Spontaneous preterm delivery presents one of the most complex challenges in obstetrics and is a leading cause of perinatal morbidity and mortality. Although it is a common endpoint for multiple pathological processes, the mechanisms governing the etiological complexity of spontaneous preterm birth and the placental responses are poorly understood. This study examined placental tissues collected between May 2019 and May 2022 from a well-defined cohort of women who experienced spontaneous preterm birth (n = 72) and healthy full-term deliveries (n = 30). Placental metabolomic profiling of polar metabolites was performed using Ultra-High Performance Liquid Chromatography/Mass Spectrometry (UHPLC/MS) analysis. The resulting data were analyzed using multi- and univariate statistical methods followed by unsupervised clustering. A comprehensive metabolomic evaluation of the placenta revealed that spontaneous preterm birth was associated with significant changes in the levels of 34 polar metabolites involved in intracellular energy metabolism and biochemical activity, including amino acids, purine metabolites, and small organic acids. We found that neither the preterm delivery phenotype nor the inflammatory response explain the reported differential placental metabolome. However, unsupervised clustering revealed two molecular subtypes of placentas from spontaneous preterm pregnancies exhibiting differential enrichment of clinical parameters. We also identified differences between early and late preterm samples, suggesting distinct placental functions in early spontaneous preterm delivery. Altogether, we present evidence that spontaneous preterm birth is associated with significant changes in the level of placental polar metabolites. Dysregulation of the placental metabolome may underpin important (patho)physiological mechanisms involved in preterm birth etiology and long-term neonatal outcomes.

• Klíčová slova
• inflammation, metabolism, metabolomics, placenta, preterm birth,
• Publikační typ
• časopisecké články MeSH

Spontaneous preterm birth is a serious medical condition responsible for substantial perinatal morbidity and mortality. Its phenotypic characteristics, preterm labor with intact membranes (PTL) and preterm premature rupture of the membranes (PPROM), are associated with significantly increased risks of neurological and behavioral alterations in childhood and later life. Recognizing the inflammatory milieu associated with PTL and PPROM, here, we examined expression signatures of placental tryptophan metabolism, an important pathway in prenatal brain development and immunotolerance. The study was performed in a well-characterized clinical cohort of healthy term pregnancies (n = 39) and 167 preterm deliveries (PTL, n = 38 and PPROM, n = 129). Within the preterm group, we then investigated potential mechanistic links between differential placental tryptophan pathway expression, preterm birth and both intra-amniotic markers (such as amniotic fluid interleukin-6) and maternal inflammatory markers (such as maternal serum C-reactive protein and white blood cell count). We show that preterm birth is associated with significant changes in placental tryptophan metabolism. Multifactorial analysis revealed similarities in expression patterns associated with multiple phenotypes of preterm delivery. Subsequent correlation computations and mediation analyses identified links between intra-amniotic and maternal inflammatory markers and placental serotonin and kynurenine pathways of tryptophan catabolism. Collectively, the findings suggest that a hostile inflammatory environment associated with preterm delivery underlies the mechanisms affecting placental endocrine/transport functions and may contribute to disruption of developmental programming of the fetal brain.

• MeSH
• biologické markery MeSH
• lidé MeSH
• metabolické sítě a dráhy MeSH
• náchylnost k nemoci MeSH
• placenta metabolismus   MeSH
• předčasný porod diagnóza   etiologie   metabolismus   MeSH
• regulace genové exprese MeSH
• rizikové faktory MeSH
• stanovení celkové genové exprese MeSH
• těhotenství MeSH
• transkriptom * MeSH
• tryptofan metabolismus   MeSH
• výpočetní biologie metody   MeSH
• výsledek těhotenství MeSH
• zánět komplikace   etiologie   MeSH
• Check Tag
• lidé MeSH
• těhotenství MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• biologické markery MeSH
• tryptofan MeSH

Kleine-Levin syndrome (KLS) is a rare disorder characterized by severe episodic hypersomnia, with cognitive impairment accompanied by apathy or disinhibition. Pathophysiology is unknown, although imaging studies indicate decreased activity in hypothalamic/thalamic areas during episodes. Familial occurrence is increased, and risk is associated with reports of a difficult birth. We conducted a worldwide case-control genome-wide association study in 673 KLS cases collected over 14 y, and ethnically matched 15,341 control individuals. We found a strong genome-wide significant association (rs71947865, Odds Ratio [OR] = 1.48, P = 8.6 × 10-9) within the 3'region of TRANK1 gene locus, previously associated with bipolar disorder and schizophrenia. Strikingly, KLS cases with rs71947865 variant had significantly increased reports of a difficult birth. As perinatal outcomes have dramatically improved over the last 40 y, we further stratified our sample by birth years and found that recent cases had a significantly reduced rs71947865 association. While the rs71947865 association did not replicate in the entire follow-up sample of 171 KLS cases, rs71947865 was significantly associated with KLS in the subset follow-up sample of 59 KLS cases who reported birth difficulties (OR = 1.54, P = 0.01). Genetic liability of KLS as explained by polygenic risk scores was increased (pseudo R2 = 0.15; P < 2.0 × 10-22 at P = 0.5 threshold) in the follow-up sample. Pathway analysis of genetic associations identified enrichment of circadian regulation pathway genes in KLS cases. Our results suggest links between KLS, circadian regulation, and bipolar disorder, and indicate that the TRANK1 polymorphisms in conjunction with reported birth difficulties may predispose to KLS.

• Klíčová slova
• GWAS, Kleine-Levin syndrome, bipolar disorder, birth difficulties, hypersomnia,
• MeSH
• bipolární porucha etiologie   MeSH
• cytokiny genetika   MeSH
• genetická predispozice k nemoci MeSH
• genetická variace * MeSH
• genetické asociační studie MeSH
• hodnocení rizik MeSH
• Kleineho-Levinův syndrom komplikace   epidemiologie   genetika   MeSH
• komplikace porodu epidemiologie   etiologie   MeSH
• lidé MeSH
• náchylnost k nemoci * MeSH
• odds ratio MeSH
• polymorfismus genetický MeSH
• poruchy nadměrné spavosti etiologie   MeSH
• rizikové faktory MeSH
• těhotenství MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• těhotenství MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Názvy látek
• cytokiny MeSH
• TRANK1 protein, human MeSH Prohlížeč

The review examines Attention Deficit Hyperactivity Disorder (ADHD in its Child and Adult form) and its various presentations (Hyperactive Impulsive, Inattentive, and Combined) with a particular focus on environmental (incl. social factors), lifestyles and comorbidities. It is argued that ADHD is best understood in a holistic and interactive context and a vast empirical literature is presented to illustrate the point: Environmental factors include stress in general as well as exposure to toxins (phthalates, bisphenol A). Social factors are illustrated by effects of social deprivation and seduction to unhealthy lifestyles. Maternal lifestyle during pregnancy is pointed out (particularly her exposure to nicotine, alcohol, caffeine, and drugs, even seemingly benign medications like acetaminophen), which all tend to be related to ADHD. Family environment is discussed with respect to protective effect of (mainly authoritative and autocratic) parenting styles. Societal factors include mainly economic and political issues: income inequality and poverty (low SES is an ADHD risk factor) and a growing moral dilemma between a humanistic effort to globally spread the knowledge of ADHD and the medicalization and commercialization of the disorder. The second part of the review is devoted to ADHD related lifestyles and resulting comorbidities (e.g., food addiction and obesity, substance abuse, electronic media dependencies and conduct and personality disorders). Although ADHD is a neurodevelopmental disorder, its assessment and treatment are also linked to environmental, behavioral and social factors and their interactions.

• Klíčová slova
• ADHD, alcohol, childhood, comorbidities, obesity, pollution, smoking, substance abuse,
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH