[Timing of gonadectomy in patients with complete androgen insensitivity syndrome]. / Quand proposer une gonadectomie chez les patientes présentant une insensibilité complète aux androgènes ?

Complete androgen insensitivity syndrome is the most frequent cause of disorder of sexual development in 46 XY patients. It is caused by mutations of the AR gene coding for the androgen receptor. Transmission is X-linked and mutations are most of the time inherited. It leads to a complete lack of response to androgen resulting in the presence of female external genitalia in 46 XY patients, normal but undescended testes and lack of female internal genitalia due to the secretion of anti-Müllerian hormone by male gonads. Traditionally, gonadectomy was proposed before puberty to decrease the risk of gonadal malignancy. However, more recent studies underlined the benefits of postponing gonadectomy until after pubertal development. Benefits of deferred gonadectomy are spontaneous pubertal development through peripheral aromatization of testosterone into oestrogens and the chance for the patient to have an active role in the decision-making process. After gonadectomy, hormone replacement therapy is required in order to prevent complications due to hypogonadism such as osteoporosis, cardiovascular diseases and a reduction of life expectancy.

L'insensibilité aux androgènes est l'étiologie principale des troubles du développement sexuel chez des patientes 46 XY. Elle est due à des mutations du gène AR qui code pour le récepteur des androgènes. Le mode de transmission est lié à l'X et les mutations sont le plus souvent héritées. Il en résulte une absence d'action des androgènes sur leurs récepteurs entraînant la présence d'organes génitaux externes féminins chez des patientes 46 XY, de testicules normalement développés en position abdominale ou inguinale et en l'absence d'organes génitaux internes féminins due à la sécrétion d'hormone anti-müllérienne par les gonades masculines. La gonadectomie était auparavant effectuée en période pré-pubertaire en raison du risque suspecté de développement de néoplasie maligne. Des données récentes suggèrent la possibilité de postposer cette intervention après le développement pubertaire. Le risque de transformation maligne pré-pubertaire des gonades est faible, et différer la gonadectomie permet un développement pubertaire naturel grâce à l'aromatisation périphérique de la testostérone en œstradiol. Ce délai permet d'impliquer activement la patiente dans la prise en charge de sa pathologie. Après la gonadectomie, un traitement hormonal substitutif par œstrogènes est indiqué pour prévenir les complications dues à l'hypogonadisme telles que l'ostéoporose, les maladies cardio-vasculaires et la réduction de l'espérance de vie.

Development of a comprehensive database for research on foetal acidosis.

OBJECTIVE: To develop a research database for mother-and-child clinical and laboratory data and digital foetal heart rate (FHR) recordings. METHODS: The Base Bien Naître (BBN) database was derived from a single-centre health data warehouse. It contains exhaustive data on all parturients with a singleton pregnancy, a vaginal or caesarean delivery in labour with a cephalic presentation after at least 37 weeks of amenorrhea, and a live birth between February 1st, 2011, and December 31st, 2018. On arrival in the delivery room, the FHR was recorded digitally for at least 30 min. A cord blood sample was always taken in order to obtain arterial pH (pHa). More than 6,000 recordings were analyzed visually for the risk of foetal acidosis and classified into five groups (according to the French College of Gynaecologists and Obstetricians (CNGOF) classification) or three groups (according to the International Federation of Gynaecology and Obstetrics (FIGO) classification). RESULTS: Of the 16,089 files in the health data warehouse, 11,026 were complete and met the BBN's inclusion criteria. The FHR digital recordings were of good quality, with low signal loss (median [interquartile range]: 7.0% [4.3;10.9]) and a median recording time of 304 min [190;438]). In 3.7% of the children, the pHa was below 7.10. We selected a subset of 6115 records with good-quality FHR recordings over 120 min and reliable cord blood gas data: 692 (11.3%) had at least a significant risk of acidosis (according to the CNGOF classification), and 1638 (26.8%) were at least suspicious (according to the FIGO classification). CONCLUSION: The BBN database has been designed as a searchable tool with data reuse. It currently contains over 11,000 records with comprehensive data.

[Living with endometriosis, sexual experiences of patients and their partners: A French qualitative study]. / Vécu de la sexualité des patientes atteintes d'endométriose et de leurs partenaires : une étude qualitative en population française.

AIM: Endometriosis is a disabling gynecological pathology. Couples who face it frequently encounter sexual difficulties related to dyspareunia. This study aims to understand the sexual experiences of endometriosis patients and their partners. METHODS: A total of 13 patients and 13 partners were interviewed prior to surgery. Semi-structured interviews were conducted separately and explored their sexual experiences. The interviews were transcribed verbatim and analyzed using content analysis. RESULTS: Both members of the couple reported pain during intercourses; decreased sexual desire; adaptation during sexual intercourses; communication about sexuality, which can be either open or a source of conflict, and the search for explanations for endometriosis. As for the emotional sphere, patients report anticipatory anxiety while partners report frustration and hope. CONCLUSION: These couples are in difficulty regarding sexuality, it is necessary to take care of both members of the couple and to encourage communication between them.

The density of calretinin striatal interneurons is decreased in 6-OHDA-lesioned mice.

Interneurons play a significant role in the functional organization of the striatum and some of them display marked plastic changes in dopamine-depleted conditions. Here, we applied immunohistochemistry on brain sections from 6-hydroxydopamine (6-OHDA) mouse model of Parkinson's disease and sham animals to characterize the regional distribution and the morphological and neurochemical changes of striatal interneurons expressing the calcium-binding protein calretinin (CR). Two morphological subtypes of calretinin-immunostained (CR +) interneurons referred, respectively, as small- and medium-sized CR + interneurons were detected in 6-OHDA- and sham-lesioned animals. The small cells (9-12 µm) prevail in the anterior and dorsal striatal regions; they stain intensely for CR and display a single slightly varicose and moderately arborized process. The medium-sized CR + interneurons (15-20 µm) are more numerous than the small CR + cells and rather uniformly distributed within the striatum; they stain weakly for CR and display 2-3 long, slightly varicose and poorly branched dendrites. The density of medium CR + interneurons is significantly decreased in the dopamine-depleted striatum (158 ± 15 neurons/mm3), when compared to sham animals (370 ± 41 neurons/mm3), whereas that of the small-sized CR + interneurons is unchanged (174 ± 46 neurons/mm3 in 6-OHDA-lesioned striatum and 164 ± 22 neurons/mm3 in sham-lesioned striatum). The nucleus accumbens is populated only by medium-sized CR + interneurons, which are distributed equally among the core and shell compartments and whose density is unaltered after dopamine denervation. Our results provide the first evidence that the medium-sized striatal interneurons expressing low level of CR are specifically targeted by dopamine denervation, while the small and intensely immunoreactive CR + cells remain unaffected. These findings suggest that high expression of the calcium-binding protein CR might protect striatal interneurons against an increase in intracellular calcium level that is believed to arise from altered glutamate corticostriatal transmission in Parkinson's disease.

[Technological progress and novelty in insulin therapy during those last ten years for diabetes children and adolescents]. / Progrès technologiques et nouveautés en insulinothérapie au cours de la dernière décennie chez l'enfant et l'adolescent diabétiques.

These last few years, new advances in technologies and modern insulin regimens have improved diabetes care for children and adolescents and have led to the definition of new therapeutic goals.

Au cours de ces dernières années, les nouvelles avancées technologiques et thérapeutiques ont marqué la prise en charge du diabète de l'enfant et de l'adolescent amenant ainsi à définir de nouveaux objectifs thérapeutiques.

Health tourism: an opportunity for sustainable development.

In February 2017, the "Programma Mattone Internazionale Salute" (ProMis), that is the Italian Program for Internationalization of Regional Health Systems of the Ministry of Health (MoH), presented the first version of its Position Paper on Health Tourism, which embeds a first shared approach to the recommendations expressed by the European Committee of Regions (CoR) on "Age-Friendly" tourism. The CoR stresses the importance of local and regional authorities in the coordination of multi-sectoral policies such as healthcare, social assistance, transport, urban planning and rural development in relation to the promotion of mobility, security, accessibility of services, including health care and social services. "Age-friendly" tourism is an example of an innovative tourist offer that strives to meet the health needs of the entire "traveling" population, with an integrated and cross-sector approach that involves various organizations operating in sectors such as healthcare, accessibility and transport. The aim of the workshop was to explore the interest of the stakeholders to participate in a systemic action in the field of "health" tourism, and to identify priority implementation areas that offer opportunities to take advantage of validated, innovative experiences that strengthen the accessibility to health and social services in regional, national and international contexts. This effort provides the opportunity to take advantage of aligning the European Structural and Investment Funds (ESIF) to the development of tourism, coherently with the needs and resources of local and regional health authorities.

The calretinin interneurons of the striatum: comparisons between rodents and primates under normal and pathological conditions.

This paper reviews the major organizational features of calretinin interneurons in the dorsal striatum of rodents and primates, with some insights on the state of these neurons in Parkinson's disease and Huntington's chorea. The rat striatum harbors medium-sized calretinin-immunoreactive (CR+) interneurons, whereas the mouse striatum is pervaded by medium-sized CR+ interneurons together with numerous small and highly immunoreactive CR+ cells. The CR interneuronal network is even more elaborated in monkey and human striatum where, in addition to the small- and medium-sized CR+ interneurons, a set of large CR+ interneurons occurs. The majority of these giant CR+ interneurons, which are unique to the primate striatum, also display immunoreactivity for choline acetyltransferase (ChAT), a faithful marker of cholinergic neurons. The expression of CR and/or ChAT by the large striatal interneurons appears to be seriously compromised in Parkinson's disease and Huntington's chorea. The species differences noted above have to be considered to better understand the role of CR interneurons in striatal organization in both normal and pathological conditions.

Striatal Neurons Expressing D1 and D2 Receptors are Morphologically Distinct and Differently Affected by Dopamine Denervation in Mice.

The loss of nigrostriatal dopamine neurons in Parkinson's disease induces a reduction in the number of dendritic spines on medium spiny neurons (MSNs) of the striatum expressing D1 or D2 dopamine receptor. Consequences on MSNs expressing both receptors (D1/D2 MSNs) are currently unknown. We looked for changes induced by dopamine denervation in the density, regional distribution and morphological features of D1/D2 MSNs, by comparing 6-OHDA-lesioned double BAC transgenic mice (Drd1a-tdTomato/Drd2-EGFP) to sham-lesioned animals. D1/D2 MSNs are uniformly distributed throughout the dorsal striatum (1.9% of MSNs). In contrast, they are heterogeneously distributed and more numerous in the ventral striatum (14.6% in the shell and 7.3% in the core). Compared to D1 and D2 MSNs, D1/D2 MSNs are endowed with a smaller cell body and a less profusely arborized dendritic tree with less dendritic spines. The dendritic spine density of D1/D2 MSNs, but also of D1 and D2 MSNs, is significantly reduced in 6-OHDA-lesioned mice. In contrast to D1 and D2 MSNs, the extent of dendritic arborization of D1/D2 MSNs appears unaltered in 6-OHDA-lesioned mice. Our data indicate that D1/D2 MSNs in the mouse striatum form a distinct neuronal population that is affected differently by dopamine deafferentation that characterizes Parkinson's disease.

Early exposure to Aroclor 1254 in vivo disrupts the functional synaptic development of newborn hippocampal granule cells.

Neurogenesis in the dentate gyrus is sensitive to endogenous and exogenous factors that influence hippocampal function. Ongoing neurogenesis and the integration of these new neurons throughout life thus may provide a sensitive indicator of environmental stress. We examined the effects of Aroclor 1254 (A1254), a mixture of polychlorinated biphenyls (PCBs), on the development and function of newly generated dentate granule cells. Early exposure to A1254 has been associated with learning impairment in children, suggesting potential impact on the development of hippocampus and/or cortical circuits. Oral A1254 (from the 6th day of gestation to postnatal day 21) produced the expected increase in PCB levels in brain at postnatal day 21, which persisted at lower levels into adulthood. A1254 did not affect the proliferation or survival of newborn neurons in immature animals nor did it cause overt changes in neuronal morphology. However, A1254 occluded the normal developmental increase in sEPSC frequency in the third post-mitotic week without altering the average sEPSC amplitude. Our results suggest that early exposure to PCBs can disrupt excitatory synaptic function during a period of active synaptogenesis, and thus could contribute to the cognitive effects noted in children exposed to PCBs.

Exposure to endocrine disrupting chemicals and neurodevelopmental alterations.

The developing brain is remarkably malleable as neural circuits are formed and these circuits are strongly dependent on hormones for their development. For those reasons, the brain is very vulnerable to the effects of endocrine-disrupting chemicals (EDCs) during critical periods of development. This review focuses on three ubiquitous endocrine disruptors that are known to disrupt the thyroid function and are associated with neurobehavioral deficits: polychlorinated biphenyls, polybrominated diphenyl ethers, and bisphenol A. The human and rodent data suggesting effects of those EDCs on memory, cognition, and social behavior are discussed. Their mechanisms of action go beyond relative hypothyroidism with effects on neurotransmitter release and calcium signaling.

Custom sizing of lower limb exoskeleton actuators using gait dynamic modelling of children with cerebral palsy.

The use of exoskeletons as an aid for people with musculoskeletal disorder is the subject to an increasing interest in the research community. These devices are expected to meet the specific needs of users, such as children with cerebral palsy (CP) who are considered a significant population in pediatric rehabilitation. Although these exoskeletons should be designed to ease the movement of people with physical shortcoming, their design is generally based on data obtained from healthy adults, which leads to oversized components that are inadequate to the targeted users. Consequently, the objective of this study is to custom-size the lower limb exoskeleton actuators based on dynamic modeling of the human body for children with CP on the basis of hip, knee, and ankle joint kinematics and dynamics of human body during gait. For this purpose, a multibody modeling of the human body of 3 typically developed children (TD) and 3 children with CP is used. The results show significant differences in gait patterns especially in knee and ankle with respectively 0.39 and -0.33 (Nm/kg) maximum torque differences between TD children and children with CP. This study provides the recommendations to support the design of actuators to normalize the movement of children with CP.

Descending nociceptive inhibition is modulated in a time-dependent manner in a double-hit model of chronic/tonic pain.

Clinical evidences suggest that an imbalance between descending inhibition and facilitation drives the development of chronic pain. However, potential mechanisms promoting the establishment of a persistent pain state and the increased pain vulnerability remain unknown. This preclinical study was designed to evaluate temporal changes in descending pain modulation at specific experimental endpoints (12, 28, 90 and 168 days) using a novel double-hit model of chronic/tonic pain (first hit: chronic constriction injury (CCI) model; second hit: tonic formalin pain in the contralateral hindpaw). Basal activity of bulbo-spinal monoaminergic systems was further assessed through liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) screening of cerebrospinal fluid (CSF). We found that CCI-operated rats exhibited a reduced nociceptive response profile, peaking on day 28, when subjected to tonic pain. This behavioral response was accompanied by a rapid increase in basal CSF serotonin and norepinephrine levels 12 days after neuropathy, followed by a return to sham levels on day 28. These molecular and behavioral adaptive changes in descending pain inhibition seemed to slowly fade over time. We therefore suggest that chronic neuropathic pain produces a transient hyperactivation of bulbo-spinal monoaminergic drive when previously primed using a tonic pain paradigm (i.e., formalin test), translating into inhibition of subsequent nociceptive behaviors. Altogether, we propose that early hyperactivation of descending pain inhibitory mechanisms, and its potential ensuing exhaustion, could be part of the temporal neurophysiological chain of events favoring chronic neuropathic pain establishment.

Apoptosis of Sertoli cells after conditional ablation of murine double minute 2 (Mdm2) gene is p53-dependent and results in male sterility.

Beside its well-documented role in carcinogenesis, the function of p53 family has been more recently revealed in development and female reproduction, but it is still poorly documented in male reproduction. We specifically tested this possibility by ablating Mdm2, an E3 ligase that regulates p53 protein stability and transactivation function, specifically in Sertoli cells (SCs) using the AMH-Cre line and created the new SC-Mdm2(-/-) line. Heterozygous SC-Mdm2(-/+) adult males were fertile, but SC-Mdm2(-/-) males were infertile and exhibited: a shorter ano-genital distance, an extra duct along the vas deferens that presents a uterus-like morphology, degenerated testes with no organized seminiferous tubules and a complete loss of differentiated germ cells. In adults, testosterone levels as well as StAR, P450c17 (Cyp17a1) and P450scc (Cyp11a1) mRNA levels decreased significantly, and both plasma LH and FSH levels increased. A detailed investigation of testicular development indicated that the phenotype arose during fetal life, with SC-Mdm2(-/-) testes being much smaller at birth. Interestingly, Leydig cells remained present until adulthood and fetal germ cells abnormally initiated meiosis. Inactivation of Mdm2 in SCs triggered p53 activation and apoptosis as early as 15.5 days post conception with significant increase in apoptotic SCs. Importantly, testis development occurred normally in SC-Mdm2(-/-) lacking p53 mice (SC-Mdm2(-/-)p53(-/-)) and accordingly, these mice were fertile indicating that the aforementioned phenotypes are entirely p53-dependent. These data not only highlight the importance of keeping p53 in check for proper testicular development and male fertility but also certify the critical role of SCs in the maintenance of meiotic repression.

[Endocrine disruption: a challenge in research, public health and clinical practice]. / La perturbation endocrinienne: entre enjeux de recherche, enjeux de santé publique et enjeux de pratique quotidienne.

Epidemiological and experimental data highlight the fetal and early postnatal life as critical periods for the effects of endocrine disrupting chemicals (EDCs), since exposure to EDCs during these periods can predispose to disease later in life. EDCs' effects include disorders of the reproductive system throughout life (abnormalities of sexual differentiation, infertility or subfertility and some neoplasia) and disorders of energy balance (obesity and metabolic syndrome). They could also influence the development of the cerebral cortex. However, the demonstration of the involvement of a single EDC remains difficult in human since we are virtually exposed to a mixture of several ubiquitous EDCs which are variably persistent in the environment and the body and have lifelong consequences. Moreover, since their dose-response relationship can be non-monotonic, setting a threshold dose for EDCs effects has become meaningless. Pregnant women, newborns and young children appear to be mostly at risk. However, the role of the physician remains difficult and raises several questions: how can we formulate justified, applicable and updated recommendations that are not counterproductive or alarmist...in a society that has to take the necessary steps to regulate production and protect the population?

[Neonatal hyperthyroidism: clinical pattern and therapy]. / L'hyperthyroidie néonatale: clinique et prise en charge thérapeutique.

Neonatal hyperthyroidism is a rare pathology, most often the consequence of Graves' disease in the mother. Around 0.2% of pregnant women have Graves disease and 1 to 2% of newborns of mother with Graves' disease. This article will describe the case of 4 newborns who have been diagnosed and treated in CHU-NDB between 2007 and 2011. The second part will focus on the new recommendations about the management of these young patients from foetal period to birth.

Early neuroendocrine disruption in hypothalamus and hippocampus: developmental effects including female sexual maturation and implications for endocrine disrupting chemical screening.

The timing of puberty has been mainly studied in females for several reasons, including the possible evaluation of a precise timer (i.e. menarcheal age) and concerns with respect to the high prevalence of precocity in females as opposed to males. Human evidence of altered female pubertal timing after exposure to endocrine disrupting chemicals (EDCs) is equivocal. Among the limiting factors, most studies evaluate exposure to single EDCs at the time of puberty and hardly assess the impact of lifelong exposure to mixtures of EDCs. Some rodent and ovine studies indicate a possible role of foetal and neonatal exposure to EDCs, in accordance with the concept of an early origin of health and disease. Such effects possibly involve neuroendocrine mechanisms because the hypothalamus is a site where homeostasis of reproduction, as well as control of energy balance, is programmed and regulated. In our previous studies, pulsatile gonadotrophin-releasing hormone (GnRH) secretion control via oestrogen, glutamate and aryl hydrocarbon receptors was shown to be involved in the mechanism of sexual precocity after early postnatal exposure to the insecticide dichlorodiphenyltrichloroethane. Very recently, we have shown that neonatal exposure to the potent synthetic oestrogen diethylstilbestrol (DES) is followed by early or delayed puberty depending on the dose, with consistent changes in developmental increase of GnRH pulse frequency. Moreover, DES results in reduced leptin stimulation of GnRH secretion in vitro, an effect that is additive with prenatal food restriction. Thus, using puberty as an endpoint of the effects of EDC, it appears necessary to consider pre- and perinatal exposure to low doses and to pay attention to the other conditions of prenatal life, such as energy availability, keeping in mind the possibility that puberty could not only be advanced, but also delayed through neuroendocrine mechanisms.

[How to explore ... congenital isolated hypogonadotrophic hypogonadism]. / Comment j'EXPLORE ... un hypogonadisme hypogonadotrope congénital isolé.

Congenital Isolated hypogonadotropic hypogonadism (CIHH) is caused by an inherited mechanism of impairment of the pituitary-gonadal axis, interfering with gonads' control. Currently, different forms of HHCI with (Kallmann syndrome or KS) or without anosmia-hyposmia are known. There are six forms of KS already described but in several cases no genetic mutation is found. The genetic anomalies already described are: KAL1 (locus Xp23) coding for anosmine-1, KAL-2 or FGFRI (8p11. locus 2 - p11.1) coding for Fibroblast Growth Factor Receptor 1 (FGFR1), KAL4 or PROk2 (locus 3p21.1) and KAL3 or ProKR2 (locus 20p13) coding respectively for the Prokinecitin-2 and its receptor, KAL5 or CHD7 (locus_8q12.1) coding for a chromodomain helicase DNA-binding protein-7 gene (CHD7) and lastly KAL6 or FGF8 (10Q 24 loci) coding for Fibroblast Growth Factor 8. The other genetic anomalies without anosmia are less frequent. These are associated either with Gnrhl gene (8p2-11. 2), GnRHR (4q21.2), GPR54 (19p13),TAC3R or neurokinine receptor 3 (4 q 25), LH (19q13.32) or FSH (11p13). The isolated congenital hypogonadotrophic hypogonadism phenotype is variable depending on gender, the importance of the deficit, and ultimately, according to a specific regulatory mechanism of the axis, affected by an inherited genetic anomaly. In this review, we describe the essential aspects of the different phenotypes and genotypes of HHCI, in order to assess clinicians an early disease's diagnosis and management.