Based on their clinical practice and an extensive review of the literature, the authors propose a framework of procedures to be followed to provide services to all women of childbearing age who use ...psychoactive substances (alcohol, cannabis, cocaine, amphetamines, and opioids), especially during pregnancy or during the postpartum and breastfeeding periods, in view of their individual situations and environmental contexts.
The treatment of sepsis and septic shock remains a major public health issue due to the associated morbidity and mortality. Despite an improvement in the understanding of the physiological and ...pathological mechanisms underlying its genesis and a growing number of studies exploring an even higher range of targeted therapies, no significant clinical progress has emerged in the past decade. In this context, mesenchymal stem cells (MSCs) appear more and more as an attractive approach for cell therapy both in experimental and clinical models. Pre-clinical data suggest a cornerstone role of these cells and their secretome in the control of the host immune response. Host-derived factors released from infected cells (i.e., alarmins, HMGB1, ATP, DNA) as well as pathogen-associated molecular patterns (e.g., LPS, peptidoglycans) can activate MSCs located in the parenchyma and around vessels to upregulate the expression of cytokines/chemokines and growth factors that influence, respectively, immune cell recruitment and stem cell mobilization. However, the way in which MSCs exert their beneficial effects in terms of survival and control of inflammation in septic states remains unclear. This review presents the interactions identified between MSCs and mediators of immunity and tissue repair in sepsis. We also propose paradigms related to the plausible roles of MSCs in the process of sepsis and septic shock. Finally, we offer a presentation of experimental and clinical studies and open the way to innovative avenues of research involving MSCs from a prognostic, diagnostic, and therapeutic point of view in sepsis.
Cilia have a unique diffusion barrier ("gate") within their proximal region, termed transition zone (TZ), that compartmentalises signalling proteins within the organelle. The TZ is known to harbour ...two functional modules/complexes (Meckel syndrome MKS and Nephronophthisis NPHP) defined by genetic interaction, interdependent protein localisation (hierarchy), and proteomic studies. However, the composition and molecular organisation of these modules and their links to human ciliary disease are not completely understood. Here, we reveal Caenorhabditis elegans CEP-290 (mammalian Cep290/Mks4/Nphp6 orthologue) as a central assembly factor that is specific for established MKS module components and depends on the coiled coil region of MKS-5 (Rpgrip1L/Rpgrip1) for TZ localisation. Consistent with a critical role in ciliary gate function, CEP-290 prevents inappropriate entry of membrane-associated proteins into cilia and keeps ARL-13 (Arl13b) from leaking out of cilia via the TZ. We identify a novel MKS module component, TMEM-218 (Tmem218), that requires CEP-290 and other MKS module components for TZ localisation and functions together with the NPHP module to facilitate ciliogenesis. We show that TZ localisation of TMEM-138 (Tmem138) and CDKL-1 (Cdkl1/Cdkl2/Cdkl3/Cdlk4 related), not previously linked to a specific TZ module, similarly depends on CEP-290; surprisingly, neither TMEM-138 or CDKL-1 exhibit interdependent localisation or genetic interactions with core MKS or NPHP module components, suggesting they are part of a distinct, CEP-290-associated module. Lastly, we show that families presenting with Oral-Facial-Digital syndrome type 6 (OFD6) have likely pathogenic mutations in CEP-290-dependent TZ proteins, namely Tmem17, Tmem138, and Tmem231. Notably, patient fibroblasts harbouring mutated Tmem17, a protein not yet ciliopathy-associated, display ciliogenesis defects. Together, our findings expand the repertoire of MKS module-associated proteins--including the previously uncharacterised mammalian Tmem80--and suggest an MKS-5 and CEP-290-dependent assembly pathway for building a functional TZ.
Fetal Alcohol Spectrum Disorders (FASD) refer to physical, cognitive, and behavioural symptoms in an individual whose mother consumed alcohol during pregnancy. It is the leading cause of non-genetic ...avoidable mental disability, with an estimated worldwide prevalence of 1%. Attention Deficit Hyperactivity Disorder (ADHD) diagnostic criteria are met for 50-80% of patients with FASD. Methylphenidate (MPH) is the first-line pharmacological treatment for ADHD. This study aims to explore the lived experience of children with FASD taking MPH and their caregivers to adapt prescribing modalities by considering different ways to administer the drugs. We hope to improve the therapeutic alliance between the children and their caregivers by gaining an insiders' view of the medication perception. Semi-structured interviews with children and their caregivers were conducted in this qualitative study. Data collection by purposive sampling continued until we reached theoretical sufficiency. Data were analysed using interpretative phenomenological analysis. We conducted 16 semi-structured interviews: 8 with the children aged 7-12, 5 boys and 3 girls and 8 with their caregivers. The analysis showed that inadequate palatability and capsule form experiences were the leading causes of children's non-adherence to the treatment. MPH appeared to be a valuable aid for caregivers even if they had concerns about its potential toxicity. However, it is necessary to identify caregivers' expectations concerning MPH to adapt the prescription in terms of choice of specialty and intake modalities. Regular support was required to reduce caregivers' fears of dependence, personality transformation and long-term adverse effects. Information on palatability should be given when prescribing MPH to children with ADHD as well as its possible side effects or toxicity. It highlights the need for further studies of the experience of palatability of drugs prescribed to children. When prescribing a treatment, children should be more involved in medical counselling and it is necessary to understand the child's perspectives to co-construct common representations for better therapeutical adherence.
Interstitial lung diseases (ILDs) can be caused by mutations in the
and
genes, which encode the surfactant protein (SP) complex SP-A. Only 11
or
mutations have so far been reported worldwide, of ...which five have been functionally assessed. In the framework of ILD molecular diagnosis, we identified 14 independent patients with pathogenic
or
mutations. The present study aimed to functionally assess the 11 different mutations identified and to accurately describe the disease phenotype of the patients and their affected relatives.
The consequences of the 11
or
mutations were analysed both
, by studying the production and secretion of the corresponding mutated proteins and
, by analysing SP-A expression in lung tissue samples. The associated disease phenotypes were documented.
For the 11 identified mutations, protein production was preserved but secretion was abolished. The expression pattern of lung SP-A available in six patients was altered and the family history reported ILD and/or lung adenocarcinoma in 13 out of 14 families (93%). Among the 28
mutation carriers, the mean age at ILD onset was 45 years (range 0.6-65 years) and 48% underwent lung transplantation (mean age 51 years). Seven carriers were asymptomatic.
This study, which expands the molecular and clinical spectrum of SP-A disorders, shows that pathogenic
or
mutations share similar consequences for SP-A secretion in cell models and in lung tissue immunostaining, whereas they are associated with a highly variable phenotypic expression of disease, ranging from severe forms requiring lung transplantation to incomplete penetrance.
Foetal alcohol spectrum disorder (FASD) is the leading preventable cause of nongenetic mental disability. Given the patient care pathway, the General Practitioner (GP) is in the front line of ...prevention and identification of FASD. Acknowledging the importance of the prevalence of FASD, general practitioners are in the front line both for the detection and diagnosis of FASD and for the message of prevention to women of childbearing age as well as for the follow-up.
The main objective of the scoping review was to propose a reference for interventions that can be implemented by a GP with women of childbearing age, their partners and patients with FASD. The final aim of this review is to contribute to the improvement of knowledge and quality of care of patients with FASD.
A scoping review was performed using databases of peer-reviewed articles following PRISMA guidelines. The search strategy was based on the selection and consultation of articles on five digital resources. The advanced search of these publications was established using the keywords for different variations of FASD: "fetal alcohol syndrome," "fetal alcohol spectrum disorder," "general medicine," "primary care," "primary care"; searched in French and English.
Twenty-three articles meeting the search criteria were selected. The interventions of GPs in the management of patients with FASD are multiple: prevention, identification, diagnosis, follow-up, education, and the role of coordinator for patients, their families, and pregnant women and their partners. FASD seems still underdiagnosed.
The interventions of GPs in the management of patients with FASD are comprehensive: prevention, identification, diagnosis, follow-up, education, and the role of coordinator for patients, their families, and pregnant women and their partners. Prevention interventions would decrease the incidence of FASD, thereby reducing the incidence of mental retardation, developmental delays, and social, educational and legal issues. A further study with a cluster randomized trial with a group of primary care practitioners trained in screening for alcohol use during pregnancy would be useful to measure the impact of training on the alcohol use of women of childbearing age and on the clinical status of their children.
Intellectual disability (ID) is characterised by an extreme genetic heterogeneity. Several hundred genes have been associated to monogenic forms of ID, considerably complicating molecular ...diagnostics. Trio-exome sequencing was recently proposed as a diagnostic approach, yet remains costly for a general implementation.
We report the alternative strategy of targeted high-throughput sequencing of 217 genes in which mutations had been reported in patients with ID or autism as the major clinical concern. We analysed 106 patients with ID of unknown aetiology following array-CGH analysis and other genetic investigations. Ninety per cent of these patients were males, and 75% sporadic cases.
We identified 26 causative mutations: 16 in X-linked genes (ATRX, CUL4B, DMD, FMR1, HCFC1, IL1RAPL1, IQSEC2, KDM5C, MAOA, MECP2, SLC9A6, SLC16A2, PHF8) and 10 de novo in autosomal-dominant genes (DYRK1A, GRIN1, MED13L, TCF4, RAI1, SHANK3, SLC2A1, SYNGAP1). We also detected four possibly causative mutations (eg, in NLGN3) requiring further investigations. We present detailed reasoning for assigning causality for each mutation, and associated patients' clinical information. Some genes were hit more than once in our cohort, suggesting they correspond to more frequent ID-associated conditions (KDM5C, MECP2, DYRK1A, TCF4). We highlight some unexpected genotype to phenotype correlations, with causative mutations being identified in genes associated to defined syndromes in patients deviating from the classic phenotype (DMD, TCF4, MECP2). We also bring additional supportive (HCFC1, MED13L) or unsupportive (SHROOM4, SRPX2) evidences for the implication of previous candidate genes or mutations in cognitive disorders.
With a diagnostic yield of 25% targeted sequencing appears relevant as a first intention test for the diagnosis of ID, but importantly will also contribute to a better understanding regarding the specific contribution of the many genes implicated in ID and autism.
Fetal Alcohol Spectrum Disorder (FASD) is the leading cause of non-genetic intellectual disability and social maladjustment in children. International guidelines recommend abstinence from alcohol ...during pregnancy. Réunion is the most affected of all French regions with an estimated Fetal Alcohol Spectrum (FAS) prevalence of 1.2‰ births. General practitioners (GPs) are at the forefront of identifying patients with FASD.
To understand how GPs identify FASD.
Qualitative study using a grounded theory approach, through semi-structured face-to-face interviews with GPs. Interviews were conducted with the aim of reaching theoretical saturation. These were transcribed verbatim and then analyzed by four researchers to ensure triangulation of the data.
GPs reported barriers to the identification of FASD: challenges in overcoming social taboos and paradoxical injunctions, the influence of limited knowledge and experience, non-specific and highly variable symptoms, ambiguous classification and method of diagnosis involving the mobilization of a multidisciplinary team and lengthy consultations. Conversely, they felt competent to identify neurodevelopmental disorders of any cause, but were concerned about the long waiting time to access specialized care. From the perspective of GPs, it is crucial to prioritize promotion and training aimed at improving the identification and coordination of care pathways for children diagnosed with neurodevelopmental disorders, such as FASD.
Oral-facial-digital syndromes (OFDS) gather rare genetic disorders characterised by facial, oral and digital abnormalities associated with a wide range of additional features (polycystic kidney ...disease, cerebral malformations and several others) to delineate a growing list of OFDS subtypes. The most frequent, OFD type I, is caused by a heterozygous mutation in the
gene encoding a centrosomal protein. The wide clinical heterogeneity of OFDS suggests the involvement of other ciliary genes. For 15 years, we have aimed to identify the molecular bases of OFDS. This effort has been greatly helped by the recent development of whole-exome sequencing (WES). Here, we present all our published and unpublished results for WES in 24 cases with OFDS. We identified causal variants in five new genes (
,
,
,
and
) and related the clinical spectrum of four genes in other ciliopathies (
,
,
and
) to OFDS. Mutations were also detected in two genes previously implicated in OFDS. Functional studies revealed the involvement of centriole elongation, transition zone and intraflagellar transport defects in OFDS, thus characterising three ciliary protein modules: the complex KIAA0753-FOPNL-OFD1, a regulator of centriole elongation; the Meckel-Gruber syndrome module, a major component of the transition zone; and the CPLANE complex necessary for IFT-A assembly. OFDS now appear to be a distinct subgroup of ciliopathies with wide heterogeneity, which makes the initial classification obsolete. A clinical classification restricted to the three frequent/well-delineated subtypes could be proposed, and for patients who do not fit one of these three main subtypes, a further classification could be based on the genotype.
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