Multi-Omics Data Integration Reveals Sex-Dependent Hippocampal Programming by Maternal High-Fat Diet during Lactation in Adult Mouse Offspring.

Early-life exposure to high-fat diets (HF) can program metabolic and cognitive alterations in adult offspring. Although the hippocampus plays a crucial role in memory and metabolic homeostasis, few studies have reported the impact of maternal HF on this structure. We assessed the effects of maternal HF during lactation on physiological, metabolic, and cognitive parameters in young adult offspring mice. To identify early-programming mechanisms in the hippocampus, we developed a multi-omics strategy in male and female offspring. Maternal HF induced a transient increased body weight at weaning, and a mild glucose intolerance only in 3-month-old male mice with no change in plasma metabolic parameters in adult male and female offspring. Behavioral alterations revealed by a Barnes maze test were observed both in 6-month-old male and female mice. The multi-omics strategy unveiled sex-specific transcriptomic and proteomic modifications in the hippocampus of adult offspring. These studies that were confirmed by regulon analysis show that, although genes whose expression was modified by maternal HF were different between sexes, the main pathways affected were similar with mitochondria and synapses as main hippocampal targets of maternal HF. The effects of maternal HF reported here may help to better characterize sex-dependent molecular pathways involved in cognitive disorders and neurodegenerative diseases.

[Exploration and management of thyroid nodules]. / Exploration et prise en charge des nodules thyroïdiens.

EXPLORATION AND MANAGEMENT OF THYROID NODULES. Most thyroid nodules are benign (95%) and can benefit from clinical and ultrasound monitoring. Cancers (approximately 5% of nodules) could be suspected, particularly in subjects whose neck was irradiated, in cases of a hard, irregular, evolving nodule, or with very high serum calcitonin (> 100 pg/ml). It is crucial to recognize cancers when nodules exceed the supracentimeter stage. Thyroid ultrasonography is the most common, handy, safe, and cost-effective tool to image thyroid nodules. It classifies thyroid nodules according to the EU-TIRADS score, which comprises 5 categories associated with an increasing risk of malignancy. An ultrasound-guided fine needle aspiration (FNA) biopsy is performed only in nodules staged EU-TIRADS classes 5, 4, and 3 over 1, 1.5, and 2 cm, respectively. Cytologic analysis of FNA material classifies thyroid nodules according to the Bethesda system into 6 classes, each with its own prognostic value. The difficulties in cytological evaluation are related to the uninterpretable (Bethesda I) and indeterminate (especially III and IV) results, for which have to be discussed opportunities of reassessment and follow-up by scintiscans and cytological molecular markers. Management is imperfectly codifiable: from surveillance in the absence of suspicious elements initially to total thyroidectomy in their presence.

EXPLORATION ET PRISE EN CHARGE DES NODULES THYROÏDIENS. La plupart des nodules thyroïdiens sont bénins (95 %) et peuvent bénéficier d'une surveillance clinique et échographique. La malignité (5 % des nodules environ) est à suspecter, particulièrement chez les sujets dont le cou a été irradié, en cas de nodule dur, irrégulier, évolutif, avec une calcitoninémie très élevée (supérieure à 100 pg/mL). C'est au stade de nodule supracentimétrique qu'il importe de reconnaître les cancers. L'échographie est l'examen d'imagerie de référence ; elle permet de classer les nodules selon le score EU-TIRADS, composé de cinq catégories associées à un risque croissant de malignité. Les ponctions échoguidées en vue de l'analyse cytologique sont réservées aux catégories EU-TIRADS 5, 4 et 3 de plus de 1, 1,5 et 2 cm respectivement. Les caractéristiques cytologiques sont présentées selon la nomenclature de Bethesda en six classes dont chacune quantifie aussi le risque de malignité, en complément des données échographiques. Les difficultés de l'évaluation cytologique sont liées aux résultats ininterprétables (Bethesda I) et indéterminés (surtout Bethesda III et IV) pour lesquels se discutent l'opportunité de la réévaluation et de la surveillance, des scintigraphies dites de seconde intention, et également des marqueurs moléculaires sur le produit de cytoponction. La prise en charge est imparfaitement codifiable : de la surveillance en l'absence d'éléments suspects initialement à la thyroïdectomie totale en leur présence.

Efficacy of lanreotide 120 mg primary therapy on tumour shrinkage and ophthalmologic symptoms in acromegaly after 1 month.

INTRODUCTION: Few studies have attempted to evaluate the early efficacy of first-generation somatostatin analogues in somatotroph macroadenomas. OBJECTIVE: To investigate the short-term efficacy of primary therapy with lanreotide 120 mg at 1 and 3 months on tumour shrinkage and ophthalmologic symptoms in newly diagnosed patients with acromegaly. DESIGN AND PATIENTS: This single-centre retrospective study included 21 patients with de novo acromegaly resulting from pituitary macroadenoma, with optic chiasm compression (Grade ≤ 2) and/or cavernous sinus invasion, treated with a monthly injection of lanreotide 120 mg. Clinical, hormonal, ophthalmologic and magnetic resonance imaging scan evaluations were conducted after the first and the third months of treatment. RESULTS: Tumour volume reduction was more pronounced at 1 month; mean volume change: -31.4 ± 19.5%, p < .0001 than between the first and third month of treatment; mean volume reduction: -20.6 ± 13.4%, p = .0009. The mean volume change between baseline and the third month was - 46.4 ± 21.6, (p < .0001). A significant volume reduction (≥25%) was observed in 61.9% of individuals (13/21) at the first month. Among 14 individuals with optic chiasm compression and visual field defects, visual field normalization or improvement were observed in seven cases (50%), stabilization in four cases (28.5%), and mild worsening in three cases (21.4%) at 1 month. The decrease in growth hormone and IGF-1 serum values was significant at 1 month. CONCLUSIONS: Primary treatment with lanreotide 120 mg in patients with somatotroph macroadenomas provides early significant tumour shrinkage with rapid improvement of visual symptoms at the end of the first month in 50% of patients.

Defining Reference Ranges for Serum Anti-Müllerian Hormone on a Large Cohort of Normozoospermic Adult Men Highlights New Potential Physiological Functions of AMH on FSH Secretion and Sperm Motility.

BACKGROUND: Few studies to date have attempted to measure serum anti-Müllerian hormone (AMH) levels in adult men, and solid references ranges have not yet been defined in a large cohort. OBJECTIVE: In this study, we aimed, first, to establish the reference ranges for serum AMH and AMH-to-total testosterone ratio (AMH/tT) in adult males. Second, we investigated the relationship between serum AMH and both reproductive hormones and semen parameters. METHODS: This single-center retrospective study included 578 normozoospermic adult men. Serum AMH concentrations were determined with an automated sandwich chemiluminescent immunoassay. RESULTS: The median serum AMH was 43.5 pmol/L. The 2.5th and 97.5th percentile values for serum AMH and AMH/tT were 16.4 and 90.3 pmol/L and 0.45 and 3.43, respectively. AMH was positively correlated with inhibin B and sperm concentration and negatively correlated with age, follicle-stimulating hormone (FSH), and progressive sperm motility. Interestingly, using immunofluorescence, we documented for the first time that AMH type II receptor (AMH-R2) is expressed in ejaculated human spermatozoa and gonadotrophic cells in the postmortem pituitary gland. CONCLUSIONS: We establish a new age-specific reference range for serum AMH and AMH/tT. Moreover, AMH-R2 expression in human spermatozoa and gonadotrophic cells, together with the relationship between serum AMH levels and sperm motility or mean FSH levels, highlight new potential functions of AMH in regulating sperm motility or FSH secretion in adult men.

Impaired Glucose Homeostasis in a Tau Knock-In Mouse Model.

Alzheimer's disease (AD) is the leading cause of dementia. While impaired glucose homeostasis has been shown to increase AD risk and pathological loss of tau function, the latter has been suggested to contribute to the emergence of the glucose homeostasis alterations observed in AD patients. However, the links between tau impairments and glucose homeostasis, remain unclear. In this context, the present study aimed at investigating the metabolic phenotype of a new tau knock-in (KI) mouse model, expressing, at a physiological level, a human tau protein bearing the P301L mutation under the control of the endogenous mouse Mapt promoter. Metabolic investigations revealed that, while under chow diet tau KI mice do not exhibit significant metabolic impairments, male but not female tau KI animals under High-Fat Diet (HFD) exhibited higher insulinemia as well as glucose intolerance as compared to control littermates. Using immunofluorescence, tau protein was found colocalized with insulin in the ß cells of pancreatic islets in both mouse (WT, KI) and human pancreas. Isolated islets from tau KI and tau knock-out mice exhibited impaired glucose-stimulated insulin secretion (GSIS), an effect recapitulated in the mouse pancreatic ß-cell line (MIN6) following tau knock-down. Altogether, our data indicate that loss of tau function in tau KI mice and, particularly, dysfunction of pancreatic ß cells might promote glucose homeostasis impairments and contribute to metabolic changes observed in AD.

Early-Life Environment Influence on Late-Onset Alzheimer's Disease.

With the expand of the population's average age, the incidence of neurodegenerative disorders has dramatically increased over the last decades. Alzheimer disease (AD) which is the most prevalent neurodegenerative disease is mostly sporadic and primarily characterized by cognitive deficits and neuropathological lesions such as amyloid -ß (Aß) plaques and neurofibrillary tangles composed of hyper- and/or abnormally phosphorylated Tau protein. AD is considered a complex disease that arises from the interaction between environmental and genetic factors, modulated by epigenetic mechanisms. Besides the well-described cognitive decline, AD patients also exhibit metabolic impairments. Metabolic and cognitive perturbations are indeed frequently observed in the Developmental Origin of Health and Diseases (DOHaD) field of research which proposes that environmental perturbations during the perinatal period determine the susceptibility to pathological conditions later in life. In this review, we explored the potential influence of early environmental exposure to risk factors (maternal stress, malnutrition, xenobiotics, chemical factors … ) and the involvement of epigenetic mechanisms on the programming of late-onset AD. Animal models indicate that offspring exposed to early-life stress during gestation and/or lactation increase both AD lesions, lead to defects in synaptic plasticity and finally to cognitive impairments. This long-lasting epigenetic programming could be modulated by factors such as nutriceuticals, epigenetic modifiers or psychosocial behaviour, offering thus future therapeutic opportunity to protect from AD development.

Contribution of serum anti-Müllerian hormone in the management of azoospermia and the prediction of testicular sperm retrieval outcomes: a study of 155 adult men.

BACKGROUND: Testicular sperm extraction (TESE) is the method of choice for recovering spermatozoa in patients with azoospermia. However, the lack of reliable biomarkers makes it impossible to predict sperm retrieval outcomes at TESE. To date, little attention has been given to anti-Müllerian hormone (AMH) serum levels in adult men with altered spermatogenesis. In this study we aimed to investigate whether serum concentrations of AMH and the AMH to total testosterone ratio (AMH/T) might be predictive factors for sperm retrieval outcomes during TESE in a cohort of 155 adult Caucasian men with azoospermia. RESULTS: AMH serum levels were significantly lower in nonobstructive azoospermia (NOA) that was unexplained, cryptorchidism-related, cytotoxic and genetic (medians [pmol/l] = 30.1; 21.8; 26.7; 7.3; and p = 0.02; 0.001; 0.04; <0.0001, respectively]) compared with obstructive azoospermia (OA) (median = 44.8 pmol/l). Lowest values were observed in cases of genetic NOA (p < 0.0001, compared with unexplained NOA) and especially in individuals with non-mosaic Klinefelter syndrome (median = 2.3 pmol/l, p <0.0001). Medians of AMH/T values were significantly lower in genetic NOA compared to unexplained, cryptorchidism-related NOA as well as OA. Only serum concentrations of AMH differed significantly between positive and negative groups in men with non-mosaic Klinefelter syndrome. The optimal cut-off of serum AMH was set at 2.5 pmol/l. The sensitivity, specificity, positive predictive value, negative predictive value and accuracy of this cut-off to predict negative outcomes of SR were 100 %, 76.9 %, 66.6 %, 100 and 84.2 %, respectively. CONCLUSIONS: Serum AMH levels, but not AMH/T values, are a good marker for Sertoli and germ cell population dysfunction in adult Caucasian men with non-mosaic Klinefelter syndrome and could help us to predict negative outcomes of SR at TESE with 100 % sensitivity when serum levels of AMH are below 2.5 pmol/l.

RéSUMé: INTRODUCTION: L'extraction chirurgicale de spermatozoïdes testiculaires (ECST) est la méthode qui permet d'offrir aux hommes ayant une azoospermie des chances de paternité via l'assistance médicale à la procréation. Cependant, le manque de biomarqueurs fiables rend impossible de prédire les résultats de l'ECST. À ce jour, peu d'attention a été accordée aux valeurs sériques d'hormone anti-müllérienne (AMH) chez les hommes adultes ayant une spermatogenèse altérée. Dans cette étude, nous avons cherché à déterminer si les concentrations sériques d'AMH et le rapport AMH sur testostérone totale (AMH/T) pouvaient être des facteurs prédictifs des résultats de l'ECST dans une cohorte de 155 hommes adultes caucasiens ayant une azoospermie. RéSULTATS: Les concentrations sériques d'AMH étaient significativement plus faibles dans l'azoospermie non-obstructive (ANO) non inexpliquée, ANO associée à un antécédent de cryptorchidie, ANO d'origine cytotoxique et génétique (médianes [pmol/l] = 30,1; 21,8; 26,7; 7,3; et p = 0,02; 0,001; 0,04; <0,0001, respectivement) comparativement au groupe contrôle d'azoospermie obstructive (AO) (médiane = 44,8 pmol/l). Les plus faibles valeurs ont été observées dans le groupe d'ANO d'origine génétique (p = 0,0001, par rapport à l'ANO non inexpliquée) et particulièrement chez les individus avec un syndrome de Klinefelter (médiane = 2,3 pmol/l, p <0,0001). Seules les concentrations sériques d'AMH différaient significativement entre les individus avec résultats positifs et négatifs d'extraction de spermatozoïdes chez les hommes atteints d'un syndrome de Klinefelter non mosaïque. Un seuil optimal du taux sérique d'AMH a été fixé à 2,5 pmol/l. La sensibilité, la spécificité, la valeur prédictive positive, la valeur prédictive négative et l'exactitude de ce seuil pour prédire un résultat négatif étaient de 100 %, 76,9 %, 66,6 %, 100 % et 84,2 %, respectivement. CONCLUSIONS: Seules les concentrations sérique d'AMH, et non pas le rapport AMH/T, sont un bon marqueur du dysfonctionnement des cellules de Sertoli ainsi que des cellules germinales chez les hommes adultes caucasiens atteints du syndrome de Klinefelter non mosaïque. Elles peuvent prédire un résultat négatif du prélèvement de spermatozoïdes lors de l'ECST avec une sensibilité de 100 % lorsque les niveaux sériques sont inférieurs à 2,5 pmol/l.

Quantitative dual isotope 123iodine/99mTc-MIBI scintigraphy: A new approach to rule out malignancy in thyroid nodules.

BACKGROUND: The aim of this study was to evaluate the role of dual isotope 123Iodine/99mTc-MIBI thyroid scintigraphy (IMS) in discriminating between malignant and benign lesions in indeterminate nodules using quantitative analysis methods. METHODS: Thirty-five consecutive patients with thyroid nodules of indeterminate or non-diagnostic cytology and cold on 123Iodine scintigraphy (10 Bethesda I, 24 Bethesda III-IV, 1 in which cytology was impossible) underwent IMS between 2017 and 2019 with uptake quantification at two time points ahead of thyroidectomy: early and late. Images were analyzed by two blinded physicians. RESULTS: Twelve nodules were malignant and 23 benign on histopathology. Mean uptake values were lower in benign than in malignant nodules at both time points: early, 8.7±4.1 versus 12.9±3.5 (P=0.005); and late, 5.3±2.7 versus 7.7±1.1 (P=0.008). Interobserver reproducibility was excellent. The intraclass correlation coefficient was 0.86 in benign and 0.92 in malignant lesions for early uptake result (ER) and 0.94 and 0.85 respectively for late uptake result (LR). The optimal LR cut-off  to exclude a diagnosis of malignancy was set at 5.9 . The sensitivity, specificity, positive predictive value, negative predictive value and accuracy of this cut-off were, respectively, 100%, 65.2%, 60%, 100% and 77.1%. CONCLUSION: Despite some study limitations, quantitative analysis of 99mTc-MIBI thyroid scintigraphy had a good reproducibility, which could help to rule out malignancy in non-diagnostic or indeterminate thyroid nodules and thereby reducing the number of patients undergoing unnecessary surgery when LR is below 5.9.

[Brain insulin signaling and Tau: impact for Alzheimer's disease and Tauopathies]. / Relation mutuelle entre Tau et signalisation centrale de l'insuline - Quelles conséquences pour la maladie d'Alzheimer et les tauopathies ?

Alzheimer's disease (AD) is a neurodegenerative disease primarily characterized by cognitive deficits and neuropathological lesions such as Tau aggregates and amyloid plaques, but also associated with metabolic and neuroendocrine abnormalities, such as impairment of cerebral insulin. However, the origin of these symptoms and their relationship to pathology and cognitive disorders remain poorly understood. Insulin is a hormone involved in the control of peripheral and central energy homeostasis, and insulin-resistant state has been linked to increased risk of dementia. It is now well established that brain insulin resistance can exacerbate Tau lesions. Conversely, recent data indicate that Tau protein can modulate insulin signalling in the brain, creating a vicious circle precipitating the pathological AD. This review aims to highlight our current understanding of the role of insulin in the brain and its relationship with Tau protein in the context of AD and Tauopathies.