Normosmic Congenital Hypogonadotropic Hypogonadism Due to TAC3/TACR3 Mutations: Characterization of Neuroendocrine Phenotypes and Novel Mutations

CONTEXT: TAC3/TACR3 mutations have been reported in normosmic congenital hypogonadotropic hypogonadism (nCHH) (OMIM #146110). In the absence of animal models, studies of human neuroendocrine phenotypes associated with neurokinin B and NK3R receptor dysfunction can help to decipher the pathophysiology of this signaling pathway. OBJECTIVE: To evaluate the prevalence of TAC3/TACR3 mutations, characterize novel TACR3 mutations and to analyze neuroendocrine profiles in nCHH caused by deleterious TAC3/TACR3 biallelic mutations. RESULTS: From a cohort of 352 CHH, we selected 173 nCHH patients and identified nine patients carrying TAC3 or TACR3 variants (5.2%). We describe here 7 of these TACR3 variants (1 frameshift and 2 nonsense deleterious mutations and 4 missense variants) found in 5 subjects. Modeling and functional studies of the latter demonstrated the deleterious consequence of one missense mutation (Tyr267Asn) probably caused by the misfolding of the mutated NK3R protein. We found a statistically significant (p<0.0001) higher mean FSH/LH ratio in 11 nCHH patients with TAC3/TACR3 biallelic mutations than in 47 nCHH patients with either biallelic mutations in KISS1R, GNRHR, or with no identified mutations and than in 50 Kallmann patients with mutations in KAL1, FGFR1 or PROK2/PROKR2. Three patients with TAC3/TACR3 biallelic mutations had an apulsatile LH profile but low-frequency alpha-subunit pulses. Pulsatile GnRH administration increased alpha-subunit pulsatile frequency and reduced the FSH/LH ratio. CONCLUSION: The gonadotropin axis dysfunction associated with nCHH due to TAC3/TACR3 mutations is related to a low GnRH pulsatile frequency leading to a low frequency of alpha-subunit pulses and to an elevated FSH/LH ratio. This ratio might be useful for pre-screening nCHH patients for TAC3/TACR3 mutations

Protein misfolding and dysregulated protein homeostasis in autoinflammatory diseases and beyond.

Cells have a number of mechanisms to maintain protein homeostasis, including proteasome-mediated degradation of ubiquitinated proteins and autophagy, a regulated process of ‘self-eating’ where the contents of entire organelles can be recycled for other uses. The unfolded protein response prevents protein overload in the secretory pathway. In the past decade, it has become clear that these fundamental cellular processes also help contain inflammation though degrading pro-inflammatory protein complexes such as the NLRP3 inflammasome. Signaling pathways such as the UPR can also be co-opted by toll-like receptor and mitochondrial reactive oxygen species signaling to induce inflammatory responses. Mutations that alter key inflammatory proteins, such as NLRP3 or TNFR1, can overcome normal protein homeostasis mechanisms, resulting in autoinflammatory diseases. Conversely, Mendelian defects in the proteasome cause protein accumulation, which can trigger interferon-dependent autoinflammatory disease. In non-Mendelian inflammatory diseases, polymorphisms in genes affecting the UPR or autophagy pathways can contribute to disease, and in diseases not formerly considered inflammatory such as neurodegenerative conditions and type 2 diabetes, there is increasing evidence that cell intrinsic or environmental alterations in protein homeostasis may contribute to pathogenesis

The Effect of a Robotic Unit Dose Drug Dispensing System on Medicines Administration Errors and the Cost of Drug Dispensing

A Unit Dose Drug Dispensing System (UDDDS) by a robot (PillPick system, Swisslog) with daily pharmaceutical monitoring of medical prescriptions is being implemented in our hospital, to gradually replace the ward stock distribution system (WSDS), which allowed a low level of pharmaceutical monitoring. In 2011, UDDDS was used for 374 beds. UDDDS allows named “ready-to-use” treatments to be dispensed daily, avoiding nurse preparation of pillboxes, necessary with WSDS

Narcolepsie et hypersomnie idiopathique : évaluation du besoin d’information des pharmaciens d’officine et de la pertinence de l’usage d’une messagerie sécurisée pour assurer le lien ville-hôpital

International audienceIntroductionAfin d’assurer une dispensation de qualité avec les conseils adaptés, il est important que les pharmaciens disposent de toutes les informations sur la pathologie concernée. Cette étude a pour objectif d’évaluer les connaissances du pharmacien d’officine sur la narcolepsie et l’hypersomnie idiopathique et de mettre en place via la messagerie sécurisée, l’envoi de fiches d’informations pour les pharmaciens d’officines et les patients.MéthodesUn questionnaire portant sur l’évaluation des connaissances des pharmaciens d’officines sur ces pathologies et leurs traitements, a été envoyé à 5117 pharmaciens d’officines. Par ailleurs, des fiches d’informations sur la prise en charge de la narcolepsie et de l’hypersomnie idiopathique ont été envoyées par messagerie sécurisée aux pharmaciens d’officines (n = 103) de patients suivis dans les centres lyonnais de référence pédiatrique et de compétence adulte pour la narcolepsie et l’hypersomnie idiopathique.RésultatsCent vingt-trois pharmaciens ont répondu au questionnaire d’évaluation des connaissances. La note moyenne d’autoévaluation des connaissances des pharmaciens était de 0,96/3. Au total, 99,2 % des répondants ont déclaré avoir besoin de plus d’information sur ces pathologies. Un retour très positif a été reçu de la part des pharmaciens d’officines ayant bénéficié d’un envoi d’information par messagerie sécurisée MonSisra.DiscussionCette étude a montré qu’il existe un besoin d’information des pharmaciens d’officines pour la prise en charge des patients atteints de narcolepsie ou d’hypersomnie idiopathique. Le transfert d’informations par messagerie sécurisée pourrait favoriser le lien ville/hôpital dans ce contexte et permettre d’optimiser la prise en charge des patients atteints de maladies rares tout au long de leur parcours

Apport du PMSI pour l'appariement de données cliniques hospitalières avec le SNDS : cas d'usage en pharmacovigilance sur les patients consommateurs de statines

International audienc

ANTIFON-CLIC®, a new clinical decision support system for the treatment of invasive aspergillosis: is it clinically relevant?

International audienc

Fatores de risco para diabetes mellitus gestacional na coorte de nascimentos de Pelotas, Rio Grande do Sul, Brasil, 2004 Risk factors for gestational diabetes mellitus in the birth cohort in Pelotas, Rio Grande do Sul State, Brazil, 2004

Consensos de diversos países referem idade, obesidade e história familiar de diabetes mellitus como fatores de risco para diabetes mellitus gestacional. Outros fatores permanecem controversos. O objetivo deste estudo foi investigar fatores associados ao diabetes mellitus gestacional entre mães dos recém-nascidos da coorte de nascimentos de Pelotas, Rio Grande do Sul, Brasil, em 2004. Foram entrevistadas 4.243 puérperas no hospital, havendo 0,5% de recusas. O diagnóstico de diabetes mellitus gestacional foi auto-referido. A prevalência de diabetes mellitus gestacional foi 2,95% (IC95%: 2,53-3,64). Análise bruta realizada por meio de testes qui-quadrado mostrou associação direta com aumento da idade, escolaridade, nível econômico e índice de massa corporal (IMC) e inversa com altura materna. Cor não branca, história familiar de diabetes mellitus, tabagismo no primeiro e segundo trimestres e atividade física antes da gestação e no primeiro trimestre mostraram-se associados. A análise ajustada hierarquizada realizada através de regressão logística mostrou associação com maior idade, cor não branca, maior escolaridade, história familiar de diabetes mellitus e maior IMC. A altura ficou no limiar da significância. Tabagismo no primeiro e segundo trimestres foi protetor.<br>Consensus statements by various countries have reported age, obesity, and family history of diabetes mellitus as risk factors for gestational diabetes mellitus. Other factors remain controversial. The aim of this study was to investigate factors associated with gestational diabetes among mothers of newborns from the birth cohort in Pelotas, Rio Grande do Sul State, Brazil, in 2004. We interviewed 4,243 postpartum women in hospital, with a 0.5% refusal rate. Diagnosis of gestational diabetes was self-reported. Prevalence of gestational diabetes was 2.95% (95%CI: 2.53-3.64). Crude analysis using the chi-square test showed a direct association with age, schooling, socioeconomic status, and body mass index (BMI) and an inverse association with maternal height. Non-white color, family history of diabetes mellitus, smoking in the first and second trimesters, and physical activity before the pregnancy and in the first trimester were associated with the outcome. Adjusted hierarchical analysis using logistic regression showed an association with age, non-white color, higher schooling, family history of diabetes, and BMI. Height showed borderline significance. Smoking in the first and second trimesters showed a protective effect