Spermatogonia differentiation requires retinoic acid receptor γ

Vitamin A is instrumental to mammalian reproduction. Its metabolite, retinoic acid (RA), acts in a hormone-like manner through binding to and activating three nuclear receptor isotypes, RA receptor (RAR)α (RARA), RARβ, and RARγ (RARG). Here, we show that 1) RARG is expressed by A aligned (A(al)) spermatogonia, as well as during the transition from A(al) to A(1) spermatogonia, which is known to require RA; and 2) ablation of Rarg, either in the whole mouse or specifically in spermatogonia, does not affect meiosis and spermiogenesis but impairs the A(al) to A(1) transition in the course of some of the seminiferous epithelium cycles. Upon ageing, this phenomenon yields seminiferous tubules containing only spermatogonia and Sertoli cells. Altogether, our findings indicate that RARG cell-autonomously transduces, in undifferentiated spermatogonia of adult testes, a RA signal critical for spermatogenesis. During the prepubertal spermatogenic wave, the loss of RARG function can however be compensated by RARA, as indicated by the normal timing of appearance of meiotic cells in Rarg-null testes. Accordingly, RARG- and RARA-selective agonists are both able to stimulate Stra8 expression in wild-type prepubertal testes. Interestingly, inactivation of Rarg does not impair expression of the spermatogonia differentiation markers Kit and Stra8, contrary to vitamin A deficiency. This latter observation supports the notion that the RA-signaling pathway previously shown to operate in Sertoli cells also participates in spermatogonia differentiation.     

Retinoic acid induces Sertoli cell paracrine signals for spermatogonia differentiation but cell autonomously drives spermatocyte meiosis

Direct evidence for a role of endogenous retinoic acid (RA), the active metabolite of vitamin A in the initial differentiation and meiotic entry of spermatogonia, and thus in the initiation of spermatogenesis is still lacking. RA is synthesized by dedicated enzymes, the retinaldehyde dehydrogenases (RALDH), and binds to and activates nuclear RA receptors (RARA, RARB, and RARG) either within the RA-synthesizing cells or in the neighboring cells. In the present study, we have used a combination of somatic genetic ablations and pharmacological approaches in vivo to show that during the first, prepubertal, spermatogenic cycle (i) RALDH-dependent synthesis of RA by Sertoli cells (SC), the supporting cells of the germ cell (GC) lineage, is indispensable to initiate differentiation of A aligned into A1 spermatogonia; (ii) RARA in SC mediates the effects of RA, possibly through activating Mafb expression, a gene whose Drosophila homolog is mandatory to GC differentiation; (iii) RA synthesized by premeiotic spermatocytes cell autonomously induces meiotic initiation through controlling the RAR-dependent expression of Stra8. Furthermore, we show that RA of SC origin is no longer necessary for the subsequent spermatogenic cycles but essential to spermiation. Altogether, our data establish that the effects of RA in vivo on spermatogonia differentiation are indirect, via SC, but direct on meiotic initiation in spermatocytes, supporting thereby the notion that, contrary to the situation in the female, RA is necessary to induce meiosis in the male.     

Multiple episodes of sodium depletion in the rat: a remodeling of the electrical properties of median preoptic nucleus neurons

In rat brain, the detection and integration of chemosensory and neural signals are achieved, inter alia, by the median preoptic nucleus (MnPO) during a disturbance of the hydromineral balance. This is allowed through the presence of the sodium (Na⁺) sensor neurons. Interestingly, enkephalins and mu‐opioid receptors (μ‐ORs) are known for their role in ingestive behaviors and have previously been shown to regulate the excitability of MnPO neurons following a single Na⁺ depletion. However, little is known about the role of these μ‐ORs in the response enhancement following repeated Na⁺ challenge. Therefore, we used whole‐cell recordings in acute brain slices to determine neuronal plasticity in the electrical properties of the MnPO Na⁺ sensor‐specific neuronal population following multiple Na⁺ depletions. Our results show that the population of Na⁺ sensor neurons was represented by 80% of MnPO neurons after a single Na⁺ depletion and was reduced after three Na⁺ depletions. Interestingly, the subpopulation of Na⁺ sensors responding to D‐Ala²,N‐MePhe⁴,Gly‐ol‐enkephalin (DAMGO), a specific μ‐OR agonist, represented 11% of MnPO neurons after a single Na⁺ depletion and the population doubled after three Na⁺ depletions. Moreover, Na⁺ sensor neurons displayed modifications in the discharge pattern distribution and shape of calcium action potentials after three Na⁺ depletions but these changes did not occur in Na⁺ sensors responding to DAMGO. Thus, the reinforced μ‐OR functionality in Na⁺ sensors might take place to control the neuronal hyperexcitability and this plasticity in opioid‐sensitive and Na⁺ detection MnPO networks might sustain the enhanced salt ingestion induced by repeated exposure to Na⁺ depletion.     

Clinical isolates of Escherichia coli solely resistant to mecillinam: prevalence and epidemiology

In routine susceptibility testing of Gram-negative bacteria, a particular resistance phenotype was observed: an Escherichia coli isolate from a urine sample exhibited resistance solely to mecillinam (MEC) but was fully susceptible to other β-lactam antibiotics (MEC-R-BL-S). The objectives as this study were to determine the prevalence of this phenotype and to describe the phenotype, molecular epidemiology and genetic background. Between 1 January 2014 and 31 January 2016, MEC-R-BL-S E. coli isolates from urine were collected and genes previously reported as mostly involved in MEC resistance were analysed. The genetic relatedness among isolates was investigated by repetitive element sequence-based PCR (rep-PCR) and multilocus sequence typing (MLST). Ten MEC-R-BL-S isolates were collected, accounting for 0.4% (10/2547) of all E. coli obtained from urine samples, 0.9% (10/1135) of ampicillin-susceptible E. coli isolates and 9.6% (10/104) of MEC-R E. coli isolates. The isolates appeared as small colonies with round morphology and had impaired fitness. The isolates were not clonal and belonged to various extraintestinal or commensal E. coli phylogroups. Mutations in the cysB gene were evidenced in all clinical isolates. In conclusion, microbiologists should be aware of these isolates with a particular susceptibility phenotype, which is not due to error in disk diffusion but is a real non-enzymatic antibiotic resistance pattern.     

Psoriasis during angiotensin receptor blocker exposure: an underestimated adverse drug reaction

Background: Angiotensin receptor blockers (ARBs) can induce or exacerbate psoriasis. Psoriasis is unlisted in the Summary of Product Characteristics (SmPC) of ARBs. We aimed to investigate the association between psoriasis and ARB exposure.

Methods: We reviewed spontaneous reports recorded in the French national Pharmacovigilance Database (FPVD). The association between psoriasis and ARB exposure was assessed using the case/non-case method. We also analyzed literature reports.

Results: We identified 89 reports of psoriasis during ARB exposure in the FPVD. Time to onset was most often less than 1 year. Outcome was favorable in 67% of reports after ARB discontinuation. Almost all ARBs were concerned. The reporting odds ratio (ROR) for psoriasis with this therapeutic class was 4.86 (95%CI 3.92–6.03). In the literature, we found 14 published reports of psoriasis with ARB exposure. Time to onset ranged from 6 weeks to 9 months. Outcome was also favorable after ARB discontinuation in the literature.

Conclusions: This underestimated adverse drug reaction is a class effect, time to onset is most often less than 1 year and outcome seems favorable after ARB discontinuation. The case/non-case approach highlights a potential safety signal. The SmPC of ARBs should be updated, increased awareness among healthcare professionals is warranted.     

Silver-nanoparticles increase bactericidal activity and radical oxygen responses against bacterial pathogens in human osteoclasts

Bone infections are difficult to treat and can lead to severe tissue destruction. Acute bone infections are usually caused by Staphylococcus aureus. Osteoclasts, which belong to the monocyte/macrophage lineage, are the key cells in bone infections. They are not well equipped for killing bacteria and may serve as a reservoir for bacterial pathogens. Silver has been known for centuries for its bactericidal activity. Here, we investigated the bactericidal effects of nano-silver particles in bacteria infected human osteoclasts. We found that nano-silver in per se non-toxic concentration enhanced the bactericidal activity in osteoclasts against intracellular Methicillin-resistant, virulent Staphylococcus aureus. The reduced bacterial survival in nano-silver pretreated cells correlated with increased reactive oxygen responses towards the invading pathogens. Overall, these results indicate that nano-silver compounds should be considered as an effective treatment and prevention option for bacterial bone and orthopedic implant infections.     

Drug-induced adverse reactions via breastfeeding: a descriptive study in the French Pharmacovigilance Database

Purpose

Most drugs are excreted in maternal milk and may therefore be ingested by children during breastfeeding. Data concerning the safety of the use of drugs by breastfeeding women are patchy, and almost nothing is known about this issue for many drugs.

Methods

The aim of this study was to describe the adverse drug reactions of drugs transmitted in breast milk on the basis of the data collected in the French Pharmacovigilance Database. All spontaneous reports of adverse drug reactions (ADRs) in breastfed infants recorded in the National Pharmacovigilance Database by the 31 French regional pharmacovigilance centres between 1984 and June 2011 were investigated.

Results

Between January 1985 and June 2011, 276 adverse drug reactions in 174 breastfed children were notified to the French Pharmacovigilance Network. The most frequently reported adverse drug reactions were neurological (28.6 %) and gastrointestinal (20.3 %). Sixty-five of the adverse drug reactions recorded were considered to be serious (37.4 %). The results of our study confirm that certain drugs were frequently implicated in serious adverse drug reactions. Two cases of ADRs (1.1 %) had a ‘certain’ causality score (I4) and 13 (7.5 %) a ‘likely’ score (I3). The suspected drugs include antiepileptic drugs, opiate analgesics and benzodiazepines. These results also demonstrate that some drugs that were thought to be anodyne or for which no data were available, such as ketoprofen and hydroxyzine, may be implicated in adverse effects. Finally, these data show that certain drugs, like pseudoephedrine, which should not be used during breastfeeding, were nevertheless implicated in several of the adverse drug reactions recorded.

Conclusion

This study shows that ADR via breastfeeding are rarely reported due to low awareness or low occurrence of ADR via breast milk. These results highlight the need for additional pharmacokinetic, clinical and epidemiological studies, given the paucity of published data. They also demonstrate the need to improve information for the general public about drugs and self-medication during breastfeeding.