[Steroid anti-hormones: anti-progesterone activity of RU 486 and its contragestational and other applications].
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Biomedical subjects
Publications and source records attributed to A Ulmann.
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Aetiological diagnoses obtained by means of an algorithm were retrospectively compared with those made in the Internal Medicine Department of the La Pitié Hospital, Paris, in 22 cases of hypercalcaemia (24 causes detected). These cases covered all the usual causes of the disease. The algorithm produced no erroneous diagnosis. In 2 cases it would not have resulted in a precise diagnosis, but in all other patients the diagnosis obtained by this method was in agreement with the clinical diagnosis. Proposals are put forward for an improved version of the algorithm that would provide more rapid diagnoses and avoid the risk of a "no diagnosis" answer.
A quantitative microdensitometric study has been designed to characterize in situ intestinal brush border-bound alkaline phosphatase of rat duodenal villosities. Intestinal slices were incubated with beta-glycerophosphate as substrate. Free phosphate liberated was precipitated in presence of a lead reagent as lead sulfide. The precipitate was quantified in situ by scanning and integrating microdensitometry. Kinetic parameters of the reaction were determined at 37 degrees C, pH 8.8, in the middle part of the villosities. Apparent Michaelis constant (Km) for beta-glycerophosphate was found to be 8.16 +/- 0.56 mM (mean +/- S.E.). Maximal enzyme activation was obtained at pH 8.5. Maximal inhibition of enzyme activity was observed in the presence of L-phenylalanine (30 mM) or theophylline (5 mM). Along the villosity axis, enzyme activity rose from the crypt up to the midportion of the villosity and finally decreased at the tip region. In phosphate-depleted rats, enzyme activity was increased in all portions of the villosity, with conservation of the same activity gradient. In this situation, kinetic analysis showed a marked decrease of Km, i.e. 4.56 +/- 0.39 mM (mean +/- S.E.) as compared to normal rats.
The preventive affects on recurrent renal calcium stones of water diuresis alone or combined with drugs aimed at lowering urinary calcium were evaluated prospectively in 51 patients with calcium nephrolithiasis. Following clinical and metabolic examination, the patients were allocated at random to 3 treatment groups: water diuresis alone (group I, n = 19) or associated with hydrochlorothiazide 50 mg/day (group II, n = 19) or with a neutral phosphate preparation 1500 mg/day (group III, n = 13). Results were assessed on the number of recurrences; 24-h urinary calcium was measured at regular intervals. The mean follow-up (2 years; range 1-4 years) was the same in all 3 groups. A significant fall in recurrence rate as compared with pre-treatment values was observed in groups I and II. The recurrence rate was the same in both groups during treatment. However, less patients had recurrences in group I (1/19) than in group II (5/19). No significant fall in recurrence rate was observed in group III, owing to some patients in this group having frequent recurrences. The recurrence rate was unrelated to clinical findings and biochemical values ( oxaluria , calciuria) measured before treatment and to the urinary Ca/Cr ratio calculated during treatment. This study confirms that water diuresis is effective in preventing recurrent renal calcium stones and that diuretics of the thiazide group reduce the number of patients with recurrences.
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Following earlier studies using a simplified cryopreservation method in rats, we report the successful use of this technique in a hemodialysis patient who had previously undergone total parathyroidectomy. In additional studies, parathyroid glands from rats were conserved by this rapid freezing procedure after total parathyroidectomy. Six weeks after parathyroid autotransplantation the animals were submitted to a low-calcium diet and their parathyroid gland function compared to that of rats that had previously undergone sham operation, immediate autotransplantation, or delayed autotransplantation using the classical cryopreservation method. With both cryopreservation techniques, plasma calcium, phosphorus, and 1,25 (OH)2 vitamin D concentrations after low-calcium diet were similar although results were less satisfactory than with immediate autotransplantation or after sham operation. We suggest that this simplified cryopreservation technique, developed in rats, yields functioning parathyroid gland tissue and can be successfully used in the human.
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We looked systematically for the presence of receptor like binding sites for 1,25-dihydroxyvitamin D3 (1,25-(OH)2D3) in the cytosol from 22 breast cancers. Cytosols were centrifuged on 5-20% sucrose gradients after labeling with tritiated 1,25 (OH)2D3 (3H-1,25(OH)2D3 or 25-hydroxyvitamin D3 (25(OH)D3 alone or in the presence of a large excess of these unlabeled sterols. Binding sites for 1,25 (OH)2D3 migrating in the 3.5-3.7 S region were found in 7 out of 22 cancers, while 5.5-6.5 binding sites for 25 (OH)D3 were found in all cytosols. In a patient in whom cytosol containing a 3.5-3.7 S binding site was in sufficient amount, quantification of 1,25 (OH)2D3 binding indicated a KD of 0.28 nM and a maximal binding capacity of 0.15 pmol/mg prot. No relation was found between the presence or the absence of 1,25 (OH)2D3 binding sites and the histological type, the extension of the cancer, the presence of radiological or histological calcifications, the amount of estrogen or progesterone receptors, the plasma calcium or phosphate concentration and the emergence of metastases after 1 year. The significance of the presence of receptor-like binding sites for 1,25-(OH)2D3 in one third of breast cancers remains therefore unknown at the present time.
The association of pericarditis and pulmonary embolism may be the source of diagnostic error and delay in the administration of anticoagulant therapy. Two cases are reported. Pericarditis occurred late in patients with severe, chronic pulmonary embolism with electrocardiographic changes of acute cor pulmonale. Two physiopathological mechanisms for this association have been proposed. The first, haemodynamic, suggests friction between the pericardium and distended right ventricle and pulmonary artery. The second, an immunological hypothesis, compares the association of pericarditis and pulmonary embolism to that of the Dressler syndrome after myocardial infarction. This assimilation would imply the constitution of an anatomical pulmonary infarction. It is not justifiable to accept this pathogenesis on the evidence of transient pulmonary opacities resulting from intra-alveolar haemorrhage or of linear opacities of pulmonary atelectasis secondary to hypocapnic pneumoconstriction which are radiological signs of anatomo-physiological stages of pre-infarction.
Three studies have been undertaken to evaluate the predictive value for new stone formation of urinary calcium excretion. In study 1, 24-hr calciuria was similar in 52 patients with benign stone disease (less than 3 new stones or 1 staghorn calculus in the 5 preceeding years) and in 46 patients with severe lithiasis (more than 3 stones or 1 staghorn calculus), based on a retrospective assessment of stone disease evolution. In study 2, urinary fasting Ca/Creat was identical in 43 non-hyperparathyroid stone formers (including 31 with severe lithiasis) and in 35 patients with proven or suspected primary hyperparathyroidism (including 19 with benign lithiasis, 8 with severe lithiasis and 8 with no stone). In study 3, stone recurrence, assessed prospectively, felt significantly in patients given a high fluid intake alone or associated with 50 mg/d of hydrochlorothiazide, independently of urinary calcium excretion. Urinary calcium determination therefore appears useless for stone recurrence prediction.
The authors report a case of hypophosphoremic osteomalacia due to a soft tissue tumor. This case confirm 1,25 (OH)2 cholecalciferol deficiency. Treatment with phosphorus and 1,25 (OH)2 cholecalciferol cured osteomalacia. Accountable tumor (villonodular synovitis) had never been described previously.
We studied the modification of tubular reabsorption of phosphate (TRPi) in conscious rats given glucose either intravenously or orally. These rats served as their own controls, and were also compared to rats given vehicle intravenously or orally. 30-min urine collections were performed just before the administration of glucose or vehicle, and 15 and 75 min afterwards. Plasma was sampled at the end of each urine collection. Plasma glucose (PG) increased significantly in rats given glucose either intravenously or orally. Intravenous administration of glucose reduced TRPi slightly but significantly, a result also observed in control rats infused with vehicle. On the other hand, a significant decline in TRPi was noted in rats given oral glucose whether or not they had been fasted for the preceding 24 h, but not in those given oral vehicle. The maximal decrease in TRPi was of the same order of magnitude in both fasted and nonfasted rats given glucose orally, although it was delayed in the latter group and significantly higher than in rats infused with glucose. These results suggest a relationship between some factor secreted concomitantly with the ingestion of glucose and the renal handling of phosphate.
The author reports certain data from the literature and based upon his own experience. The urinary excretion of calcium is dependent upon diet and in particular sodium intake. Urinary calcium decreases when sodium intake is reduced. The administration of rapidly absorbed sugars and protein rich diets cause an increase in urinary calcium. It is thus of fundamental importance to be aware of the nature of the diet in patients in whom 24 hour urinary calcium is measured. In particular, such measurements are of no value during the immediate postoperative period. Is the existence of hypercalciuria (defined by a urinary calcium greater than 0.1 mmol/kg/day) truly responsible for an increase in the frequency of recurrences of lithiasis? In two groups of patients, one with progressive lithiasis and the other with non-progressive lithiasis, the mean urinary calcium for each of the two groups was the same. In addition, patients with a high daily calcium excretion were not necessarily those with progressive lithiasis. Three groups of patients were also compared, according to whether they had a high fluid intake, a fluid intake associated with a hydrochlorothiazide or a fluid intake associated with a neutral phosphorus salt. Phosphate therapy was a failure. In comparison with their previous state, patients receiving merely a high fluid intake or in combination with thiazides had less recurrences than before such treatment. The group treated with thiazides had significantly less recurrences than the group treated by simple high fluid intake. However urinary calcium was not lowered by thiazides. Thus the role of thiazides probably does not lie in hypocalciuria but merely in an increase in urine output.
The urinary excretion of various substances involved in kidney stone formation was evaluated in 67 patients with hypercalciuric lithiasis (HCl), 36 lithiasis patients with normal calciuria (NCl) and 21 controls without urinary stones. All subjects were hospitalized for 3 days and given a calcium, phosphorous and sodium-controlled diet. The 24-hour urine volume was significantly larger in the HCl and NCl groups than in controls. The 24-hour Ca, Na and uric acid excretion was significantly greater in the HCl group than in the NCl and control groups. Oxalate and pyrophosphate excretion was the same in all three groups. Urinary Ca correlated with urinary creatinine in the HCl and control groups, but the slope and ordinate of the regression line were significantly higher in the former group. Similarly, urinary Na correlated with urinary creatinine in the HCl and control groups with a significantly steeper slope in the HCl group. These data are suggestive of abnormalities in the tubular reabsorption of Ca and Na in HCl patients. Finally, there was no correlation between the values obtained and the activity of the disease, as evaluated by the finding of at least 3 urinary stones or one staghorn calculus during the 5 years preceding the study. It is concluded that measurements of Ca, Na, uric acid, creatine, oxalates and phosphates during a stay in hospital provide pathophysiological information but cannot be taken as indices of urolithiasis activity.
The amount of reducing equivalents from NADPH generated by glucose 6-phosphate dehydrogenase activity (G6PD) used in mixed function oxidation (pathway I) or in reductive biosynthesis (pathway II) has been determined by cytochemical methods and microdensitometry in cells from the pars recta (PR) and distal convoluted tubule (DCT) of the kidney and from centrilobular (CL) and periportal (PP) hepatocytes from rats fed a normal or a vitamin D-deficient diet. In the kidney, pathway I activity was similar to that of pathway II in PR, whereas in DCT pathway II was markedly predominant. Feeding a vitamin D-deficient diet resulted in an increase in the total amount of reducing equivalents in PR and DCT. This increase was due to a rise in pathway I activity in the PR, whereas in the DCT the increase resulted from a stimulation of pathway II activity. Pathway I activity in PR was inversely correlated with plasma calcium, and was significantly decreased when calcium (1 mM) was added in vitro. In the liver the total amount of reducing equivalents generated by G6PD and both hydrogen pathways, was higher in CL than in PP hepatocytes. In CL cells, a vitamin D-deficient diet induced a significant increase in both NADPH pathways. Furthermore, in these cells pathway I activity was inversely related to plasma calcium and was significantly lowered when 1 mM calcium was added in vitro. It is concluded that vitamin D status and calcium influence the production and utilization of cytosolic reducing equivalents both in kidney and liver.
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Systematic study undertaken of 44 transplant patients with plasma creatinine below 0.11 mmol/L indicated renal phosphorus leak in approximately two-thirds of them and increased plasma PTH in all but one. Plasma 1,25(OH)2D was elevated in half the patients in whom it was measured. The lack of correlation found between plasma 1,25(OH)2D and plasma PTH or phosphorus probably indicates tubular lesions resulting in decreased production of 1,25(OH)2D. A phosphorus restriction test in 12 hypophosphatemic patients demonstrated that the reduced renal phosphorus reabsorption probably was due to both persisting hyperparathyroidism and a PTH-independent phosphorus leak.
Calcium calculi are by far the most frequent of urinary stones. In many cases their formation is enhanced by lithogenetic abnormalities, including idiopathic calciuria. The basis of the treatment is to promote diuresis by absorbing for an indefinite period a mineral water containing less than 100 mg/l of calcium. There is no evidence that drugs reducing calciuria (thiazides, phosphorus) or uraturia (allopurinol) are effective, and they should be reserved to cases of rapidly progressive lithiasis. A long-term strategy for the prevention of lithiasis is discussed.