Disorder Of Early Childhood Research Articles

Oral Elesclomol Treatment Alleviates Copper Deficiency in Animal Models.

Copper (Cu) is an essential trace element for key biochemical reactions. Dietary or genetic copper deficiencies are associated with anemia, cardiomyopathy, and neurodegeneration. The essential requirement for copper in humans is illustrated by Menkes disease, a fatal neurodegenerative disorder of early childhood caused by mutations in the ATP7A copper transporter. Recent groundbreaking studies have demonstrated that a copper delivery small molecule compound, elesclomol (ES), is able to substantially ameliorate pathology and lethality in a mouse model of Menkes disease when injected as an ES-Cu2+ complex. It is well appreciated that drugs administered through oral means are more convenient with better efficacy than injection methods. Here we show, using genetic models of copper-deficient C. elegans and mice, that dietary ES supplementation fully rescues copper deficiency phenotypes. Worms lacking either the homolog of the CTR1 copper importer or the ATP7 copper exporter showed normal development when fed ES. Oral gavage with ES rescued intestine-specific Ctr1 knockout mice from early postnatal lethality without additional copper supplementation. Our findings reveal that ES facilitates copper delivery from dietary sources independent of the intestinal copper transporter CTR1 and provide insight into oral administration of ES as an optimal therapeutic for Menkes disease and possibly other disorders of copper insufficiency.

Expert System Diagnosa Gangguan Autisme Secara Dini Pada Anak dengan Metode Forward Chaining

Autism is a developmental and behavioral disorder of children where social relationships are disrupted, namely children with autism cannot interact with other people, including their parents. Autistic children experience disorders such as communication disorders, social relationship disorders, and behavioral disorders, resulting in a child. Parents often do not realize the differences and abnormalities that appear in their children until they are three years old. They just realized that their child is different from other children. There are several basics of treating autism and there are some teachers who can help cure autism in children. The teacher treats autistic children with an approach that is adapted to the problem. Types of autism basically this child is divided into four categories, including social interaction disorders, behavioral generalized disorders, communication disorders, and self-stimulation disorders. This research designs and builds an expert system (expert system) for diagnosing Autism disorders in early childhood based on the web Method of Forward Chaining. This Forward Chaining is very good to use if the work starts with recording the initial information and wants to reach the completion or final goal. This expert system is considered capable of providing information and solutions for parents, about the types of autism disorders in early childhood, based on the symptoms entered and can provide solutions

Quantile Mixed Hidden Markov Models for Multivariate Longitudinal Data: An Application to Children's Strengths and Difficulties Questionnaire Scores

AbstractThe identification of factors associated with mental and behavioural disorders in early childhood is critical both for psychopathology research and the support of primary health care practices. Motivated by the Millennium Cohort Study, in this paper we study the effect of a comprehensive set of covariates on children's emotional and behavioural trajectories in England. To this end, we develop a quantile mixed hidden Markov model for joint estimation of multiple quantiles in a linear regression setting for multivariate longitudinal data. The novelty of the proposed approach is based on the multivariate asymmetric Laplace distribution which allows to jointly estimate the quantiles of the univariate conditional distributions of a multivariate response, accounting for possible correlation between the outcomes. Sources of unobserved heterogeneity and serial dependency due to repeated measures are modelled through the introduction of individual-specific, time-constant random coefficients and time-varying parameters evolving over time with a Markovian structure respectively. The inferential approach is carried out through the construction of a suitable expectation–maximization algorithm without parametric assumptions on the random effects distribution.

Histopathology of Duchenne muscular dystrophy in correlation with changes in proteomic biomarkers.

Duchenne muscular dystrophy is an inherited disorder of early childhood that affects multiple systems in the body. Besides late-onset cardio-respiratory syndrome and various body-wide pathophysiological changes, X-linked muscular dystrophy is primarily classified as a disorder of the skeletal musculature. This is reflected by severe histopathological alterations in voluntary contractile tissues, including progressive fibre degeneration, fat substitution, reactive myofibrosis and chronic inflammation. The underlying cause for dystrophinopathy are genetic abnormalities in the DMD gene, which can result in the almost complete loss of the membrane cytoskeletal protein dystrophin, which triggers the collapse of the dystrophin-associated glycoprotein complex and disintegration of sarcolemmal integrity. This in turn results in an increased frequency of membrane micro-rupturing and abnormal calcium ion fluxes through the impaired plasmalemma, which renders muscle fibres more susceptible to enhanced proteolytic degradation and necrosis. This review focuses on the complexity of skeletal muscle changes in X-linked muscular dystrophy and outlines cell biological and histological alterations in correlation to proteome-wide variations as judged by mass spectrometric analyses. This includes a general outline of sample handling, subcellular fraction protocols and modern proteomic approaches using gel electrophoretic and liquid chromatographic methods for efficient protein separation prior to mass spectrometry. The proteomic profiling of the dystrophic and highly fibrotic diaphragm muscle is described as an example to swiftly identify novel proteomic markers of complex histopathological changes during skeletal muscle degeneration. The potential usefulness of new protein markers is examined in relation to key histopathological hallmarks for establishing improved diagnostic, prognostic and therapy-monitoring approaches in the field of dystrophinopathy.

The Efficacy of the Ketogenic Diet in Improving Seizures and EEG Findings in Patients with Refractory Infantile Spasms.

Infantile spasm is an epileptic disorder of early childhood and infancy and is characterized by cluster epileptic spasms and abnormal EEG findings. Developmental delay is prevalent. Some studies have indicated the significant effect of the Ketogenic Diet (KD) on intractable spasms in children who are unresponsive to first-line treatments. It has been used successfully as a first-line treatment with fewer side effects than ACTH. This was an interventional study in which the effectiveness of KD over a six-month period was evaluated in patients with infantile spasms. Those who fulfilled the inclusion criteria and were willing to use the diet received free cans of the 4:1 ketogenic formula. The diet was prescribed based on the Johns Hopkins protocol in the outpatient setting. All patients used a full formula diet for one month. After a month, the patients were examined by a neurologist and a dietitian, and an EEG was obtained to compare pre- and post-KD findings. In order to compare pre- and post-KD seizures, the maximum number of seizures was multiplied by the longest duration of seizures. Ten patients were assessed for one month. Using the KD led to significant changes in seizures/clusters and EEG findings. Nine parents reported improvement in their children's social interactions after using the KD. Based on the findings of this study, the KD can control seizures in patients suffering from infantile spasms by reducing seizure frequency & duration and improving EEG findings.

Association of Gestational Age at Birth With Subsequent Suspected Developmental Coordination Disorder in Early Childhood in China

It remains unknown whether children born at different degrees of prematurity, early term, and post term might have a higher risk of developmental coordination disorder (DCD) compared with completely full-term children (39-40 gestational weeks). To differentiate between suspected DCD in children with different gestational ages based on a national representative sample in China. A retrospective cohort study was conducted in China from April 1, 2018, to December 31, 2019. A total of 152 433 children aged 3 to 5 years from 2403 public kindergartens in 551 cities of China were included in the final analysis. A multilevel regression model was developed to determine the strength of association for different gestational ages associated with suspected DCD when considering kindergartens as clusters. Children's motor performance was assessed using the Little Developmental Coordination Disorder Questionnaire, completed by their parents. Gestational age was determined according to the mother's medical records and divided into 7 categories: completely full term (39 to 40 weeks' gestation), very preterm (<32 weeks), moderately preterm (32-33 weeks), late preterm (34-36 weeks), early term (37-38 weeks), late term (41 weeks), and post term (>41 weeks). A total of 152 433 children aged 3 to 5 years (mean [SD] age, 4.5 [0.8] years), including 80 370 boys (52.7%) and 72 063 girls (47.3%), were included in the study. There were 45 052 children (29.6%) aged 3 years, 59 796 (39.2%) aged 4 years, and 47 585 (31.2%) aged 5 years. Children who were born very preterm (odds ratio [OR], 1.35; 95% CI, 1.23-1.48), moderately preterm (OR, 1.18; 95% CI, 1.02-1.36), late preterm (OR, 1.24; 95% CI, 1.16-1.32), early term (OR, 1.11; 95% CI, 1.06-1.16), and post term (OR, 1.17; 95% CI, 1.07-1.27) were more likely to be classified in the suspected DCD category on the Little Developmental Coordination Disorder Questionnaire than completely full-term children after adjusting for the same characteristics. Additionally, there was no association with suspected DCD in younger (aged 3 years) early-term and postterm children by stratified analyses. In this cohort study, every degree of prematurity at birth, early-term birth, and postterm birth were associated with suspected DCD when compared with full-term birth. These findings have important implications for understanding motor development in children born at different gestational ages. Long-term follow-up and rehabilitation interventions should be considered for children born early and post term.

Sleep Disorders in Early Childhood and the Development of Mental Health Problems in Adolescents: A Systematic Review of Longitudinal and Prospective Studies.

The association between sleep problems, particularly sleep disorders, and mental health has long been studied and recognized. However, the causal relationship between sleep disorders, particularly during early childhood, on mental health problems in adolescence are yet to be established. From a preventive perspective, it is important to understand the causality of mental health problems in adolescents so that intervention measures can be derived and implemented as early as possible for maximum effectiveness. To provide more precise information on the effect of early childhood sleep disorders on mental health problems during adolescence, a systematic review was conducted on longitudinal and prospective studies reported in the literature. Following the PRISMA guidelines with an extensive search of the literature 26 studies were identified. Seven of these identified studies satisfied all selection criteria with sufficient data on the effect of early childhood sleep disorders and mental health problems in adolescence. Information was extracted and analyzed systematically from each study and tabulated. The overall results obtained from these studies indicate a significant and possible causal relationship between early childhood sleep disorders and the development of mental health problems, such as anxiety, depression, and ADHD in adolescence. These results are discussed with regards to the theoretical and practical implications as well as preventive strategies.

Geospatial analysis of access to healthcare: child development needs and available care

Abstract Developmental delay (DD) is one of the most frequent disorders in early childhood affecting 10-15% of all preschool children. Early identification of children with DD is critical to ensure appropriate therapeutic interventions, to support the families, and finally to prevent chronic, life-long health, educational, and social consequences. It is widely acknowledged that early intervention (EI) programs are both ethically mandatory and cost-effective for a society on a long-term perspective. However, data shows that many cases are missed in early childhood. Although research has identified potential risk factors for under-utilization of EI, the spatial distribution of children in need, referring doctors, and therapeutic places have been neglected in many research studies so far. Consequently, we do not know much about the spatial variation in EI, and knowledge on potential influencing factors for spatial variation in referral and utilization is lacking. Therefore, we aimed to quantify accessibility of care in the Canton of Zurich, Switzerland. To do so, a comprehensive data set from all children (age 0-4) admitted to the two Units of Special Needs Education (USNE) in the Canton of Zurich in 2017 (n = 1971) was used and analyzed with the Floating Catchment Area (FCA) set of methods. Our results show major differences between rural and urban regions and better accessibility closer to greater therapy institutions. Our findings highlight spatial inequalities between healthcare needs and services. Our research contributes to a better understanding of spatial access to healthcare and informs healthcare policy to help increase accessibility to EI for children with DD. Key messages The Canton of Zurich shows regional inequalities between EI needs and services. Spatial analyses are a valuable tool to find areas of high and low accessibility and understand spatial access to healthcare.

Congenital Zika Infection and the Risk of Neurodevelopmental, Neurological, and Urinary Track Disorders in Early Childhood. A Systematic Review.

It was late 2015 when Northeast Brazil noticed a worrying increase in neonates born with microcephaly and other congenital malformations. These abnormalities, characterized by an abnormally small head and often neurological impairment and later termed Congenital Zika Syndrome, describe the severity of neurodevelopmental and nephrological outcomes in early childhood, and the implication of microcephaly at birth. The purpose of the study was to describe the neurodevelopmental outcomes in children exposed to Zika virus during fetal life, with and without microcephaly at birth. The systematic review included research studies about the neurodevelopmental outcomes with and without microcephaly, as well as nephrological outcomes in early childhood. We searched PubMed, Crossref, PsycINFO, Scopus, and Google Scholar publications and selected 19 research articles published from 2018 to 2021. Most studies have linked the severity of microcephaly in childbirth to the neurodevelopmental and urinary outcomes in early childhood. However, most children without microcephaly at birth develop typically, while others may be at risk for language impairment.

Changes in Children’s Speech and Language Difficulties from Age Five to Nine: An Irish National, Longitudinal Study

In many countries, information on the prevalence of persistent speech and language disorders in early childhood is sparse due to the lack of nationally representative samples and longitudinal studies. Secondary analysis of data collected on over 7500 Irish children at ages 5 and 9 years, found that the prevalence of speech and language difficulties reported by the primary caregivers of Irish children decreased from one in six at age 5 to one in 12 at age 9. However, one in 20 children were reported to have difficulties at both ages. Regression analysis compared children with difficulties at both age 5 and age 9 to those who had been reported to have them at age 5 but no longer had such difficulties at age 9. Children with speech and language difficulties at both age 5 and age 9 were more likely to have two or more developmental impairments as well as current or past hearing impairments. Teachers and parents also reported a greater number of social-emotional difficulties. Family characteristics did not differ significantly across the two groupings. At best, up to one third of the children at ages 5 and 9 with speech and language difficulties had two or more contacts with a speech and language therapists in the preceding 12 month period. Increased support to these children, their parents and teachers would seem to be warranted.

COMPARISON BETWEEN KINESITHERAPY, MAGNETIC FIELD AND THEIR COMBINATION FOR CEREBRAL MOTOR DISORDERS IN EARLY CHILDHOOD

Introduction:- There are no comparative studies between kinesitherapy, magnetic field, and their combination for cerebral motor disorders in early childhood. There is a consensus on the short-term but not on the long-term efficiency of magnetotherapy. There is a consensus on kinesitherapy but not on its optimal frequency. Aim: The first purpose of the study is to compare the short and long-term effects of kinesitherapy, magnetic field, and their combination for cerebral motor disorders in early childhood. The second purpose was to determine the optimal frequency of kinesitherapy. Material and methods:- Seventy-four children (age 6.91 ± 4.78 m corrected age 6.40 ± 5.08 m) with cerebral motor disorders participated in the study. The followed-up periods were two weeks and six months. Four of the groups were physiotherapeutic. One group was the control. The control group, consisting of 15 children, received once-daily placebo magnetic therapy for two weeks. The magnetotherapy group, including 14 children, received once-daily magnetotherapy for two weeks. The kinesitherapy group consisted of 18 children. They received once-daily kinesitherapy. The group with kinesitherapy + placebo magnetic therapy included 15 children. They received once-daily placebo magnetic therapy and once-daily kinesitherapy for two weeks. The combined group (kinesitherapy with magnetotherapy) consisted of 15 children. They received once-daily magnetic therapy and kinesitherapy for two weeks. The groups with kinesitherapy received instructions to perform it as often as possible at home. The following factors were registered and analyzed: pathological and primitive reflexes, kinesiology tests, cranial ultrasound, and frequency of kinesitherapy. Results:- At the beginning of the follow-up, there was no difference between the five groups regarding all factors (P&gt;0.05). The combined group with kinesitherapy and magnetic field showed the best results at the end of the second week and the sixth month (P&lt;0.05). The group with kinesitherapy and placebo magnetic therapy showed the second-best results (P&lt;0.05). The results of the kinesitherapy group were worst than the previous groups but better than the control group (P&lt;0.05). At a frequency of kinesitherapy twice daily, the binary index of kinesiology tests was 0.102, primitive reflexes - 0.308, and cranial ultrasound - 0.487. At a frequency of kinesitherapy three times daily, the binary index of kinesiology tests was 0.833, primitive reflexes - 0.955, and cranial ultrasound - 0.651. Conclusion:- Cranial ultrasound revealed relatively stationary morphological changes. However, the developing nervous system in cerebral motor disorders at early childhood showed significant positive dynamics and plasticity, verified by kinesiology tests, primitive and pathological reflexes. The best results showed the combined group with kinesitherapy and magnetic field. The effects of kinesitherapy and magnetic field upgraded over each other. Twice daily frequency of kinesitherapy achieved insignificant effectiveness, while three times daily - significant. The recommendation for cerebral motor disorders in early childhood to perform kinesitherapy at least three times daily is very important.

Hyperthermia-induced seizures during neonatal period alter the functionality of A1 and A2A receptors in the cerebellum and evoke fine motor impairment and gait disturbances in adult rats

Febrile seizures (FS) are one of the most common types of convulsive disorder of early childhood and they can be classified into simple and prolonged depending on the duration. Nowadays, simple FS have a good prognosis but there is controversy about the outcome of prolonged FS. In a previous work using an animal model of prolonged FS, we showed that hiperthermia-induced seizures (HIS) evoked fine motor coordination impairment and gait disturbances in adolescent rats in a process in which seemed to be involved modulation of the cerebellar adenosinergic system. The aim of the present work was to verify whether the effect was maintained in adulthood. To this end, neonatal rats (PD 12) were exposed to HIS and after 48 days (PD 60) they were assayed on balance beam and footprint tests. Animals were sacrificed 53 days after HIS and adenosine A1 and A2A receptor signalling pathways were studied in cerebellar plasma membranes by using radioligand binding assays and by measuring the activities of 5´-nucleotidase and adenylyl cyclase. Results obtained revealed that adult rats exposed to HIS showed gait disturbances and motor impairments. Besides, animals exposed to hyperthermic insult showed an increase in adenosine A2A receptor functionality and 5´-nucleotidase activity. Surprisingly, the functionality of the adenosine A1 receptor resulted significantly changed causing stimulation instead of inhibition of adenylate cyclase activity. These results showed that the effect of prolonged FS at the early age also persist in adulthood suggesting on must pay attention to FS in children.

Prevalence and course of anxiety disorders and symptoms from preschool to adolescence: a 6-wave community study.

The rate of various anxiety disorders in early childhood and whether they continue into middle childhood or adolescence is not known. We therefore report on the prevalence and stability of DSM-5-defined anxiety disorders and their symptoms, capturing the period from preschool to adolescence. By means of interviewer-based clinical interviews, anxiety was measured in a sample of Norwegian children at six measurement points from age 4 to 14 (n = 1,041). To adjust for time-invariant factors, we applied random intercept cross-lagged panel models (RI-CLPMs) capturing within-person changes. Nearly 10% (95% CI = 7.29, 12.63) had an anxiety disorder at some timepoint. Specific phobia was the most prevalent disorder in early and middle childhood, whereas generalized anxiety disorder (GAD) increased in prevalence and became the most common anxiety disorder at age 14 (4.51%, 95% CI = 2.78, 6.23). When time-invariant confounding was adjusted for, homotypic continuity in anxiety symptoms typically first emerged in late middle childhood or adolescence. Even so, such within-person analyses revealed a heterotypic path from increased number of early childhood symptoms of specific phobia to increased number of GAD symptoms in middle childhood (B = .41, 95% CI = .06, .75). Increased separation anxiety in middle childhood predicted increased symptoms of GAD in adolescence (B = .38, 95% CI = .14, .62), and vice versa (B = .05, 95% CI = .00, .09). Only minor gender differences were revealed. Anxiety disorders are prevalent in childhood. In early childhood, anxiety symptoms generally do not predict later anxiety symptoms. In middle childhood, however, such symptoms are less likely to vanish, indicating this developmental period to be particularly important for preventive and treatment efforts.

Evaluation of Short-term Psychoanalytic Child Therapy (PaCT) for Young Children with Depressive Disorders: Results from a Pilot Study

Depressive disorders in early childhood are associated with high psychosocial impairment and tend to remain stable over time without adequate treatment. Short-term psychoanalytic therapy is a common form of child psychotherapy, yet there is a lack of empirical evaluation of this approach for young children with depressive disorders. Therefore, this secondary evaluation of a study on the treatment of anxiety disorders used an uncontrolled pre-post design in a clinical setting to investigate whether children with depressive comorbidity would evidence significant diagnostic and symptomatic remission after treatment with manualized short-term Psychoanalytic Child Therapy (PaCT). Nineteen children who had an anxiety disorder and a (subclinical) depressive disorder (assessed with the Preschool Age Psychiatric Assessment using DSM-IV criteria) were treated with PaCT. After treatment, 15 of 19 children (78.94 %) were remitted and 15 of 17 children (88.24 %; 2 were lost to follow-up) were free of depressive disorders at the 6-month follow-up. Further analyses revealed significant effects for pre- to post and pre- to follow-up comparisons regarding internalizing symptoms and overall problems using parent- and (nursery-)teacher-ratings. These results suggest that short-term PaCT shows promise as a treatment for childhood depressive disorders.

SIX-MONTH FOLLOW-UP OF KINESITHERAPY FOR CEREBRAL MOTOR DISORDERS IN EARLY CHILDHOOD

Introduction:- There is a consensus about the positive effect of kinesitherapy in cerebral motor disorders, but not about its recommended frequency. There is no consensus on the statistical significance of predictive factors. Aim:- To compare the effect of kinesitherapy versus control, as well as to compare the statistical significance of the following factors: age, corrected age, weight, gender, pregnancy, number of pregnancies, conception, birth, twins, pathological reflexes, primitive reflexes, kinesiology tests, cranial ultrasound, follow-up and frequency of kinesitherapy. Material and methods:- 27 children (age 8.21 ± 5.49 months) with cerebral motor disorders were followed for six months. They were divided into kinesitherapy group and control group. The control group (n = 15) was followed up in the beginning, at the second week, and at the sixth month. The treatment group (n = 12) was followed up in the same way but received kinesitherapy once daily for two weeks at the beginning of every month. Parents were instructed to perform the same techniques with their children as often as possible at home. The following factors were recorded and analyzed: age, corrected age, weight, gender, pregnancy (normal or pathological), number of pregnancies, conception (normal or in vitro), birth (normal or pathological), twins (yes or no), pathological reflexes, primitive reflexes, kinesiology tests, cranial ultrasound, follow-up (short-term and long-term) and frequency of kinesitherapy. Results:- At the beginning of the follow-up, there was no difference between the two groups regarding all factors (P&gt;0.05). Both groups showed better results after two weeks (P&lt;0.05) and after six months (P&lt;0.05) regarding kinesiology tests, pathological and primitive reflexes. The kinesitherapy group showed better results versus the control group at the end of the second week (P&lt;0.05) and at the end of the sixth month (P&lt;0.05) regarding kinesiology tests, pathological and primitive reflexes. The regression coefficients of the factors decreased in the following sequence: frequency of kinesitherapy (0.787), kinesiology tests (0.412), primitive reflexes (0.352), conception (0.298) , birth (0.282), twins (0.221), corrected age (0.220), age (0.197), pregnancy (0.197), pathological reflexes (0.143), cranial ultrasound (0.127), number of pregnancies (0.0501), gender (0.0306), follow-up (0.00547), and weight (0.0000031). Conclusion:- Kinesitherapy has a significant short-term and long-term effect that exceeds the placebo effect. Significance of the factors decreased in the following order: frequency of kinesitherapy, kinesiology tests, primitive reflexes, conception, birth, pregnancy, corrected age, age, pathological reflexes, cranial ultrasound, pregnancy, gender, follow-up, and weight. The frequency of kinesitherapy is the most important factor, which should be recommended at least three times daily in cerebral motor disorders in early childhood.

Association Between Prenatal Opioid Exposure and Neurodevelopmental Outcomes in Early Childhood: A Retrospective Cohort Study.

Several studies have reported increasing prevalence of prescription opioid use among pregnant women. However, little is known regarding the effects of maternal opioid use on neurodevelopmental disorders in early childhood in pregnant women with no evidence of opioid use disorders or drug dependence. The aim of this study was to quantify the association between prenatal opioid exposure from maternal prescription use and neurodevelopmental outcomes in early childhood. This retrospective study included pregnant women aged 12-55 years and their live-birth infants born from 2010 to 2012 present in Optum's deidentified Clinformatics® Data Mart database. Eligible infants born to mothers without opioid use disorders or drug dependence were followed till occurrence of neurodevelopmental disorders, loss to follow-up, or study end (December 31, 2017), whichever came first. Propensity score by fine stratification was applied to adjust for confounding by demographic characteristics, obstetric characteristics, maternal comorbid mental and pain conditions, and measures of burden of illnesses and to obtain adjusted hazard ratios (HR) and 95% confidence intervals (CI). Exposed and unexposed infants were compared on the incidence of neurodevelopmental disorders. Of 24,910 newborns, 7.6% (1899) were prenatally exposed to prescription opioids. Overall, 1562 children were diagnosed with neurodevelopmental disorders, with crude incidence rates of 2.9 per 100 person-years in exposed children versus 2.5 per 100 person-years in unexposed children. After adjustment, we observed no association between fetal opioid exposure and the risk of neurodevelopmental disorders (HR 1.10; 95% CI 0.92-1.32). However, increased risk of neurodevelopmental disorders were observed in children with longer cumulative exposure duration (HR 1.70; 95% CI 1.05-2.96) or high cumulative opioid doses (HR 1.22; 95% CI 1.01-1.54). In pregnant women without opioid use disorders or drug dependence, maternal opioid use was not associated with increased risk of neurodevelopmental disorders in early childhood. However, increased risks of early neurodevelopmental disorders were observed in children born to women receiving prescription opioids for longer duration and at higher doses during pregnancy.

Long non-coding RNAs as novel therapeutic targets in juvenile myelomonocytic leukemia

Juvenile myelomonocytic leukemia (JMML) treatment primarily relies on hematopoietic stem cell transplantation and results in long-term overall survival of 50–60%, demonstrating a need to develop novel treatments. Dysregulation of the non-coding RNA transcriptome has been demonstrated before in this rare and unique disorder of early childhood. In this study, we investigated the therapeutic potential of targeting overexpressed long non-coding RNAs (lncRNAs) in JMML. Total RNA sequencing of bone marrow and peripheral blood mononuclear cell preparations from 19 untreated JMML patients and three healthy children revealed 185 differentially expressed lncRNA genes (131 up- and 54 downregulated). LNA GapmeRs were designed for 10 overexpressed and validated lncRNAs. Molecular knockdown (≥ 70% compared to mock control) after 24 h of incubation was observed with two or more independent GapmeRs in 6 of them. For three lncRNAs (lnc-THADA-4, lnc-ACOT9-1 and NRIR) knockdown resulted in a significant decrease of cell viability after 72 h of incubation in primary cultures of JMML mononuclear cells, respectively. Importantly, the extent of cellular damage correlated with the expression level of the lncRNA of interest. In conclusion, we demonstrated in primary JMML cell cultures that knockdown of overexpressed lncRNAs such as lnc-THADA-4, lnc-ACOT9-1 and NRIR may be a feasible therapeutic strategy.

Electrophysiological Profile Remodeling via Selective Suppression of Voltage-Gated Currents by CLN1/PPT1 Overexpression in Human Neuronal-Like Cells.

CLN1 disease (OMIM #256730) is an inherited neurological disorder of early childhood with epileptic seizures and premature death. It is associated with mutations in CLN1 coding for Palmitoyl-Protein Thioesterase 1 (PPT1), a lysosomal enzyme which affects the recycling and degradation of lipid-modified (S-acylated) proteins by removing palmitate residues. Transcriptomic evidence from a neuronal-like cellular model derived from differentiated SH-SY5Y cells disclosed the potential negative roles of CLN1 overexpression, affecting the elongation of neuronal processes and the expression of selected proteins of the synaptic region. Bioinformatic inquiries of transcriptomic data pinpointed a dysregulated expression of several genes coding for proteins related to voltage-gated ion channels, including subunits of calcium and potassium channels (VGCC and VGKC). In SH-SY5Y cells overexpressing CLN1 (SH-CLN1 cells), the resting potential and the membrane conductance in the range of voltages close to the resting potential were not affected. However, patch-clamp recordings indicated a reduction of Ba2+ currents through VGCC of SH-CLN1 cells; Ca2+ imaging revealed reduced Ca2+ influx in the same cellular setting. The results of the biochemical and morphological investigations of CACNA2D2/α2δ-2, an accessory subunit of VGCC, were in accordance with the downregulation of the corresponding gene and consistent with the hypothesis that a lower number of functional channels may reach the plasma membrane. The combined use of 4-AP and NS-1643, two drugs with opposing effects on Kv11 and Kv12 subfamilies of VGKC coded by the KCNH gene family, provides evidence for reduced functional Kv12 channels in SH-CLN1 cells, consistent with transcriptomic data indicating the downregulation of KCNH4. The lack of compelling evidence supporting the palmitoylation of many ion channels subunits investigated in this study stimulates inquiries about the role of PPT1 in the trafficking of channels to the plasma membrane. Altogether, these results indicate a reduction of functional voltage-gated ion channels in response to CLN1/PPT1 overexpression in differentiated SH-SY5Y cells and provide new insights into the altered neuronal excitability which may underlie the severe epileptic phenotype of CLN1 disease. It remains to be shown if remodeling of such functional channels on plasma membrane can occur as a downstream effect of CLN1 disease.

Decreased Histone Acetylation Levels at Th1 and Regulatory Loci after Induction of Food Allergy.

Immunoglobulin E (IgE)-mediated allergy against cow’s milk protein fractions such as whey is one of the most common food-related allergic disorders of early childhood. Histone acetylation is an important epigenetic mechanism, shown to be involved in the pathogenesis of allergies. However, its role in food allergy remains unknown. IgE-mediated cow’s milk allergy was successfully induced in a mouse model, as demonstrated by acute allergic symptoms, whey-specific IgE in serum, and the activation of mast cells upon a challenge with whey protein. The elicited allergic response coincided with reduced percentages of regulatory T (Treg) and T helper 17 (Th17) cells, matching decreased levels of H3 and/or H4 histone acetylation at pivotal Treg and Th17 loci, an epigenetic status favoring lower gene expression. In addition, histone acetylation levels at the crucial T helper 1 (Th1) loci were decreased, most probably preceding the expected reduction in Th1 cells after inducing an allergic response. No changes were observed for T helper 2 cells. However, increased histone acetylation levels, promoting gene expression, were observed at the signal transducer and activator of transcription 6 (Stat6) gene, a proallergic B cell locus, which was in line with the presence of whey-specific IgE. In conclusion, the observed histone acetylation changes are pathobiologically in line with the successful induction of cow’s milk allergy, to which they might have also contributed mechanistically.

The Relative Utility of Concurrent Sources of Information for Diagnosis of Autism Spectrum Disorder in Early Childhood.

The development of effective screening methods for Autism Spectrum Disorder (ASD) in early childhood remains a public health priority for communities around the world. Little is known regarding the concurrence between parent concerns about ASD and formal ASD diagnostic methods. This study aimed to examine the relationships among a priori parental ASD concern, ADOS classification, and a physician specialist's diagnosis. One hundred and thirty-four toddlers (74% male; mean age = 31.8 months, SD 4.4) received an evaluation at a university center specializing in ASD and neurodevelopmental disorders. Correspondence between a priori parental ASD suspicion and physician diagnosis of ASD was 61% (p = 0.028). Correspondence between a priori parental suspicion of ASD and ADOS ASD classification was 57% (p = 0.483). Correspondence between ADOS classification and physician diagnosis of ASD was 88% (p = 0.001). Our results have implications for evaluations in low resource regions of the world where access to physician specialists may be limited; the high correspondence between ADOS classification and a physician specialist's diagnosis supports the use of trained ADOS evaluators, such as field health workers or early childhood educators, in a tiered screening process designed to identify those most in need of a specialist's evaluation. Our results also have implications for public health efforts to provide parent education to enable parents to monitor their child's development and share concerns with their providers. Parent awareness and expression of concern coupled with timely responses from providers may lead toward earlier identification of ASD, and other neurodevelopmental disorders, and hence, generate opportunities for earlier and more personalized intervention approaches, which in turn may help improve long-term outcomes. Empowering parents and community members to screen for ASD may be especially important in regions of the world where access to formal diagnosis is limited.