Survey of spiking in the mouse visual system reveals functional hierarchy.

The anatomy of the mammalian visual system, from the retina to the neocortex, is organized hierarchically1. However, direct observation of cellular-level functional interactions across this hierarchy is lacking due to the challenge of simultaneously recording activity across numerous regions. Here we describe a large, open dataset-part of the Allen Brain Observatory2-that surveys spiking from tens of thousands of units in six cortical and two thalamic regions in the brains of mice responding to a battery of visual stimuli. Using cross-correlation analysis, we reveal that the organization of inter-area functional connectivity during visual stimulation mirrors the anatomical hierarchy from the Allen Mouse Brain Connectivity Atlas3. We find that four classical hierarchical measures-response latency, receptive-field size, phase-locking to drifting gratings and response decay timescale-are all correlated with the hierarchy. Moreover, recordings obtained during a visual task reveal that the correlation between neural activity and behavioural choice also increases along the hierarchy. Our study provides a foundation for understanding coding and signal propagation across hierarchically organized cortical and thalamic visual areas.

Radiation Reveal: Moving from research engagement to involvement.

Here, we report on the process of a highly impactful and successful creative, collaborative, and multi-partner public engagement project, Radiation Reveal. It brought together ten young adults aged 17-25-year-olds with experience of radiotherapy with researchers at Cancer Research UK RadNet City of London across three 2-hour online workshops. Our aims were to 1) initiate discussions between young adults and radiation researchers, and 2) identify what people wish they had known about radiotherapy before or during treatment. These aims were surpassed; other benefits included peer support, participants' continued involvement in subsequent engagement projects, lasting friendships, creation of support groups for others, and creation and national dissemination of top ten tips for medical professionals and social media resources. A key learning was that this project required a dedicated and (com)passionate person with connections to national cancer charities. When designing the project, constant feedback is also needed from charities and young adults with and without radiotherapy experience. Finally, visually capturing discussions and keeping the door open beyond workshops further enhanced impact. Here, we hope to inform and inspire people to help project the patient voice in all we do.

Beliefs and needs of fathers of newborns hospitalised in a neonatal unit: A descriptive correlational study.

BACKGROUND: Transition to parenthood is a wonderful yet stressful period especially when it involves the newborn's hospitalisation. To support and facilitate this transition, it is essential to understand parental beliefs and needs. The father's perspective remains an understudied yet fundamental question. OBJECTIVES: The objective of the study was to measure beliefs and needs of fathers of newborns hospitalised in a neonatal intensive care unit (NICU) and their correlations with sociodemographic variables. METHODS: Fathers with a newborn hospitalised for 4-15 days in a level III NICU in Western Switzerland completed the NICU Parental Beliefs Scale and the short form of the NICU Family Needs Inventory. For each item of the NICU Family Needs Inventory, fathers also answered with regard to their satisfaction level. Additional needs were collected with an added open-ended question. Simple linear regressions were used to correlate beliefs, needs, and the sociodemographic data. RESULTS: Seventy fathers were included. The average score for paternal beliefs was 68.44 (standard deviation = 10.29), indicating a good perception of their role. The majority (77%) considered all needs as very important or important, and 70% were very satisfied or satisfied. Fathers described communication as a very important, but unmet, need. Fathers' beliefs were higher in those who were not first-time fathers (71.88 ± 8.27 vs 66.06 ± 10.97, p = 0.028), who had a paternity leave (72.68 ± 10.19 vs 66.05 ± 9.68, p = 0.014), and who were of foreign nationality (71.86 ± 9.39 vs 63.85 ± 9.80, p = 0.002). CONCLUSIONS: Fathers with a newborn hospitalised in the neonatal unit had good paternal beliefs. Most of the listed needs were perceived as very important and had a good level of satisfaction. Significant differences between Swiss fathers and fathers of foreign nationality were measured. Reasons of these differences should be explored in a forthcoming study.

Loss of Function of the Nuclear Receptor NR2F2, Encoding COUP-TF2, Causes Testis Development and Cardiac Defects in 46,XX Children.

Emerging evidence from murine studies suggests that mammalian sex determination is the outcome of an imbalance between mutually antagonistic male and female regulatory networks that canalize development down one pathway while actively repressing the other. However, in contrast to testis formation, the gene regulatory pathways governing mammalian ovary development have remained elusive. We performed exome or Sanger sequencing on 79 46,XX SRY-negative individuals with either unexplained virilization or with testicular/ovotesticular disorders/differences of sex development (TDSD/OTDSD). We identified heterozygous frameshift mutations in NR2F2, encoding COUP-TF2, in three children. One carried a c.103_109delGGCGCCC (p.Gly35Argfs∗75) mutation, while two others carried a c.97_103delCCGCCCG (p.Pro33Alafs∗77) mutation. In two of three children the mutation was de novo. All three children presented with congenital heart disease (CHD), one child with congenital diaphragmatic hernia (CDH), and two children with blepharophimosis-ptosis-epicanthus inversus syndrome (BPES). The three children had androgen production, virilization of external genitalia, and biochemical or histological evidence of testicular tissue. We demonstrate a highly significant association between the NR2F2 loss-of-function mutations and this syndromic form of DSD (p = 2.44 × 10-8). We show that COUP-TF2 is highly abundant in a FOXL2-negative stromal cell population of the fetal human ovary. In contrast to the mouse, these data establish COUP-TF2 as a human "pro-ovary" and "anti-testis" sex-determining factor in female gonads. Furthermore, the data presented here provide additional evidence of the emerging importance of nuclear receptors in establishing human ovarian identity and indicate that nuclear receptors may have divergent functions in mouse and human biology.

SRY-negative 46,XX testicular/ovotesticular DSD: Long-term outcomes and early blockade of gonadotropic axis.

OBJECTIVE: SRY-negative 46,XX testicular and ovotesticular disorders/differences of sex development (T/OTDSD) represent a very rare and unique DSD condition where testicular tissue develops in the absence of a Y chromosome. To date, very few studies have described the phenotype, clinical and surgical management and long-term outcomes of these patients. Particularly, early blockade of the gonadotropic axis in patients raised in the female gender to minimize postnatal androgenization has never been reported. DESIGN: Retrospective description of sixteen 46,XX T/OTDSD patients. RESULTS: Sixteen 46,XX SRY-negative T/OTDSD were included. Most (12/16) were diagnosed in the neonatal period. Sex of rearing was male for six patients and female for ten, while the clinical presentation varied, with an external masculinization score from 1 to 10. Five patients raised as girl were successfully treated with GnRH analog to avoid virilization during minipuberty. Ovotestes/testes were found bilaterally for 54% of the patients and unilaterally for the others (with a contralateral ovary). Gonadal surgery preserved appropriate tissue in the majority of cases. Spontaneous puberty occurred in two girls and one boy, while two boys required hormonal induction of puberty. One of the girls conceived spontaneously and had an uneventful pregnancy. DNA analyses (SNP-array, next-generation sequencing and whole-exome sequencing) were performed. A heterozygous frameshit mutation in the NR2F2 gene was identified in one patient. CONCLUSIONS: This study presents a population of patients with 46,XX SRY-negative T/OTDSD. Early blockade of gonadotropic axis appears efficient to reduce and avoid further androgenization in patients raised as girls.

Reflective practice improves Basic Life Support training outcomes: A randomized controlled study.

INTRODUCTION: Practical skills training is an essential part of medical education. An important example is the training of Basic Life Support (BLS) skills, which are key to improve patient outcomes in life-threatening situations. However, despite practical training, BLS performance is often sub-optimal even among healthcare professionals and medical students. Finding more effective training methods is therefore of high importance. A promising method to enhance learning outcomes is reflective practice. The goal of the present study was to evaluate whether a short reflective practice intervention following standard BLS training (Peyton's 4-step approach) improves BLS training outcomes, reflected in higher BLS performance and higher self-confidence to perform BLS. METHOD: 287 first-year medical students were randomly assigned to one of two BLS training conditions: 1) standard BLS training (ST), 2) ST followed by a 15-minute reflective practice exercise. Outcome parameters included objective BLS performance data assessed by a resuscitation manikin, and students' self-reported confidence in their BLS skills. Outcomes were assessed directly after the training (T0) and re-assessed one week later (T1). A two-way mixed model analysis of variance (ANOVA) was conducted to examine the effect of the intervention on BLS performance and self-reported confidence. Significance was determined by two-sided 95% confidence intervals. RESULTS: The intervention group performed significantly more effective compressions at T1 and began significantly faster with performing their first chest compression at T0 and T1, in comparison to the control group. No significant differences between study groups regarding their self-reported confidence to perform BLS were observed. CONCLUSION: This research shows that standard BLS training accompanied with a simple, cost-effective reflective practice exercise can improve learners' BLS skill acquisition and retention. This shows that reflective practice has the potential to enhance practical skills training in medicine; yet, more empirical studies are needed to examine its broader applicability.

An integrative review on the acceptance of artificial intelligence among healthcare professionals in hospitals.

Artificial intelligence (AI) in the domain of healthcare is increasing in prominence. Acceptance is an indispensable prerequisite for the widespread implementation of AI. The aim of this integrative review is to explore barriers and facilitators influencing healthcare professionals' acceptance of AI in the hospital setting. Forty-two articles met the inclusion criteria for this review. Pertinent elements to the study such as the type of AI, factors influencing acceptance, and the participants' profession were extracted from the included studies, and the studies were appraised for their quality. The data extraction and results were presented according to the Unified Theory of Acceptance and Use of Technology (UTAUT) model. The included studies revealed a variety of facilitating and hindering factors for AI acceptance in the hospital setting. Clinical decision support systems (CDSS) were the AI form included in most studies (n = 21). Heterogeneous results with regard to the perceptions of the effects of AI on error occurrence, alert sensitivity and timely resources were reported. In contrast, fear of a loss of (professional) autonomy and difficulties in integrating AI into clinical workflows were unanimously reported to be hindering factors. On the other hand, training for the use of AI facilitated acceptance. Heterogeneous results may be explained by differences in the application and functioning of the different AI systems as well as inter-professional and interdisciplinary disparities. To conclude, in order to facilitate acceptance of AI among healthcare professionals it is advisable to integrate end-users in the early stages of AI development as well as to offer needs-adjusted training for the use of AI in healthcare and providing adequate infrastructure.

A whole-brain monosynaptic input connectome to neuron classes in mouse visual cortex.

Identification of structural connections between neurons is a prerequisite to understanding brain function. Here we developed a pipeline to systematically map brain-wide monosynaptic input connections to genetically defined neuronal populations using an optimized rabies tracing system. We used mouse visual cortex as the exemplar system and revealed quantitative target-specific, layer-specific and cell-class-specific differences in its presynaptic connectomes. The retrograde connectivity indicates the presence of ventral and dorsal visual streams and further reveals topographically organized and continuously varying subnetworks mediated by different higher visual areas. The visual cortex hierarchy can be derived from intracortical feedforward and feedback pathways mediated by upper-layer and lower-layer input neurons. We also identify a new role for layer 6 neurons in mediating reciprocal interhemispheric connections. This study expands our knowledge of the visual system connectomes and demonstrates that the pipeline can be scaled up to dissect connectivity of different cell populations across the mouse brain.

Les récepteurs d'entrée du HTLV-1 : un ménage à trois.

The identification of the cellular receptor used by viruses to enter their target cells is always a challenge and to date entry receptors remain to be identified for a variety of pathogenic human viruses. Human T-lymphotropic virus type 1 (HTLV-1), the unique oncogenic retrovirus in human, was identified in the early 1980 's. The nature of its entry receptor has remained a mystery for over 20 years, until the independent identification of three proteins presenting the expected criteria, the glucose transporter Glut1, Neuropilin 1, a VEGF receptor, and heparan sulfate proteoglycans. In this review, we summarize the data pertaining to HTLV-1 entry molecules and present a new model, in which these three proteins successively intervene during the entry process.

Innovative Tele-Instruction Approach Impacts Basic Life Support Performance: A Non-inferiority Trial.

Background: Sustaining Basic Life Support (BLS) training during the COVID-19 pandemic bears substantial challenges. The limited availability of highly qualified instructors and tight economic conditions complicates the delivery of these life-saving trainings. Consequently, innovative and resource-efficient approaches are needed to minimize or eliminate contagion while maintaining high training standards and managing learner anxiety related to infection risk. Methods: In a non-inferiority trial 346 first-year medical, dentistry, and physiotherapy students underwent BLS training at AIXTRA-Competence Center for Training and Patient Safety at the University Hospital RWTH Aachen. Our objectives were (1) to examine whether peer feedback BLS training supported by tele-instructors matches the learning performance of standard instructor-guided BLS training for laypersons; and (2) to minimize infection risk during BLS training. Therefore, in a parallel group design, we compared arm (1) Standard Instructor Feedback (SIF) BLS training (Historical control group of 2019) with arm (2) a Tele-Instructor Supported Peer-Feedback (TPF) BLS training (Intervention group of 2020). Both study arms were based on Peyton's 4-step approach. Before and after each training session, objective data for BLS performance (compression depth and rate) were recorded using a resuscitation manikin. We also assessed overall BLS performance via standardized instructor evaluation and student self-reports of confidence via questionnaire. Non-inferiority margins for the outcome parameters and sample size calculation were based on previous studies with SIF. Two-sided 95% confidence intervals were employed to determine significance of non-inferiority. Results: The results confirmed non-inferiority of TPF to SIF for all tested outcome parameters. A follow-up after 2 weeks found no confirmed COVID-19 infections among the participants. Conclusion: Tele-instructor supported peer feedback is a powerful alternative to in-person instructor feedback on BLS skills during a pandemic, where infection risk needs to be minimized while maximizing the quality of BLS skill learning. Trial registration: https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00025199, Trial ID: DRKS00025199.

Video-Assisted Peer Teaching for Surgical Skills Training - Innovative Potential for the Medical Curriculum and Beyond: A Randomized Controlled Trial.

OBJECTIVE: Hygienic healthcare standards are essential for avoiding hospital infections. However, medical students and staff lack training in this field, which may be due to high personnel resources of present educational approaches. Thus, there is an urgent need for a novel and efficient approach. Aim of the study is to compare a newly developed video-assisted peer feedback (VAPF) method for teaching wound dressings to the traditional teaching method with qualified instructor feedback (QIF) with respect to essential learning outcomes. DESIGN, SETTING AND PARTICIPANTS: In this randomized controlled noninferiority trial, 251 medical undergraduates were randomly assigned to one of two interventions (QIF n = 127; VAPF n = 124). In QIF, participants received feedback from a qualified instructor. In VAPF, participants video-recorded each other while performing a wound dressing and gave each other feedback assisted by a standardized checklist. Outcome measures were participants' score in an objective structured practical examination (OSPE) and a written exam after the course. RESULTS: Noninferiority of VAPF (n = 123) compared to QIF (n = 127) was confirmed for both OSPE (QIF: 8.83 ± 1.30; VAPF: 8.88 ± 1.04; mean difference -0.04, 95% CI -0.34 to 0.25) and written exam (QIF: 8.99 ± 1.06; VAPF: 9.14 ± 1.05; mean difference -0.15, 95% CI -0.41 to 0.12). CONCLUSIONS: VAPF is a cost-efficient and viable alternative to QIF commonly used in medical education. It provides comparable training outcomes to the traditional training method with lower personnel investment. VAPF is a promising educational method for improving essential clinical competencies.

Safety management in times of crisis: Lessons learned from a nationwide status-analysis on German intensive care units during the COVID-19 pandemic.

Background: The status of Safety Management is highly relevant to evaluate an organization's ability to deal with unexpected events or errors, especially in times of crisis. However, it remains unclear to what extent Safety Management was developed and sufficiently implemented within the healthcare system during the COVID-19 pandemic. Providing insights of potential for improvement is expected to be directional for ongoing Safety Management efforts, in times of crisis and beyond. Method: A nationwide survey study was conducted among healthcare professionals and auxiliary staff on German Intensive Care Units (ICUs) evaluating their experiences during the first wave of the COVID-19 pandemic. Error Management and Patient Safety Culture (PSC) measures served to operationalize Safety Management. Data were analyzed descriptively and by using quantitative content analysis (QCA). Results: Results for n = 588 participants from 53 hospitals show that there is a gap between errors occurred, reported, documented, and addressed. QCA revealed that low quality of safety culture (27.8%) was the most mentioned reason for errors not being addressed. Overall, ratings of PSC ranged from 26.7 to 57.9% positive response with Staffing being the worst and Teamwork Within Units being the best rated dimension. While assessments showed a similar pattern, medical staff rated PSC on ICUs more positively in comparison to nursing staff. Conclusion: The status-analysis of Safety Management in times of crisis revealed relevant potential for improvement. Human Factor plays a crucial role in the occurrence and the way errors are dealt with on ICUs, but systemic factors should not be underestimated. Further intensified efforts specifically in the fields of staffing and error reporting, documentation and communication are needed to improve Safety Management on ICUs. These findings might also be applicable across nations and sectors beyond the medical field.

Measuring Stimulus-Evoked Neurophysiological Differentiation in Distinct Populations of Neurons in Mouse Visual Cortex.

Despite significant progress in understanding neural coding, it remains unclear how the coordinated activity of large populations of neurons relates to what an observer actually perceives. Since neurophysiological differences must underlie differences among percepts, differentiation analysis-quantifying distinct patterns of neurophysiological activity-has been proposed as an "inside-out" approach that addresses this question. This methodology contrasts with "outside-in" approaches such as feature tuning and decoding analyses, which are defined in terms of extrinsic experimental variables. Here, we used two-photon calcium imaging in mice of both sexes to systematically survey stimulus-evoked neurophysiological differentiation (ND) in excitatory neuronal populations in layers (L)2/3, L4, and L5 across five visual cortical areas (primary, lateromedial, anterolateral, posteromedial, and anteromedial) in response to naturalistic and phase-scrambled movie stimuli. We find that unscrambled stimuli evoke greater ND than scrambled stimuli specifically in L2/3 of the anterolateral and anteromedial areas, and that this effect is modulated by arousal state and locomotion. By contrast, decoding performance was far above chance and did not vary substantially across areas and layers. Differentiation also differed within the unscrambled stimulus set, suggesting that differentiation analysis may be used to probe the ethological relevance of individual stimuli.

HTLV-1 uses HSPG and neuropilin-1 for entry by molecular mimicry of VEGF165.

Human T-cell lymphotropic virus type 1 (HTLV-1) entry involves the interaction between the surface (SU) subunit of the Env proteins and cellular receptor(s). Previously, our laboratories demonstrated that heparan sulfate proteoglycans (HSPGs) and neuropilin-1 (NRP-1), a receptor of VEGF(165), are essential for HTLV-1 entry. Here we investigated whether, as when binding VEGF(165), HSPGs and NRP-1 work in concert during HTLV-1 entry. VEGF(165) binds to the b domain of NRP-1 through both HSPG-dependent and -independent interactions, the latter involving its exon 8. We show that VEGF(165) is a selective competitor of HTLV-1 entry and that HTLV-1 mimics VEGF(165) to recruit HSPGs and NRP-1: (1) the NRP-1 b domain is required for HTLV-1 binding; (2) SU binding to target cells is blocked by the HSPG-binding domain of VEGF(165); (3) the formation of Env/NRP-1 complexes is enhanced by HSPGs; and (4) the HTLV SU contains a motif homologous to VEGF(165) exon 8. This motif directly binds to NRP-1 and is essential for HTLV-1 binding to, internalization into, and infection of CD4(+) T cells and dendritic cells. These findings demonstrate that HSPGs and NRP-1 function as HTLV-1 receptors in a cooperative manner and reveal an unexpected mimicry mechanism that may have major implications in vivo.

Immunization with a heat-killed bacterium, Mycobacterium vaccae NCTC 11659, prevents the development of cortical hyperarousal and a PTSD-like sleep phenotype after sleep disruption and acute stress in mice.

STUDY OBJECTIVES: Sleep deprivation induces systemic inflammation that may contribute to stress vulnerability and other pathologies. We tested the hypothesis that immunization with heat-killed Mycobacterium vaccae NCTC 11659 (MV), an environmental bacterium with immunoregulatory and anti-inflammatory properties, prevents the negative impacts of 5 days of sleep disruption on stress-induced changes in sleep, behavior, and physiology in mice. METHODS: In a 2 × 2 × 2 experimental design, male C57BL/6N mice were given injections of either MV or vehicle on days -17, -10, and -3. On days 1-5, mice were exposed to intermittent sleep disruption, whereby sleep was disrupted for 20 h per day. Immediately following sleep disruption, mice were exposed to 1-h social defeat stress or novel cage (control) conditions. Object location memory (OLM) testing was conducted 24 h after social defeat, and tissues were collected 6 days later to measure inflammatory markers. Sleep was recorded using electroencephalography (EEG) and electromyography (EMG) throughout the experiment. RESULTS: In vehicle-treated mice, only the combination of sleep disruption followed by social defeat (double hit): (1) increased brief arousals and NREM beta (15-30 Hz) EEG power in sleep immediately post-social defeat compared to baseline; (2) induced an increase in the proportion of rapid-eye-movement (REM) sleep and number of state shifts for at least 5 days post-social defeat; and (3) induced hyperlocomotion and lack of habituation in the OLM task. Immunization with MV prevented most of these sleep and behavioral changes. CONCLUSIONS: Immunization with MV ameliorates a stress-induced sleep and behavioral phenotype that shares features with human posttraumatic stress disorder.

Alteration of blood-brain barrier integrity by retroviral infection.

The blood-brain barrier (BBB), which forms the interface between the blood and the cerebral parenchyma, has been shown to be disrupted during retroviral-associated neuromyelopathies. Human T Lymphotropic Virus (HTLV-1) Associated Myelopathy/Tropical Spastic Paraparesis (HAM/TSP) is a slowly progressive neurodegenerative disease associated with BBB breakdown. The BBB is composed of three cell types: endothelial cells, pericytes and astrocytes. Although astrocytes have been shown to be infected by HTLV-1, until now, little was known about the susceptibility of BBB endothelial cells to HTLV-1 infection and the impact of such an infection on BBB function. We first demonstrated that human cerebral endothelial cells express the receptors for HTLV-1 (GLUT-1, Neuropilin-1 and heparan sulfate proteoglycans), both in vitro, in a human cerebral endothelial cell line, and ex vivo, on spinal cord autopsy sections from HAM/TSP and non-infected control cases. In situ hybridization revealed HTLV-1 transcripts associated with the vasculature in HAM/TSP. We were able to confirm that the endothelial cells could be productively infected in vitro by HTLV-1 and that blocking of either HSPGs, Neuropilin 1 or Glut1 inhibits this process. The expression of the tight-junction proteins within the HTLV-1 infected endothelial cells was altered. These cells were no longer able to form a functional barrier, since BBB permeability and lymphocyte passage through the monolayer of endothelial cells were increased. This work constitutes the first report of susceptibility of human cerebral endothelial cells to HTLV-1 infection, with implications for HTLV-1 passage through the BBB and subsequent deregulation of the central nervous system homeostasis. We propose that the susceptibility of cerebral endothelial cells to retroviral infection and subsequent BBB dysfunction is an important aspect of HAM/TSP pathogenesis and should be considered in the design of future therapeutics strategies.

Spleen immune status is affected after acute handling stress but not regulated by cortisol in Eurasian perch, Perca fluviatilis.

The effects of acute stress on immune status and its regulation by cortisol/corticosteroid receptors have received little attention in percids. To address that question, we investigated the physiological and immune responses of Eurasian perch, Perca fluviatilis to acute stress. We exposed immature perch to an 1-min exondation and measured at 1 h, 6 h, 24 h and 72 h post-stress: (1) stress-related parameters including plasma cortisol and glucose levels, (2) immune parameters in the plasma and in the spleen (complement, respiratory burst and lysozyme activity, total immunoglobulins; gene expression of lysozyme, complement unit 3, apolipoprotein A1 and 14 kDa, hepcidin and chemotaxin) (3) the corticosteroid receptors gene expression in the spleen after having cloned them. In addition, the in vitro effects of cortisol on the spleen immune parameters were also investigated. Plasma cortisol and glucose levels increased markedly 1h post-stress and returned at basal levels after 24 h. P. fluviatilis mineralocorticoid receptor, but not glucocorticoid receptors, was significantly up-regulated both in vivo after the stress and in vitro by cortisol at a physiological concentration (100 ng/ml). The plasma immune parameters were not significantly affected by the stress. In contrast, spleno-somatic index, spleen lysozyme activity, lysozyme and hepcidin gene expression were depleted and total immunoglobulins increased along the whole time-course (1-72 h). But, these immune parameters were not regulated in vitro by cortisol at physiological or supra-physiological doses. Our results indicate that handling stress may affect spleen antibacterial defences without clear effects on circulating immune compounds and that the elevation of plasma cortisol after handling stress may not be related to the regulation of this splenic response.

Expanding phenotype of p.Ala140Val mutation in MECP2 in a 4 generation family with X-linked intellectual disability and spasticity.

Mutations in MECP2 (MIM #312750), located on Xq28 and encoding a methyl CpG binding protein, are classically associated with Rett syndrome in female patients, with a lethal effect in hemizygous males. However, MECP2 mutations have already been reported in surviving males with severe neonatal-onset encephalopathy, or with X-linked intellectual disability associated with psychosis, pyramidal signs, parkinsonian features and macro-orchidism (PPM-X syndrome; MIM3 #300055). Here we report on the identification of the p.Ala140Val mutation in the MECP2 gene in 4 males and 3 females of a large Caucasian family affected with X-linked intellectual disability. Females present with mild cognitive impairment and speech difficulties. Males have moderate intellectual disability, impaired language development, friendly behavior, slowly progressive spastic paraparesis and dystonic movements of the hands. Two of them show microcephaly. The p.Ala140Val mutation is recurrent, as it was already described in 4 families with X-linked mental retardation and in three sporadic male patients with intellectual disability. We further delineate the phenotype associated with the p.Ala140Val mutation, illustrating a variable expressivity even within a given family, and we compare our patients with previous reported cases in the literature.

Congenital Hypothyroidism: Long-Term Experience with Early and High Levothyroxine Dosage.

AIM: To assess the management and outcome of the congenital hypothyroidism (CH) patients followed at our institution since the introduction of systemic neonatal screening for CH. STUDY DESIGN: The records of 139 CH patients referred to our center between 1978 and 2014 were retrospectively reviewed. Biochemical and imaging data at diagnosis, initial treatment and growth were analyzed. RESULTS: 111 patients had thyroid dysgenesis (64 ectopy, 46 athyreosis and 1 hypoplasia) and 28 patients had a gland in situ (17 dyshormonogenesis/goiter and 11 normal-sized gland). Levothyroxine treatment was initiated at a median age of 11 days with a mean dose of 11.4 µg/kg/day. Compared to those with ectopy, patients with athyreosis had higher thyroid-stimulating hormone (TSH) and lower thyroxine at diagnosis as well as more delayed bone maturation. Between 1978 and 2014, we observed earlier treatment and earlier TSH normalization. Birth auxology was slightly above the mean of the reference population. Growth at 1 and 6 years and school progression at 11 years were similar to those of the reference population. CONCLUSION: Ectopy is the commonest cause of CH. Children with CH treated early with a mean levothyroxine dose of 11.4 µg/kg/day had a median TSH of 3.07 mU/l at 1 month of age and normal growth.