A summary of the EAS consensus concerning the causal relationship between low-density lipoproteins and atherosclerotic cardiovascular diseases, prepared by the Board of the Czech Society for Atherosclerosis.

This article summarised opinion of the European Society for Atherosclerosis on the causal relationship between low density lipoprotein (LDL) and the development of atherosclerosis. The fact that there is a clear causal relationship between the LDL concentration and the development of atherosclerotic cardiovascular disease (ASKVO) is evidenced by congenital lipid metabolism disorders and results of prospective epidemiological studies, Mendelian randomized trials, and randomized controlled trials. It is documented that the effect of LDL exposure on ASKVO development is cumulative; the additive effect of other risk factors is also discussed. In conclusion the facts, underlying the rational approach to the therapy of patients with dyslipidemia, are summarized. Key words: atherosclerotic cardiovascular disease - LDL - low density lipoprotein - EAS.

[Hyperlipoproteinemia in children]. / Hyperlipoproteinemie u detí.

Hyperlipoproteinemia (HLP) is one of the most common metabolic disorder in childhood. We assume that 20 % of children have a disorder of the lipid metabolism. Some HLP are very common in the population, and moderate, and some are very rare, but are very severe. These may occur secondary to pathological conditions, or are formed on the basis of the primary monogenic or polygenic disorders of lipid metabolism. The detection of children with HLP in the Czech Republic is either random, or more often by selective screening of children with familial history of cardiovascular disease, provided by general pediatric practitioners for children and adolescents. Treatment in childhood is primarily dietetic, some of them, especially children with familial hypercholesterolemia are treated from 8-10 years pharmacologically.Key words: diagnosis - hyperlipoproteinemia - children - treatment.

[PCSK9 inhibitors - new possibilities in the treatment of hypercholesterolemia: For which patients will be indicated?Czech atherosclerosis society statement]. / PCSK9 inhibitory - nové moznosti v lécbe hypercholesterolemie: U koho budou indikovány?Stanovisko Ceské spolecnosti pro aterosklerózu.

First line drug for the treatment of hypercholesterolemia are statins, which reduce LDL-cholesterol up to 50 %; such reduction is sufficient for most patients to achieve the target values. The exceptions are patients with familial hypercholesterolemia and patients with statin intolerance. To achieve target LDL-cholesterol in these two groups of patients will be possible with new drugs - PCSK9 inhibitors, which decrease LDL-cholesterol by an additional 50-60 %. The first two PCSK9 inhibitors (alirocumab and evolocumab) already had been approved for clinical use by European regulatory authorities. The primary indication for combination statin with PCSK9 inhibitor should be undoubtedly patients with a confirmed diagnosis of familial hypercholesterolemia, who are treated in the Czech Republic primarily in specialized centers of MedPed project. Furthermore, this treatment should be available for other patients at very high risk of cardiovascular diseases, who cannot achieve target LDL-cholesterol (eg. for statins intolerance).

[Non-pharmacological treatment - results from Podebrady]. / Nefarmakologická lécba - výsledky z Podebrad.

OBJECTIVES: The study was aimed to determine risk factors of atherosclerosis after one month lifestyle intervention in overweight/obese children and also FTO and MC4R gene variants associated with obesity. DESIGN AND METHODS: 350 non-diabetic Czech children (age 13.7 ± 2.1 years, 163 ± 10.6 cm hight) was examined. Before and after 4 weeks of lifestyle intervention (comprising a reduction of energy intake), biochemical and anthropometrical measurements were performed. RESULTS: The mean weight loss achieved was 6.2 ± 2.1 kg (P < 0.001). Significant associations between BMI decrease and FTO and MC4R variants were found. Carriers of the FTO GG genotype and/or MC4R CC genotype lost significantly more body weight in comparison to the non-carriers (P < 0.0009 for BMI and P < 0.002 for body weight). The differences remain significant after adjustment for sex age and baseline values (P = 0.004 for BMI and P = 0.01 for body weight). CONCLUSIONS: It is necessary to look for the risk individuals with wrong response to the regime intervention. This individuals is necessary early treat with drugs to prevention clinically complications.Key words: childhood obesity - components of metabolic syndrome - predisposition - response to intervention.

[Familial hypercholesterolemia - past and present. My experiences and findings in our group of patients with familial hypercholesterolemia]. / Familiární hypercholesterolemie vcera a dnes. Vlastní zkusenosti a nálezy u naseho souboru nemocných s familiární hypercholesterolemií

Currently, the familial hypercholesterolemia (FH) rises the interest. The reason is that this genetic disorder is targeted by newly emerged and highly effective hypolipidemic agents, PCSK-9 inhibitors, lomitapid and mipomersen. Present paper discusses 2 patient study groups, before 50 years and nowadays. Although direct statistical analysis is impossible some changes in clinical features of FH might be found over the course of the time. In fact, the basic FH characteristic has not changed dramatically. Severe isolated hypercholesterolemia with total cholesterol 9-10 mmol/l, LDL-cholesterol 7-8 mmol/l and normal values of triglycerides dominates in laboratory analysis. Interestingly, the values of triglycerides increase and almost reach the pathological range in comparison to the values from the period 50 years ago. The values of HDL-cholesterol are normal. Manifestation of CHD in male patients over 40 years of age and in female patients over 50 years of age is not exceptional (rarely occur cases of myocardial infarction in third decade of age). Typical clinical manifestation of FH is xanthomatosis. The early detection and aggressive treatment in FH patients cause that xanthoma tendinosum, xanthelesma and arcus lipoides are less frequent as decades ago. Obesity, diabetes mellitus (DM) and hypertension do not belong to typical clinical sign of FH.

Revisiting the concept of 'enzymic latch' on carbon in peatlands.

Peatlands are long-term sinks of atmospheric carbon (C) largely due to water-saturated soil conditions, decay-resistant plant litter, and the presence of biochemical compounds such as soluble phenolics. As phenolics are known inhibitors of microbial enzymes in soils, the concept of the 'enzymic latch' on peat C was introduced, assuming that phenolics accumulate in peat water due to protection from degradation by oxidative enzymes as a result of anoxia. However, their inhibitory role in peat has not been unambiguously confirmed. We aimed to verify whether peat phenolics inhibit microbial and enzyme activities in laboratory-incubated Sphagnum litter, and bog and fen peat. Soluble humic substances were extracted from bog water as a source of natural phenolics and separated into two molecular-weight fractions. We tested the effects of (1) phenolics concentration, (2) their molecular weight and (3) anoxia on the activity of hydrolytic and oxidative enzymes, and on microbial respiration rate. The added phenolics did not suppress hydrolytic enzyme activities nor microbial respiration. Quite the contrary, phenolics addition (up to 1000 mg L-1) sometimes supported enzyme and microbial activities, indicating that phenolics (or another constituent of peat humic substances) served as a source of C. The activities of hydrolytic enzymes did not vary between oxic and anoxic peat but were double in oxic than anoxic conditions in Sphagnum litter. Differences in enzymatic and microbial activities were driven by peat type with about three times greater microbial respiration rates and enzyme activities in fen peats. Our results do not support the concept of the enzymic latch, particularly its key assumption that peat phenolics inhibit hydrolytic enzymes. While the concept was established on oceanic peatlands with low phenolic concentrations, the peat microbial community in our experiments seemed acclimated to the naturally high phenolic concentrations, characteristic for other, non-oceanic northern peatlands. Thus, the enzymic latch should not be considered as a determinative mechanism preserving the global C store in peatlands.

Modulation of the Immune Response by Deferasirox in Myelodysplastic Syndrome Patients.

Deferasirox (DFX) is an oral iron chelator used to reduce iron overload (IO) caused by frequent blood cell transfusions in anemic myelodysplastic syndrome (MDS) patients. To study the molecular mechanisms by which DFX improves outcome in MDS, we analyzed the global gene expression in untreated MDS patients and those who were given DFX treatment. The gene expression profiles of bone marrow CD34+ cells were assessed by whole-genome microarrays. Initially, differentially expressed genes (DEGs) were determined between patients with normal ferritin levels and those with IO to address the effect of excessive iron on cellular pathways. These DEGs were annotated to Gene Ontology terms associated with cell cycle, apoptosis, adaptive immune response and protein folding and were enriched in cancer-related pathways. The deregulation of multiple cancer pathways in iron-overloaded patients suggests that IO is a cofactor favoring the progression of MDS. The DEGs between patients with IO and those treated with DFX were involved predominantly in biological processes related to the immune response and inflammation. These data indicate DFX modulates the immune response mainly via neutrophil-related genes. Suppression of negative regulators of blood cell differentiation essential for cell maturation and upregulation of heme metabolism observed in DFX-treated patients may contribute to the hematopoietic improvement.

Spatial heterogeneity of belowground microbial communities linked to peatland microhabitats with different plant dominants.

Peatland vegetation is composed mostly of mosses, graminoids and ericoid shrubs, and these have a distinct impact on peat biogeochemistry. We studied variation in soil microbial communities related to natural peatland microhabitats dominated by Sphagnum, cotton-grass and blueberry. We hypothesized that such microhabitats will be occupied by structurally and functionally different microbial communities, which will vary further during the vegetation season due to changes in temperature and photosynthetic activity of plant dominants. This was addressed using amplicon-based sequencing of prokaryotic and fungal rDNA and qPCR with respect to methane-cycling communities. Fungal communities were highly microhabitat-specific, while prokaryotic communities were additionally directed by soil pH and total N content. Seasonal alternations in microbial community composition were less important; however, they influenced the abundance of methane-cycling communities. Cotton-grass and blueberry bacterial communities contained relatively more α-Proteobacteria but less Chloroflexi, Fibrobacteres, Firmicutes, NC10, OD1 and Spirochaetes than in Sphagnum. Methanogens, syntrophic and anaerobic bacteria (i.e. Clostridiales, Bacteroidales, Opitutae, Chloroflexi and Syntrophorhabdaceae) were suppressed in blueberry indicating greater aeration that enhanced abundance of fungi (mainly Archaeorhizomycetes) and resulted in the highest fungi-to-bacteria ratio. Thus, microhabitats dominated by different vascular plants are inhabited by unique microbial communities, contributing greatly to spatial functional diversity within peatlands.

Genetic Variant Screening of DNA Repair Genes in Myelodysplastic Syndrome Identifies a Novel Mutation in the XRCC2 Gene.

BACKGROUND: We aimed to detect single nucleotide polymorphisms (SNPs) and mutations in DNA repair genes and their possible association with myelodysplastic syndrome (MDS). METHODS: Targeted enrichment resequencing of 84 DNA repair genes was initially performed on a screening cohort of MDS patients. Real-time polymerase chain reaction was used for genotyping selected SNPs in the validation cohort of patients. RESULTS: A heterozygous frameshift mutation in the XRCC2 gene was identified. It leads to the formation of a truncated non-functional protein and decreased XRCC2 expression level. Decreased expression levels of all DNA repair genes functionally connected with mutated XRCC2 were also present. Moreover, a synonymous substitution in the PRKDC gene and 2 missense mutations in the SMUG1 and XRCC1 genes were also found. In the screening cohort, 6 candidate SNPs were associated with the tendency to develop MDS: rs4135113 (TDG, p = 0.03), rs12917 (MGMT, p = 0.003), rs2230641 (CCNH, p = 0.01), rs2228529 and rs2228526 (ERCC6, p = 0.04 and p = 0.03), and rs1799977 (MLH1, p = 0.04). In the validation cohort, only a polymorphism in MLH1 was significantly associated with development of MDS in patients with poor cytogenetics (p = 0.0004). CONCLUSION: Our study demonstrates that genetic variants are present in DNA repair genes of MDS patients and may be associated with susceptibility to MDS.

Microbial community composition and in silico predicted metabolic potential reflect biogeochemical gradients between distinct peatland types.

It is not well understood how the ecological status and microbial community composition of spruce swamp forests (SSF) relate to those found in bogs and fens. To clarify this, we investigated biogeochemical parameters and microbial community composition in a bog, a fen and two SSF using high throughput barcoded sequencing of the small ribosomal subunit (SSU) variable region V4. The results demonstrated that the microbial community of SSF is positioned between those of bogs and fens, and this was confirmed by in silico predicted metabolic potentials. This corresponds well with the position of SSF on the trophic gradient and reflects distinct responses of microbial communities to environmental variables. Species richness and microbial diversity increased significantly from bog to fen, with SSF in between, reflecting the variation in pH, nutrient availability and peat decomposability. The archaeal community, dominated by hydrogenotrophic methanogens, was more similar in SSF and the bog compared with the fen. The composition of the bacterial community of SSF was intermediate between those of bog and fen. However, the production of CO2 (an indicator of peat decomposability) did not differ between SSF and bog, suggesting the limiting effect of low pH and poor litter quality on the functioning of the bacterial community in SSF. These results help to clarify the transitional position of SSF between bogs and fens and showed the strong effect of environmental conditions on microbial community composition and functioning.

Early cardiac changes in children with anderson-fabry disease.

OBJECTIVE: Limited evidence is available about the early cardiac manifestation of Fabry disease (FD) in children. We aimed to evaluate cardiac involvement in children with FD by analysing serial structural and electrocardiographic changes. METHODS: The data were acquired from 22 children with FD [11 males; median age 9.8 (ranging 2.5-16) years]. Seven patients (5 males) were on enzyme replacement therapy (ERT) with Agalasidase alpha. Echocardiography, ECG and 24-h ECG monitoring recordings were acquired during routine annual clinical controls. ECG data were compared to a group of age-and gender-matched controls. RESULTS: At baseline, ECG and ECHO parameters of left ventricular mass were similar in both males and females. Three boys (all were on ERT) developed left ventricular hypertrophy (LVH) during two-year follow-up. The progression to LVH was accompanied by the appearance of frequent ventricular premature beats in two cases and supraventricular premature beats (SPBs) with T wave inversion in one case. T wave inversion and SPBs were detected in two younger relatives of a patient with LVH, in the absence of detectable LVH. Seven out of 22 patients had T wave abnormalities. Five of them were males (p = 0.03) all carrying the N215S mutation (p = 0.03). At baseline, median PR intervals were prolonged in FD subjects compared to controls [143 (122-177) vs. 122 (82-165) ms; p < 0.0001]. CONCLUSIONS: Cardiac complications of FD become apparent in childhood as subtle changes with slow but detectable progression over time, with males more frequently affected than females. Progression of LVH was apparent in three children despite ERT.