Transmembrane Protein TMEM230, Regulator of Glial Cell Vascular Mimicry and Endothelial Cell Angiogenesis in High-Grade Heterogeneous Infiltrating Gliomas and Glioblastoma.

High-grade gliomas (HGGs) and glioblastoma multiforme (GBM) are characterized by a heterogeneous and aggressive population of tissue-infiltrating cells that promote both destructive tissue remodeling and aberrant vascularization of the brain. The formation of defective and permeable blood vessels and microchannels and destructive tissue remodeling prevent efficient vascular delivery of pharmacological agents to tumor cells and are the significant reason why therapeutic chemotherapy and immunotherapy intervention are primarily ineffective. Vessel-forming endothelial cells and microchannel-forming glial cells that recapitulate vascular mimicry have both infiltration and destructive remodeling tissue capacities. The transmembrane protein TMEM230 (C20orf30) is a master regulator of infiltration, sprouting of endothelial cells, and microchannel formation of glial and phagocytic cells. A high level of TMEM230 expression was identified in patients with HGG, GBM, and U87-MG cells. In this study, we identified candidate genes and molecular pathways that support that aberrantly elevated levels of TMEM230 play an important role in regulating genes associated with the initial stages of cell infiltration and blood vessel and microchannel (also referred to as tumor microtubule) formation in the progression from low-grade to high-grade gliomas. As TMEM230 regulates infiltration, vascularization, and tissue destruction capacities of diverse cell types in the brain, TMEM230 is a promising cancer target for heterogeneous HGG tumors.

Quantitative brainstem and spinal MRI in amyotrophic lateral sclerosis: implications for predicting noninvasive ventilation needs.

BACKGROUND: Respiratory complications resulting from motor neurons degeneration are the primary cause of death in amyotrophic lateral sclerosis (ALS). Predicting the need for non-invasive ventilation (NIV) in ALS is important for advance care planning and clinical trial design. The aim of this study was to assess the potential of quantitative MRI at the brainstem and spinal cord levels to predict the need for NIV during the first six months after diagnosis. METHODS: Forty-one ALS patients underwent MRI and spirometry shortly after diagnosis. The need for NIV was monitored according to French health guidelines for 6 months. The performance of four regression models based on: clinical variables, brainstem structures volumes, cervical spinal measurements, and combined variables were compared to predict the need for NIV within this period. RESULTS: Both the clinical model (R2 = 0.28, AUC = 0.85, AICc = 42.67, BIC = 49.8) and the brainstem structures' volumes model (R2 = 0.30, AUC = 0.85, AICc = 40.13, BIC = 46.99) demonstrated good predictive performance. In addition, cervical spinal cord measurements model similar performance (R2 = 0.338, AUC = 0.87, AICc = 37.99, BIC = 44.49). Notably, the combined model incorporating predictors from all three models yielded the best performance (R2 = 0.60, AUC = 0.959, AICc = 36.38, BIC = 44.8). These findings are supported by observed positive correlations between brainstem volumes, cervical (C4/C7) cross-sectional area, and spirometry-measured lung volumes. CONCLUSIONS: Our study shows that brainstem volumes and spinal cord area are promising measures to predict respiratory intervention needs in ALS.

Occurrence of L1M Elements in Chromosomal Rearrangements Associated to Chronic Myeloid Leukemia (CML): Insights from Patient-Specific Breakpoints Characterization.

Chronic myeloid leukemia (CML) is a rare myeloproliferative disorder caused by the reciprocal translocation t(9;22)(q34;q11) in hematopoietic stem cells (HSCs). This chromosomal translocation results in the formation of an extra-short chromosome 22, called a Philadelphia chromosome (Ph), containing the BCR-ABL1 fusion gene responsible for the expression of a constitutively active tyrosine kinase that causes uncontrolled growth and replication of leukemic cells. Mechanisms behind the formation of this chromosomal rearrangement are not well known, even if, as observed in tumors, repetitive DNA may be involved as core elements in chromosomal rearrangements. We have participated in the explorative investigations of the PhilosoPhi34 study to evaluate residual Ph+ cells in patients with negative FISH analysis on CD34+/lin- cells with gDNA qPCR. Using targeted next-generation deep sequencing strategies, we analyzed the genomic region around the t(9;22) translocations of 82 CML patients and one CML cell line and assessed the relevance of interspersed repeat elements at breakpoints (BP). We found a statistically higher presence of LINE elements, in particular belonging to the subfamily L1M, in BP cluster regions of both chromosome 22 and 9 compared to the whole human genome. These data suggest that L1M elements could be potential drivers of t(9;22) translocation leading to the generation of the BCR-ABL1 chimeric gene and the expression of the active BCR-ABL1-controlled tyrosine kinase chimeric protein responsible for CML.

Comparison of spinal magnetic resonance imaging and classical clinical factors in predicting motor capacity in amyotrophic lateral sclerosis.

BACKGROUND: Motor capacity is crucial in amyotrophic lateral sclerosis (ALS) clinical trial design and patient care. However, few studies have explored the potential of multimodal MRI to predict motor capacity in ALS. This study aims to evaluate the predictive value of cervical spinal cord MRI parameters for motor capacity in ALS compared to clinical prognostic factors. METHODS: Spinal multimodal MRI was performed shortly after diagnosis in 41 ALS patients and 12 healthy participants as part of a prospective multicenter cohort study, the PULSE study (NCT00002013-A00969-36). Motor capacity was assessed using ALSFRS-R scores. Multiple stepwise linear regression models were constructed to predict motor capacity at 3 and 6 months from diagnosis, based on clinical variables, structural MRI measurements, including spinal cord cross-sectional area (CSA), anterior-posterior, and left-to-right cross-section diameters at vertebral levels from C1 to T4, and diffusion parameters in the lateral corticospinal tracts (LCSTs) and dorsal columns. RESULTS: Structural MRI measurements were significantly correlated with the ALSFRS-R score and its sub-scores. And as early as 3 months from diagnosis, structural MRI measurements fit the best multiple linear regression model to predict the total ALSFRS-R (R2 = 0.70, p value = 0.0001) and arm sub-score (R2 = 0.69, p value = 0.0002), and combined with DTI metric in the LCST and clinical factors fit the best multiple linear regression model to predict leg sub-score (R2 = 0.73, p value = 0.0002). CONCLUSIONS: Spinal multimodal MRI could be promising as a tool to enhance prognostic accuracy and serve as a motor function proxy in ALS.

[Crisis consultations in child and adolescent psychiatry in Reims: Cross-sectional study of the population of accompanied minors]. / Dispositif de crise en psychiatrie de l'enfant et de l'adolescent à Reims : étude transversale de la population des mineurs accompagnés.

INTRODUCTION: The crisis consultation unit (CCU) of the child psychiatry department of the Reims University Hospital was created to respond to an increasing demand for rapid interventions with minors. OBJECTIVE: The objective of this study is to observe the characteristics of the population received in this facility and to explore the links between the data, to hypothesize about its specificities. METHOD: We conducted a cross-sectional study of data collected during telephone assessments between June 2016 and January 2018. A univariate analysis was performed using EpiInfo© software and the pvalue.io© statistical interface using R statistical software. A total of 263 telephone contacts were counted. RESULTS: A greater activity of the service is found during the school period. The majority of minors did not have any psychiatric or psychological follow-up at the time of the call. Boys consulted earlier, preferably for externalized disorders. The youngest children are often referred to prevent symptoms following an acute stress. CONCLUSION: Our study allowed us to draw up a sociodemographic profile and to show certain trends observed within the CCU of the child psychiatry department of the Reims University Hospital, in particular the multiplicity of reasons for consultation. At a time when the health crisis is impacting the mental health of the entire population and increasing the time required for treatment, this type of system is particularly relevant to the possible reorganization of the care offered by the CMP. The CCU would make it possible to report the most urgent situations, which would then benefit from specific care (hospitalization, medication, specific consultations).

Microendoscopic transventricular deep brain stimulation of the anterior nucleus of the thalamus as a safe treatment in intractable epilepsy: A feasibility study.

INTRODUCTION: Deep brain stimulation (DBS) of the anterior nucleus of the thalamus (ANT) is proposed in patients with severe intractable epilepsy. When used, the transventricular approach increases the risk of bleeding due the anatomy around the entry point in the thalamus. To avoid such a complication, we used a transventricular microendoscopic technique. METHODS: We performed a retrospective study of nine adult patients who were surgically treated for refractory epilepsy between 2010 and 2019 by DBS of the anterior thalamic nucleus. RESULTS: Endoscopy provides a direct visual control of the entry point of the lead in the thalamus through the ventricle by avoiding ependymal vessels. No hemorrhage was recorded and accuracy was systematically checked by intraoperative stereotactic MRI. We reported a responder rate improvement in 88.9% of patients at 1 year and in 87.5% at 2 years. We showed a significant decrease in global seizure count per month one year after DBS (68.1%; P=0.013) leading to an overall improvement in quality of life. No major adverse effect was recorded during the follow-up. ANT DBS showed a prominent significant effect with a decrease of the number of generalized seizures. CONCLUSION: We aimed at a better ANT/lead collimation using a vertical transventricular approach under microendoscopic monitoring. This technique permitted to demonstrate the safety and the accuracy of the procedure.

Prenatally Symptomatic Suprasellar Arachnoid Cyst: When to treat? A case-base update.

INTRODUCTION: Suprasellar Arachnoid Cysts (SAC) are rare heterogeneous entities. Though prenatally diagnosed, they are rarely treated pre-birth. Symptomatic cases are mainly seen in infants. CASE DESCRIPTION: We describe a case of a prenatally symptomatic suprasellar arachnoid cyst treated postnatally. The cyst was diagnosed on a routine ultrasound at 22 weeks, was rapidly evolving in the ultrasounds and the MRI of the 29th week. It then became symptomatic at 30 weeks with episodes of fetal bradycardia, independent to the uterine contractions. Antenatal treatment was discussed but delivery decided in emergency despite the prematurity via C-section. Though well tolerated postnatally, the cyst continued to grow. Endoscopic ventriculo-cysto-cisternostomy was performed on the 5th day of birth. Despite progressive reduction of the cyst, residual brainstem compression and evolving ventriculomegaly lead to a transient extrathecal internal shunting. DISCUSSION/CONCLUSION: Our case suggests that prenatally diagnosed cysts require a close follow-up. Treatment options and timing should be adapted to anatomy, cyst evolution and symptoms whether it is before or after birth.

Generation of two hiPSC lines (UMILi027-A and UMILi028-A) from early and late-onset Congenital Central hypoventilation Syndrome (CCHS) patients carrying a polyalanine expansion mutation in the PHOX2B gene.

Congenital Central Hypoventilation Syndrome (CCHS) is a rare disorder of the autonomic nervous system (ANS), characterized by inadequate control of autonomic ventilation and global autonomic dysfunction. Heterozygous polyalanine repeat expansion mutations in exon 3 of the transcription factor Paired-like homeobox 2B (PHOX2B) gene occur in 90% of CCHS cases. In this study, we describe the generation and characterization of two human induced pluripotent stem cell (hiPSC) lines from female CCHS patients carrying a heterozygous + 5 alanine expansion mutation. The generated iPSC lines show a normal karyotype, express pluripotency markers and are able to differentiate into the three germ layers.

Pregnancy denial: a complex symptom with life context as a trigger? A prospective case-control study.

OBJECTIVE: To identify risk factors for a woman to experience pregnancy denial. DESIGN, SETTING AND POPULATION: A French multicentric prospective case-control study with 71 mother-infant dyads having experienced a pregnancy denial versus a control group of 71 dyads. METHODS: Data were collected in the week after delivery using an observational leaflet and two psychiatric scales (MINI and QSSP). MAIN OUTCOME MEASURES: Statistically significant differences between the two groups regarding social, demographic, medical and psychiatric data. RESULTS: Not being in a stable relationship (odds ratio [OR] 17.18, 95% CI 3.37-87.60]; P < 0.0001), not having a high school diploma (OR 1.11, 95% CI 1.04-1.38]; P < 0.0001) and having a psychiatric history (OR 6.33, 95% CI 1.62-24.76; P = 0.0002) were risk factors to experience pregnancy denial, whereas being older was a protective factor (OR 0.86, 95% CI 0.79-0.93; P = 0.0054) (logistic regression, Wald 95% CI). Other risk factors included late declarations of pregnancy history and past pregnancy denials (case n = 7, 9.7% versus 0% in controls; P = 0.01), past pregnancy denials in the family (case n = 13, 18% versus control n = 4, 5.6%; P = 0.03), and use of a contraceptive method (75% for cases versus 7% in control; P < 0.0001), primarily an oral contraceptive (75%). CONCLUSION: Family or personal history of pregnancy denial should be part of the systematic anamnesis during the first visit of a patient of child-bearing age. Further, our study points out that life context (young age, single status, socio-economic precarity, pill-based contraception) could be a trigger for pregnancy denial in certain women. TWEETABLE ABSTRACT: Life context can be a trigger for pregnancy denial.

[Evaluation of the success of medical abortion by a plasma hCG control threshold]. / Évaluation du succès de l'interruption volontaire de grossesse médicamenteuse par un seuil d'hCG sérique.

OBJECTIVES: In France, monitoring of the success of medical abortion is recommended 2 to 3 weeks after the procedure. However, there is no clear consensus on the modalities of this monitoring. The main objective of this study is to identify a threshold of serum hCG (human chorionic gonadotropin) control for medical abortions ≤7 weeks of gestation below which success can be confirmed without recourse to pelvic ultrasound. METHODS: This is a retrospective multicenter study conducted over a 14-month period. The serum hCG level, measured between the 15th and 25th day following the abortion, was compared with the results of the pelvic ultrasound performed at the follow-up visit. Ultrasound failure was defined as retention or persistent pregnancy. RESULTS: Among the 624 women included, the failure rate was 22.3%, including 86.3% of retentions, 8.6% of pregnancies stopped and 5% of pregnancies progressed. Using a ROC curve, the threshold value of hCG found to exclude failure at 95% was 253 IU/l (AUC=0.9202, sensitivity=84.17%, specificity=85.95% and positive predictive value [PPV]=63%). CONCLUSIONS: A serum hCG level ≤253 IU/l is sufficient to affirm the efficacy of medical abortion. However, since PPV is only 63% for this threshold, ultrasound should be reserved for women with high hCG levels.

[Benefit-risk balance of hormone replacement therapy: Cancers and mortality. Postmenopausal women management - CNGOF and GEMVi clinical practice guidelines]. / La balance bénéfice­risque du traitement hormonal de la ménopause : cancers et mortalité. RPC Les femmes ménopausées CNGOF ­ GEMVi.

The use of hormone replacement therapy (HRT) for menopausal women has been the subject of much controversy in recent years, particularly concerning the carcinologic risks. The purpose of this review is to evaluate the impact of the use of HRT on the risk of gynecological but also extra-gynecological cancers. The effect of the type and the duration of use of HRT in menopausal women will also be discussed. The beneficial impact of HRT on overall mortality is also an element that will be discussed and must be taken into account when evaluating the benefit-risk balance of HRT for menopausal women.

Surgery for recurrent medulloblastoma: A review.

INTRODUCTION: Medulloblastoma (MB) is the most common malignant brain tumour in children. Despite significant progress in its management, a proportion of children relapse; tumour recurrence still carries a poor prognosis. While surgery is a mainstay of the management of primary MB, its role in recurrent MB is unclear. The objective of this literature review is to explore current practice and potential benefits of surgery in recurrent MB. MATERIAL AND METHODS: We reviewed all articles published in PubMed and Scholar from 1990 to 2018 with the following terms: "medulloblastoma" AND "recurrence" AND "neurosurgical procedures". Among 69 articles, 12 were directly relevant. RESULTS: A total of 581 cases of recurrent MB were identified from published series. Median time from diagnosis to relapse was 20.4months. The majority of relapses involved disseminated craniospinal disease and only one-fifth relapses was located in the posterior fossa. The outcome was consistently poor, with a median survival of 12.4% and a median survival time after relapse of 18.5months. In the HIP-SIOP-PNET4 study, surgery at relapse was performed in 25% of cases and was associated with improved prognosis in solitary posterior fossa recurrence. CONCLUSION: Recurrent medulloblastoma is often fatal in children who have previously received radiotherapy. The role of surgery in improving survival is unclear, but there is some evidence that resection of a focal single posterior fossa recurrence can bring survival benefit. The value of biopsy lies in the optimisation and selection of appropriate targeted therapy and in excluding a second malignancy.

Management of patients suffering from hemorrhagic intracranial metastases: Propositions to help the neurosurgeon in emergency situations based on a literature review.

INTRODUCTION: Brain metastases are the most common intracranial neoplasm in adult patients, and one of the fearsome complications proves to be intratumoral hemorrhage. The neurosurgical management of patients harboring a bleeding brain metastasis is not fully established and there is still today an ongoing debate on the optimal management of these patients. The aim of this article is to provide the neurosurgeons with practical tools to assist in their decision-making process in the management of BMs. METHODS: We conducted a literature review of the relevant Pubmed, Cochrane, and Google scholar-indexed articles published between 2000 and 2019. The following key words were entered in the Pubmed search engine: [metastasis], [metastases], [brain metastases], [brain metastasis], [hemorrhage], [hematoma], [blood clot], [intracerebral hemorrhage], [intracranial hemorrhage]. The review was performed in accordance with the PRISMA recommendations. RESULTS: Based on PubMed, Cochrane, and Google scholar, 459 articles were retained, 392 were then removed because of their non-adequacy with the topic and, 9 articles were removed because they were not written in English language. So, 58 articles were analyzed. Radiological evaluation is crucial, but few traps exist. The frequency of overall brain tumor-related with intracranial hematoma is 7.2%, with a higher frequency for secondary tumors. The local recurrence rate after resection of a hemorrhagic metastasis seems to be better probably because of an easier "en bloc" resection thanks to the hematoma. An atypical presentation is reported in up to 4% in patients with chronic or acute subdural hematoma. Patients with subarachnoid hemorrhage and epidural hematoma are rare. A clear-cut correlation between the incidence of bleeding event in brain mets and prior stereotactic radiosurgery was not established. CONCLUSION: The current literature pertaining to the neurosurgical management of acute bleeding in brain metastasis is scant and the level of evidence remains low (experts 'opinions; class C). Herein we suggest a flowchart to assist in dealing with those difficult patients.

Integrating Microstructured Electrospun Scaffolds in an Open Microfluidic System for in Vitro Studies of Human Patient-Derived Primary Cells.

Recent studies have suggested that microenvironmental stimuli play a significant role in regulating cellular proliferation and migration, as well as in modulating self-renewal and differentiation processes of mammary cells with stem cell (SCs) properties. Recent advances in micro/nanotechnology and biomaterial synthesis/engineering currently enable the fabrication of innovative tissue culture platforms suitable for maintenance and differentiation of SCs in vitro. Here, we report the design and fabrication of an open microfluidic device (OMD) integrating removable poly(ε-caprolactone) (PCL) based electrospun scaffolds, and we demonstrate that the OMD allows investigation of the behavior of human cells during in vitro culture in real time. Electrospun scaffolds with modified surface topography and chemistry can influence attachment, proliferation, and differentiation of mammary SCs and epigenetic mechanisms that maintain luminal cell identity as a function of specific morphological or biochemical cues imparted by tailor-made fiber post-treatments. Meanwhile, the OMD architecture allows control of cell seeding and culture conditions to collect more accurate and informative in vitro assays. In perspective, integrated systems could be tailor-made to mimic specific physiological conditions of the local microenvironment and then analyze the response from screening specific drugs for more effective diagnostics, long-term prognostics, and disease intervention in personalized medicine.

RNA profiling of human testicular cells identifies syntenic lncRNAs associated with spermatogenesis.

STUDY QUESTION: Is the noncoding transcriptional landscape during spermatogenesis conserved between human and rodents? SUMMARY ANSWER: We identified a core group of 113 long noncoding RNAs (lncRNAs) and 20 novel genes dynamically and syntenically transcribed during spermatogenesis. WHAT IS KNOWN ALREADY: Spermatogenesis is a complex differentiation process driven by a tightly regulated and highly specific gene expression program. Recently, several studies in various species have established that a large proportion of known lncRNAs are preferentially expressed during meiosis and spermiogenesis in a testis-specific manner. STUDY DESIGN, SIZE, DURATION: To further investigate lncRNA expression in human spermatogenesis, we carried out a cross-species RNA profiling study using isolated testicular cells. PARTICIPANTS/MATERIALS, SETTING, METHODS: Human testes were obtained from post-mortem donors (N = 8, 51 years old on average) or from prostate cancer patients with no hormonal treatment (N = 9, 80 years old on average) and only patients with full spermatogenesis were used to prepare enriched populations of spermatocytes, spermatids, Leydig cells, peritubular cells and Sertoli cells. To minimize potential biases linked to inter-patient variations, RNAs from two or three donors were pooled prior to RNA-sequencing (paired-end, strand-specific). Resulting reads were mapped to the human genome, allowing for assembly and quantification of corresponding transcripts. MAIN RESULTS AND THE ROLE OF CHANCE: Our RNA-sequencing analysis of pools of isolated human testicular cells enabled us to reconstruct over 25 000 transcripts. Among them we identified thousands of lncRNAs, as well as many previously unidentified genes (novel unannotated transcripts) that share many properties of lncRNAs. Of note is that although noncoding genes showed much lower synteny than protein-coding ones, a significant fraction of syntenic lncRNAs displayed conserved expression during spermatogenesis. LARGE SCALE DATA: Raw data files (fastq) and a searchable table (.xlss) containing information on genomic features and expression data for all refined transcripts have been submitted to the NCBI Gene Expression Omnibus under accession number GSE74896. LIMITATIONS, REASONS FOR CAUTION: Isolation procedures may alter the physiological state of testicular cells, especially for somatic cells, leading to substantial changes at the transcriptome level. We therefore cross-validated our findings with three previously published transcriptomic analyses of human spermatogenesis. Despite the use of stringent filtration criteria, i.e. expression cut-off of at least three fragments per kilobase of exon model per million reads mapped, fold-change of at least three and false discovery rate adjusted P-values of less than <1%, the possibility of assembly artifacts and false-positive transcripts cannot be fully ruled out. WIDER IMPLICATIONS OF THE FINDINGS: For the first time, this study has led to the identification of a large number of conserved germline-associated lncRNAs that are potentially important for spermatogenesis and sexual reproduction. In addition to further substantiating the basis of the human testicular physiology, our study provides new candidate genes for male infertility of genetic origin. This is likely to be relevant for identifying interesting diagnostic and prognostic biomarkers and also potential novel therapeutic targets for male contraception. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by l'Institut national de la santé et de la recherche médicale (Inserm); l'Université de Rennes 1; l'Ecole des hautes études en santé publique (EHESP); INERIS-STORM to B.J. [N 10028NN]; Rennes Métropole 'Défis scientifiques émergents' to F.C (2011) and A.D.R (2013). The authors have no competing financial interests.

[Effectiveness and use of hormonal contraceptives (except for intrauterine devices): CNGOF Contraception Guidelines]. / Contraception hormonale en pratique hors dispositifs intra-utérins. RPC Contraception CNGOF.

Hormonal contraceptives remain among the most popular methods used by women. The purpose of this work is to review the effectiveness and use of these different methods. In addition, some side-effects are feared and/or frequently reported by users of hormonal contraceptives: unscheduled bleeding, acne, catamenial migraines, weight gain, libido and/or mood disorders. In this review of the literature, the accountability of hormonal contraceptives for the occurrence of some of these side-effects was discussed and a management strategy was proposed.

TRANSPARENT TESTA 16 and 15 act through different mechanisms to control proanthocyanidin accumulation in Arabidopsis testa.

Flavonoids are secondary metabolites that fulfil a multitude of functions during the plant life cycle. In Arabidopsis proanthocyanidins (PAs) are flavonoids that specifically accumulate in the innermost integuments of the seed testa (i.e. endothelium), as well as in the chalaza and micropyle areas, and play a vital role in protecting the embryo against various biotic and abiotic stresses. PAs accumulation in the endothelium requires the activity of the MADS box transcription factor TRANSPARENT TESTA (TT) 16 (ARABIDOPSIS B-SISTER/AGAMOUS-LIKE 32) and the UDP-glycosyltransferase TT15 (UGT80B1). Interestingly tt16 and tt15 mutants display a very similar flavonoid profiles and patterns of PA accumulation. By using a combination of genetic, molecular, biochemical, and histochemical methods, we showed that both TT16 and TT15 act upstream the PA biosynthetic pathway, but through two distinct genetic routes. We also demonstrated that the activity of TT16 in regulating cell fate determination and PA accumulation in the endothelium is required in the chalaza prior to the globular stage of embryo development. Finally this study provides new insight showing that TT16 and TT15 functions extend beyond PA biosynthesis in the inner integuments of the Arabidopsis seed coat.

Could myo-inositol soft gel capsules outperform clomiphene in inducing ovulation? Results of a pilot study.

OBJECTIVE: Insulin resistance is known to worsen polycystic ovarian syndrome (PCOS). The management of insulin resistance is crucial in the treatment of PCOS and insulin-sensitizing molecule as myo-inositol (MYO) seems to have promising effects. The aim of our pilot study was to study whether supplementation with MYO can improve patients' sensitivity to clomiphene citrate (CC) in terms of ovulation and pregnancy rates. PATIENTS AND METHODS: This study included 26 patients with PCOS, eligible to ovulation induction with CC. All of them received MYO in combination with CC and folic acid, following the usual protocol. Results concerning ovulation and pregnancy rates were compared to those from our historical cohort of PCOS patients treated with CC alone. RESULTS: Ovulation rate was significantly higher with MYO+CC than with CC alone (65.5% vs. 42%, p=0.0001). The number of patients sensitive to 50 mg/d was 54% with MYO vs. 40% in our reference cohort (NS). The total resistance rate was 19% vs. 27% in the reference cohort (NS). Cumulative pregnancy rate with MYO+CC was 53.8% vs. 42.2% with CC alone (NS). Pregnancy rates per initiated cycle were 16.1% with MYO vs. 12.6% in the historical cohort (NS). DISCUSSION: Although the differences were not significant for most outcomes, probably due to the small number of patients, our pilot study seemed to show a benefit of supplementation with MYO during ovulation induction with CC in PCOS patients. CONCLUSIONS: This study proves the great interest of a RCT and re-opens the possibilities of insulin-sensitizing agents in the treatment of anovulatory patients with PCOS, such as natural products like MYO.

Test of Special Relativity Using a Fiber Network of Optical Clocks.

Phase compensated optical fiber links enable high accuracy atomic clocks separated by thousands of kilometers to be compared with unprecedented statistical resolution. By searching for a daily variation of the frequency difference between four strontium optical lattice clocks in different locations throughout Europe connected by such links, we improve upon previous tests of time dilation predicted by special relativity. We obtain a constraint on the Robertson-Mansouri-Sexl parameter |α|≲1.1×10^{-8}, quantifying a violation of time dilation, thus improving by a factor of around 2 the best known constraint obtained with Ives-Stilwell type experiments, and by 2 orders of magnitude the best constraint obtained by comparing atomic clocks. This work is the first of a new generation of tests of fundamental physics using optical clocks and fiber links. As clocks improve, and as fiber links are routinely operated, we expect that the tests initiated in this Letter will improve by orders of magnitude in the near future.

Meiotic Genes Are Enriched in Regions of Reduced Archaic Ancestry.

About 1-6% of the genetic ancestry of modern humans today originates from admixture with archaic humans. It has recently been shown that autosomal genomic regions with a reduced proportion of Neanderthal and Denisovan ancestries (NA and DA) are significantly enriched in genes that are more expressed in testis than in other tissues. To determine whether a cellular segregation pattern would exist, we combined maps of archaic introgression with a cross-analysis of three transcriptomic datasets deciphering the transcriptional landscape of human gonadal cell types. We reveal that the regions deficient in both NA and DA contain a significant enrichment of genes transcribed in meiotic germ cells. The interbreeding of anatomically modern humans with archaic humans may have introduced archaic-derived alleles that contributed to genetic incompatibilities affecting meiosis that were subsequently purged by natural selection.