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Background: Cladribine tablets are contraindicated during pregnancy; therefore, safety data on pregnancies exposed to this treatment are limited. CLEAR collects and describes pregnancy outcomes in this understudied population. Objectives: To describe the main features of the CLEAR study design, including the data sources and the methodological approach, and provide a status update. Design: CLEAR is a non-interventional, multi-database, comparative cohort study. Four cohorts are included: pregnancies of women with multiple sclerosis (MS) exposed to cladribine tablets (maternal cohort exposed); pregnancies of women with MS unexposed to any disease-modifying therapy (DMT; maternal cohort unexposed); pregnancies fathered by men with MS exposed to cladribine tablets; and pregnancies fathered by men with MS unexposed to any DMT. Methods: A staggered methodological approach, using data from Denmark, Finland, France, Germany, Norway, Scotland, and Sweden, will be applied to analyze the occurrence of major congenital anomalies (primary outcome) and selected pregnancy outcomes. The first interim analysis (performed using German pregnancy cohorts) was conducted when ⩾75 pregnant women (including 25 women from the maternal cohort exposed) were cumulatively reached across all participating countries. The end of the study period will be established once pregnancy counts reach 149 in the maternal cohort exposed and 298 in the maternal cohort unexposed in all countries combined, or 5 years after pregnancy counts are first assessed (whichever occurs first). Results: As of January 2024, data on pregnancies of women exposed to cladribine tablets (n = 28–36 (numbers are approximate due to masking of some counts)), and pregnancies of women unexposed to cladribine tablets (n = 2834) were available from Denmark, Finland, Germany, Scotland, and Sweden. Conclusion: The CLEAR study, using a staggered methodological approach, aims to provide further insight into the safety outcome data for cladribine tablets in pregnant women, as a regulatory commitment with the European Medicines Agency. Trial registration: EU PAS Register number, EUPAS25027. [ABSTRACT FROM AUTHOR]

Appropriate animal models of human diseases are a cornerstone in the advancement of science and medicine. To create animal models of neuropsychiatric and neurobehavioral diseases such as autism spectrum disorder (ASD) necessitates the development of sufficient neurobehavioral measuring tools to translate human behavior to expected measurable behavioral features in animals. If possible, the severity of the symptoms should also be assessed. Indeed, at least in rodents, adequate neurobehavioral and neurological tests have been developed. Since ASD is characterized by a number of specific behavioral trends with significant severity, animal models of autistic-like behavior have to demonstrate the specific characteristic features, namely impaired social interactions, communication deficits, and restricted, repetitive behavioral patterns, with association to several additional impairments such as somatosensory, motor, and memory impairments. Thus, an appropriate model must show behavioral impairment of a minimal number of neurobehavioral characteristics using an adequate number of behavioral tests. The proper animal models enable the study of ASD-like-behavior from the etiologic, pathogenetic, and therapeutic aspects. From the etiologic aspects, models have been developed by the use of immunogenic substances like polyinosinic-polycytidylic acid (PolyIC), lipopolysaccharide (LPS), and propionic acid, or other well-documented immunogens or pathogens, like Mycobacterium tuberculosis. Another approach is the use of chemicals like valproic acid, polychlorinated biphenyls (PCBs), organophosphate pesticides like chlorpyrifos (CPF), and others. These substances were administered either prenatally, generally after the period of major organogenesis, or, especially in rodents, during early postnatal life. In addition, using modern genetic manipulation methods, genetic models have been created of almost all human genetic diseases that are manifested by autistic-like behavior (i.e., fragile X, Rett syndrome, SHANK gene mutation, neuroligin genes, and others). Ideally, we should not only evaluate the different behavioral modes affected by the ASD-like behavior, but also assess the severity of the behavioral deviations by an appropriate scoring system, as applied to humans. We therefore propose a scoring system for improved assessment of ASD-like behavior in animal models. [ABSTRACT FROM AUTHOR]

Valproic acid (VPA) is a very effective anticonvulsant and mood stabilizer with relatively few side effects. Being an epigenetic modulator, it undergoes clinical trials for the treatment of advanced prostatic and breast cancer. However, in pregnancy, it seems to be the most teratogenic antiepileptic drug. Among the proven effects are congenital malformations in about 10%. The more common congenital malformations are neural tube defects, cardiac anomalies, urogenital malformations including hypospadias, skeletal malformations and orofacial clefts. These effects are dose related; daily doses below 600 mg have a limited teratogenic potential. VPA, when added to other anti-seizure medications, increases the malformations rate. It induces malformations even when taken for indications other than epilepsy, adding to the data that epilepsy is not responsible for the teratogenic effects. VPA increases the rate of neurodevelopmental problems causing reduced cognitive abilities and language impairment. It also increases the prevalence of specific neurodevelopmental syndromes like autism (ASD) and Attention Deficit Hyperactivity Disorder (ADHD). High doses of folic acid administered prior to and during pregnancy might alleviate some of the teratogenic effect of VPA and other AEDs. Several teratogenic mechanisms are proposed for VPA, but the most important mechanisms seem to be its effects on the metabolism of folate, SAMe and histones, thus affecting DNA methylation. VPA crosses the human placenta and was found at higher concentrations in fetal blood. Its concentrations in milk are low, therefore nursing is permitted. Animal studies generally recapitulate human data. [ABSTRACT FROM AUTHOR]

Objectives: Prenatal exposure to heroin may have long-term consequences for development during early and middle childhood. The present research studied the cognitive, social, and emotional functioning of adolescents exposed to drugs prenatally, and investigated the extent to which the early adoption of children exposed prenatally to drugs would alleviate the possible effects of exposure. Methods: The study included 191 adolescents (12-16 years of age) and their parents in Israel, who had or had not been exposed prenatally to drugs and differing in socio-economic status (SES), and in adoptive status. They were administered five subtests of the Wechsler Intelligence Scale for Children (WISC-III), and the Youth Self-Report Form for assessing behavior problems that measures problems associated with attention deficit, self-esteem and risk-taking. Parents were administered the Child Behavior Checklist (CBCL) for assessing behavior problems, the Conners Rating Scale (CRS) for assessing attention deficit problems in their children and the Wender Utah Rating Scale (WURS), a self-report measure of ADHD-related problems. Results: Adolescents exposed to at least one risk factor (exposure to drugs, low SES, or adoption) performed more poorly than those exposed to none of these risk factors on the WISC-III subtests, the CBCL and the CRS. The effects of risk factors did not cumulate. Contrary to our hypothesis, adoption did not mitigate the effects of prenatal exposure to drugs: for cognitive functioning exposure to drugs was associated with poorer performance among the exposed High SES Adopted versus non-exposed High SES non-adopted children on three of the WISC-III subtests. Exposed low SES children living with their parents performed at the same relatively low level as non-exposed low SES controls. Exposure to drugs was associated with adult ADHD-related problems assessed by the WURS. There were no direct or interaction effects of exposure on neurological functioning, self-competence, behavior problems on the CBCL or risk-taking. Conclusions: Children exposed to drugs of abuse prenatally, including those adopted away, and children who grow up in low SES backgrounds, may be at risk of relatively reduced cognitive functioning (though still within the normal range) in adolescence. Children exposed to drugs, who are from low SES backgrounds, or who are adopted, may be at risk for lower cognitive or social functioning than children who have not experienced such risks. Practice implications: There is a need for implementing early monitoring and long-term intervention programs featuring encouragement of cognitive and social skills for children prenatally exposed to drugs in order to alleviate the possible long-term effects of exposure to risk. (Contains 6 tables.)

Aim: There is a lack of investigation into the functional developmental profile of children with Down syndrome. On the basis of current international health paradigms, the purpose of this study was to assess the developmental profile of these children. Method: Sixty children (33 males, 27 females) with Down syndrome (age range 6-16y; mean age 9y 3mo, SD 28.8mo), who had received standard, holistic, early intervention, were assessed. Of these, 42 (70%) had congenital anomalies, 12 had severe congenital heart defects. Participants were assessed on measures of cognitive function (Beery-Buktenica Developmental Test of Visual-Motor Integration; Stanford-Binet Intelligence Scale) and participation (Vineland Adaptive Behaviour Scales). Results: No difference was found on any measure on the basis of severity of congenital anomaly. Results showed improvements in age-related body function and correlations between specific body functions and participation. No decline in IQ was found with age, and significant correlations between IQ and all other measures were noted. Although sex differences were found in the body functions of short-term memory and motor function, no difference in measures of activity performance and participation was found. Interpretation: Our findings emphasize the need for paediatric Down syndrome intervention to encourage improved body functions while emphasizing the acquisition of functional skills that enable enhanced participation in age-appropriate activities. (Contains 2 tables.)

During the early phases of embryonic development, the yolk sac serves as an initial placenta in many animal species. While in some, this role subsides around the end of active organogenesis, it continues to have important functions in rodents, alongside the chorio‐allantoic placenta. The yolk sac is the initial site of hematopoiesis in many animal species including primates. Cells of epiblastic origin form blood islands that are the forerunners of hematopoietic cells and of the primitive endothelial cells that form the vitelline circulation. The yolk sac is also a major route of embryonic and fetal nutrition apparently as long as it functions. In mammals and especially rodents, macro and micronutrients are absorbed by active pinocytosis into the visceral yolk sac, degraded and the degradation products (i.e., amino acids) are then transferred to the embryo. Interference with the yolk sac function may directly reflect on embryonic growth and development, inducing congenital malformations or in extreme damage, causing embryonic and fetal death. In rodents, many agents were found to damage the yolk sac (i.e., anti–yolk sac antibodies or toxic substances interfering with yolk sac pinocytosis) subsequently affecting the embryo/fetus. Often, the damage to the yolk sac is transient while embryonic damage persists. In humans, decreased yolk sac diameter was associated with diabetic pregnancies and increased diameter was associated with pregnancy loss. In addition, culture of rat yolk sacs in serum obtained from pregnant diabetic women or from women with autoimmune diseases induced severe damage to the visceral yolk sac epithelium and embryonic malformations. It can be concluded that as a result of the crucial role of the yolk sac in the well‐being of the early embryo, any damage to its normal function may severely and irreversibly affect further development of the embryo/fetus. [ABSTRACT FROM AUTHOR]

The role of hippocampal monoamines and their related genes in the etiology and pathogenesis of depression-like behavior, particularly in impaired sociability traits and the meaning of changes in USVs emitted by pups, remains unknown. We assessed the effects of prenatal administration of S-adenosyl-methionine (SAMe) in Sub mice that exhibit depressive-like behavior on serotonergic, dopaminergic and noradrenergic metabolism and the activity of related genes in the hippocampus (HPC) in adulthood in comparison to saline-treated control Sub mice. During postnatal days 4 and 8, we recorded and analyzed the stress-induced USVs emitted by the pups and tried to understand how the changes in the USVs' calls may be related to the changes in the monoamines and the activity of related genes. The recordings of the USVs showed that SAMe induced a reduction in the emitted flat and one-frequency step-up call numbers in PND4 pups, whereas step-down type calls were significantly increased by SAMe in PND8 pups. The reduction in the number of calls induced by SAMe following separation from the mothers implies a reduction in anxiety, which is an additional sign of decreased depressive-like behavior. Prenatal SAMe increased the concentrations of serotonin in the HPC in both male and female mice without any change in the levels of 5HIAA. It also decreased the level of the dopamine metabolite DOPAC in females. There were no changes in the levels of norepinephrine and metabolites. Several changes in the expression of genes associated with monoamine metabolism were also induced by prenatal SAMe. The molecular and biochemical data obtained from the HPC studies are generally in accordance with our previously obtained data from the prefrontal cortex of similarly treated Sub mice on postnatal day 90. The changes in both monoamines and their gene expression observed 2–3 months after SAMe treatment are associated with the previously recorded behavioral improvement and seem to demonstrate that SAMe is effective via an epigenetic mechanism. [ABSTRACT FROM AUTHOR]

The long-term relations of socioeconomic status (SES) and early-life exposures with cognitive development at preadolescence are not fully understood, especially in low SES populations. We examined associations of SES and early-life exposures including feeding practices, physical growth and infections with cognitive development among preadolescents from underprivileged communities. A prospective study was conducted among 146 healthy children from two relatively low SES Arab villages in Israel, who were recruited at age 1–9 weeks and followed until age 18 months. Information was obtained on their feeding practices, health status and growth indicators. Cognitive development at age 10–12 years was assessed using the Wechsler Intelligence Scale, including the full-scale intelligence quotient (FSIQ) and scores of four cognitive domains. Multiple linear regression models were performed. Nearly all the children (98%) were breastfed in infancy. Bivariate correlations were found of SES, growth indices and rates of diarrheal and respiratory illnesses in infancy, but not of feeding practices, with cognitive scores. In multivariable models, SES was positively (p < 0.001) associated with all the cognitive domains (beta coefficient ranges 4.3 to 8.2). Birthweight was positively associated with FSIQ (p = 0.039) and the perceptual reasoning index (p = 0.002). Weight for age Z score at age 10–14 months was positively associated with the verbal comprehension index (p = 0.003). The rate of respiratory illnesses was negatively associated with the perceptual reasoning index (p = 0.05). SES is strongly associated with cognitive development even in relatively low SES communities. Birthweight, weight indicators and respiratory illness in infancy might affect cognitive development through preadolescence. [ABSTRACT FROM AUTHOR]

Children born to heroin-dependent mothers (n=83) were compared to 76 children born to heroin-dependent fathers and to 3 control groups with and without environmental deprivation and health problems. Results found that developmental delays and behavioral disorders found among heroin-exposed children resulted primarily from severe environmental deprivation and less from in utero exposure. (Author/PB)

The etiology of autism spectrum disorder (ASD) is genetic, environmental, and epigenetic. In addition to sex differences in the prevalence of ASD, which is 3–4 times more common in males, there are also distinct clinical, molecular, electrophysiological, and pathophysiological differences between sexes. In human, males with ASD have more externalizing problems (i.e., attention-deficit hyperactivity disorder), more severe communication and social problems, as well as repetitive movements. Females with ASD generally exhibit fewer severe communication problems, less repetitive and stereotyped behavior, but more internalizing problems, such as depression and anxiety. Females need a higher load of genetic changes related to ASD compared to males. There are also sex differences in brain structure, connectivity, and electrophysiology. Genetic or non-genetic experimental animal models of ASD-like behavior, when studied for sex differences, showed some neurobehavioral and electrophysiological differences between male and female animals depending on the specific model. We previously carried out studies on behavioral and molecular differences between male and female mice treated with valproic acid, either prenatally or early postnatally, that exhibited ASD-like behavior and found distinct differences between the sexes, the female mice performing better on tests measuring social interaction and undergoing changes in the expression of more genes in the brain compared to males. Interestingly, co-administration of S-adenosylmethionine alleviated the ASD-like behavioral symptoms and the gene-expression changes to the same extent in both sexes. The mechanisms underlying the sex differences are not yet fully understood. [ABSTRACT FROM AUTHOR]

Childhood obesity is a major health problem. We examined differences between children with obesity and normal weight in nutritional and inflammation biomarkers. A cross-sectional study was conducted among healthy children aged 10–12 years from Arab villages in Israel. Parents were interviewed regarding sociodemographic and children's health status. Body weight and height measurements were performed and weight categories were defined using the 2007 WHO growth curves. Blood samples were tested for complete blood count, levels of iron, ferritin, lipids, uric acid, and C-reactive protein (CRP). Overall, 146 children (59.0% males, mean age = 11.3 [SD = 0.5]) were enrolled. In total 43.8%, 14.1% and 42.3% of the participants had normal weight, overweight and obesity, respectively. A multivariable logistic regression model showed that children with overweight and obesity had lower iron, and HDL-C levels than children with normal weight. Levels of CRP, uric acid, LDL-C and lymphocytes were higher among children with overweight and obesity. In conclusion, our findings highlight the worse metabolic and nutritional status in overweight and obese children. Such markers play a role in metabolic syndrome, thus suggesting that metabolic syndrome might start in childhood. [ABSTRACT FROM AUTHOR]

Reduction in the levels of monoamines, such as serotonin and dopamine in the brain, were reported in patients and animals with depression. SAMe, a universal methyl donor and an epigenetic modulator, is successfully used as an adjunct treatment of depression. We previously found that prenatal treatment with SAMe of Submissive (Sub) mice that serve as a model for depression alleviated many of the behavioral depressive symptoms. In the present study, we treated pregnant Sub mice with 20 mg/kg of SAMe on days 12–15 of gestation and studied the levels of monoamines and the expression of genes related to monoamines metabolism in their prefrontal cortex (PFC) at the age of 3 months. The data were compared to normal saline-treated Sub mice that exhibit depressive-like symptoms. SAMe increased the levels of serotonin in the PFC of female Sub mice but not in males. The levels of 5-HIAA were not changed. SAMe increased the levels of dopamine and of DOPAC in males and females but increased the levels of HVA only in females. The levels of norepinephrine and its metabolite MHPG were unchanged. SAMe treatment changed the expression of several genes involved in the metabolism of these monoamines, also in a sex-related manner. The increase in several monoamines induced by SAMe in the PFC may explain the alleviation of depressive-like symptoms. Moreover, these changes in gene expression more than 3 months after treatment probably reflect the beneficial effects of SAMe as an epigenetic modulator in the treatment of depression. [ABSTRACT FROM AUTHOR]