Focal expression and final activity of matrix metalloproteinases may explain irregular dysfunctional endometrial bleeding

Irregular dysfunctional bleeding of the endometrium (ie, metrorrhagia without organic lesion) is common in women, whether treated or not with ovarian hormones. Several matrix metalloproteinases (MMPs) become normally expressed and/or activated at menstruation and cause extracellular matrix breakdown. We therefore explored whether episodes of irregular dysfunctional bleeding could be associated with untimely MMP activity. By histology, foci of stromal breakdown were exclusively found in the endometrium of metrorrhagic women at bleeding. In these foci, 1) expression of estrogen receptor-alpha and progesterone receptor was altered; 2) collagenase-1 (MMP-1), stromelysin-1 (MMP-3), and gelatinase B (MMP-9) became detected in stromal cells, together with MMP-9 in neutrophils; and 3) gelatinase A (MMP-2) was more expressed and immunolocalized at the membrane of stromal cells. By biochemistry, endometrial lysates from nonbleeding metrorrhagic patients contained more latent and active MMP-2 and -9 than age-matched controls; at bleeding, collagenase activity, MMP-9, and active MMP-2 were strikingly increased whereas tissue inhibitor of metalloproteinases-1 (TIMP-1) was considerably decreased. As a functional assay, in situ gelatin zymography revealed large areas of gelatinolytic activity only in endometrium of bleeding patients. Altogether, these results strongly suggest that inappropriate focal expression and activation of several MMPs, combined with decreased inhibition, trigger irregular dysfunctional endometrial bleeding.     

Persistent increase in the incidence of acute male urethritis diagnosed in general practices in France

BACKGROUND: At-risk sexual behaviour seems to have increased in Europe, possibly due to the reassuring efficacy of highly active antiretroviral treatments. AIM: To follow, from 1990 to 2003, in France, the trends in the incidence of acute male urethritis diagnosed in general practice, a marker of at-risk sexual behaviour. DESIGN OF STUDY: Electronic disease surveillance. SETTING: General practices located all over mainland France. METHOD: The GPs of the French Sentinelles network reported, via online computer systems, the acute urethritis cases they diagnosed, and for each case the characteristics of the patients. RESULTS: After a striking decrease between 1990 and 1995 from 460 per 100 000 men aged 15-64 years (95% confidence interval [CI] = 390 to 520) to 180 (95% CI = 150 to 200), when antiretroviral drugs became available on the French market, the incidence of acute male urethritis stopped decreasing. Between 1996 and 2003, it may have risen again from 190 per 100 000 men (95% CI = 160 to 210) to 325 per 100 000 men (95% CI = 280 to 370) aged 15-64 years. The percentage of homosexual/bisexual men among the cases reported was higher than in the general population (10% versus 4%, P<0.001). Homosexual/bisexual patients were younger than heterosexual patients (34 versus 37 years, P = 0.04), more of them had a discharge (88% versus 59%, P<0.001), a history of sexually transmitted disease (65% versus 32%, P<0.001), and at least two sexual partners (74% versus 38%, P<0.001). The most frequent pathogens were Chlamydia trachomatis (25%), Neisseria gonorrhoea (21%), Mycoplasma genitalium (8%), Ureaplasma urealyticum (5%), Trichomonas vaginalis (3%) and other bacteria (32%). Presence of co-infections was observed in 8.3% of patients. CONCLUSIONS: This increase in the incidence of urethritis, shows that the sexual health of men has worsened in France, and calls for urgent new preventive measures.     

Spontaneous increase of DNA turnover in murine systemic lupus erythematosus

DNA synthesis and release was studied in unstimulated splenocytes of strains of mice known to develop spontaneous systemic lupus erythematosus (SLE)-like disease and in non-SLE age- and sex-matched strains as well. Newly synthesized DNA was measured as total acid-insoluble radioactive material present in cell pellet plus supernatant of unstimulated 0–72 h cell cultures [³H]thymidine-pulsed, whereas DNA release was measured as amount of acid-precipitable radioactivity found in supernatant of those cultures. In all strains known to develop spontaneous murine SLE the amount of newly synthesized DNA was 1.3–2.1-fold increased when compared to normal strains studied concomitantly. Furthermore, a significant increase in DNA release into medium, unrelated to cell viability, was observed in those strains as well. These observations clearly demonstrate different metabolic rates of synthesis and release of DNA in murine SLE. This difference suggests the existance of an underlying mechanism responsible for extracellular DNA abundancy, which may be important for the formation of circulating DNA-anti-DNA immune complexes.     

Specific-impedance measurements of brain tissues

A technique that allowsin vivo measurements of the specific impedance of brain structures is analysed and implemented. This technique uses the 4-electrode method. The system includes an optically isolated current source and an interchangeable electrode module. Tests on the measuring system, including the electrodes and calibration procedures, are presented. Experiments in media of known resistivity and in cat brains define the present limits of the spatial resolution.     

Degeneration of germ cells in normal,hypophysectomized and hormone treated hypophysectomized rats

In normal adult rats some germ cells degenerate at several vulnerable steps of spermatogenesis. These are the type A spermatogonia, midpachytene spermatocytes, primary and secondary spermatocytes which degenerate during their respective maturation divisions and step 7 and 19 spermatids. In the present study, these degenerating cells were examined under the electron microscope, and their frequency was determined in toluidine blue stained semithin sections of testes from normal, hypophysectomized (at 5.5 days after operation) and hypophysectomized rats injected with FSH and LH separately or in combination. With the exception of the step 19 spermatids, the degenerating germ cells underwent necrosis in vacuolated spaces delimited by Sertoli cells. In the case of the affected step 19 spermatids, an apical cytoplasmic process of the Sertoli cell initially ensheathed a long segment of their flagellum, and then each degenerating cell was drawn deep in the seminiferous epithelium where it was phagocytozed by the Sertoli cell. Soon after hypophysectomy the incidence of degenerating mid-pachytene spermatocytes, step 7 and 19 spermatids which are present in stages VII or VIII of the cycle of the seminiferous epithelium, increased significantly. In contrast the number of degenerating primary or secondary spermatocytes during the meiotic divisions seen in stage XIV of the cycle or of any other germinal cell was not significantly modified. While the injection of FSH alone had no influence on the number of degenerating cells in hypophysectomized rats, injections of LH at the two doses administered (0.7 μg or 20 μg) reduced significantly the number of degenerating cells seen in stages VII-VIII of the cycle; combined injections of FSH and LH (20 μg) reduced the number of these degenerating cells to the normal low values. Thus it appeared that the mid-pachytene spermatocytes and the step 7 and 19 spermatids, all present in the adluminal compartment of the seminiferous epithelium in stages VII or VIII of the cycle, were more sensitive to the presence of absence of gonadotropic hormones than the other germ cells present in the seminiferous epithelium.     

Myd88-dependent in vivo maturation of splenic dendritic cells induced by Leishmania donovani and other Leishmania species

The usual agent of visceral leishmaniasis in the Old World is Leishmania donovani, which typically produces systemic diseases in humans and mice. L. donovani has developed efficient strategies to infect and persist in macrophages from spleen and liver. Dendritic cells (DC) are sentinels of the immune system. Following recognition of evolutionary conserved microbial products, DC undergo a maturation process and activate antigen-specific na?ve T cells. In the present report we provide new insights into how DC detect Leishmania in vivo. We demonstrate that in both C57BL/6 and BALB/c mice, systemic injection of L. donovani induced the migration of splenic DC from marginal zones to T-cell areas. During migration, DC upregulated the expression of major histocompatibility complex II and costimulatory receptors (such as CD40, CD80, and CD86). Leishmania-induced maturation requires live parasites and is not restricted to L. donovani, as L. braziliensis, L. major, and L. mexicana induced a similar process. Using a green fluorescent protein-expressing parasite, we demonstrate that DC undergoing maturation in vivo display no parasite internalization. We also show that L. donovani-induced DC maturation was partially abolished in MyD88-deficient mice. Taken together, our data suggest that Leishmania-induced DC maturation results from direct recognition of Leishmania by DC, and not from DC infection, and that MyD88-dependent receptors are implicated in this process.     

Systemic and mucosal antibody responses specific to SARS-CoV-2 during mild versus severe COVID-19

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Genotype-phenotype correlation in von Hippel-Lindau families with renal lesions

von Hippel-Lindau (VHL) disease arises from mutations in the VHL gene and predisposes patients to develop a variety of tumors in different organs. In the kidney, single or multiple cysts and renal cell carcinomas (RCC) may occur. Both inter- and intrafamilial heterogeneity in clinical expression are well recognized. To identify VHL-dependent genetic factors, we investigated the renal phenotype in 274 individuals from 126 unrelated VHL families in whom 92 different VHL mutations were characterized. The incidence of renal involvement was increased in families with mutations leading to truncated protein (MLTP) or large rearrangement, as compared to families with missense changes (81 vs. 63%, respectively; P=0.03). In the latter group, we identified two mutation cluster regions (MCRs) associated with a high risk of harboring renal lesions: MCR-1 (codons 74-90) and MCR-2 (codons 130-136). In addition, the incidence of RCC was higher in families with MLTP than in families with missense changes (75 vs. 57%; P=0.04). Furthermore, mutations within MCR-1 but not MCR-2 conferred genetic susceptibility to develop RCC. Overall, our data argued for a substantial contribution of the genetic change in the VHL gene to susceptibility to renal phenotype in VHL patients.