Changes in the Subcellular Distribution of the Rat Uterus Oestrogen Receptor as Induced by Oestradiol,Tamoxifen and ZD 182,780

The aim of this work was to compare the subcellular distribution of the oestrogen receptor from the uteri of rats treated with vehicle alone (control group), oestradiol or one of the antio-estrogenic drugs tamoxifen and ZD 182,780. The nuclear, microsomal and cytosolic oestrogen receptor contents were evaluated by an immunoenzymatic method (“ER-EIA” kit from Abbott Laboratories) and the results in each fraction were expressed as a percentage of the total number of receptors. Parallel studies were performed to assess the uterotrophic effect of these drugs and to assess that they had reached the uterus. In the control group, we found that the oestrogen receptor was distributed mainly between the microsomal (29.1 ± 1.3%) and cytosolic (68.1 ±0.9%) fractions, with only a small amount located in the nucleus (2.8 ± 0.5%). When oestradiol was administered, the oestrogen receptor distribution was: nuclear 11.7 ± 2.0, microsomal 15.5 ± 1.3 and cytosolic 72.8 ± 3.3% and, in the tamoxifen group, the results were: nuclear 18.5 ± 1.5, microsomal 26.0 ± 31 and cytosolic 55.5 ± 3.4%, which shows a relative shift both to the control and the oestradiol-treated groups. In the uteri of rats treated with ZD 182,780 the results were very similar to those obtained in the control group. Our results indicate that the subcellular distribution of the oestrogen receptor varies according to the drug administered and that this receptor may not be located in a single subcellular compartment. Moreover, the nuclear uptake of the ZD 182,780-oestrogen receptor complex seems to be blocked, possibly due to impaired receptor dimerization. In the case of tamoxifen, the intracellular transport of the receptor also seems to be blocked, probably due to the nuclear retention of the receptor, thus suggesting that tamoxifen must impair the oestrogen receptor function on a step subsequent to the receptor dimerization.     

Assessment of proliferating cell nuclear antigen expression in precursor stages of gastric carcinoma using the PC10 antibody to PCNA

Immunohistochemistry using the PC10 antibody to proliferating cell nuclear antigen (PCNA) was applied to archival material from mucosa adjacent to gastric carcinoma ('normal', hyperplasia, complete and incomplete intestinal metaplasia and dysplasia) and non-cancer controls (normal and complete intestinal metaplasia). Overall, increased PCNA indices, with expansion and altered location of the proliferative zones, were observed in carcinoma fields and compared with controls ( P ≤0.001). These differences were particularly significant in 'normal' mucosa far from carcinoma as compared with normal in controls ( P ≤0.001). In carcinoma 'fields' distinct patterns of PCNA expression were noted in complete and incomplete intestinal metaplasia. Similarly, in dysplastic lesions high PCNA indices were present either throughout the gland or found predominantly in the upper compartment. We conclude that these differences in PCNA index and staining patterns might prove useful in monitoring the evolution of the disease in the follow-up of patients at risk of developing gastric cancer.     

Vital exhaustion, extent of atherosclerosis, and the clinical course after successful percutaneous transluminal coronary angioplasty

It has been observed that vital exhaustion, a state characterizedby unusual tiredness, increased irritability and feelings ofdemoralization not uncommonly precedes myocardial infarctionin apparently healthy individuals. This observation raised thequestion as to whether vital exhaustion is a marker of subclinicalcoronary disease. To answer that question the condition wasassessed in 105 male patients (mean age 54·8 year) beforeand 2 weeks after successful percutaneous transluminal coronaryangioplasty (PTCA) by the Maastricht questionnaire. Vital exhaustionwas found to be significantly correlated with the number ofdiseased vessels before PTCA and to decrease significantly afterPTCA. However, the association was rather modest (R²=0·08)and most patients remained exhausted after PTCA. During a follow-upperiod of 1·5 years, 32 patients (30%) experienced anew cardiac event (cardiac death, myocardial infarction, coronaryartery bypass grafting, repeat PTCA, a new coronary lesion orrecurrent angina with documented ischaemia). Univariate andmultivariate analyses showed that the number of diseased vessels,hypercholesterolaemia, and vital exhaustion were independentlyassociated with future events. The odds ratios were 3·74(P=0·02), 3·08 (P=0·08) and 3·07(P=0·04), respectively. It is concluded that the tirednesspreceding a cardiac event is only modestly associated with theextent of coronary artery disease and that a state of exhaustionafter PTCA increases the risk for a new cardiac event.     

Canine Exocrine Pancreatic Secretory Changes Induced by an Intragastric Ethanol Test Meal

In five dogs with chronic gastric fistulas (Thomas cannula) and a new type of chronic pancreatic fistula which permits collection of pure nonactivated pancreatic juice after ingestion of a test meal, the following series of experiments were performed: In the first series, a test meal (400 gm. canned dog meat) was given with 200 ml. saline simultaneously infused through the gastric cannula. In response to this stimulus, the 20-minute peak pancreatic flow rate and bicarbonate output were respectively 33% and 34%, of the maximal secretion of the pancreatic gland obtained with secretin in six control dogs provided with gastric and the classical Thomas duodenal fistula. The 20-minute peak protein output represented 84% of the maximal secretory capacity attained with dose-response curves to CCK in the same group of control animals.
In the second series either 1.5 or 2.0 gm./kg. ethanol were given instead of saline. Intragastric ethanol induced a dissociation of pancreatic secretion: a significant inhibition of flow rate, of bicarbonate concentration and output and a significant rise of protein concentration; protein output remaining unchanged.
It is postulated that ethanol, acting on the stomach and duodenojejunum, evokes, independently of its gastrin-releasing capacity', an unknown humoral or nervous mechanism that counteracts the ethanol-elicited cholinergic-mediated inhibition of pancreatic protein secretion which has been previously described.     

THE EFFECTS OF THE ATYPICAL ANTIPSYCHOTICS CLOZAPINE, REMOXIPRIDE AND RISPERIDONE ON THE CONTRACTILE CHARACTERISTICS OF RAT SKELETAL MUSCLEIN VITRO

The therapeutic use of the atypical antipsychotics clozapine, remoxipride and risperidone has been reported to be associated with a reduced occurrence of the extrapyramidal side-effects seen during therapy with classical (or typical) antipsychotics such as trifluoperazine and haloperidol. The aim of this study was to determine the effects of the atypical antipsychotics clozapine, remoxipride and risperidone on rat skeletal musclein vitro. Remoxipride and risperidone did not produce contracture in muscle. Clozapine induced a small muscle contracture at high concentrations. Pre-treatment of muscle with trifluoperazine or haloperidolin vitrocaused the muscle to display contracture responses to halothane, and haloperidol also potentiated a contracture response to caffeine. Pre-treatment of muscle with remoxipride and risperidone did not induce contracture in response to halothane and did not potentiate caffeine contracture. Clozapine pre-treatment caused muscle fibre bundles to display a small halothane-induced contracture and caused significant potentiation of caffeine-induced contracture.