Effect of androgenic steroids on rat thymus and thymocytes in suspension.
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Biomedical subjects
Publications and source records attributed to M Mayer.
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Proteolytic activity was measured in murine erythroleukemic 745 cell line grown in culture, before and after the addition of agents which promote differentiation. The 36,000 X g soluble fraction of the cells degraded [14C]globin with maximal activity at pH 3.6, while the insoluble fraction failed to degrade [14C]globin within a pH range of 2.5-9.0. The acid protease activity in the soluble fraction of the undifferentiated murine erythroleukemic cells increased during the first 2 days in culture and remained constant during the following 4 days. We suggest that this activity resides in the lysosomes since it migrates together with the lysosomal marker alpha-mannosidase on colloidal silica gradients, shows maximum activity at acid pH and is sensitive towards inhibition by pepstatin. Induced differentiation of the cells by dimethyl sulfoxide, butyric acid or hexamethylene bisacetamide was concomitantly associated with a marked reduction in protease activity and the accumulation of hemoglobin within the cells. In contrast, in a non-inducible variant of 745 cell line DMSO failed to affect proteolysis. It is suggested that in murine erythroleukemic cells changes in acid protease activity are associated with the cellular triggered by chemical inducers.
Age-related and muscle tissue-specific alterations in myofibrillar protease activity were observed in different muscles of the rat. Utilizing exogenous, denatured and 3 H-labelled hemoglobin as substrate, proteolytic activity of the myofibrillar enzyme was found to decrease with age in the gastrocnemius muscle while the same activity in the diaphragm and heart muscles increased with age. The extent of response of the enzymes to administration of the potent glucocorticoid triamcinolone was, however, found to be similar in young and old animals, and each muscle retained its specific mode of response to the exogenous glucocorticoid, for example enhancement of the activity in skeletal and diaphragm muscles and diminution of the activity in the heart. Development was associated with a marked reduction in the number of glucocorticoid-specific binding sites in the cytosol of both gastrocnemius and heart muscles, with only negligible changes in the affinity of hormone binding. It is concluded that while the ability of the enzyme to response to exogenous, pharmacological doses of glucocorticoids is not affected by development, development does modify the myofibrillar protease activity in a tissue-specific manner.
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The origin of the additional chromosome was studied in 45 trisomic-21 Down-syndrome patients. In 17 patients the additional chromosome was maternal, in 2 it was paternal and in the remaining 26 the parental origin could not be determined. Acrocentric chromosome association was studied in parents of Down-syndrome offspring and in parents of spontaneous abortions that were trisomic for an acrocentric chromosome. Parents of trisomic 16 abortuses and parents of triploid and chromosomally normal abortuses were used as controls. No increased association index was found for the specific acrocentric chromosome involved in the trisomy, either for the liveborn or for the aborted trisomics. However, the overall association index of the parent in whom the non-disjunctional event leading to the acrocentric trisomy occurred was increased by comparison with that of the parent in whom non-disjunction did not occur and with that of the controls. The reasons why we consider satellite associations to play an insignificant role in the aetiology of non-disjunction are discussed.
Induction of nephrosis in rats with aminonucleoside of puromycin (ANP) was followed by an increase in urinary protease activity, measured by the cleavage of 14C-globin, as well as in antiprotease activity measured by trypsin inhibition. The excretion of protease and protease inhibitor coincided with but did precede the onset of proteinuria when the ANP was injected subcutaneously for 5 days and lagged after proteinuria when the ANP was given as a single intravenous dose. Serum protease activity did not change throughout ANP treatment or later, whereas serum antiprotease capacity declined coincidently with proteinuria, most probably due to the loss in urine. Kidney proteolytic activity was markedly reduced in ANP nephrosis. Treatment of rats with proteolysis inhibitors, trasylol, episilon-aminocaproic acid, soybean trypsin inhibitor, or hexapron, together with ANP failed to prevent, delay or reduce the proteinuria. We believe that the urinary protease in ANP nephrosis does not originate from the circulation but from the release of kidney protease as a consequence of the glomerular lesion, and does not appear to be involved in its causation.
The potent androgens testosterone and 5 alpha-dihydrotestosterone, but not the inactive androgens etiocholanolone and androsterone, display antiglucocorticoid activity in rat thymus-derived lymphocytes. At a concentration of 10(-5) M, the potent androgens markedly lower the in vitro cytolytic response of isolated thymic lymphocytes to 10(-8) M dexamethasone. AT 2.5 X 10(-5) M, these androgens completely prevent the inhibition produced by 5 X 10(-8) M dexamethasone on 2-deoxyglucose uptake and uridine uptake and incorporation in isolated thymic lymphocytes. In the cytosol fraction obtained from rat thymus homogenate, the active androgens competitively inhibit the binding of [3H]dexamethasone to glucocorticoid-specific receptors with Ki values of 1.2 X 10(-6) and 2.5 X 10(-6) M for testosterone and 5 alpha-dihydrotestosterone, respectively. Thymus-derived lymphocytes and nuclei isolated from these cells exhibit binding of [3H]dexamethasone. The bound dexamethasone is avidly displaced by an excess of nonradioactive dexamethasone as well as by nonradioactive testosterone or 5 alpha-dihydrotestosterone. In contrast to their antiglucocorticoid activity in vitro, these androgens fail to elicit antiglucocorticoid activity when administered in vivo. This work shows that androgens are potent antiglucocorticoids in vitro due to competition with the active glucocorticoid on binding to cytoplasmic and nuclear receptor sites.
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An isolated case of Duchenne muscular dystrophy in a female who has a de novo t(X;5)(p21;q35) translocation is described. The similarities between this patient and four previously reported females with Duchenne muscular dystrophy are discussed. It is concluded that the locus for Duchenne muscular dystrophy is at Xp21 and, furthermore, that this site may be particularly susceptible both to chromosome breakage and exchange and to gene mutation.
151 women were treated for potentially curable breast cancer. Their tumors were routinely analysed for estrogen receptors by the dextran-coated charcoal technic. Data were analyzed in relation to several parameters: age, age of menstruation, menopausal status, tumor size, TNN staging, axillary node status, nature of treatment. We have examined the pronostic implication of an ER negative content (ER-) in the primary tumor. We have found that the absence of detectable estrogen receptor in primary breast tumor appears to be correlated with a short disease free interval. In positive axillary node patients the value of the disease free interval is significantly shorter in ER- than in ER+ group: 11.5 months versus 23.5 (p less than 0.01).
Seven families with X-linked mental retardation (MR) have been studied clinically and cytogenetically. All affected males in six of the families were found to have a fragile site on Xq in a number of their peripheral lymphocytes. The fragile site was not seen in any of the affected males in the seventh family. The affected males in the six families with the fragile X had a syndrome characterized by a variable degree of MR, macro-orchidism, a characteristic repetitive, jocular speech, normal body proportions, and large jaws and ears. The fragile X chromosome could only be detected in a proportion of female carriers and its frequency in females was found to be correlated with their mental status to be inversely correlated with their age.
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Myofibrillar alkaline protease activity was shown to be present in human skeletal muscle. Endogenous myofibrillar proteins and 14C-labelled, exogenous haemoglobin were both active as substrates, and the enzymic activity appeared to be similar to the myofibrillar protease previously described in rodent muscles. The activity of this enzyme was determined in patients undergoing surgery for a variety of diseases. Significant elevations in proteolytic activity were found in the abdominal wall muscle of patients in wasting conditions as compared with non-catabolic diseases. In cachectic patients on total parenteral nutrition the protease activity was similar to reference values. The results imply that increased activity of the myofibrillar alkaline protease plays a role in the development of cachexia in human wasting diseases by prompting degradation of muscle proteins.
Diclofenac sodium (Voltaren) was tested over a period of six months in a double-blind experiment for its antiphlogistic and analgesic effect. A retained or impacted lower third molar was removed from each of the 138 patients studied. The postoperative course was evaluated in terms of the criteria of pain, trismus, swelling, and side effects; and the results were recorded. The swelling was objectified by photographic documentation and planimetric measurements. Our studies indicated that diclofenac sodium can also be recommended for the medicamentous prophylaxis of swelling and pain resulting from dental procedures.
From 1953 to 1972, 149 patients at Centre Leon Bérard, were treated by pelvic exenteration for carcinoma of the cervix. A review of the literature and of our cases showed that the mortality rate varied between 12 and 38 per cent according to the authors. In our experience, the final cause of death has been essentially pelvic reccurences within 18 months of the operation. For Ketcham, the patients died principally from metastases. To illustrate these results, criteria for patient selection for pelvic exenteration are outlined, with some suggestions for operative and post-operative management. The pre-operative medical status, the roentgenographic studies and finally exploratory laparotomy eliminated all but a very small number of patients, 15 to 20 per cent. Pelvic exenteration is appreciably beneficial only for this small group. Indeed, the exenteration is acceptable only when it does not result in excessive mutilation disproportinate with the chances of survival. It is conceivable only as curative treatment requiring a radical loco-regional excision, not only for the involved viscerae but also for the pelvic lymph nodes.
In a prospective, multi-centre, randomized study of 109 patients with metastatic gastro-intestinal adenocarcinomas the response rate, survival time and side-effects of two drug combinations, carmustin +5-fluorouracil and carmustin + ftorafur, were compared (same carmustin dosage in both groups). Response to the treatment was 32.7% in those receiving carmustin +5-fluorouracil, 26.3% in those on carmustin + ftorafur. This difference occurred among the 42 patients with gastric adenocarcinoma (33.3% compared with 25%), as well as in 11 with pancreatic adenocarcinoma, and in 56 with colorectal adenocarcinoma (32.1% and 28.6%). Median survival time for 5-fluorouracil + carmustin was 330 days, double that for ftorafur + carmustin (163 days). Bone-marrow toxicity (leukopenia, thrombopenia) was below 10% for both drug combinations. Alopecia occurred in only a few patients. Gastro-intestinal toxicity was common (20% and 18.5%, respectively), but there was no difference between the two groups. The somewhat lower effectiveness of ftorafur compared with 5-fluorouracil was probably due to the deliberately smaller dosage of the former.
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