Regulation of the vascular endothelial growth factor (VEGF) receptor Flk-1/KDR by estradiol through VEGF in uterus.

The induction of vascular endothelial growth factor (VEGF) expression by 17beta-estradiol (E(2)) in many target cells, including epithelial cells, fibroblasts and smooth muscle cells, suggests a role for this hormone in the modulation of angiogenesis and vascular permeability. We have already described a cyclic increase in Flk-1/KDR-expressing capillaries in the human endometrium during the proliferative and mid-secretory phases, strongly suggestive of an E(2) effect on Flk-1/KDR expression in the endometrial capillaries. However, it is unclear whether these processes are due to a direct effect of E(2) on endothelial cells. Using immunohistochemistry, we report an increase in Flk-1/KDR expression in endometrial capillaries of ovariectomized mice treated with E(2), or both E(2) and progesterone. This process is mediated through estrogen receptor (ER) activation. In vitro experiments using quantitative RT-PCR analysis demonstrate that Flk-1/KDR expression was not regulated by E(2) in human endothelial cells from the microcirculation (HMEC-1) or macrocirculation (HUVEC), even in endothelial cells overexpressing ERalpha or ERbeta after ER-mediated adenovirus infection. In contrast, Flk-1/KDR expression was up-regulated by VEGF itself, in a time- and dose-dependent manner, with the maximal response at 10 ng/ml. Thus, we suggest that E(2) up-regulates Flk-1/KDR expression in vivo in endothelial cells mainly through the modulation of VEGF by a paracrine mechanism. It is currently unknown whether or not the endothelial origin might account for differences in the E(2)-modulation of VEGF receptor expression, particularly in relation to the vascular bed of sex steroid-responsive tissues.

Transendothelial migration of two metastatic breast carcinoma cells depend on the SDF-lalpha-CXCR4 complexes.

The role of the SDF-1alpha chemokine-CXCR4 receptor system on tumor cell transendothelial migration was studied by culturing metastatic breast tumor cell lines, MDA-MB-231 and MDA-MB-435, either alone or on a HUVEC monolayer pre-established on a "Transwell" filter. After a 24-hour culture in the presence or absence of SDF-1alpha, tumor cell transmigration rates were compared. We showed that: CXCR4 is present on both cell lines; MDA-MB-231 but not MDA-MB-435 cell migration is stimulated by increasing concentrations of SDF-1alpha; neutralizing anti-CXCR4 antibody inhibits the SDF-1alpha chemoattractant effect; CXCR4 expression, measured by cytofluorometry, was enhanced after treatment with SDF-1alpha on MDA-MB-231 cells but remained unchanged on MDA-MB-435 cells; Scatchard analysis evidences 8.10(5) and 2.10(5) high affinity sites (KD range: 20 to 30 nM) on, respectively, MDA-MB-231 and MDA-MB-435 cells. These significant differences could explain the distinctive transendothelial migration responses of these two cell lines in the presence of SDF-1alpha.

Renin-angiotension-aldosterone system, urinary prostaglandins and kallikrein in pregnancy-induced hypertension: evidence for a dysregulation of the renin-angiotensin-prostacyclin loop.

Plasma renin activity (PRA) and aldosterone concentrations were measured simultaneously with urinary excretion of kallikrein and of four prostaglandins (PGE2, PGF2 alpha, 6-keto-PGF1 alpha and TXB2) in 23 patients with pregnancy-induced hypertension (PIH; 17 with permanent PIH (PH) and six with labile PIH (LH), i.e. patients whose hypertension was controlled only by home bed-rest) and in 16 normotensive pregnant women. Plasma renin activity was lower in PH than in controls or in LH. No difference between the three groups was observed for plasma aldosterone and urinary excretion of kallikrein and prostaglandins except that TXB2 was higher in LH than in PH. Thus patients with LH have a different biological profile from that of PH, since they have higher PRA and higher TXB2 excretion, an association that suggests a more pronounced ureteral compression by the gravid uterus in this group. Although no decreased synthesis of vasodilating prostaglandins was found in PH, a dysregulation of the renin-angiotensin-prostacyclin loop is suggested by a negative correlation between PRA and 6-keto-PGF1 alpha. An independent vasopressive substance which would stimulate PGI2 and suppress renin secretion is therefore postulated.

Liver in obesity.

We report on clinical, nutritional, and hepatic histological findings in 50 non-selected obese subjects (mean overweight +74%; range +21-138%). The pathogenesis of the liver damage was assessed with the help of multidimensional analysis of a number of clinical variables. According to the severity of the hepatic lesions, the patients have been ranged in five groups: O (normal liver) 10%; I (fatty liver) 48%; II (fatty hepatitis) 26%; III (fatty fibrosis) 8%; IV (fatty cirrhosis) 8%. The more severe changes (groups III and IV) were constantly associated with excessive alcohol intake. The multidimensional analysis was unable to find a relationship between obesity and the development of fibrosis and cirrhosis whereas it showed that: (a) there was a highly significant correlation between the daily ethanol intake and the degree of overweight, (b) severe fatty metamorphosis was significantly associated with the degree of overweight, the existence of diabetes mellitus, and the amount of alcohol and fat intake, (c) nutritional factors, in particular deficient protein intake, have only an accessory effect in the development of mild inflammation and fibrosis, (d) the consumption of potentially hepatotoxic drugs, very high in the obese (about five drugs per day) could have a role in the development of cirrhosis. In conclusion in our study, there was no evidence that obesity per se could result in severe liver damage.

Renin angiotensin aldosterone system, urinary prostaglandins and kallikrein in pregnancy induced hypertension. Evidence for a disregulation of the renin-angiotensin-prostacyclin loop.

Plasma renin activity and aldosterone concentrations were measured simultaneously with urinary excretion of kallikrein and four prostaglandins (PGE2, PGF2 alpha, 6 keto PFG1 alpha and TXB2) in 23 patients with pregnancy induced hypertension (17 with permanent PIH and six with labile PIH, since in these latter their hypertension was controlled only by home bed rest) and in 16 normotensive pregnant women at the same stage of gestation (31 +/- 3 weeks). PRA was lower in permanent PIH than in controls and in labile PIH. No difference between the three groups was observed for plasma aldosterone and the urinary excretion of kallikrein and of the prostaglandins except that TXB2 was higher in labile PIH than in permanent PIH. Correlation studies of kallikrein disclosed correlations with most prostaglandin excretions, explained by the physiological stimulation of phospholipase A2 by kallidin. Correlation studies of PRA disclosed unexpected negative correlation with PGE2 and 6 keto PGF1 alpha in the permanent PIH group. In conclusion, labile PIH has a different biological profile than permanent PIH since they have higher PRA and higher TXB2 excretion, an association which suggests a more pronounced ureteral compression by the gravid uterus in this group. Permanent PIH has a disregulation of the renin angiotensin-prostacyclin loop since PRA and 6 keto PGF1 are negatively correlated. This suggests the role of an independent vasopressive substance which would stimulate PGI2 and suppress renin secretion.

Influence of biochemical and hormonal factors on the bone histomorphometric features of uraemic patients.

A multidimensional analysis was used to evaluate, the influence on bone histology of various biochemical and hormonal factors in 20 uraemic patients on chronic haemodialysis or haemofiltration. A positive relationship (p less than 0.1) was found between PTH and osteoclastic and osteoblastic surfaces but not with mineral apposition and bone formation rates. The mineral appositional rate which reflects the cellular activity of osteoblasts was positively related to D metabolites 25(OH)D3 and 1,25(OH)2D3 and to phosphate (p less than 0.1). Mineral appositional rate and bone formation rate were negatively related to bone aluminium (p less than 0.05). These data indicate that: 1) PTH simulates bone turnover but has no direct effect on the bone cellular activity of osteoblasts which is mainly dependent on D metabolites and phosphate; 2) mild aluminium overload not severe enough to cause osteomalacia decreases bone formation in uraemic patients. This study evaluates the role of various simultaneously measured biochemical and hormonal factors on bone histological parameters in uraemic patients.

[Renin-angiotensin-aldosterone system, blood volume, serum uric acid and urinary excretion of prostaglandins and kallikrein in the arterial hypertension induced by pregnancy]. / Système rénine-angiotensine-aldostérone, volémie, uricémie et excrétion urinaire de prostaglandines et kallicréine au cours de l'hypertension artérielle induite par la grossesse.

The plasma renin activity (PRA), plasma volume (PV), urinary excretion of Kallikrein (UK) and PGE2, PGF2 alpha, 6-keto PGF1 alpha and TXB2 were measured in 24 ambulant patients without treatment on normal sodium diets with pregnancy-induced hypertension (HT) (diastolic BP greater than or equal to 90 mmHg, appearing after 20 weeks' pregnancy and absent 2 months after delivery). The UK was measured by an esterase technique, prostaglandins by radioimmunological assay and PV by dye dilution (Evans blue). Two subgroups of patients were identified according to the evolution of their blood pressure at rest at home; the first (7 patients) with labile HT, and the second (14 patients) with permanent HT. The PRA was significantly lower (p less than 0,001) in patients with permanent compared to labile hypertension (4,7 +/- 0,3 compared to 12,2 +/- 0,8 ng/ml/h) and compared to a control group of normotensive pregnant women (6,5 +/- 0,5). The PV, expressed as a percentage of the theoretical volume with respect to the stage of pregnancy and body surface area was low in both groups. In permanent HT: 1) there was no correlation between PV and PRA, 2) a positive correlation between UK and urinary 6-keto PGF1 alpha (r = 0,62; p less than 0,001) and PGE2 (r = -0,51, p less than 0,05). Discriminative linear analysis showed that urinary 6-keto PGF1 alpha was mainly related to PRA and to a lesser degree to UK.(ABSTRACT TRUNCATED AT 250 WORDS)

[Primary hyperparathyroidism. Lack of effect of cimetidine on plasma levels of parathyroid hormone and calcium]. / Hyperparathyroïdie primitive. Absence d'effet de la cimétidine sur les taux plasmatiques de parathormone et de calcium.

Because of the contradictory results formerly published as regards the effect of cimetidine in primary hyperparathyroidism, we have studied the effect of cimetidine at the daily dose of 1200 mg in 14 cases of primary hyperparathyroidism. The diagnosis was ascertained in all cases by the coexistence of an otherwise unexplained hypercalcemia and of a concomitantly elevated plasma concentration of immunoreactive parathyroid hormone (PiPTH) measured by 2 different antibodies and confirmed in 10 cases by surgical neck exploration. In 5 cases with severe hypercalcemia (greater than 12.0 mg/l) cimetidine was discontinued after 5 days because of its lack of effect on both plasma concentrations of calcium and PiPTH, and the patients were successfully operated. In 8 cases with milder hypercalcemia, cimetidine was given for 1.5-6 months. There was no significant change in both plasma concentrations of calcium (PCa) and PiPTH but a regression analysis showed that PCa was negatively correlated to time with a correlation coefficient which would have become significant if the follow-up had been 9 months. In the last patient severe hypercalcemia was controlled by simultaneous administration of phosphate, indomethacin and cimetidine without concomitant decrease of PiPTH; and 6 weeks after cimetidine discontinuation no significant increase of PCa and PiPTH occurred. These data show that cimetidine has no clinically therapeutic value in primary hyperparathyroidism.

Metronidazole in prevention of cholestasis associated with total parenteral nutrition.

The effect of metronidazole on liver function tests was studied in patients given total parenteral nutrition (TPN) for an acute attack of Crohn's disease. In those receiving TPN and metronidazole, serum activities of alkaline phosphatase and gamma-glutamyl-transferase decreased or remained normal after 30 days of TPN. In contrast, serum activities of these enzymes increased significantly after 30 days of TPN alone. These results suggest that intrahepatic cholestasis associated with TPN may be related to intestinal overgrowth of anaerobic bacteria.

Filterability in children.

The filterability of total blood and erythrocytes has been investigated in 36 children from 2 to 14 years old by the filtration method developed by Reid. Red blood cells being obtained by centrifugation, were washed three times and resuspended in saline. Filterability was recorded as the filtration time of 1 ml of total blood or red cells suspension. The filtration time of total blood was: 49.10 +/- 14.5 s/ml; that of resuspended cells was: 18.19 +/- 6.16 s/ml. These results have been correlated with age, fibrinogen, white blood cells, glycaemia, haematocrit, and compared with the results obtained in 42 adults whose filtration times were: 33.04 +/- 7.40; and red cells' time: 13.99 +/- 2.95. Statistical analysis shows that the difference is very significant and not correlated with the investigated factors. Erythrocyte filterability may be influenced by still unknown factor.

[Adult Still's disease (author's transl)]. / La Maladie de Still de l'adulte.

The study of 36 published cases of adult Still's disease shows the following features: the onset takes place usually during the third decade of life, most often as a polyarthralgia characterized by sometimes starting fever, evanescent rash, neutrophil leukocytosis, negativity of the serological tests for rheumatoid arthritis and systemic lupus; lymphadenopathy and splenomegaly are frequent but not constant; serous cavities, particularly pericardium, are rather frequently involved; evolution is characterized by a succession of relapses and remissions, the far prognosis being rather good (1/3 of cures, 1/3 of mild articular relapses, 1/3 of articular sequelae, involving chiefly neck and hips); corticosteroids and heavy doses of aspirin seem to give the best therapeutic results, the usefulness of a maintenance treatment is debatable.

[Adult Still's disease with constrictive pericarditis, Sjögren's syndrome and varied leucocytic abnormalities (author's transl)]. / Maladie de Still de l'adulte avec péricaedite chronique, syndrome SEC et anomalies leucocytaires diverses.

Adult Still's disease is a newly described disorder that is of interest not only for the rheumatologist but also for the internist since fever or extra-articular symptoms can reveal this disorder, which appears to be identical to the Wissler-Fanconi's syndrome. We report a new case characterized by the occurrence of a constrictive pericarditis with clinical features of protracted fever, by the late appearance of a Sjögren's syndrome and by peculiar blood abnormalities: hyperleucocytosis up to 80 000 after splenectomy, transient Felty's syndrome, blood monocytosis and bone marrow mastocytosis.