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BACKGROUNDGiven the heightened tolerance to self-starvation in anorexia nervosa (AN), a hypothalamic dysregulation of energy and glucose homeostasis has been hypothesized. Therefore, we investigated whether hypothalamic reactivity to glucose metabolism is impaired in AN.METHODSTwenty-four participants with AN, 28 normal-weight participants, and 24 healthy participants with obesity underwent 2 MRI sessions in a single-blind, randomized, case-controlled crossover study. We used an intragastric infusion of glucose and water to bypass the cephalic phase of food intake. The responsivity of the hypothalamus and the crosstalk of the hypothalamus with reward-related brain regions were investigated using high-resolution MRI.RESULTSNormal-weight control participants displayed the expected glucose-induced deactivation of hypothalamic activation, whereas patients with AN and participants with obesity showed blunted hypothalamic reactivity. Furthermore, patients with AN displayed blunted reactivity in the nucleus accumbens and amygdala. Compared with the normal-weight participants and control participants with obesity, the patients with AN failed to show functional connectivity between the hypothalamus and the reward-related brain regions during water infusion relative to glucose infusion. Finally, the patients with AN displayed typical baseline levels of peripheral appetite hormones during a negative energy balance.CONCLUSIONThese results indicate that blunted hypothalamic glucose reactivity might be related to the pathophysiology of AN. This study provides insights for future research, as it is an extended perspective of the traditional primary nonhomeostatic understanding of the disease.FUNDINGThis study was supported by a grant from the DFG (SI 2087/2-1).

In recent years, neurological and neurodegenerative disorders research has focused on altered molecular mechanisms in search of potential pharmacological targets, e.g., imbalances in mechanisms of response to oxidative stress, inflammation, apoptosis, autophagy, proliferation, differentiation, migration, and neuronal plasticity, which occur in less common neurological and neurodegenerative pathologies (Huntington disease, multiple sclerosis, fetal alcohol spectrum disorders, and Down syndrome). Here, we assess the effects of different catechins (particularly of epigalocatechin-3-gallate, EGCG) on these disorders, as well as their use in attenuating age-related cognitive decline in healthy individuals. Antioxidant and free radical scavenging properties of EGCG -due to their phenolic hydroxyl groups-, as well as its immunomodulatory, neuritogenic, and autophagic characteristics, makes this catechin a promising tool against neuroinflammation and microglia activation, common in these pathologies. Although EGCG promotes the inhibition of protein aggregation in experimental Huntington disease studies and improves the clinical severity in multiple sclerosis in animal models, its efficacy in humans remains controversial. EGCG may normalize DYRK1A (involved in neural plasticity) overproduction in Down syndrome, improving behavioral and neural phenotypes. In neurological pathologies caused by environmental agents, such as FASD, EGCG enhances antioxidant defense and regulates placental angiogenesis and neurodevelopmental processes. As demonstrated in animal models, catechins attenuate age-related cognitive decline, which results in improvements in long-term outcomes and working memory, reduction of hippocampal neuroinflammation, and enhancement of neuronal plasticity; however, further studies are needed. Catechins are valuable compounds for treating and preventing certain neurodegenerative and neurological diseases of genetic and environmental origin. However, the use of different doses of green tea extracts and EGCG makes it difficult to reach consistent conclusions for different populations.

Hao-Fountain syndrome (HAFOUS) is a rare autosomal dominant neurodevelopmental disorder caused by pathogenic variants. A diagnostic blood DNA methylation episignature has been established, yet the broader regulatory consequences of haploinsufficiency and their tissue specificity remain incompletely characterized. We performed genome-wide DNA methylation profiling, RNA sequencing, and cis expression quantitative trait methylation (eQTM) analysis in whole blood (n = 9) and patient-derived skin fibroblasts (n = 4). Differential methylation was assessed and methylation-expression coupling within ±250 kb of each DMR. DMRs were further interpreted using BCOR, H2AK119ub1, and H3K27me3 ChIP-Rx datasets from neural models. Blood reproduced the established hypermethylation episignature and yielded 17 significant DMRs, accompanied by modest numbers of differentially expressed genes and eQTMs. Fibroblasts displayed internally coherent regulatory patterns, including 2,143 nominal DMRs, 310 differentially expressed genes, and 559 significant eQTMs. Convergent methylation-expression changes prominently involved the HOXB cluster (HOXB3, HOXB5, HOXB6). Both blood- and fibroblast-derived DMRs showed significant enrichment for BCOR- and H2AK119ub1-marked regions, consistent with disruption of non-canonical PRC1.1-associated chromatin. Cross-tissue comparison revealed limited overlap, supporting marked tissue specificity in methylation-expression relationships. haploinsufficiency is associated with a restricted set of regulatory loci enriched within PRC1-associated chromatin domains. Fibroblasts revealed coherent methylation and expression changes at developmental genes, whereas blood captured the diagnostic episignature and a smaller set of downstream regulatory alterations. Together, this dual-tissue integrative analysis refines the molecular consequences of reduced dosage and provides a framework for future mechanistic studies in disease-relevant cellular models.

The perinatal period is crucial to the establishment of lifelong gut microbiota. The abundance and composition of microbiota can be altered by several factors such as preterm delivery, formula feeding, infections, antibiotic treatment, and lifestyle during pregnancy. Gut dysbiosis affects the development of innate and adaptive immune responses and resistance to pathogens, promoting atopic diseases, food sensitization, and infections such as necrotizing enterocolitis (NEC). Recent studies have indicated that the gut microbiota imbalance can be restored after a single or multi-strain probiotic supplementation, especially mixtures of Lactobacillus and Bifidobacterium strains. Following the systematic search methodology, the current review addresses the importance of probiotics as a preventive or therapeutic tool for dysbiosis produced during the perinatal and infant period. We also discuss the safety of the use of probiotics in pregnant women, preterm neonates, or infants for the treatment of atopic diseases and infections.

Maternal tobacco smoking during pregnancy remains a major public health issue. The neurotoxic properties of nicotine are associated with fetal neurodevelopmental disorders and perinatal morbimortality. Recent research has demonstrated the effects of nicotine toxicity on genetic and epigenetic alterations. Smoking cessation strategies including nicotine replacement therapy (NRT) and electronic nicotine delivery systems (ENDS) show lack of clear evidence of effectiveness and safety in pregnant women. Limited trials using randomized controls concluded that the intermittent use formulation of NRT (gum, sprays, inhaler) in pregnant women is safe because the total dose of nicotine delivered to the fetus is less than continuous-use formulations (transdermal patch). Electronic nicotine delivery systems (ENDS) were hyped as a safer alternative during pregnancy. However, refill liquids of ENDS are suspected to be cytotoxic for the fetus. Animal studies revealed the impact of ENDS on neural stem cells, showing a similar risk of pre- and postnatal neurobiological and neurobehavioral disorders to that associated with the exposure to traditional tobacco smoking during early life. There is currently no clear evidence of impact on fetal brain development, but recent research suggests that the current guidelines should be reconsidered. The safety of NRT and ENDS is increasingly being called into question. In this review, we discuss the special features (pharmacodynamics, pharmacokinetics, and metabolism) of nicotine, NRT, and ENDS during pregnancy and postnatal environmental exposure. Further, we assess their impact on pre- and postnatal neurodevelopment.

Pregnancy induces a number of immunological, hormonal, and metabolic changes that are necessary for the mother to adapt her body to this new physiological situation. The microbiome of the mother, the placenta and the fetus influence the fetus growth and undoubtedly plays a major role in the adequate development of the newborn infant. Hence, the microbiome modulates the inflammatory mechanisms related to physiological and pathological processes that are involved in the perinatal progress through different mechanisms. The present review summarizes the actual knowledge related to physiological changes in the microbiota occurring in the mother, the fetus, and the child, both during neonatal period and beyond. In addition, we approach some specific pathological situations during the perinatal periods, as well as the influence of the type of delivery and feeding.

Foetal Alcohol Syndrome (FAS) is the most deleterious health effect derived from alcohol consumption during pregnancy and is placed at the end of the Foetal Alcohol Spectrum Disorders (FASD). Few studies have proposed potential molecular biomarkers of physical and neurological damage associated with prenatal alcohol exposure. We prospectively recruited 55 children from 8 to 12 years old, with a prenatal assessment for ethanol exposure using meconium analysis of fatty acid ethyl esters (FAEE). The control group was established for FAEE < 2 nmol/g (n = 31) and a Prenatal Ethanol Exposure (PEE) group for FAEEs > 2 nmol/g (n = 33). Moreover, 98 children adopted from Eastern European Countries (EEC) were also recruited to evaluate FASD diagnosis comprising 31 cases with complete FAS, 42 with partial FAS, 6 with ARBD and 5 with ARND. Serum values of IGF-I and IGF-II for all children recruited were determined by immunoassay. Anthropometric and neurocognitive evaluation showed severe impairments in FAS children, moderate effects in PEE and no harmful effects in the control group with no prenatal exposure to alcohol. Analysis of IGF-I and IGF-II serum concentrations revealed that FASD from EEC as well as PEE children showed significantly lower concentrations of both IGF-I and IFG-II than the control group and reference values. Moreover, Spearman correlations showed a significant effect of IGF-I on anthropometric measurements in girls, whereas IGF-II affected the neuropsychological variables in both genders. These findings validate the use of growth factors IGF-I and IGF-II as surrogate biomarkers of damage induced by prenatal exposure to ethanol and could be used in the diagnosis of foetal alcohol spectrum disorders.

Kohl is a traditional cosmetic widely used in Asia and Africa. In recent years, demand for kohl-based eyelids and lipsticks has increased in Europe, linked to migratory phenomena of populations from these continents. Although the European legislation prohibits the use of heavy metals in cosmetics due to the harmful effects to human health, particularly to pregnant women and children, these elements are still present in certain products. The European Union recommended levels are Pb < 20 ppm, As < 5 ppm, Cd < 5 ppm, Sb < 100 ppm, and Ni < 200 ppm. In Germany, levels are more restrictive: Pb < 2 ppm, As < 0.5 ppm, Cd < 0.1 ppm, Sb < 0.5 ppm, and Ni < 10 ppm. Here, we analyzed 12 kohl-based cosmetics in different presentations (powder, paste, and pencil) that were purchased in Spanish and German local shops. An inductively coupled plasma optical emission spectrophotometer was used to identify toxic elements and heavy metals. Levels of Pb ranged between 1.7 and 410,000 ppm in six of the study samples, four of which had levels above the recommended limit of at least two heavy metals. Arsenic (a carcinogenic element) values were within the range allowed by the EU in only 58% of the studied samples. Moreover, two products doubled this limit, reaching levels of 9.2 and 12.6 ppm. In one of the products, cadmium, related to toxic keratitis, was four times higher (20.7 ppm) than that allowed, while in two other products, these limits were doubled (11.8 and 12.7 ppm). Our results indicate the need to supervise the manufacture of kohl-based traditional products and the analysis of their composition prior distribution in European countries.

Formalin-fixed and paraffin-embedded (FFPE) tissues represent a valuable source for biomarker studies and clinical routine diagnostics. However, they suffer from degradation of nucleic acids due to the fixation process. Since genetic and epigenetic studies usually require PCR amplification, this degradation hampers its use significantly, impairing PCR robustness or necessitating short amplicons. In routine laboratory medicine a highly robust PCR performance is mandatory for the clinical utility of genetic and epigenetic biomarkers. Therefore, methods to improve PCR performance using DNA from FFPE tissue are highly desired and of wider interest. The effect of template DNA derived from FFPE tissues on PCR performance was investigated by means of qPCR and conventional PCR using PCR fragments of different sizes. DNA fragmentation was analyzed via agarose gel electrophoresis. This study showed that poor PCR amplification was partly caused by inhibition of the DNA polymerase by fragmented DNA from FFPE tissue and not only due to the absence of intact template molecules of sufficient integrity. This PCR inhibition was successfully minimized by increasing the polymerase concentration, dNTP concentration and PCR elongation time thereby allowing for the robust amplification of larger amplicons. This was shown for genomic template DNA as well as for bisulfite-converted template DNA required for DNA methylation analyses. In conclusion, PCR using DNA from FFPE tissue suffers from inhibition which can be alleviated by adaptation of the PCR conditions, therefore allowing for a significant improvement of PCR performance with regard to variability and the generation of larger amplicons. The presented solutions to overcome this PCR inhibition are of tremendous value for clinical chemistry and laboratory medicine.