[Comparative relevance of declaration of side effects by patients and health professionals]. / Pertinence comparée des notifications d'effets indésirables de patients et professionnels de santé.

INTRODUCTION: Drug-induced adverse events have been accessible to patient's spontaneous reporting in France and such notifications have been steadily increasing since 2011. However, these notifications are still shrouded with medical perplexity and are sometimes subjected to partial caution in their interpretation by the patient's physician. We aimed to evaluate and compare prospectively the relevance of such spontaneous notifications with those provided by healthcare professionals to the French Pharmacovigilance Center of Nice-Alpes-Côte d'Azur. METHODS: Spontaneous reporting of drug adverse events notified by patients and health care professionals were compared in terms of critical (name, date, effect, drug involved, chronological compatibility) and non-critical (posology, dosage) information, whereas the plausibility of the cases were assessed in weekly multispecialty staffs. Each patient's notification was matched with the immediate pre- and post-notifications declared by health care providers. RESULTS: Spontaneous notifications from 61 patients were compared with 122 notifications from health care providers. Neither the critical information necessary for declaring the case in the national database (7/61 versus 16/122, P=0.75), nor the uncritical elements allowing to assess the case (30/61 versus 51/122, P=0.22), its plausibility or the causality of the drug (P=0.10) differed significantly between the two groups. 107 cases out of 122 (88%) notified by health care providers were classified as serious, as compared with 19 out of 61 (15%) of patient's ones (P<0.001). CONCLUSION: Despite concerns from pharmacovigilance specialists in France, the medical relevance of spontaneous reported drug-associated adverse events does not differ from that of health care providers.

[Serious adverse drug reactions with tramadol reported to the French pharmacovigilance database between 2011 and 2015]. / Effets indésirables « graves ¼ du tramadol : bilan 2011­2015 de pharmacovigilance en France.

BACKGROUND: Tramadol is an opioid and a serotonin reuptake inhibitor drug. It is approved for moderate to severe pain in adults. The aim of this study was to assess tramadol safety through a national pharmacovigilance study in France since dextropropoxyphen withdrawal in 2011. METHODS: We described all serious adverse drug reactions (SADRs) reported with tramadol in adults in the French National PharmacoVigilance Database from August 1st, 2011 to December 31st, 2015. RESULTS: We identified 1512 SADRs during the study period. The most frequently reported SADRs were neurological (29.4%, including troubles of consciousness [13.2%] and seizures [6.7%]), psychiatric (22.8%, including confusions [14.6%] and hallucinations [7.3%]) and gastrointestinal (17.0%, mostly nausea and vomiting [9.6%]). Unexpected SADRs were also reported: hyponatremia, cholestatic hepatitis, serotonin syndrome. CONCLUSIONS: This study demonstrates new unexpected hepatic and metabolic SADRs. Tramadol alone can induce serotonin syndrome in overdose situations.

XY Sox9 embryonic loss-of-function mouse mutants show complete sex reversal and produce partially fertile XY oocytes.

Gonadal differentiation is the first step of mammalian sex determination. The expression of the Y chromosomal testis determining factor Sry leads to up-regulation of the transcription factor Sox9 which promotes testis differentiation. Previous studies showed that Sox9 deficiency induces expression of ovarian markers in XY mutant fetal gonads before they die. To better understand the genome-wide transcriptional profile underlying this process we compared samples from XY Sf1:Cre(Tg/+); Sox9(flox/flox) mutant gonads in which Sox9 is ablated in Sertoli-precursor cells during early stages of gonad development to XX Sox9(flox/flox) ovaries and XY Sox9(flox/flox) testes at E13.5. We found a complex mRNA signature that indicates wide-spread transcriptional de-regulation and revealed for XY mutants at E13.5 an intermediate transcript profile between male and female gonads. However, XY Sf1:Cre(Tg/+); Sox9(flox/flox) mutant gonads develop as ovaries containing XY developing follicles at P0 but less frequently so than in XX control ovaries. Furthermore, we studied the extent to which developing XY mutant ovaries are able to mediate adult fertility and observed that XY oocytes from XY mutant ovaries are competent for fertilization; however, two thirds of them fail to develop beyond two-cell stage embryos. Taken together, we found that XY Sf1:Cre(Tg/+); Sox9(flox/flox) females are capable of producing viable offspring albeit at a reduced level.