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Aicardi-Goutières syndrome (AGS) is a rare genetic early-onset progressive encephalopathy with variable clinical manifestations. The IFIH1 mutation has been confirmed to be responsible for type I interferon production and activation of the Janus kinase signaling pathway. We herein stress neurological observations and neuroimaging findings in a severe case report of an infant with AGS type 7 due to an IFIH1 mutation who was diagnosed in the first month of life. We also review neurological characteristics of IFIH1 mutations through recent literature.
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BACKGROUND: Transition from child-centered to adult-centered healthcare is a gradual process that addresses the medical, psychological, and educational needs of young people in the management of their autonomy in making decisions about their health and their future clinical assistance. This transfer is challenging across all chronic diseases but can be particularly arduous in rare neurological conditions. AIM: To describe the current practice on the transition process for young patients in centers participating in the European Reference Network for Rare Neurological Diseases (ERN-RND). METHODS: Members of the ERN-RND working group developed a questionnaire considering child-to-adult transition issues and procedures in current clinical practice. The questionnaire included 20 questions and was sent to members of the health care providers (HCPs) participating in the network. RESULTS: Twenty ERN-RND members (75% adult neurologists; 25% pediatricians; 5% nurses or study coordinators) responded to the survey, representing 10 European countries. Transition usually occurs between 16 and 18 years of age, but 55% of pediatric HCPs continue to care for their patients until they reach 40 years of age or older. In 5/20 ERN-RND centers, a standardized procedure managing transition is currently adopted, whereas in the remaining centers, the transition from youth to adult service is usually assisted by pediatricians as part of their clinical practice. CONCLUSIONS: This survey demonstrated significant variations in clinical practice between different centers within the ERN-RND network. It provided valuable data on existing transition programs and highlighted key challenges in managing transitions for patients with rare neurological disorders.
Subject(s)
Delivery of Health Care , Nervous System Diseases , Adult , Adolescent , Humans , Child , Surveys and Questionnaires , Europe , Nervous System Diseases/diagnosis , Nervous System Diseases/therapy , Rare Diseases/diagnosis , Rare Diseases/therapyABSTRACT
(1) Autism spectrum disorder (ASD) belongs to the group of complex developmental disorders. Novel studies have suggested that genetic and environmental factors equally affect the risk of ASD. Identification of environmental factors involved in the development of ASD is therefore crucial for a better understanding of its etiology. Whether there is a causal link between trace elements, brain magnetic resonance imaging (MRI), and ASD remains a matter of debate and requires further studies. (2) In the prospective part of the study, we included 194 children, including an age-matched control group; in the retrospective study, 28 children with available MRI imaging were included. All children had urine analysis of trace elements performed. In those with available brain MRI, linear indexes for the ventricular volumes were measured and calculated. (3) We found the highest vanadium, rubidium, thallium, and silver levels in children with ASD. These elements also correlated with the estimated ventricular volume based on MRI indexes in children with ASD in the subanalysis. However, the severity of the deficits did not correlate with brain MRI indexes of our elements, except negatively with magnesium. (4) Trace elements have an impact on children with ASD, but further multi-centric studies are needed to explain the pathophysiological mechanisms.
Subject(s)
Autism Spectrum Disorder , Magnetic Resonance Imaging , Trace Elements , Humans , Autism Spectrum Disorder/diagnostic imaging , Autism Spectrum Disorder/metabolism , Male , Trace Elements/metabolism , Magnetic Resonance Imaging/methods , Female , Child , Child, Preschool , Brain/diagnostic imaging , Brain/metabolism , Brain/pathology , Retrospective Studies , Prospective Studies , Case-Control StudiesABSTRACT
A new type of research has emerged with United States and European Union pediatric laws that request/demand separate clinical studies for vaccines and drugs in minors less than 18 years of age. Physiologically, minors mature before their 18th birthday. Medicine treats the body, not the administrative status. Many "pediatric" studies are performed in minors that bodily are no longer children, which makes them pointless. Traditional malpractice litigation in clinical research involves patients that were harmed in clinical studies. In the new type of "pediatric" studies, drugs known to work in humans are retested, pretending that "children" are uniquely different, which is incorrect. Minors are not another species. Patients are not treated at all (placebo group) or below standard-of-care (comparison to outdated treatment). Pediatric laws are the law, but not a free pass for harming patients. Where "pediatric" studies violate accepted norms of medical practice, lawyers should be aware of this challenge at the interface of medicine and law.
Subject(s)
Biomedical Research , Child Abuse , Malpractice , Child , Humans , United States , Lawyers , European UnionABSTRACT
The climate models of the Intergovernmental Panel on Climate Change list black carbon (BC) as an important contributor to global warming based on its radiative forcing (RF) impact. Examining closely these models, it becomes apparent that they might underpredict significantly the direct RF for BC, largely due to their assumed spherical BC morphology. Specifically, the light absorption and direct RF of BC agglomerates are enhanced by light scattering between their constituent primary particles as determined by the Rayleigh-Debye-Gans theory interfaced with discrete dipole approximation and recent relations for the refractive index and lensing effect. The light absorption of BC is enhanced by about 20% by the multiple light scattering between BC primary particles regardless of the compactness of their agglomerates. The resulting light absorption agrees very well with the observed absorption aerosol optical depth of BC. ECHAM-HAM simulations accounting for the realistic BC morphology and its coatings reveal high direct RF = 3-5 W/m2 in East, South Asia, sub-Sahara, western Africa, and the Arabian peninsula. These results are in agreement with satellite and AERONET observations of RF and indicate a regional climate warming contribution by 0.75-1.25 °C, solely due to BC emissions.
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AIM: The aim is to study access to intrathecal baclofen (ITB) for children with cerebral palsy (CP) in Europe, as an indicator of access to advanced care. METHODS: Surveys were sent to CP registers, clinical networks, and pump manufacturers. Enquiries were made about ITB treatment in children born in 1990 to 2005 by sex, CP type, level of gross motor function classification system (GMFCS) and age at the start of treatment. Access to ITB was related to the country's gross domestic product (GDP) and % GDP spent on health. RESULTS: In 2011 population-based data from Sweden, Norway, England, Portugal, Slovenia, and Denmark showed that 114 (3.4%) of 3,398 children with CP were treated with ITB, varying from 0.4 to 4.7% between centers. The majority of the children were at GMFCS levels IV-V and had bilateral spastic CP. In Sweden, dyskinetic CP was the most commonly treated subtype. Boys were more often treated with ITB than girls (p = 0.014). ITB was reported to be available for children with CP in 25 of 43 countries. Access to ITB was associated with a higher GDP and %GDP spent on health (p < 0.01). Updated information from 2019 showed remaining differences between countries in ITB treatment and sex difference in treated children was maintained. CONCLUSION: There is a significant difference in access to ITB for children with CP across Europe. More boys than girls are treated. Access to ITB for children with CP is associated with GDP and percent of GDP spent on health in the country.
Subject(s)
Baclofen/therapeutic use , Cerebral Palsy/drug therapy , Gross Domestic Product/statistics & numerical data , Health Expenditures/statistics & numerical data , Health Services Accessibility/statistics & numerical data , Muscle Relaxants, Central/therapeutic use , Adolescent , Baclofen/administration & dosage , Child , Child, Preschool , Europe , Female , Health Care Surveys , Humans , Injections, Spinal , Male , Muscle Relaxants, Central/administration & dosageABSTRACT
Characterization of the exposome, the totality of all environmental factors that one is exposed to from conception onwards, has been recommended to better evaluate the role of environmental influences on developmental programming and life-course vulnerability to major chronic diseases. In the framework of the Health and Environment-wide Associations based on Large population Surveys (HEALS) project we considered the pregnancy exposome exploiting two databases (PHIME and REPRO_PL) that include birth cohorts from three EU countries (Croatia, Slovenia and Poland). The databases contained information on several chemical exposures, socio-demographic, lifestyle and health related factors from conception to child birth, and neuropsychological scores assessed by the Bayley Scales of Infant and Toddler Development in the first two years of life. Our main goal was to assess consistency of environmental influences on neurodevelopment, if any, across European countries differing for geographical, socio-demographic characteristics and levels of chemical exposures to metals such as lead (Pb), mercury (Hg), cadmium (Cd) and trace elements, including micronutrients such as zinc (Zn) and selenium (Se). To this aim, we first selected variables common to the different databases, then applied univariate and multivariate regression analyses to identify factors linked to neurodevelopment, and finally performed meta-analysis to detect potential heterogeneity among cohorts and pooled estimates. Significant differences in exposure levels among the three sub-cohorts were observed as for Hg and Se; exposure levels under study were relatively low and within the range described in existing EU biomonitoring studies. The univariate analyses did not show any common pattern of association as only in the Polish cohort chemical exposure had an impact on neuropsychological outcome. In the meta-analysis, some consistent trends were evident, relative to the adverse influence of Pb on children's language and cognition and the positive influence of Se on language abilities. The effects of the neurotoxic metal Hg positively influenced the motor scores in the Polish cohorts, while it decreased the motor scores in the Slovenia and Croatian sub-cohorts. The only socio-demographic factor consistently associated to the outcome among cohorts was child's sex, with females performing better than males on cognitive and language scores. These findings point to the need of harmonizing existing cohorts or creating prospective study designs that facilitate comparisons in the exposome over time, places and kind of environmental exposures.
Subject(s)
Child Development , Exposome , Prenatal Exposure Delayed Effects , Croatia , Environmental Exposure , Europe , Female , Humans , Infant , Male , Poland , Pregnancy , Prospective Studies , SloveniaABSTRACT
Much of the uncertainty in estimates of the anthropogenic forcing of climate change comes from uncertainties in the instantaneous effect of aerosols on cloud albedo, known as the Twomey effect or the radiative forcing from aerosol-cloud interactions (RFaci), a component of the total or effective radiative forcing. Because aerosols serving as cloud condensation nuclei can have a strong influence on the cloud droplet number concentration (Nd ), previous studies have used the sensitivity of the Nd to aerosol properties as a constraint on the strength of the RFaci. However, recent studies have suggested that relationships between aerosol and cloud properties in the present-day climate may not be suitable for determining the sensitivity of the Nd to anthropogenic aerosol perturbations. Using an ensemble of global aerosol-climate models, this study demonstrates how joint histograms between Nd and aerosol properties can account for many of the issues raised by previous studies. It shows that if the anthropogenic contribution to the aerosol is known, the RFaci can be diagnosed to within 20% of its actual value. The accuracy of different aerosol proxies for diagnosing the RFaci is investigated, confirming that using the aerosol optical depth significantly underestimates the strength of the aerosol-cloud interactions in satellite data.
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In recent years, several studies have addressed the issue of prenatal exposure to methylmercury (MeHg); however, few have actually analysed MeHg blood concentrations. Our study population included mothers and their new-borns from Slovenia (central region; Nâ¯=â¯584) and Croatia (coastal region; Nâ¯=â¯234). We have measurements of total Hg (THg) and MeHg in maternal hair, maternal peripheral blood, and cord blood. Cord blood Hg concentrations were low to moderate (median THgâ¯=â¯1.84â¯ng/g and MeHgâ¯=â¯1.69â¯ng/g). The proportion of THg as MeHg (%MeHg) in maternal and cord blood varied between 4% and 100% (coefficient of variation, CVâ¯=â¯32%) and between 8% and 100% (CVâ¯=â¯20%), respectively. Our data shows that variability of %MeHg was higher at lower blood THg levels. Concentrations of MeHg in maternal blood and cord blood were highly correlated (Rsâ¯=â¯0.943), in the case of inorganic Hg correlation was significant but weaker (Rsâ¯=â¯0.198). MeHg levels in maternal blood and cord blood were positively associated with seafood intake, maternal age, and negatively associated with pre-pregnancy BMI. Additionally, MeHg in maternal blood was positively associated with plasma selenium levels, and cord blood MeHg was negatively associated with parity. The results of multiple linear regression models showed that speciation analysis provides more defined estimation of prenatal exposure in association modelling. Associations between Hg exposure and cognitive performance of children (assessed using Bayley Scales of Infant and Toddler development) adjusted for maternal or child Apolipoprotein E genotypes showed higher model R2 and lower p-values when adjusted for MeHg compared to THg. This study demonstrates that Hg speciation improves the association between exposure and possible negative health effects.
Subject(s)
Maternal Exposure , Mercury/blood , Methylmercury Compounds/blood , Croatia , Female , Fetal Blood , Humans , Infant, Newborn , Pregnancy , SloveniaABSTRACT
A large number of processes are involved in the chain from emissions of aerosol precursor gases and primary particles to impacts on cloud radiative forcing. Those processes are manifest in a number of relationships that can be expressed as factors dlnX/dlnY driving aerosol effects on cloud radiative forcing. These factors include the relationships between cloud condensation nuclei (CCN) concentration and emissions, droplet number and CCN concentration, cloud fraction and droplet number, cloud optical depth and droplet number, and cloud radiative forcing and cloud optical depth. The relationship between cloud optical depth and droplet number can be further decomposed into the sum of two terms involving the relationship of droplet effective radius and cloud liquid water path with droplet number. These relationships can be constrained using observations of recent spatial and temporal variability of these quantities. However, we are most interested in the radiative forcing since the preindustrial era. Because few relevant measurements are available from that era, relationships from recent variability have been assumed to be applicable to the preindustrial to present-day change. Our analysis of Aerosol Comparisons between Observations and Models (AeroCom) model simulations suggests that estimates of relationships from recent variability are poor constraints on relationships from anthropogenic change for some terms, with even the sign of some relationships differing in many regions. Proxies connecting recent spatial/temporal variability to anthropogenic change, or sustained measurements in regions where emissions have changed, are needed to constrain estimates of anthropogenic aerosol impacts on cloud radiative forcing.
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Winter quiescence in fishes is not uncommon, however understanding the mechanisms that cause dormancy are poorly understood. This study highlights the physiological stress temperature places on locomotor musculature and its consequences on whole organism locomotion. Cunner and tautog experience temperatures ranging from 0 to 25⯰C and enter dormancy at ~10⯰C. We aimed to address the question: how do winter temperatures affect steady swimming and muscle contraction kinetics in cunner? Fishes were collected and housed at 5, 10, 15, or 20⯰C. Gait transition speed and fin beat frequency were measured at each acclimation temperature. Twitch and tetanus kinetics were recorded from the aerobic locomotor muscle, which is responsible for the power stroke during swimming. Fish acclimated to colder temperatures (5, 10⯰C) demonstrated lower gait transition speeds than the warm temperature treatments. Similarly, twitch kinetics were slower in muscle acclimated at ≤10⯰C. Locomotor muscle from tautog was significantly slower to contract and relax than cunner when tested at 5 and 10⯰C. These results suggest that muscle acclimation differs in these closely related labrids from the same habitat. Additionally, these results suggest that cunner locomotor musculature can maintain greater performance at a wider range of temperatures. Cunner occupy more northern latitudes which likely allows for greater performance shifts in response to temperature. However, when temperatures get cold enough muscle function is reduced, perhaps contributing to their overwintering ecology.
Subject(s)
Fishes/physiology , Locomotion , Muscles/physiology , Temperature , AnimalsABSTRACT
BACKGROUND: US and EU pediatric laws promote industry-sponsored pediatric studies, based on the therapeutic orphans concept that claims discrimination of children in drug treatment and drug development. OBJECTIVE: We investigated the medical validity of international pediatric studies with centers in Slovenia, an EU member state, and challenge their medical utility. METHODS: We analyzed international industry-sponsored pediatric studies with centers in Slovenia, listed in www.ClinicalTrials.gov, for their medical value. RESULTS: Most pediatric studies triggered by the US Food and Drug Administration and by the European Medicines Agency were/are without medical or scientific value. They were/are formally and regulatorily justified, but lack medical sense and thus were/are unethical. Several even harm children and/or adolescents with serious diseases by exposing them to placebo or substandard treatment. CONCLUSIONS: Pediatric studies triggered by US and EU regulatory demands are a serious abuse of nonneonatal children and adolescents in Slovenia and worldwide. They are medically redundant at best and often deter patients from effective innovative personalized therapy. They also exclude young patients from reasonable studies. Institutional review boards/ethics committees should be alerted, should critically review all ongoing pediatric studies, should suspend those found to be questionable, and should reject newly submitted questionable ones.
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PURPOSE: Refractory epilepsies in children present a major burden for patients and their families. Cannabidiol (CBD) has been suggested as a potential treatment for refractory epilepsies. The aim of this study was to evaluate the effectiveness of add-on therapy with CBD for the treatment of refractory childhood epilepsies. METHOD: Patients with childhood-onset refractory epilepsy, treated at the tertiary epilepsy center of the University Children's Hospital Ljubljana, Slovenia, were included in the study. Add-on therapy with CBD was initiated once the child's epilepsy was categorized as pharmacoresistant to other antiepileptic drugs/therapies. The dosage of CBD was gradually increased to at least 8mg/kg/day. The effect of CBD treatment was evaluated by the reduction in seizure burden and presence of side effects (positive and negative). Serial electroencephalography was performed in some children. RESULTS: Sixty-six patients were included in the analysis. Thirty-two (48.5%) patients had a more than 50% improvement regarding seizure burden, 14 of whom (21.2%) became seizure-free. None of the patients reported worsening of seizure frequency, but CBD had no effect in 15 (22.7%) patients. Some patients reported less vigorous seizures, shorter duration of seizures, shorter time to recovery, and other positive side effects of CBD treatment. Adverse effects were reported in 5/66 children. CONCLUSIONS: In our cohort of patients, CBD was found to have potential benefits as add-on therapy for refractory childhood epilepsies, mainly by reducing seizure burden.
Subject(s)
Anticonvulsants/therapeutic use , Cannabidiol/therapeutic use , Drug Resistant Epilepsy/drug therapy , Seizures/drug therapy , Adolescent , Child , Child, Preschool , Electroencephalography , Female , Humans , Male , SloveniaABSTRACT
Child trafficking is among the most lucrative criminal activities in the world and growing rapidly. Poverty, natural disasters, armed conflicts and, in particular, migration put vulnerable children at high risk of trafficking. Accurate statistics on child trafficking are not available due to its illegal nature. Moreover, trafficking may not be consistently recorded and reported by European countries, mainly because of different perceptions as to who is considered a victim of trafficking. Around 4000-5000 children were identified as presumed victims of trafficking in European Union countries from 2013 to 2014; this is an underestimate of the problem because many victims go unrecognised. Trafficking is linked with issues, such as forced marriage, begging, labour or domestic servitude, slavery and prostitution as well as sexual abuse and child pornography. It may also involve the use of children as soldiers or for criminal activities, such as theft and drug smuggling. Child trafficking also involves the removal of organs and the selling neonates, infants, and children for adoption. Child victims of trafficking should be promptly identified in order to provide them with the necessary care as well as to prosecute the traffickers and stop their illegal activity. Healthcare professionals should be appropriately trained to keep a careful eye out for any signs of trafficking in children. CONCLUSION: The European Academy of Paediatrics calls on our governments, intergovernmental organisations, paediatricians, and healthcare professionals to collaborate so as to improve the identification and healthcare of victims and to contribute to the disbanding and prosecution of child traffickers by reporting such situations. What is Known: ⢠Child trafficking is a fast growing and among the most lucrative criminal activities in the world. ⢠Poverty, natural disasters, armed conflicts and in particular migration put vulnerable children at high risk of trafficking. What is New: ⢠Child trafficking is an underestimated and often ignored issue, with around 4000-500children identified as presumed victims in European Union countries from 2013 to 2014. ⢠The European Academy of Paediatrics strongly encourages Paediatricians to identify victims as well as provide them with adequate health care and support; it calls on governments, intergovernmental organisations, and fellow compatriots to act within the full extent of the law to identify, disband, and prosecute child traffickers.
Subject(s)
Human Trafficking , Physician's Role , Academies and Institutes , Child , Crime Victims , Europe , Humans , Pediatricians , PediatricsABSTRACT
This study reviewed the link between social media and the growing epidemic of childhood obesity in Europe. A task force from the European Academy of Paediatrics and the European Childhood Obesity Group searched published literature and developed a consensus statement. It found that there was evidence of a strong link between obesity levels across European countries and childhood media exposure and that parents and society needed a better understanding of the influence of social media on dietary habits. CONCLUSION: Health policies in Europe must take account of the range of social media influences that promote the development of childhood obesity.
Subject(s)
Mass Media , Pediatric Obesity/epidemiology , Advisory Committees , Consensus , Diet , Europe/epidemiology , Health Behavior , HumansABSTRACT
We identify two heteroallelic mutations in the acetylcholine receptor δ-subunit from a patient with severe myasthenic symptoms since birth: a novel δD140N mutation in the signature Cys-loop and a mutation in intron 7 of the δ-subunit gene that disrupts splicing of exon 8. The mutated Asp residue, which determines the disease phenotype, is conserved in all eukaryotic members of the Cys-loop receptor superfamily. Studies of the mutant acetylcholine receptor expressed in HEK 293 cells reveal that δD140N attenuates cell surface expression and apparent channel gating, predicting a reduced magnitude and an accelerated decay of the synaptic response, thus reducing the safety margin for neuromuscular transmission. Substituting Asn for Asp at equivalent positions in the α-, ß-, and ϵ-subunits also suppresses apparent channel gating, but the suppression is much greater in the α-subunit. Mutant cycle analysis applied to single and pairwise mutations reveals that αAsp-138 is energetically coupled to αArg-209 in the neighboring pre-M1 domain. Our findings suggest that the conserved αAsp-138 and αArg-209 contribute to a principal pathway that functionally links the ligand binding and pore domains.
Subject(s)
Acetylcholine/metabolism , Models, Molecular , Mutation , Myasthenic Syndromes, Congenital/genetics , Receptors, Nicotinic/genetics , Acetylcholine/chemistry , Amino Acid Substitution , Bungarotoxins/pharmacology , Child , Conserved Sequence , DNA Mutational Analysis , Female , HEK293 Cells , Humans , Introns , Ligands , Muscle Weakness/etiology , Myasthenic Syndromes, Congenital/metabolism , Myasthenic Syndromes, Congenital/physiopathology , Nicotinic Agonists/pharmacology , Protein Conformation , Protein Interaction Domains and Motifs , RNA Splicing , Receptors, Nicotinic/chemistry , Receptors, Nicotinic/metabolism , Recombinant Proteins/chemistry , Recombinant Proteins/metabolism , Severity of Illness IndexABSTRACT
The aim of the present study was to evaluate the association between prenatal exposure to mercury (Hg) and neurodevelopment of the child, taking into account genetic polymorphism of apolipoprotein E (Apoe) and other relevant confounders. Six hundred and one mother-child pairs were recruited from the central Slovenia region and 243 from Rijeka, on the Croatian coast of the northern Adriatic. The total Hg in cord blood, Bayley Scales of Infant and Toddler Development, Third Edition (Bayley-III) assessment at 18 months of age and Apoe genotyping was performed on 361 children; 237 of them were from Slovenia and 124 from Croatia. The results showed negative association between low-to-moderate Hg exposure in children with normal neurodevelopmental outcome and cognitive and fine motor scores at 18 months of age as assessed by Bayley III. The Hg-related decrease in cognitive score was observed only in children carrying at least one Apoe ε4 allele, while the decrease in fine motor scores was independent of the Apoe genotype. Adjusting for selenium (Se) and lead (Pb) levels, a positive association between Se and the language score and a negative association between Pb and the motor score was observed, but not in the subgroup of children carrying the ε4 allele.
Subject(s)
Apolipoproteins E/genetics , Cognition/drug effects , Environmental Pollutants/toxicity , Mercury/toxicity , Motor Skills/drug effects , Polymorphism, Genetic , Prenatal Exposure Delayed Effects/epidemiology , Adult , Apolipoproteins E/metabolism , Child Development/drug effects , Croatia/epidemiology , Environmental Pollutants/blood , Female , Food Contamination/analysis , Humans , Infant , Male , Mercury/blood , Pregnancy , Prenatal Exposure Delayed Effects/chemically induced , Selenium/blood , Slovenia/epidemiology , Young AdultABSTRACT
The European Academy of Paediatrics (EAP) is dedicated to promoting healthy lifestyles for children from birth into young adulthood. Physical exercise and leisure are essential to the development of healthy bodies, strong minds, and social skills. All children, without regard to their physical or mental capacities, should be provided with the time, the leadership, the facilities, and the equipment needed to exercise through sports while enjoying playing, even competing, in an environment appropriate to their capacities and aspirations. During exercise and sports, children should be assured of a safe and an appropriate environment that protects and promotes their human rights. Top sports that engage the best competitive athletes in an age group, in a region, in a country, or in the world should provide role models and even dreams for all children. These top sports, however, are also most usually surrounded by large political, economic, and/or business interests where only the best can compete while at times exacting a too high physical and/or psychological cost for those who have survived the cut, made the grade. Alongside this more and more children are being raised in environments with fewer open spaces as well as inside a media and digital culture making significantly less room for the enjoyment of physical exercise and leisure. Children's diets have also been changed dramatically by a significant intake of calorierich foods, which often have little nutritional value and which even a child's high metabolism rates not able to burn off efficiently. Conclusion With this Resolution, the EAP is calling for a renewed look at the role of sports and leisure in the lives of children and, by implication, at the way we structure, finance, and promote sports in Europe. The EAP is also asking that this Resolution be adopted by all organizers of sports involving children and young adults in Europe (and beyond), be that on the playground, in schools, in clubs, or in professional sporting organizations. The EAP would like that every child, throughout his or her childhood years and into young adulthood, can fully participate in sports in a safe environment where winning is playing and playing is winning.
Subject(s)
Adolescent Health , Child Advocacy , Child Health , Doping in Sports/prevention & control , Health Promotion/methods , Youth Sports/ethics , Adolescent , Child , Doping in Sports/ethics , Europe , Health Promotion/ethics , Humans , Young AdultABSTRACT
BACKGROUND: Joubert syndrome (JS) is a recessive ciliopathy characterised by a distinctive brain malformation 'the molar tooth sign'. Mutations in >27 genes cause JS, and mutations in 12 of these genes also cause Meckel-Gruber syndrome (MKS). The goals of this work are to describe the clinical features of MKS1-related JS and determine whether disease causing MKS1 mutations affect cellular phenotypes such as cilium number, length and protein content as potential mechanisms underlying JS. METHODS: We measured cilium number, length and protein content (ARL13B and INPP5E) by immunofluorescence in fibroblasts from individuals with MKS1-related JS and in a three-dimensional (3D) spheroid rescue assay to test the effects of disease-related MKS1 mutations. RESULTS: We report MKS1 mutations (eight of them previously unreported) in nine individuals with JS. A minority of the individuals with MKS1-related JS have MKS features. In contrast to the truncating mutations associated with MKS, all of the individuals with MKS1-related JS carry ≥ 1 non-truncating mutation. Fibroblasts from individuals with MKS1-related JS make normal or fewer cilia than control fibroblasts, their cilia are more variable in length than controls, and show decreased ciliary ARL13B and INPP5E. Additionally, MKS1 mutant alleles have similar effects in 3D spheroids. CONCLUSIONS: MKS1 functions in the transition zone at the base of the cilium to regulate ciliary INPP5E content, through an ARL13B-dependent mechanism. Mutations in INPP5E also cause JS, so our findings in patient fibroblasts support the notion that loss of INPP5E function, due to either mutation or mislocalisation, is a key mechanism underlying JS, downstream of MKS1 and ARL13B.