Sustained meningeal lymphatic vessel atrophy or expansion does not alter Alzheimer's disease-related amyloid pathology.

Discovery of meningeal lymphatic vessels (LVs) in the dura mater, also known as dural LVs (dLVs) that depend on vascular endothelial growth factor C expression, has raised interest in their possible involvement in Alzheimer's disease (AD). Here we find that in the APdE9 and 5xFAD mouse models of AD, dural amyloid-β (Aβ) is confined to blood vessels and dLV morphology or function is not altered. The induction of sustained dLV atrophy or hyperplasia in the AD mice by blocking or overexpressing vascular endothelial growth factor C, impaired or improved, respectively, macromolecular cerebrospinal fluid (CSF) drainage to cervical lymph nodes.

Population-specific validation and comparison of the performance of 77- and 313-variant polygenic risk scores for breast cancer risk prediction.

Background: The polygenic risk score (PRS) allows the quantification of the polygenic effect of many low-penetrance alleles on the risk of breast cancer (BC). This study aimed to evaluate the performance of two sets comprising 77 or 313 low-penetrance loci (PRS77 and PRS313) in patients with BC in the Czech population.

Methods: In a retrospective case-control study, variants were genotyped from both the PRS77 and PRS313 sets in 1329 patients with BC and 1324 noncancer controls, all women without germline pathogenic variants in BC predisposition genes.

A deep intronic recurrent CHEK2 variant c.1009-118_1009-87delinsC affects pre-mRNA splicing and contributes to hereditary breast cancer predisposition.

Germline CHEK2 pathogenic variants confer an increased risk of female breast cancer (FBC). Here we describe a recurrent germline intronic variant c.1009-118_1009-87delinsC, which showed a splice acceptor shift in RNA analysis, introducing a premature stop codon (p.

Long-Term Evaluation of Biomarkers in the Czech Cohort of Gaucher Patients.

A personalized treatment decision for Gaucher disease (GD) patients should be based on relevant markers that are specific to GD, play a direct role in GD pathophysiology, exhibit low genetic variation, reflect the therapy, and can be used for all patients. Thirty-four GD patients treated with enzyme replacement therapy (ERT) or substrate reduction therapy (SRT) were analyzed for platelet count, chitotriosidase, and tartrate-resistant acid phosphatase activity in plasma samples, and quantitative measurement of Lyso-Gb1 was performed in dried blood spots. In our ERT and SRT study cohorts, plasma lyso-GL1 correlated significantly with chito-triosidase (ERT: r = 0.

Pitfalls of X-chromosome inactivation testing in females with Fabry disease.

Fabry disease (FD) is an X-linked lysosomal storage disorder caused by mutations in the GLA gene encoding alpha-galactosidase A (AGAL). The impact of X-chromosome inactivation (XCI) on the phenotype of female FD patients remains unclear. In this study we aimed to determine pitfalls of XCI testing in a cohort of 35 female FD patients.

Light sedation with short habituation time for large-scale functional magnetic resonance imaging studies in rats.

Traditionally, preclinical resting state functional magnetic resonance imaging (fMRI) studies have been performed in anesthetized animals. Nevertheless, as anesthesia affects the functional connectivity (FC) in the brain, there has been a growing interest in imaging in the awake state. Obviously, awake imaging requires resource- and time-consuming habituation prior to data acquisition to reduce the stress and motion of the animals.

Clinical and Genetic Study of X-Linked Juvenile Retinoschisis in the Czech Population.

The aim of this study was to identify pathogenic variants in Czech patients with X-linked retinoschisis (XLRS) and to describe the associated phenotypes, including natural history, in some cases. Twenty-one affected males from 17 families were included. The coding region of was directly sequenced and segregation of the identified mutations was performed in available family members.

X-linked adrenoleukodystrophy: phenotype-genotype correlation in hemizygous males and heterozygous females with ABCD1 mutations.

Objectives: X-linked adrenoleukodystrophy (X-ALD) causes cerebral adrenoleukodystrophy (cALD), myelopathy and/or adrenal insufficiency in males, and myelopathy/peripheral neuropathy in females. These distinct phenotypes are scarcely linked to a specific mutations. The objective herein was to find a link between the phenotype with the genotype mutation, serum very long-chain fatty acids (VLCFA), and the diet with Lorenzo´s and GTO oils in hemizygous males and heterozygous females.

Substantially Altered Expression Profile of Diabetes/Cardiovascular/Cerebrovascular Disease Associated microRNAs in Children Descending from Pregnancy Complicated by Gestational Diabetes Mellitus-One of Several Possible Reasons for an Increased Cardiovascular Risk.

Gestational diabetes mellitus (GDM), one of the major pregnancy-related complications, characterized as a transitory form of diabetes induced by insulin resistance accompanied by a low/absent pancreatic beta-cell compensatory adaptation to the increased insulin demand, causes the acute, long-term, and transgenerational health complications. The aim of the study was to assess if alterations in gene expression of microRNAs associated with diabetes/cardiovascular/cerebrovascular diseases are present in whole peripheral blood of children aged 3-11 years descending from GDM complicated pregnancies. A substantially altered microRNA expression profile was found in children descending from GDM complicated pregnancies.

Pigmentary retinopathy can indicate the presence of pathogenic LAMP2 variants even in somatic mosaic carriers with no additional signs of Danon disease.

Purpose: Danon disease (DD) is a rare X-linked disorder caused by pathogenic variants in LAMP2. DD primarily manifests as a severe cardiomyopathy. An early diagnosis is crucial for patient survival.

Transcript, protein, metabolite and cellular studies in skin fibroblasts demonstrate variable pathogenic impacts of NPC1 mutations.

Background: Niemann-Pick type C (NP-C) is a rare neurovisceral genetic disorder caused by mutations in the NPC1 or the NPC2 gene. NPC1 is a multipass-transmembrane protein essential for egress of cholesterol from late endosomes/lysosomes. To evaluate impacts of NPC1 mutations, we examined fibroblast cultures from 26 NP-C1 patients with clinical phenotypes ranging from infantile to adult neurologic onset forms.

Diabetes Mellitus and Cardiovascular Risk Assessment in Mothers with a History of Gestational Diabetes Mellitus Based on Postpartal Expression Profile of MicroRNAs Associated with Diabetes Mellitus and Cardiovascular and Cerebrovascular Diseases.

Mothers with a history of gestational diabetes mellitus (GDM) have an increased risk of developing diabetes in the future and a lifelong cardiovascular risk. Postpartal expression profile of cardiovascular/cerebrovascular disease associated microRNAs was assessed 3-11 years after the delivery in whole peripheral blood of young and middle-aged mothers with a prior exposure to GDM with the aim to identify a high-risk group of mothers at risk of later development of diabetes mellitus and cardiovascular/cerebrovascular diseases who would benefit from implementation of early primary prevention strategies and long-term follow-up. The hypothesis of the assessment of cardiovascular risk in women was based on the knowledge that a series of microRNAs play a role in the pathogenesis of diabetes mellitus and cardiovascular/cerebrovascular diseases.

Evaluation of Vascular Endothelial Function in Young and Middle-Aged Women with Respect to a History of Pregnancy, Pregnancy-Related Complications, Classical Cardiovascular Risk Factors, and Epigenetics.

The aim of the study was to examine the effect of previous pregnancies and classical cardiovascular risk factors on vascular endothelial function in a group of 264 young and middle-aged women 3 to 11 years postpartum. We examined microvascular functions by peripheral arterial tonometry and EndoPAT 2000 device with respect to a history of gestational hypertension, preeclampsia, fetal growth restriction, the severity of the disease with regard to the degree of clinical signs and delivery date. Besides, we compared Reactive Hyperemia Index (RHI) values and the prevalence of vascular endothelial dysfunction among the groups of women with normal and abnormal values of BMI, waist circumference, systolic and diastolic blood pressures, heart rate, total serum cholesterol levels, serum high-density lipoprotein cholesterol levels, serum low-density lipoprotein cholesterol levels, serum triglycerides levels, serum lipoprotein A levels, serum C-reactive protein levels, serum uric acid levels, and plasma homocysteine levels.

Alu-mediated Xq24 deletion encompassing CUL4B, LAMP2, ATP1B4, TMEM255A, and ZBTB33 genes causes Danon disease in a female patient.

Cullin 4B (CUL4B), lysosomal-associated membrane protein Type 2 (LAMP2), ATP1B4, TMEM255A, and ZBTB33 are neighboring genes on Xq24. Mutations in CUL4B result in Cabezas syndrome (CS). Male CS patients present with dysmorphic, neuropsychiatric, genitourinary, and endocrine abnormalities.

Postpartum profiling of microRNAs involved in pathogenesis of cardiovascular/cerebrovascular diseases in women exposed to pregnancy-related complications.

Background And Methods: Gestational hypertension (GH), preeclampsia (PE) and fetal growth restriction (FGR) may predispose to later onset of cardiovascular/cerebrovascular diseases. We examined if pregnancy complications induce postpartum alterations in gene expression of cardiovascular/cerebrovascular disease associated microRNAs. 29 microRNAs were tested in peripheral blood of women, compared between groups with a history of GH, PE, FGR and controls, and correlated with the severity of the disease regarding clinical signs, delivery date, and Doppler parameters.

Maternal Cardiovascular Risk Assessment 3-to-11 Years Postpartum in Relation to Previous Occurrence of Pregnancy-Related Complications.

The aim of the present study was to assess the long-term outcomes of women 3-to-11 years postpartum in relation to the previous occurrence of pregnancy-related complications such as gestational hypertension (GH), preeclampsia (PE) and fetal growth restriction (FGR). Body mass index (BMI), waist circumference values, the average values of systolic (SBP) and diastolic (DBP) blood pressures and heart rate, total serum cholesterol levels, serum HDL (high-density lipoprotein) cholesterol levels, serum LDL (low-density lipoprotein) cholesterol levels, serum triglycerides levels, serum lipoprotein A levels, serum CRP (C-reactive protein) levels, plasma homocysteine levels, serum uric acid levels, individual and relative risks of having a heart attack or stroke over the next ten years were compared between groups (50 GH, 102 PE, 34 FGR and 90 normal pregnancies) and correlated with the severity of the disease with regard to clinical signs (25 PE without severe features, 77 PE with severe features), and delivery date (36 early PE, 66 late PE). The adjustment for potential covariates was made, where appropriate.

Postnatal Expression Profile of microRNAs Associated with Cardiovascular and Cerebrovascular Diseases in Children at the Age of 3 to 11 Years in Relation to Previous Occurrence of Pregnancy-Related Complications.

Children descending from pregnancies complicated by gestational hypertension (GH), preeclampsia (PE) or fetal growth restriction (FGR) have a lifelong cardiovascular risk. The aim of the study was to verify if pregnancy complications induce postnatal alterations in gene expression of microRNAs associated with cardiovascular/cerebrovascular diseases. Twenty-nine microRNAs were assessed in peripheral blood, compared between groups, and analyzed in relation to both aspects, the current presence of cardiovascular risk factors and cardiovascular complications and the previous occurrence of pregnancy complications with regard to the clinical signs, dates of delivery, and Doppler ultrasound examination.

Periodic fevers and other autoinflammatory diseases.

Autoinflammatory diseases represent a relatively new and rapidly evolving group of rare disorders associated with mutations of genes encoding proteins with a key regulatory role in inflammatory response. Gradual discovery of mechanisms that link genetic disorder with its biochemical and immunological consequences leading to continuous or episodic inflammatory stimulation has enabled introduction of directed immunotherapies. Periodic fever syndromes belong to the so far best-known entities: familial Mediterranean fever, mevalonate kinase deficiency, cryopyrinopathies and TNF-receptor associated periodic syndrome.

LAMP2 exon-copy number variations in Danon disease heterozygote female probands: Infrequent or underdetected?

Danon disease (DD) is an X-linked disorder caused by mutations in the lysosomal-associated membrane protein 2 (LAMP2) gene (Xq24). DD is characterized by cognitive deficit, myopathy, and cardiomyopathy in male patients. The phenotype is variable and mitigated in females.

Variable X-chromosome inactivation and enlargement of pericentral glutamine synthetase zones in the liver of heterozygous females with OTC deficiency.

Ornithine transcarbamylase (OTC) deficiency is an X-linked disorder that causes recurrent and life-threatening episodes of hyperammonemia. The clinical picture in heterozygous females is highly diverse and derives from the genotype and the degree of inactivation of the mutated X chromosome in hepatocytes. Here, we describe molecular genetic, biochemical, and histopathological findings in the livers explanted from two female patients with late-onset OTC deficiency.

Expression profile of heat shock proteins in placental tissues of patients with preterm prelabor rupture of membranes and spontaneous preterm labor with intact membranes.

Problem: Investigating the stress response in the central cotyledon zone of placental tissue in pregnancies with PPROM, PTB, and at term in labor.

Method Of Study: Gene expression of Hsp27, Hsp60, Hsp70, Hsp90, and HspBP1 was compared between these particular groups. Correlation between variables including Hsp gene expression in placental tissue and the gestational age at delivery, WBC count at admission, and serum levels of CRP at admission in patients with PPROM and PTB was determined.

Activity of the liver enzyme ornithine carbamoyltransferase (OTC) in blood: LC-MS/MS assay for non-invasive diagnosis of ornithine carbamoyltransferase deficiency.

Background: Liver enzymes are released from hepatocytes into circulation and their activity can be measured in the blood. We examined whether the plasma activity of the liver enzyme ornithine carbamoyltransferase, determined by a novel liquid chromatography-mass spectrometry (LC-MS/MS) assay, could be utilized for the detection of OTC deficiency (OTCD), an X-linked inborn error of the urea cycle.

Methods: The plasma ornithine carbamoyltransferase (OTC) activity was assayed in the reverse reaction using isotopically labeled citrulline-d4 as a substrate and by determination of the product, ornithine-d4, by LC-MS/MS analysis.