Souhrn: Souhrnný článek o předčasném porodu jako nezávislém rizikovém faktoru rozvoje duševního onemocnění matky. Metodika: Přehled publikované literatury k danému tématu použitím databáze PubMed. Výsledky: Perinatální duševní zdraví ovlivňuje zásadně život matky a vývoj dítěte, a proto jde v širší souvislosti o celospolečenskou problematiku. Samostatnou vysoce rizikovou skupinou, kde lze očekávat deterioraci psychického stavu, jsou ženy, kterým se narodí nezralý novorozenec <32+0 týden těhotenství Very Low Birth Weight (VLBW) a <28+0 týden těhotenství Extremely Low Birth Weight (ELBW). Závěr: Mezi nejčastější duševní poruchy tohoto období patří poporodní deprese (PPD) a úzkostná porucha (AD). Cílem je shrnout současné poznatky o vzájemném působení předčasného porodu a rozvoje psychických poruch a zdůraznit návaznost perinatální a duševní péče.

ntroduction and Objective: Folate (vitamin B9) supplementation during pregnancy to prevent neural tube defects (NTDs) in the fetus is a widely accepted standard of care. Folate is also vital for maintaining proper brain function. Additionally, folic acid works in conjunction with vitamin B12 ro produce red blood cells and aids in the proper functioning of iron in the body. The most effective form of folate supplementation remains a topic of ongoing discussion. This review aims to collect information on the effects of folic acid and its derivatives on reproductive health. Review and Methods: Review and summary of available studies found in open-access formats on Google Scholar and PubMed. State of Knowledge: Folic acid is well-established as a preventive measure against NTDs during pregnancy. However, the debate persists over the most effective form of folate supplementation, with a focus on addressing individual genetic variations and specific health needs. Individuals with MTHFR gene variants, which can impair the conversion of folic acid to its active form, 5-MTHF, may experience greater benefits from direct 5-MTHF supplementation rather than traditional folic acid. Studies aim to optimize supplementation strategies, ensuring that they are tailored to enhance efficacy and improve health outcomes for diverse populations. Conclusions: Folic acid is essential for fetal development and overall health. MTHFR polymorphisms can hinder folate metabolism, raising deficiency risk. In such cases, 5-MTHF supplementation is recommended over folic acid for better absorption and lower cardiovascular risks. Ongoing research is vital for optimizing folate-related health.

AIM: The aim of this study was to investigate the association of serum total Hcy (tHcy) levels with various demographic, clinical and genetic characteristics in healthy Greek adults. METHODS: Anthropometric characteristics (height, weight), systolic and diastolic blood pressure, complete blood count and biochemical assessments, were recorded and measured among 383 Greek adults (199 men). Serum folate, Cobalamin (Cbl) and tHcy levels were determined using immunoassays methods. The MTHFR C677T and A1298C gene polymorphisms were genotyped using polymerase chain reaction and reverse hybridization. RESULTS: MTHFR C677T gene polymorphism, serum folate and Cbl levels were correlated with serum tHcy levels independently. The individuals with 677TT genotype had significantly higher serum tHcy levels than individuals with 677 CC or CT genotypes. Regarding the MTHFR C677T gene polymorphism, the existence of the T allele was associated with statistically significantly lower serum folate and higher serum tHcy levels than C allele. Regarding the MTHFR A1298C gene polymorphism, the existence of the C allele was associated with statistically significant lower serum tHcy levels than A allele. Furthermore, there was no significant correlation between the serum tHcy levels and demographic (except age) or clinical characteristics (sex, BMI, smoking status, SBP, DBP, HGB, HCT, TC, TG, HDL-C, LDL-C, TC/HDL-C). CONCLUSIONS: Serum tHcy levels are influenced by the existence of MTHFR C677T gene polymorphism (mainly 677TT genotype), serum folate and Cbl levels. Individuals with hyperhomocysteinemia should be further investigated for the existence of MTHFR C677T gene polymorphism, with the aim to determine the suitable treatment.

• MeSH
• Demography MeSH
• Adult MeSH
• Genotype MeSH
• Homocysteine genetics   MeSH
• Folic Acid * MeSH
• Humans MeSH
• Methylenetetrahydrofolate Reductase (NADPH2) genetics   MeSH
• Polymorphism, Genetic * MeSH
• Check Tag
• Adult MeSH
• Humans MeSH
• Male MeSH
• Publication type
• Journal Article MeSH
• Geographicals
• Greece MeSH

BACKGROUND: Because betaine (BET) supplementation may improve muscular strength and endurance, it seems plausible that BET will also influence CrossFit performance (CF). PURPOSE: The aim of this study was to evaluate the effects of three weeks of BET supplementation on body composition, CF performance, muscle power in the Wingate anaerobic test (WAnT), and the concentrations of selected hormones. The secondary aims were to analyze the effectiveness of two different BET doses (2.5 and 5.0 g/d) and their interaction with the methylenetetrahydrofolate reductase (MTHFR) genotype. METHODS: The study was designed in a double-blinded randomized cross-over fashion. Forty-three CF practitioners completed the entire study. CF performance was measured using the Fight Gone Bad (FGB) workout and muscle power was evaluated in a 30-second WAnT. Body composition was determined by air-displacement plethysmography. Blood was drawn to assess hormone concentrations. The C677T single nucleotide polymorphism (rs180113) in the MTHFR gene was analyzed. RESULTS: FGB total improved with BET by 8.7 ± 13.6% (p < 0.001), but no significant changes were observed with placebo (- 0.4 ± 10.0%, p = 0.128). No changes were also observed in WAnT and body composition. After BET supplementation testosterone concentration increased by 7.0 ± 15.4% with BET (p = 0.046) (no change with placebo: 1.5 ± 19.6%, p = 0.884) but had no effect on concentrations of insulin-like growth factor or cortisol. Finally, there were no significant interactions between MTHFR genotype and BET dose in any outcome. CONCLUSIONS: BET supplementation may improve CF performance and increase testosterone concentration. However, there was no evidence of a difference between dosages (2.5 and 5.0 g/d) and MTHFR genotypes. The trial was registered on clinicaltrials.gov (NCT03702205) on 10 October 2018.

• MeSH
• Betaine * pharmacology   MeSH
• Double-Blind Method MeSH
• Cross-Over Studies MeSH
• Humans MeSH
• Dietary Supplements MeSH
• Testosterone * MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Randomized Controlled Trial MeSH

Pregnancy-related complications (PRC) re-present a serious public health and healthcare challenge. In European countries, infertility among couples varies from 5 to 24 %. The cause of PRC may include autoimmune and metabolic factors, correctness of the karyotype and variants of selected genes. The impact magnitude of genetic variants in one of PRC, pregnancy loss (PL), is still unexplored. Therefore, in this study, raw data on 12 single-nucleotide polymorphisms (SNPs) that were published separately in 2017-2019 were re-examined. We analysed the co-inheritance of 12 SNPs: rs6025 FV, rs429358 and rs7412 ApoE, rs1799752 ACE, rs1799889 PAI-1, rs1799963 PT, rs1801133 MTHFR, rs9468 and rs1800547 INV 17q21.31, rs731236 and rs1544410 VDR, and rs10421768 HAMP. Each time, the same study group of 154 women with PL, mean age 33 (± 5.4) years, and 154 mothers without PL, mean age 31.4 (± 6.7) years, with at least one live-born child, a control group, was investigated. In Bosnian women, no relationship of the co-inheritance pattern of any of the studied variants with PL was confirmed: P was in the range 0.248-1.0. In conclusion, the role of co-inheritance of heterozygotes and homozygotes or homozygotes of selected genes in PL has not been fully confirmed.

• MeSH
• Child MeSH
• Adult MeSH
• Genetic Predisposition to Disease MeSH
• Genotype MeSH
• Homozygote MeSH
• Polymorphism, Single Nucleotide genetics   MeSH
• Humans MeSH
• Risk Factors MeSH
• Abortion, Spontaneous * genetics   MeSH
• Case-Control Studies MeSH
• Pregnancy MeSH
• Check Tag
• Child MeSH
• Adult MeSH
• Humans MeSH
• Pregnancy MeSH
• Female MeSH
• Publication type
• Journal Article MeSH

Betaine (BET) supplementation decreases homocysteine concentration in plasma, but it may also have an adverse effect on health by increasing blood lipid concentrations, at least in overweight and obese individuals. The aim of this study was to evaluate the effect of BET supplementation on the lipid profile and concentrations of homocysteine, inflammatory cytokines, and liver enzymes in physically active, healthy males. This was a randomized, placebo (PL)-controlled, double-blinded, crossover trial. BET (2.5 or 5.0 g/d) was administered for 21 days. Before and after supplementation with BET or PL, anthropometric measurements and blood were collected in a fasted state. Our results show that BET supplementation significantly decreased homocysteine concentration (from 17.1 ± 4.0 μmol/L before BET to 15.6 ± 3.5 μmol/L after BET, p = 0.009, η2 = 0.164). However, the intervention had no effect on total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triacylglycerol, interleukins 1β and 6, and tumour necrosis factor α concentrations, or alanine and aspartate activities. In addition, there were no interactions between the MTHFR genotype and BET dose. In conclusion, BET supplementation may be beneficial for homocysteine concentration in healthy, physically active males, with no detrimental effect on lipid profile.

• Publication type
• Journal Article MeSH

MTHFR deficiency is a severe inborn error of metabolism leading to impairment of the remethylation of homocysteine to methionine. Neonatal and early-onset patients mostly exhibit a life-threatening acute neurologic deterioration. Furthermore, data on early-onset patients' long-term outcomes are scarce. The aims of this study were (1) to study and describe the clinical and laboratory parameters of early-onset MTHFR-deficient patients (i.e., ≤3 months of age) and (2) to identify predictive factors for severe neurodevelopmental outcomes in a cohort with early and late onset MTHFR-deficient patients. To this end, we conducted a retrospective, multicentric, international cohort study on 72 patients with MTHFR deficiency from 32 international metabolic centres. Characteristics of the 32 patients with early-onset MTHFR deficiency were described at time of diagnosis and at the last follow-up visit. Logistic regression analysis was used to identify predictive factors of severe neurodevelopmental outcome in a broader set of patients with early and non-early-onset MTHFR deficiency. The majority of early-onset MTHFR-deficient patients (n = 32) exhibited neurologic symptoms (76%) and feeding difficulties (70%) at time of diagnosis. At the last follow-up visit (median follow-up time of 8.1 years), 76% of treated early-onset patients (n = 29) exhibited a severe neurodevelopmental outcome. Among the whole study population of 64 patients, pre-symptomatic diagnosis was independently associated with a significantly better neurodevelopmental outcome (adjusted OR 0.004, [0.002-0.232]; p = 0.003). This study provides evidence for benefits of pre-symptomatic diagnosis and appropriate therapeutic management, highlighting the need for systematic newborn screening for MTHFR deficiency and pre-symptomatic treatment that may improve outcome.

• MeSH
• Homocysteine MeSH
• Homocystinuria * diagnosis   drug therapy   MeSH
• Cohort Studies MeSH
• Humans MeSH
• Methylenetetrahydrofolate Reductase (NADPH2) deficiency   genetics   MeSH
• Infant, Newborn MeSH
• Psychotic Disorders MeSH
• Retrospective Studies MeSH
• Muscle Spasticity diagnosis   MeSH
• Check Tag
• Humans MeSH
• Infant, Newborn MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

Introduction: Autologous cell therapy (ACT) is one of the last options for limb salvage in patients with chronic limb-threatening ischemia (CLTI) and diabetic foot ulcers (DFU). However, some patients may still undergo a major amputation even after ACT, but the risk factors for this are not known. Therefore, the aim of our study was to assess the risk factors for major amputation in patients with CLTI and DFU during a 2-year follow-up after ACT. Methods: One hundred and thirteen patients after ACT were included in our study and divided into two groups: Group 1 with major amputation (AMP; n = 37) and Group 2 without amputation (nAMP, n = 76). The risk factors for major amputation were evaluated before ACT and included factors relating to the patient, the DFU, and the cell product. Results: The AMP group had significantly higher C-reactive protein (CRP) levels compared to the nAMP group (22.7 vs. 10.7 mg/L, p = 0.024). In stepwise logistic regression, independent predictors for major amputation were mutation of the gene for methylenetetrahydrofolate reductase (MTHFR) with heterozygote and homozygote polymorphism 1298 (OR 4.33 [95% CI 1.05-17.6]), smoking (OR 3.83 [95% CI 1.18-12.5]), and CRP > 10 mg/L (OR 2.76 [95% CI 0.93-8.21]). Lower transcutaneous oxygen pressure (TcPO2) values were observed in AMP patients compared to the nAMP group at one month (24.5 vs. 33.2, p = 0.012) and at 3 months (31.1 vs. 40.9, p = 0.009) after ACT. Conclusion: Our study showed that the risk for major amputation after ACT in patients with CLTI and DFU is increased by the presence of MTHFR heterozygote and homozygote gene mutations, smoking, and higher CRP at baseline. Lower TcPO2 at one and 3 months after ACT may also have a predictive value. Therefore, it is necessary to stop smoking before ACT, treat any infection, and, above all, consider antiaggregation or anticoagulant treatment after the procedure.

• MeSH
• Adenosine Monophosphate MeSH
• Amputation, Surgical MeSH
• Cell- and Tissue-Based Therapy MeSH
• Chronic Limb-Threatening Ischemia MeSH
• Diabetes Mellitus * MeSH
• Diabetic Foot * surgery   MeSH
• Wound Healing MeSH
• Ischemia surgery   MeSH
• Humans MeSH
• Retrospective Studies MeSH
• Risk Factors MeSH
• Treatment Outcome MeSH
• Limb Salvage MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH

Patient registries for rare diseases enable systematic data collection and can also be used to facilitate postauthorization safety studies (PASS) for orphan drugs. This study evaluates the PASS for betaine anhydrous (Cystadane), conducted as public private partnership (PPP) between the European network and registry for homocystinurias and methylation defects and the marketing authorization holder (MAH). Data were prospectively collected, 2013-2016, in a noninterventional, international, multicenter, registry study. Putative adverse and severe adverse events were reported to the MAH's pharmacovigilance. In total, 130 individuals with vitamin B6 nonresponsive (N = 54) and partially responsive (N = 7) cystathionine beta-synthase (CBS) deficiency, as well as 5,10-methylenetetrahydrofolate reductase (MTHFR; N = 21) deficiency and cobalamin C (N = 48) disease were included. Median (range) duration of treatment with betaine anhydrous was 6.8 (0-9.8) years. The prescribed betaine dose exceeded the recommended maximum (6 g/day) in 49% of individuals older than 10 years because of continued dose adaptation to weight; however, with disease-specific differences (minimum: 31% in B6 nonresponsive CBS deficiency, maximum: 67% in MTHFR deficiency). Despite dose escalation no new or potential risk was identified. Combined disease-specific treatment decreased mean ± SD total plasma homocysteine concentrations from 203 ± 116 to 81 ± 51 μmol/L (p < 0.0001), except in MTHFR deficiency. Recommendations for betaine anhydrous dosage were revised for individuals ≥ 10 years. PPPs between MAH and international scientific consortia can be considered a reliable model for implementing a PASS, reutilizing well-established structures and avoiding data duplication and fragmentation.

• MeSH
• Betaine adverse effects   MeSH
• Cystathionine beta-Synthase MeSH
• Homocysteine MeSH
• Homocystinuria * drug therapy   MeSH
• Humans MeSH
• Methylenetetrahydrofolate Reductase (NADPH2) deficiency   genetics   MeSH
• Psychotic Disorders * MeSH
• Muscle Spasticity MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Multicenter Study MeSH
• Research Support, Non-U.S. Gov't MeSH

5,10-Methylenetetrahydrofolate reductase (MTHFR) deficiency usually presents as a severe neonatal disease. This study aimed to characterize natural history, biological and molecular data, and response to treatment of patients with late-onset MTHFR deficiency. The patients were identified through the European Network and Registry for Homocystinuria and Methylation Defects and the Adult group of the French Society for Inherited Metabolic Diseases; data were retrospectively colleted. To identify juvenile to adult-onset forms of the disease, we included patients with a diagnosis established after the age of 10 years. We included 14 patients (median age at diagnosis: 32 years; range: 11-54). At onset (median age: 20 years; range 9-38), they presented with walking difficulties (n = 8), cognitive decline (n = 3) and/or seizures (n = 3), sometimes associated with mild mental retardation (n = 6). During the disease course, symptoms were almost exclusively neurological with cognitive dysfunction (93%), gait disorders (86%), epilepsy (71%), psychiatric symptoms (57%), polyneuropathy (43%), and visual deficit (43%). Mean diagnostic delay was 14 years. Vascular events were observed in 28% and obesity in 36% of the patients. One patient remained asymptomatic at the age of 55 years. Upon treatment, median total homocysteine decreased (from 183 μmol/L, range 69-266, to 90 μmol/L, range 20-142) and symptoms improved (n = 9) or stabilized (n = 4). Missense pathogenic variants in the C-terminal regulatory domain of the protein were over-represented compared to early-onset cases. Residual MTHFR enzymatic activity in skin fibroblasts (n = 4) was rather high (17%-58%). This series of patients with late-onset MTHFR deficiency underlines the still unmet need of a prompt diagnosis of this treatable disease.

• MeSH
• Child MeSH
• Adult MeSH
• Epilepsy diagnosis   pathology   MeSH
• Homocystinuria diagnosis   pathology   MeSH
• Middle Aged MeSH
• Humans MeSH
• Intellectual Disability diagnosis   pathology   MeSH
• Methylenetetrahydrofolate Reductase (NADPH2) deficiency   MeSH
• Adolescent MeSH
• Young Adult MeSH
• Delayed Diagnosis MeSH
• Psychotic Disorders diagnosis   pathology   MeSH
• Retrospective Studies MeSH
• Muscle Spasticity diagnosis   pathology   MeSH
• Age of Onset MeSH
• Seizures diagnosis   pathology   MeSH
• Check Tag
• Child MeSH
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Adolescent MeSH
• Young Adult MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Case Reports MeSH
• Research Support, Non-U.S. Gov't MeSH

INTRODUCTION: Inherited thrombophilias represent a concerning risk factor due to a proclivity to an aberrant clot formation. However, in patients with left ventricular assist device (LVAD), their impact on bleeding and thrombotic complications remains still poorly understood. The aim of the present study was to evaluate the effect of thrombophilic mutation directed anticoagulation therapy on adverse clinical outcomes in LVAD patients. MATERIALS AND METHODS: About 138 consecutive patients indicated for LVAD implant (HeartMate II, Abbott, Plymouth, USA) were prospectively screened for three major thrombophilic mutations: factor II (prothrombin), factor V Leiden, and homozygous methylenetetrahydrofolate reductase (MTHFR). Subsequently, discordant individualized anticoagulation targets of INR 2.5-3.0 in thrombophilia positive and INR 1.8-2.2 in negative patients were established; notably without anti-platelet agents given the center standard of care. RESULTS: Mean age was 50 ± 12.7 years, 83% male. Mean duration of support was 464.5 days (SD 482.9; SEM 41.1) and median of 310 days (IQR 162; 546). Full thrombophilia positive cohort analysis has not revealed any significant impact on event free survival. In contrast, detailed analysis of specific thrombophilias subsets has revealed Factor II prothrombin mutation as a significant predisposition for the pump thrombosis risk (SHR 10.48; p = 0.001) despite more aggressive prespecified anticoagulation target. Moreover, the incidence of bleeding events in prothrombin group was also significantly increased (SHR 6.0; p = 0.03). CONCLUSIONS: Our observations suggest that specific thrombophilias in LVAD patients may pose different intensity predisposition for thrombotic complications. Factor II (prothrombin) positive mutation was identified as significant risk factor associated with the pump thrombosis.

• MeSH
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Heart-Assist Devices * adverse effects   MeSH
• Prospective Studies MeSH
• Prothrombin MeSH
• Thrombophilia * diagnosis   genetics   MeSH
• Thrombosis * genetics   MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH