BACKGROUND: Proximal Femoral Focal Deficiency (PFFD) is the most proximal manifestation of a syndrome involving Congenitally Shortened lower Limbs (CSL), which also affects the fibula and midline metatarsals. This pattern of congenital human long bone deficiencies corresponds, in a time dependent manner, to the failed ingrowth pathways of new blood vessels of the growing embryonic limb. The distal femoral condyles are, in contrast, served by an alternative vascular supply from around the knee joint, and so remain resistant to the CSL deficiency. AIM: We hypothesize that embryonic vascular dysgenesis causes PFFD, as well as the cardinal features of the Femoral, Fibular and midline Metatarsal deficiencies (FFM) syndrome. RESULTS: Arteriography of CSL with PFFD reveals diminution or failed formation of the Femoral Artery (FA), which corresponds to downstream skeletal reductions. It may also reveal preservation of the primitive Axial Artery (AA) of the embryonic limb. The combination of missing and retained primitive vessels inform the time, place, and nature of the etiologic vascular events. This suggests that PFFD is the visible expression of a normally prefigured cartilaginous scaffold of the femur, which develops in conformity with the available pattern of blood vessels present. The teratogen thalidomide, known to affect the forming embryonic vasculature, also produces PFFD indistinguishable from the naturally occurring entity. CONCLUSION: The entire spectrum of PFFD, including phocomelia, fibular, and metatarsal dystrophisms, should thus be regarded as downstream skeletal results of embryonic arterial dysgeneses.

• MeSH
• Femoral Artery * abnormalities   embryology   MeSH
• Femur * abnormalities   blood supply   embryology   MeSH
• Fibula abnormalities   blood supply   MeSH
• Humans MeSH
• Metatarsal Bones abnormalities   MeSH
• Lower Extremity Deformities, Congenital * embryology   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Review MeSH

Antidepresiva, stejně jako neléčená depresivní porucha v těhotenství, představují rizikové faktory pro průběh těhotenství, vývoj plodu a poporodní adaptaci novorozence. Tento přehled shrnuje aktuálně publikované údaje o vlivu neléčené depresivní poruchy a rizicích spojených s léčbou antidepresivy na průběh těhotenství, vývoj plodu a časnou poporodní adaptaci. Dostupné studie nenaznačují, že by většina antidepresiv měla teratogenní potenciál nebo klinicky významně zvyšovala riziko těhotenských komplikací či narušení vývoje plodu. Po expozici antidepresivům však může dojít ke zvýšení rizika poruchy poporodní adaptace novorozence, která komplikuje časnou adaptaci dítěte. Těžká neléčená depresivní porucha však představuje pro plod závažnější riziko než samotná léčba antidepresivy během těhotenství.

Antidepressants, as well as untreated depressive disorder during pregnancy, represent risk factors for the course of pregnancy, fetal development, and neonatal adaptation after birth. This review summarizes currently published data on the impact of untreated depressive disorder and the risks associated with antidepressant treatment on the course of pregnancy, fetal development, and early neonatal adaptation. Available studies do not indicate that most antidepressants have teratogenic potential or clinically significantly increase the risk of pregnancy complications or impaired fetal development. However, exposure to antidepressants may increase the risk of neonatal adaptation disorders, which complicate the early adaptation of the child. Severe untreated depressive disorder, however, poses a greater risk to the fetus than antidepressant treatment during pregnancy.

• MeSH
• Abnormalities, Drug-Induced etiology   MeSH
• Antidepressive Agents * adverse effects   therapeutic use   MeSH
• Depressive Disorder drug therapy   complications   MeSH
• Clinical Studies as Topic MeSH
• Pregnancy Complications * etiology   drug therapy   MeSH
• Humans MeSH
• Infant, Newborn MeSH
• Fetus drug effects   MeSH
• Postpartum Period drug effects   MeSH
• Risk MeSH
• Pregnancy MeSH
• Check Tag
• Humans MeSH
• Infant, Newborn MeSH
• Pregnancy MeSH
• Female MeSH
• Publication type
• Review MeSH

BACKGROUND: The European Medicines Agency has recommended a series of restrictions on the use of sodium valproate (valproate) following research linking its exposure in utero to adverse congenital and neurodevelopmental effects in offspring. Recent research has highlighted a potential increased risk of neurodevelopmental disorders in children born to males taking valproate prior to conception. Clinicians and patients require guidance regarding suitable alternatives. AIM: To provide an overview of suitable alternatives to valproate in the management of bipolar disorder. METHOD: A narrative review was conducted. Only medications with an established evidence base in managing different phases of bipolar disorder and endorsed within clinical practice guidelines were considered. Eligible guidelines included those (i) where recommendations were informed by a formal guideline development process and (ii) published in English within the last 15 years. REPROTOX® was chosen as the primary information source regarding reproductive safety of alternative medications. RESULTS: Of all second-generation antipsychotics, quetiapine should be considered a first-line alternative to valproate. Lithium has been associated with an increased risk of cardiac malformations, especially Ebstein anomaly, following in utero exposure. However, given its robust efficacy as an antimanic agent and the absolute risk of cardiac abnormalities being low, it's use can still be considered in individuals of child-bearing potential with appropriate monitoring. Carbamazepine treatment should be avoided due to concerns for teratogenicity. Although considered safe in pregnancy, lamotrigine is largely effective at preventing relapse of bipolar depression. Thus, lamotrigine offers limited clinical utility as an alternative to valproate. CONCLUSION: Specific recommendations are made regarding alternatives to valproate in managing bipolar disorder.

• MeSH
• Antimanic Agents * adverse effects   therapeutic use   MeSH
• Antipsychotic Agents * adverse effects   therapeutic use   MeSH
• Bipolar Disorder * drug therapy   MeSH
• Valproic Acid * adverse effects   therapeutic use   MeSH
• Humans MeSH
• Disease Management * MeSH
• Pregnancy MeSH
• Treatment Outcome MeSH
• Check Tag
• Humans MeSH
• Pregnancy MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Review MeSH
• Comparative Study MeSH
• Geographicals
• Europe MeSH

Ciele: Predkladaný výskum sa zaoberá identifikáciou prenatálnych faktorov vplývajúcich na abnormálny neurovývin a postnatálnu manifestáciu autistického fenotypu v súbore 107 chlapcov (priemerný vek 4,31 ± 2,24). Súbor a metódy: Biologické matky autistických chlapcov poskytli údaje týkajúce sa ich reprodukčného zdravia, infekcií počas gravidity, užívaní orálnej antikoncepcie pred počatím, prípadne užívaním návykových látok pred a počas gravidity a tiež informácie týkajúce sa novorodenca. Následne boli chlapci dia gnostikovaný na poruchy autistického spektra (PAS), pomocou dia gnostických nástrojov ADOS-2 (Autism Dia gnostic Observation Schedule) a ADI-R (Autism Dia gnostic Interview – Revised). V ADOSE-2 bol zvolený dia gnostický modul podľa rečových schopností dieťaťa, buď Modul 1 – neverbálny alebo minimálne verbálny chlapci (n = 68) a verbálni chlapci (n = 39). Výsledky: Na základe našich výsledkov, má reprodukčné zdravie matky súvisiace s dĺžkou menštruačného cyklu pred graviditou s autistickým dieťaťom, súvis s mierou rečového postihnutia (p = 0,017), taktiež počet predošlých tehotenstiev (p = 0,026). Matky neverbálnych detí uvádzali kratší cyklus (27,35 dní ± 6,60) ako matky verbálnych detí (30,14 days ± 4,44) a mali viac predošlých tehotenstiev (0,93 ± 1,07 vs. 0,51 ± 0,91). Neuviedli však počet živo narodených detí pred tehotenstvom s autistickým dieťaťom. Deti, ktoré boli neskôr dia gnostikované ako neverbálne, mali dlhší pôrod (od 2 do 48 hod; v priemere 11,13 hod, SD = 9,49), ako verbálne (od 1 do 27 hod, čo bolo v priemere 7,09 hod, SD = 8,91), p = 0,0182. Spôsob pôrodu nezohrával úlohu, ani spôsob počatia (prirodzené vs. umelé). Záver: Skúmanie prenatálnych faktorov v etiológii autizmu z hľadiska rečového vývinu sa javí ako dobrý prístup.

Objectives: The presented research aimed to identify prenatal factors involved in abnormal neurodevelopment and postnatal manifestation of an autistic phenotype in 107 boys (average age 4.31 ± 2.24 years). Materials and methods: Their biological mothers were asked to fill out a comprehensive questionnaire about their reproductive health, infections during pregnancy, oral contraceptive intake before conception, and potential substance abuse before and during pregnancy as well as delivery and newborn information. The boys were subsequently diagnosed with autism spectrum disorder (ASD) using the combination of Autism Diagnostic Observation Schedule (ADOS-2) and Autism Diagnostic Interview – Revised (ADI-R). Based on the ADOS-2 module chosen during diagnosis, boys diagnosed with Module 1 can be classified as nonverbal or minimally verbal (N = 68), while those diagnosed using Module 3 are fully verbal (N = 39). Results: According to our results, reproductive health related to the length of the menstrual cycle before pregnancy with the autistic child seems to play a role with regards to the severity of the disorder (P = 0.017) as well as the number of previous pregnancies (P = 0.026). Mothers of nonverbal children reported to have had a much shorter menstrual cycle (27.35 ± 6.60 days) than those with verbal children (30.14 ± 4.44 days) and reported more previous pregnancies (0.93 ± 1.07 vs. 0.51 ± 0.91), while not reporting the number of live births before they had the autistic child. Children who were later diagnosed as non-verbal had a longer delivery time (from 2 to 48 hours; on average 11.13 hours, SD = 9.49) than verbal ones (between 1 and 27 hours, which was on average 7.09 hours, SD = 8.91), P = 0.0182. Delivery method didn’t play a role in this context, and neither did the type of conception (natural, insemination, etc.). Conclusion: Studying the involvement of prenatal factors in the etiology of autism based on the speech of the child seems to be a promising approach.

• MeSH
• Child MeSH
• Epidemiologic Studies MeSH
• Humans MeSH
• Menstrual Cycle genetics   MeSH
• Neurodevelopmental Disorders diagnosis   etiology   classification   MeSH
• Parturition MeSH
• Autism Spectrum Disorder * diagnosis   classification   complications   MeSH
• Speech Disorders * diagnosis   etiology   classification   MeSH
• Child, Preschool MeSH
• Prenatal Injuries genetics   classification   MeSH
• Surveys and Questionnaires MeSH
• Teratogens classification   MeSH
• Check Tag
• Child MeSH
• Humans MeSH
• Male MeSH
• Child, Preschool MeSH
• Publication type
• Research Support, Non-U.S. Gov't MeSH

BACKGROUND: The thalidomide disaster resulted in tremendous congenital malformations in more than 10,000 children in the late 1950s and early 1960s. SUMMARY: Although numerous putative mechanisms were proposed to explain thalidomide teratogenicity, it was confirmed only recently that thalidomide, rather its derivative 5-hydroxythalidomide (5HT) in a complex with the cereblon protein, interferes with early embryonic transcriptional regulation. 5HT induces selective degradation of SALL4, a principal transcriptional factor of early embryogenesis. Genetic syndromes caused by pathogenic variants of the SALL4 gene phenocopy thalidomide embryopathy with congenital malformations ranging from phocomelia, reduced radial ray, to defects of the heart, kidneys, ear, eye, and possibly cerebral midline and pituitary. SALL4 interacts with TBX5 and a handful of other transcriptional regulators and downregulates the Sonic hedgehog signaling pathway. Cranial midline defects, microcephaly, and short stature due to growth hormone deficiency have been occasionally reported in children carrying SALL4 pathogenic variants associated with generalized stunting of growth rather than just the loss of height attributable to the shortening of leg bones in many children with thalidomide embryopathy. KEY MESSAGES: Thus, SALL4 joins the candidate gene list for monogenic syndromic pituitary insufficiency. In this review, we summarize the journey from the thalidomide disaster through the functions of the SALL4 gene to its link to the hormonal regulation of growth.

• MeSH
• Upper Extremity MeSH
• Humans MeSH
• Abnormalities, Multiple * chemically induced   genetics   MeSH
• Fetal Diseases * MeSH
• Hedgehog Proteins MeSH
• Thalidomide * adverse effects   MeSH
• Transcription Factors * genetics   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Review MeSH

Hyperthermia along with hydrocortisone (HC) are proven teratogens that can negatively influence embryo development during early pregnancy. Proliferation of cells is one of the main developmental processes during the early embryogenesis. This study was focused on testing the effect of elevated temperature and HC addition on proliferation of cells in in vitro cultures. The V79-4 cell line was treated with HC and cultured in vitro at 37 °C or 39 °C, respectively. To reveal the effect of both factors, the proliferation of cells cultured under different conditions was evaluated using various approaches (colony formation assay, generation of growth curves, computation of doubling times, and mitotic index estimation). Our results indicate that a short-term exposure to elevated temperature slightly stimulates and a long-term exposure suppresses cell proliferation. However, HC (0.1 mg/ml) acts as a stimulator of cell proliferation. Interestingly, the interaction of HC and long-term elevated temperature (39 °C) exposure results in at least partial compensation of the negative impact of elevated temperature by HC addition and in higher proliferation if compared with cells cultured at 39 °C without addition of HC.

• MeSH
• Cricetulus MeSH
• Fibroblasts * drug effects   cytology   metabolism   MeSH
• Hydrocortisone * pharmacology   MeSH
• Cells, Cultured MeSH
• Cell Proliferation * drug effects   MeSH
• Temperature MeSH
• Hot Temperature MeSH
• Animals MeSH
• Check Tag
• Animals MeSH
• Publication type
• Journal Article MeSH

INTRODUCTION: Maternal diabetes is a recognized risk factor for both short-term and long-term complications in offspring. Beyond the direct teratogenicity of maternal diabetes, the intrauterine environment can influence the offspring's cardiovascular health. Abnormalities in the cardiac sympathetic system are implicated in conditions such as sudden infant death syndrome, cardiac arrhythmic death, heart failure, and certain congenital heart defects in children from diabetic pregnancies. However, the mechanisms by which maternal diabetes affects the development of the cardiac sympathetic system and, consequently, heightens health risks and predisposes to cardiovascular disease remain poorly understood. METHODS AND RESULTS: In the mouse model, we performed a comprehensive analysis of the combined impact of a Hif1a-deficient sympathetic system and the maternal diabetes environment on both heart development and the formation of the cardiac sympathetic system. The synergic negative effect of exposure to maternal diabetes and Hif1a deficiency resulted in the most pronounced deficit in cardiac sympathetic innervation and the development of the adrenal medulla. Abnormalities in the cardiac sympathetic system were accompanied by a smaller heart, reduced ventricular wall thickness, and dilated subepicardial veins and coronary arteries in the myocardium, along with anomalies in the branching and connections of the main coronary arteries. Transcriptional profiling by RNA sequencing (RNA-seq) revealed significant transcriptome changes in Hif1a-deficient sympathetic neurons, primarily associated with cell cycle regulation, proliferation, and mitosis, explaining the shrinkage of the sympathetic neuron population. DISCUSSION: Our data demonstrate that a failure to adequately activate the HIF-1α regulatory pathway, particularly in the context of maternal diabetes, may contribute to abnormalities in the cardiac sympathetic system. In conclusion, our findings indicate that the interplay between deficiencies in the cardiac sympathetic system and subtle structural alternations in the vasculature, microvasculature, and myocardium during heart development not only increases the risk of cardiovascular disease but also diminishes the adaptability to the stress associated with the transition to extrauterine life, thus increasing the risk of neonatal death.

• MeSH
• Child MeSH
• Hypoxia-Inducible Factor 1, alpha Subunit metabolism   MeSH
• Diabetes, Gestational * metabolism   MeSH
• Cardiovascular Diseases * metabolism   MeSH
• Humans MeSH
• Myocardium metabolism   MeSH
• Mice MeSH
• Infant, Newborn MeSH
• Heart MeSH
• Heart Failure * MeSH
• Pregnancy MeSH
• Animals MeSH
• Check Tag
• Child MeSH
• Humans MeSH
• Mice MeSH
• Infant, Newborn MeSH
• Pregnancy MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH

BACKGROUND: Malaria in the first trimester of pregnancy is associated with adverse pregnancy outcomes. Artemisinin-based combination therapies (ACTs) are a highly effective, first-line treatment for uncomplicated Plasmodium falciparum malaria, except in the first trimester of pregnancy, when quinine with clindamycin is recommended due to concerns about the potential embryotoxicity of artemisinins. We compared adverse pregnancy outcomes after artemisinin-based treatment (ABT) versus non-ABTs in the first trimester of pregnancy. METHODS: For this systematic review and individual patient data (IPD) meta-analysis, we searched MEDLINE, Embase, and the Malaria in Pregnancy Library for prospective cohort studies published between Nov 1, 2015, and Dec 21, 2021, containing data on outcomes of pregnancies exposed to ABT and non-ABT in the first trimester. The results of this search were added to those of a previous systematic review that included publications published up until November, 2015. We included pregnancies enrolled before the pregnancy outcome was known. We excluded pregnancies with missing estimated gestational age or exposure information, multiple gestation pregnancies, and if the fetus was confirmed to be unviable before antimalarial treatment. The primary endpoint was adverse pregnancy outcome, defined as a composite of either miscarriage, stillbirth, or major congenital anomalies. A one-stage IPD meta-analysis was done by use of shared-frailty Cox models. This study is registered with PROSPERO, number CRD42015032371. FINDINGS: We identified seven eligible studies that included 12 cohorts. All 12 cohorts contributed IPD, including 34 178 pregnancies, 737 with confirmed first-trimester exposure to ABTs and 1076 with confirmed first-trimester exposure to non-ABTs. Adverse pregnancy outcomes occurred in 42 (5·7%) of 736 ABT-exposed pregnancies compared with 96 (8·9%) of 1074 non-ABT-exposed pregnancies in the first trimester (adjusted hazard ratio [aHR] 0·71, 95% CI 0·49-1·03). Similar results were seen for the individual components of miscarriage (aHR=0·74, 0·47-1·17), stillbirth (aHR=0·71, 0·32-1·57), and major congenital anomalies (aHR=0·60, 0·13-2·87). The risk of adverse pregnancy outcomes was lower with artemether-lumefantrine than with oral quinine in the first trimester of pregnancy (25 [4·8%] of 524 vs 84 [9·2%] of 915; aHR 0·58, 0·36-0·92). INTERPRETATION: We found no evidence of embryotoxicity or teratogenicity based on the risk of miscarriage, stillbirth, or major congenital anomalies associated with ABT during the first trimester of pregnancy. Given that treatment with artemether-lumefantrine was associated with fewer adverse pregnancy outcomes than quinine, and because of the known superior tolerability and antimalarial effectiveness of ACTs, artemether-lumefantrine should be considered the preferred treatment for uncomplicated P falciparum malaria in the first trimester. If artemether-lumefantrine is unavailable, other ACTs (except artesunate-sulfadoxine-pyrimethamine) should be preferred to quinine. Continued active pharmacovigilance is warranted. FUNDING: Medicines for Malaria Venture, WHO, and the Worldwide Antimalarial Resistance Network funded by the Bill & Melinda Gates Foundation.

• MeSH
• Antimalarials * adverse effects   MeSH
• Artemether therapeutic use   MeSH
• Quinine adverse effects   MeSH
• Ethanolamines therapeutic use   MeSH
• Drug Combinations MeSH
• Artemether, Lumefantrine Drug Combination therapeutic use   MeSH
• Humans MeSH
• Malaria * drug therapy   MeSH
• Stillbirth epidemiology   MeSH
• Prospective Studies MeSH
• Pregnancy Trimester, First MeSH
• Abortion, Spontaneous * MeSH
• Pregnancy MeSH
• Malaria, Falciparum * drug therapy   MeSH
• Pregnancy Outcome MeSH
• Check Tag
• Humans MeSH
• Pregnancy MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Meta-Analysis MeSH
• Research Support, Non-U.S. Gov't MeSH
• Systematic Review MeSH

• MeSH
• Genetics, Medical MeSH

• Conspectus
• Obecná genetika. Obecná cytogenetika. Evoluce
• Učební osnovy. Vyučovací předměty. Učebnice
• NML Fields
• genetika, lékařská genetika
• NML Publication type
• učebnice vysokých škol
• kolektivní monografie

• MeSH
• Genetic Diseases, Inborn MeSH
• Humans MeSH
• Infant, Newborn MeSH
• Risk Factors MeSH
• Cleft Palate * epidemiology   etiology   genetics   MeSH
• Cleft Lip * epidemiology   etiology   genetics   MeSH
• Teratogens MeSH
• Check Tag
• Humans MeSH
• Infant, Newborn MeSH
• Publication type
• Interview MeSH