Leukaemia inhibitory factor modulates the differentiation of granulosa cells during sheep in vitro preantral to antral follicle development and improves oocyte meiotic competence.

In vitro follicle development from cryopreserved ovarian tissue could become an invaluable assisted reproduction technology for women with early ovarian failure. The challenge lies in producing, from small follicles present in the ovarian cortex, high-quality mature oocytes able to sustain embryo development. In vivo, an optimal combination of hormones and other factors coordinates the development of follicles and their enclosed oocyte. We have investigated the effect of the leukaemia inhibitory factor (LIF) cytokine, alone or in combination with FSH, on sheep in vitro follicle development from the preantral stage onwards. LIF did not alter follicle growth or antrum formation, but it modulated the differentiation of granulosa cells, as revealed by decreased production of anti-Müllerian hormone and abolished FSH-induced stimulation of oestradiol secretion. This modulatory role was also reflected in the abundance of mRNA from 35 genes, analysed by reverse-transcription coupled to microfluidic quantitative PCR. LIF stimulated or at least maintained the expression of genes involved in the dialogue between the oocyte and granulosa cells, through gap junctions (GJA4 encoding connexin 37) or paracrine signalling (Bone morphogenetic protein 15, KIT ligand and their receptors). Finally, the presence of both LIF and FSH during follicle growth strongly improved oocyte meiotic competence: most oocytes (56%) underwent subsequent nuclear maturation, a significant increase compared with their counterparts from follicles of similar size (550-900 µm) cultured with FSH only (28%) or developed in vivo (9%). Their ability to sustain embryo development remains to be evaluated. Combined supplementation with FSH and LIF certainly merits investigation with human follicles.

First record of the sound produced by the oldest Upper Paleolithic seashell horn.

Anthropologists and ethnomusicologists assert that there is no society without song, and more specifically, there is no ritual or celebration without accompanying sound. The production of sounds in social contexts is very ancient. Here, we report on the study of a seashell from the decorated cave of Marsoulas and demonstrate that the Magdalenian occupants of this site transformed this shell into a wind instrument. It is one of the very rare examples, if not the only one for the Paleolithic period, of a musical instrument fashioned from a large shell, and the first conch shell of this use thus far discovered. We already know that prehistoric people transformed many shells into portable ornaments and that they thus attributed substantial corporal symbolism to them. This seashell horn, with its unique sonority, both deep and strong with an enduring reverberation, sheds light on a musical dimension until now unknown in the context of Upper Paleolithic societies.

Persistence of Ebola virus in semen among Ebola virus disease survivors in Sierra Leone: A cohort study of frequency, duration, and risk factors.

BACKGROUND: Sexual transmission chains of Ebola virus (EBOV) have been verified and linked to EBOV RNA persistence in semen, post-recovery. The rate of semen persistence over time, including the average duration of persistence among Ebola virus disease (EVD) survivors, is not well known. This cohort study aimed to analyze population estimates of EBOV RNA persistence rates in semen over time, and associated risk factors in a population of survivors from Sierra Leone. METHODS AND FINDINGS: In this cohort study from May 2015 to April 2017 in Sierra Leone, recruitment was conducted in 2 phases; the first enrolled 100 male participants from the Western Area District in the capital of Freetown, and the second enrolled 120 men from the Western Area District and from Lungi, Port Loko District. Mean age of participants was 31 years. The men provided semen for testing, analyzed by quantitative reverse transcription PCR (qRT-PCR) for the presence of EBOV RNA. Follow-up occurred every 2 weeks until the endpoint, defined as 2 consecutive negative qRT-PCR results of semen specimen testing for EBOV RNA. Participants were matched with the Sierra Leone EVD case database to retrieve cycle threshold (Ct) values from the qRT-PCR analysis done in blood during acute disease. A purposive sampling strategy was used, and the included sample composition was compared to the national EVD survivor database to understand deviations from the general male survivor population. At 180 days (6 months) after Ebola treatment unit (ETU) discharge, the EBOV RNA semen positive rate was 75.4% (95% CI 66.9%-82.0%). The median persistence duration was 204 days, with 50% of men having cleared their semen of EBOV RNA after this time. At 270 days, persistence was 26.8% (95% CI 20.0%-34.2%), and at 360 days, 6.0% (95% CI 3.1%-10.2%). Longer persistence was significantly associated with severe acute disease, with probability of persistence in this population at 1 year at 10.1% (95% CI 4.6%-19.8%) compared to the probability approaching 0% for those with mild acute disease. Age showed a dose-response pattern, where the youngest men (≤25 years) were 3.17 (95% CI 1.60, 6.29) times more likely to be EBOV RNA negative in semen, and men aged 26-35 years were 1.85 (95% CI 1.04, 3.28) times more likely to be negative, than men aged >35 years. Among participants with both severe acute EVD and a higher age (>35 years), persistence remained above 20% (95% CI 6.0%-50.6%) at 1 year. Uptake of safe sex recommendations 3 months after ETU discharge was low among a third of survivors. The sample was largely representative of male survivors in Sierra Leone. A limitation of this study is the lack of knowledge about infectiousness. CONCLUSIONS: In this study we observed that EBOV RNA persistence in semen was a frequent phenomenon, with high population rates over time. This finding will inform forthcoming updated recommendations on risk reduction strategies relating to sexual transmission of EBOV. Our findings support implementation of a semen testing program as part of epidemic preparedness and response. Further, the results will enable planning of the magnitude of testing and targeted counseling needs over time.

Publisher Correction: SLX4 interacts with RTEL1 to prevent transcription-mediated DNA replication perturbations.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Author Correction: SLX4 interacts with RTEL1 to prevent transcription-mediated DNA replication perturbations.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

SLX4 interacts with RTEL1 to prevent transcription-mediated DNA replication perturbations.

The SLX4 tumor suppressor is a scaffold that plays a pivotal role in several aspects of genome protection, including homologous recombination, interstrand DNA crosslink repair and the maintenance of common fragile sites and telomeres. Here, we unravel an unexpected direct interaction between SLX4 and the DNA helicase RTEL1, which, until now, were viewed as having independent and antagonistic functions. We identify cancer and Hoyeraal-Hreidarsson syndrome-associated mutations in SLX4 and RTEL1, respectively, that abolish SLX4-RTEL1 complex formation. We show that both proteins are recruited to nascent DNA, tightly co-localize with active RNA pol II, and that SLX4, in complex with RTEL1, promotes FANCD2/RNA pol II co-localization. Importantly, disrupting the SLX4-RTEL1 interaction leads to DNA replication defects in unstressed cells, which are rescued by inhibiting transcription. Our data demonstrate that SLX4 and RTEL1 interact to prevent replication-transcription conflicts and provide evidence that this is independent of the nuclease scaffold function of SLX4.

Susceptibility of Rice to Oebalus pugnax (F.) (Hemiptera: Pentatomidae) Feeding at Different Levels of Grain Maturity and Impacts on Insecticide Termination.

The stages of rice, Oryza sativa L. (Poales: Poaceae), grain maturity that are most susceptible to rice stink bug, Oebalus pugnax (F.), damage have been identified; however, the stage at which they are no longer capable of causing appreciable damage during grain maturity is unclear. The objective of this study was to determine the susceptibility of rice to rice stink bug feeding at different levels of grain maturity and determine an insecticide termination timing. Rice stink bug damage was examined using five levels of grain maturity described as percent of kernels reaching mature straw coloration referred to as hard dough (20, 40, 60, 80, and 100%) across a range of infestation levels using single panicle sleeve cages and large cages. Hybrid and conventional cultivar rice panicles at 20, 40, and 60% hard dough were found to be susceptible to indirect yield loss, as two rice stink bugs per panicle resulted in over 7% peck. In large cage trials, 25 rice stink bugs caused 0.7-1% peck to hybrid and conventional rice plots at 20% hard dough. Much less damage was observed once rice reached 60% hard dough, where peck averages only reached 0.4%. Decreased damage at 60% hard dough was validated using uncaged trials where 0.4% additional peck was observed in unsprayed plots. These data indicate that rice in the early stages of hard dough is susceptible to large levels of indirect yield loss, but unless significant densities of rice stink bug are present at 60% hard dough, no more sampling or applications are necessary.

Glutathione-PEGylated liposomal methylprednisolone in comparison to free methylprednisolone: slow release characteristics and prolonged lymphocyte depression in a first-in-human study.

AIMS: Intravenous high-dose free methylprednisolone (MP) hemisuccinate is the primary treatment for an acute relapse in relapsing-remitting multiple sclerosis. However, it is inconvenient and its side effects are undesirable. Both dose and dosing frequency can be reduced by incorporating free MP in glutathione-PEGylated liposomes, creating a slow-release formulation with reduced toxicity and prolonged peripheral efficacy. This first-in-human study was designed to assess the safety, pharmacokinetics and pharmacodynamics of glutathione-PEGylated liposomes containing MP (2B3-201). METHODS: The first part was a double-blind, three-way cross over study in 18 healthy male subjects, receiving ascending doses of 2B3-201, active comparator (free MP) or placebo. Part 2 of the study was an open-label infusion of 2B3-201 (different doses), exploring pretreatment with antihistamines and different infusion schedules in another 18 healthy male subjects, and a cross-over study in six healthy female subjects. MP plasma concentrations, lymphocyte counts, adrenocorticotropic hormone, osteocalcin and fasting glucose were determined. Safety and tolerability profiles were assessed based on adverse events, safety measurements and central nervous system tests. RESULTS: The most frequent recorded AE related to 2B3-201 was an infusion related reaction (89%). 2B3-201 was shown to have a plasma half-life between 24 and 37 h and caused a prolonged decrease in the lymphocyte count, adrenocorticotropic hormone and osteocalcin, and a rise in fasting glucose. CONCLUSION: 2B3-201 is considered safe, with no clinically relevant changes in central nervous system safety parameters and no serious adverse events. In addition, 2B3-201 shows a long plasma half-life and prolonged immunosuppressive effects.

[Differences in access to Internet and Internet-based information seeking according to the type of psychiatric disorder]. / Différences d'accès à Internet et de recherche d'informations en santé via Internet selon le trouble psychiatrique.

BACKGROUND: Internet has become a major tool for patients to search for health-related information and to communicate on health. We currently lack data on how patients with psychiatric disorders access and use Internet to search for information on their mental health. This study aimed to assess, in patients followed for a psychiatric disorder (schizophrenia, bipolar disorder, mood and anxiety disorder, substance-related and addictive disorders and eating disorders), prevalence of Internet access and use, and patient expectations and needs regarding the use of Internet to search for mental-health information depending on the psychiatric disorder. METHODS: We conducted this cross-sectional study between May 2013 and July 2013 in 648 patients receiving psychiatric care in 8 hospitals from the Region Centre, France. We used multivariate logistic regression adjusted for age, gender, socio-educational level and professional status to compare use, expectations and needs regarding Internet-based information about the patient's psychiatric disorder (65-items self-administered questionnaires) as a function of the psychiatric disorders. We identified patients clusters with multiple correspondence analysis and ascending hierarchical classification. RESULTS: Although 65.6% of our population accessed Internet at home, prevalence for Internet access varied depending on the type of psychiatric disorder and was much more related to limited access to a computer and low income than to a lack of interest in the Internet. Most of the patients who used Internet were interested in having access to reliable Internet-based information on their health (76.8%), and most used Internet to search for Internet based health-information about their psychiatric disorder (58.8%). We found important differences in terms of expectations and needs depending on the patient's psychiatric disorder (e.g., higher interest in Internet-based information among patients with bipolar disorder, substance-related and addictive disorders and eating disorders). We identified three clusters: younger patients with depressive or anxiety disorders and higher Internet access and Internet use; older patients with low socio-economical status and low Internet access and Internet use; patients receiving long-term care for schizophrenia, with low Internet access and Internet use. CONCLUSION: Patients with psychiatric disorders reported average use, needs and expectations for Internet-based health information comparable to the overall population. However, Internet use, needs and expectations for Internet-based mental health information differed between patients depending on their psychiatric disorder. Internet-based information and communication for mental health should be designed specifically for each psychiatric disorder.

Comparison of 2 Doses for ACTH Stimulation Testing in Dogs Suspected of or Treated for Hyperadrenocorticism.

BACKGROUND: Lowering the cosyntropin dose needed for ACTH stimulation would make the test more economical. OBJECTIVES: To compare the cortisol response to 1 and 5 µg/kg cosyntropin IV in dogs being screened for hyperadrenocorticism (HAC) and in dogs receiving trilostane or mitotane for pituitary-dependent HAC. ANIMALS: Healthy dogs (n = 10); client-owned dogs suspected of having HAC (n = 39) or being treated for pituitary-dependent HAC with mitotane (n = 12) or trilostane (n = 15). PROCEDURES: In this prospective study, healthy dogs had consecutive ACTH stimulation tests to ensure 2 tests could be performed in sequence. For the first test, cosyntropin (1 µg/kg IV) was administered; the second test was initiated 4 hours after the start of the first (5 µg/kg cosyntropin IV). Dogs suspected of having HAC or being treated with mitotane were tested as the healthy dogs. Dogs receiving trilostane treatment were tested on consecutive days at the same time post pill using the low dose on day 1. RESULTS: In dogs being treated with mitotane or trilostane, the 2 doses were pharmacodynamically equivalent (90% confidence interval, 85.1-108.2%; P = 0.014). However, in dogs suspected of having HAC, the doses were not pharmacodynamically equivalent (90% confidence interval, 73.2-92.8%; P = 0.37); furthermore, in 23% of the dogs, clinical interpretation of test results was different between the doses. CONCLUSIONS AND CLINICAL RELEVANCE: For dogs suspected of having HAC, 5 µg/kg cosyntropin IV is still recommended for ACTH stimulation testing. For dogs receiving mitotane or trilostane treatment, a dose of 1 µg/kg cosyntropin IV can be used.

Categorization of common sounds by cochlear implanted and normal hearing adults.

Auditory categorization involves grouping of acoustic events along one or more shared perceptual dimensions which can relate to both semantic and physical attributes. This process involves both high level cognitive processes (categorization) and low-level perceptual encoding of the acoustic signal, both of which are affected by the use of a cochlear implant (CI) device. The goal of this study was twofold: I) compare the categorization strategies of CI users and normal hearing listeners (NHL) II) investigate if any characteristics of the raw acoustic signal could explain the results. 16 experienced CI users and 20 NHL were tested using a Free-Sorting Task of 16 common sounds divided into 3 predefined categories of environmental, musical and vocal sounds. Multiple Correspondence Analysis (MCA) and Hierarchical Clustering based on Principal Components (HCPC) show that CI users followed a similar categorization strategy to that of NHL and were able to discriminate between the three different types of sounds. However results for CI users were more varied and showed less inter-participant agreement. Acoustic analysis also highlighted the average pitch salience and average autocorrelation peak as being important for the perception and categorization of the sounds. The results therefore show that on a broad level of categorization CI users may not have as many difficulties as previously thought in discriminating certain kinds of sound; however the perception of individual sounds remains challenging.

[Validation of the French version of the Binge Eating Scale: Examination of its factor structure, internal consistency and construct validity in a non-clinical and a clinical population]. / Validation de la version française de la Binge Eating Scale : étude de sa structure factorielle, de sa consistance interne et de sa validité de construit en population clinique et non clinique.

OBJECTIVE: The Binge Eating Scale is a widely used scale to assess binge eating disorder in obese patients. Until now, this scale has not been validated on a French population, and no psychometrically sound tool assesses binge eating disorder in the French. This study aimed to test the psychometric properties of a French version of the Binge Eating Scale by establishing its factor structure, internal consistency, and construct validity in both a non-clinical population and a clinical population (obese patients who are candidates for bariatric surgery). METHODS: A total of 553 non-clinical subjects and 63 morbidly obese patients who were candidates for bariatric surgery were assessed with the BES and the Bulimic Investigatory Test, Edinburgh or BITE (which assesses both binge eating behaviours and use of inappropriate compensatory behaviours). We tested the factor structure of the instrument, its internal consistency, its construct validity with measures of binge eating, and its construct validity with measures of inappropriate compensatory behaviours to avoid weight gain. In 47 out of the 63 obese patients, we assessed binge eating disorder (SCID). RESULTS: In the non-clinical population, the BES had a one-factor structure (which accounted for 61% of the variance), excellent internal consistency (α=0.93), and high construct validity with measures of binge eating. In this population, construct validity with measures of inappropriate compensatory behaviours was confirmed in overweight and obese subjects (P=0.42), but not in underweight and optimal weight subjects (P<0.001). In obese patients candidates for bariatric surgery, we demonstrated that the BES had a one-factor structure (which accounted for 46% of the variance), had high internal consistency (α=0.88) and high construct validity with measures of binge eating and good construct validity with measures of inappropriate compensatory behaviours to avoid weight gain. In the subpopulation of 47 obese patients, sensitivity, specificity, positive predictive value and negative predictive value were respectively 75%, 88.4%, 37.5% and 97.4% (BES threshold=18). DISCUSSION: In this study, we validated a psychometrically sound French version of the Binge Eating Scale, both in a non-clinical and a clinical sample. The psychometric properties of the French version of the BES are comparable to its original version with a one-factor structure. The BES is a useful tool to assess binge eating disorder in obese patients (e.g., bariatric surgery candidates), but might not differentiate between binge eating disorder and bulimia nervosa in underweight and optimal weight subjects.

Treatment of tardive dyskinesia: A systematic review (1997-2011)

Background and Objectives: Tardive dyskinesia (TD) is a frequent and incapacitating side effect of first-generation antipsychotics. Although second-generation antipsychotics (SGAs) seem to be associated with a decreased risk of TD, it remains a severe, unresolved iatrogenic condition. Moreover, there is no commonly accepted effective treatment for TD. We conducted a systematic review of the literature to assess evidence regarding the effectiveness of different therapeutic interventions for TD. Methods: We performed a systematic review focussing exclusively on randomised controlled trials (RCTs). We searched the MEDLINE database (1997 to 2011) using the keyword "tardive dyskinesia" within the "title" search field. Twenty-six RCTs were included. Based on the evidence from RCTs, we built a decision tree that healthcare professionals can use to choose an effective therapeutic intervention for TD. Results: Four therapeutic interventions were found to be effective in TD (vitamin B6, ginkgo biloba, branched-chain amino acids, and piracetam). Conclusions: Patients with TD could benefit from the therapeutic interventions supported by the data accumulated from RCTs (AU)

Haemodialysis before emergency surgery in a patient treated with dabigatran.

Novel oral anticoagulants (NOAs) which directly inhibit thrombin (dabigatran) or factor Xa (rivaroxaban and apixaban) have recently been developed. We report the first case of perioperative management of a patient treated with dabigatran requiring haemodialysis before emergency surgery. A 62-yr-old woman visited the emergency department for a left bi-malleolar ankle fracture; she had a past medical history of severe ischaemic cardiomyopathy, alcoholic cirrhosis Child B, and moderate chronic renal insufficiency. The patient was treated with dabigatran for a left ventricular aneurysm with thrombus. Cutaneous manifestation of a voluminous haematoma required emergency surgery. Blood tests revealed dabigatran anticoagulant activity of 123 ng ml(-1) (therapeutic values: 85-200 ng ml(-1)), activated partial thromboplastin time of 63 s, and a prothrombin ratio of 68%, indicating that dabigatran disturbed coagulation. We decided to perform emergency haemodialysis before surgery. After 2 h, the anticoagulant activity of dabigatran was 11 ng ml(-1), allowing surgery. Surgery proceeded without any problems and the postoperative period was unremarkable. This case highlights the difficulties for the anaesthesiologist regarding emergency perioperative management of patients treated with NOAs and confirms the efficacy of haemodialysis in cases of dabigatran treatment. NOAs should be prescribed with caution, especially for patients with renal or hepatic disease, at least as long as no antagonist is available. In cases of deferred operative urgency in haemodynamically stable patients treated with dabigatran, haemodialysis should be considered to reverse dabigatran's anticoagulant effects.

[Free sorting task of speech disorders by expert and non-expert listeners]. / Catégorisation libre dans les troubles de la production pathologique de la parole.

Understood the strategies underlying the perception of speech motor disorders (SMD) is useful for the management of people with this kind of disorders. Our hypothesis was that intelligibility of speech is a dramatic decision factor for the classification of speech production independently of the type of listeners. Two types of listeners: 15 experts (logopedists and phoniatricians), and 15 non experts (students in the field of heath care without any experience) participated at this study performing a free sorting task of 33 stimuli. The stimuli are a sentence readed by 13 control subjects and 20 subjects with a SMD of several kinds of etiologies. The methodology used for the analysis is the visualization of proximity trees by a sorting mathematical algorithm and the analysis of the free commentaries as a discourse. The results confirm that the degree of alteration of intelligibility is the main factor distributed in the sorts, but the reference to the "normality" is an other strong criteria and this notion is frequently associated with a description of the stimuli at a level of voice more than a level of speech. These results lead to a new hypothesis of a classification of perception of speech included a speech disorders, determined at an extremity by a comparison with a "prototype of normality" and at the other extremity by the characteristic of "intelligibility or understandibility" reinforcing some concepts of speech rehabilitation.

[Cenesthopathies: a disorder of background emotions at the crossroads of the cognitive sciences and phenomenology]. / Les cénesthopathies : un trouble des émotions d'arrière plan. Regards croisés des sciences cognitives et de la phénoménologie.

BACKGROUND: Cenesthesia and cenesthopathy have played a fundamental role in 19th and early 20th century French and German psychiatry. Cenesthesia refers to the internal, global, implicit and affective perception of one's own body. The concept of cenesthopathy was coined by Dupre and Camus in 1907 to describe a clinical entity characterized by abnormal and strange bodily sensations. AIMS: In this review, we examine the history of these concepts and the influence they have had on clinical, nosographical and phenomenological psychiatry and on cognitive neuropsychiatry. METHOD: We performed a narrative review of the published research literature. RESULTS: Classical French and German psychiatrists have written extensively on cenesthesia and cenesthopathy although these notions are no longer in the mainstream of contemporary psychiatry. However, they are still present in contemporary psychiatric nosography in the form of some controversial clinical entities clearly related to cenesthesia such as cenesthetic schizophrenia, hypochondriacal monothematic delusions, or the Capgras and the Cotard syndromes. These clinical entities are all associated with a state of depersonalization. We point out the similarities between Ey's description of the depersonalization syndrome, especially in psychosis, and the characteristics of cenesthesia. Philosophers like Sartre or Merleau-Ponty have developed the concept of cenesthesia, and in particular have added new concepts like "body schema". Similarly, phenomenological psychiatrists like Minkowski or Tellenbach have attempted to describe psychiatric disorders associated with cenesthesia and have also proposed new concepts (i.e. atmospheric sense) in order to understand them better. More recently, cognitive neuropsychiatry has tried to discover the mechanisms, which cause or contribute to the genesis of delusions. The majority of delusion theories developed in cognitive neuropsychiatry consider that the explanation of monothematic delusions involves one or two explanatory stages. The first stage corresponds to an abnormal experience (the experiential stage) while the second is related to abnormal reasoning (the inferential stage). This theoretical first stage has been considered to be the result of a highly unusual or bizarre perceptual experience. According to the authors, this experience refers to a phenomenon of depersonalization, a loss of cenesthesia, or a loss of a feeling of familiarity. For example, the neurocognitive models of the Capgras and Cotard syndromes have in common the belief that they are both based on various kinds of unusual experiences. These unusual experiences are thought to include affective or emotional experiences. Capgras' syndrome is possibly triggered by an abnormal affective experience in response to the sight of closed-person's face. Similarly, the Cotard syndrome may result from a general flattening of affective responses to external stimuli. The inferential stage can also differentiate between the two syndromes. Some empirical validation has already been obtained in Capgras' syndrome but not yet in Cotard's syndrome. CONCLUSION: This review illustrates that the historical descriptions of cenesthesia and cenesthopathy remain relevant in contemporary neurocognitive models and more generally suggests that the comprehension of quite complex phenomena like delusion requires a multidisciplinary approach.

[Lethal aortic endocarditis due to Gemella morbillorum in a Djiboutian khat user]. / Endocardite aortique fatale due à Gemella morbillorum chez un consommateur de khat de Djibouti.

We report a 22-year-old man who presented in January 2009 in Djibouti for an aortic-abscessed endocarditis due to Gemella morbillorum (G. morbillorum). A voluminous aortic abscess that extended to the perimembranous ventricular septum was fistulized into the right atrium. Atrioventricular conduction abnormalities were observed. The portal of entry was dental with multiples caries and a periodontitis attributed to khat chewing. The patient died within few days. Diagnosis, severity and management of endocarditis due to this rare bacterium are discussed.