toxins responsible for its clinical manifestations. Some of them, labelled streptococcal pyrogenic exotoxins, have been characterized as superantigens. These proteins play a key role in initiating the immune response to GAS and are mostly responsible for the precipitous course of invasive infections. Death rates are high in streptococcal invasive infections, ranging from about 20% for necrotizing fasciitis to almost 100% for myositis. Therapy consists mainly of high doses of antibiotic combinations, aggressive surgery, and intravenous administration of immunoglobulins for STSS.     

Prediction of risk in noncardiac operations after cardiac operations

To determine the preoperative variables affecting the mortality rate and the development of severe complications in patients who have had myocardial revascularization or a valve replacement and who then undergo a noncardiac operation, we retrospectively studied data from 120 such patients over the 5 years from 1982 through 1986. Thirty-six percent of patients had a noncardiac operation during the first month after the cardiac operation. The mortality rate was 11%, and the morbidity rate was 56%. The statistical comparison of the predictive accuracy of postoperative complications of three simple, widely used classifications (American Society of Anesthesiologists physical status, New York Heart Association classification, Massachusetts General Hospital cardiac risk index) demonstrated the superiority of the simplified three-class cardiac risk index (Massachusetts General Hospital-cardiac risk index; predictive accuracy of 84%). In a multivariate discriminant analysis of 21 variables in this population, five variables (myocardial infarction in previous 6 months, S3 gallop or jugular vein distention, arrhythmia on last preoperative electrocardiogram, emergency operation, delay between cardiac and noncardiac operation) were identified as being the most predictive of a postoperative complication. When these variables were used in the function (DF3) obtained by linear discriminant analysis, the prediction accuracy of a postoperative complication reached 83%. Performance of the new models in a prospective validation population remained satisfactory (75% for Massachusetts General Hospital-cardiac risk index three-class index and 72% for DF3). Extensive statistical analysis of our data tested by a validation study provided simple predictive models based on clinical variables easily available even in emergency situations.     

Fluorine-18-fluorodeoxyglucose positron emission tomography for preoperative parathyroid imaging in primary hyperparathyroidism

Fluorine-18 fluorodeoxyglucose (FDG) positron emission tomography (PET) imaging was performed in seven consecutive patients with primary hyperparathyroidism to preoperatively locate parathyroid adenomas. Foci of FDG accumulation corresponding to abnormal parathyroid tissue were observed in two out of nine surgically excised parathyroid adenomas. It was concluded that FDG PET imaging demonstrated a too low sensitivity for systematic preoperative detection and localization of parathyroid glands causing primary hyperparathyroidism.     

Body composition of patients on a very low-protein diet: a two-year survey with DEXA.

BACKGROUND: It has been reported that patients on a very-low-protein diet (VLPD) maintain a satisfactory nutritional status because of a conserved adaptive metabolic response. However, only few studies have examined the course of nutritional status and body composition in the long term (2 years). METHODS: Thirteen stable patients (8 men; age, 55 +/- 12 years; glomerular filtration rate (GFR), 15 +/- 5 mL/min) receiving a VLPD (0.3 g/kg/day protein) supplemented with amino acids and ketoanalogues (SVLPD) were studied for 2 years. A joint visit with a physician and a dietitian and routine blood and urine analyses were performed every month. Dual-energy x-ray absorptiometry (DEXA), which was used to assess modification of body composition, and GFR (urinary 51Cr-EDTA) and urinary urea and creatinine excretion, which were used to assess nutritional status and compliance to the diet, were assessed every 3 months. RESULTS: GFR, albumin, and prealbumin levels remained stable. Urea urinary excretion decreased at 3 months and then slightly increased at 2 years, but the calculated protein intake remained low at 0.38 +/- 0.1 g/kg/day. Energy intake remained close to 30 kcal/kg/day. No significant change was observed for total fat mass or percent fat mass. After an initial decrease, lean body mass stabilized at 6 months and then increased significantly from 6 to 24 months (P =.02, paired t-test); the mean increase during this period was of 2 kg, that is, 4.6%. Urinary creatinine excretion showed the same profile. Total bone mass, lumbar or hip site bone mass, and Z-score significantly decreased from T0 to 1 and 2 years (P <.05). CONCLUSION: This study confirms that a supplemented VLPD is nutritionally safe for a long period, but attention must be paid to bone mass.