BACKGROUND: Hereditary angioedema (HAE) is a rare autosomal dominant genetic disease characterised by acute episodes of non-pruritic skin and submucosal swelling caused by increase in vascular permeability. OBJECTIVE: Here we present the first complex analysis of the National HAE Slovakian cohort with the detection of 12 previously un-published genetic variants in SERPING1 gene. METHODS: In patients diagnosed with hereditary angioedema caused by deficiency or dysfunction of C1 inhibitor (C1-INH-HAE) based on clinical manifestation and complement measurements, SERPING1 gene was tested by DNA sequencing (Sanger sequencing/massive parallel sequencing) and/or multiplex ligation-dependent probe amplification for detection of large rearrangements. RESULTS: The Slovakian national cohort consisted of 132 living patients with confirmed HAE. We identified 51 index cases (32 families, 19 sporadic patients/112 adults, 20 children). One hundred seventeen patients had HAE caused by deficiency of C1 inhibitor (C1-INH-HAE-1) and 15 patients had HAE caused by dysfunction of C1 inhibitor (C1-INH-HAE-2). The prevalence of HAE in Slovakia has recently been calculated to 1:41 280 which is higher than average calculated prevalence. The estimated incidence was 1:1360 000. Molecular-genetic testing of the SERPING1 gene found 22 unique causal variants in 26 index cases, including 12 previously undescribed and unreported. CONCLUSION: The first complex report about epidemiology and genetics of the Slovakian national HAE cohort expands the knowledge of the C1-INH-HAE genetics. Twelve novel causal variants were present in the half of the index cases. A higher percentage of inframe variants comparing to other studies was observed. Heterozygous deletion of exon 3 found in a large C1-INH-HAE-1 family probably causes the dysregulation of the splicing isoforms balance and leads to the decrease of full-length C1-INH level.

• Klíčová slova
• Angioedemas, Complement C1 inhibitor protein, Genetic testing, Hereditary/epidemiology, Hereditary/genetics, Slovakia,
• Publikační typ
• časopisecké články MeSH

Hereditary angioedema due to C1 inhibitor deficiency (C1-INH-HAE) is a rare and life-threatening condition characterized by recurrent localized edema. We conducted a systematic screening of SERPING1 defects in a cohort of 207 Czech patients from 85 families with C1-INH-HAE. Our workflow involved a combined strategy of sequencing extended to UTR and deep intronic regions, advanced in silico prediction tools, and mRNA-based functional assays. This approach allowed us to detect a causal variant in all families except one and to identify a total of 56 different variants, including 5 novel variants that are likely to be causal. We further investigated the functional impact of two splicing variants, namely c.550 + 3A > C and c.686-7C > G using minigene assays and RT-PCR mRNA analysis. Notably, our cohort showed a considerably higher proportion of detected splicing variants compared to other central European populations and the LOVD database. Moreover, our findings revealed a significant association between HAE type 1 missense variants and a delayed HAE onset when compared to null variants. We also observed a significant correlation between the presence of the SERPING1 variant c.-21 T > C in the trans position to causal variants and the frequency of attacks per year, disease onset, as well as Clinical severity score. Overall, our study provides new insights into the genetic landscape of C1-INH-HAE in the Czech population, including the identification of novel variants and a better understanding of genotype-phenotype correlations. Our findings also highlight the importance of comprehensive screening strategies and functional analyses in improving the C1-INH-HAE diagnosis and management.

• Klíčová slova
• C1-INH-HAE, HAE, SERPING1, genotype–phenotype relationship, hereditary angioedema, splicing, time to diagnosis,
• MeSH
• hereditární angioedémy * diagnóza   epidemiologie   genetika   MeSH
• inhibiční protein komplementu C1 * genetika   MeSH
• lidé MeSH
• messenger RNA MeSH
• sestřih RNA MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Geografické názvy
• Česká republika epidemiologie   MeSH
• Názvy látek
• inhibiční protein komplementu C1 * MeSH
• messenger RNA MeSH
• SERPING1 protein, human MeSH Prohlížeč

BACKGROUND: Inborn errors of IL-12/IL-23-IFNγ immunity underlie Mendelian susceptibility to mycobacterial diseases (MSMD), a group of immunodeficiencies characterized by a highly selective susceptibility to weakly virulent strains of mycobacteria, such as non-tuberculous mycobacteria (NTM) and bacillus Calmette-Guérin (BCG). Cutaneous mycobacterial infections are common in MSMD and may represent a red flag for this immunodeficiency. OBJECTIVES: We present a case series of four paediatric patients with MSMD, specifically with IFNγR1 and STAT1 deficiencies, and cutaneous NTM/BCG infections to increase awareness of this immunodeficiency, which may, in some cases, be intercepted by the dermatologist and thus timely referred to the immunologist. MATERIALS & METHODS: Clinical, laboratory and genetic investigations of the four paediatric patients with MSMD are presented. RESULTS: All four presented patients experienced early complications after BCG vaccination. Two patients suffered recurrent mycobacteriosis, one patient experienced delayed BCG reactivation, and one patient died of disseminated avian mycobacteriosis. The dermatological manifestation in these patients included destructive nasal ulcerations, scrofuloderma of various sites and lupus vulgaris. All patients had a normal basic immune phenotype. CONCLUSION: The presented cases demonstrate that NTM/BCG infections in otherwise seemingly immunocompetent patients should raise suspicion of MSMD. This is of utmost importance as specific therapeutic approaches, such as IFNγ treatment or haematopoietic stem cell transplantation, may be employed to improve the disease outcome.

• Klíčová slova
• MSMD, mendelian susceptibility to mycobacterial diseases, IFNγR1, STAT1, inborn error of immunity, non-tuberculous mycobacteria, BCG, necrotizing granulomas, antituberculotics,
• MeSH
• bakteriální nemoci kůže * MeSH
• BCG vakcína škodlivé účinky   MeSH
• genetická predispozice k nemoci MeSH
• interferon gama MeSH
• interleukin-12 MeSH
• interleukin-23 MeSH
• lidé MeSH
• mykobakteriózy * genetika   MeSH
• syndromy imunologické nedostatečnosti * komplikace   genetika   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH
• Názvy látek
• BCG vakcína MeSH
• interferon gama MeSH
• interleukin-12 MeSH
• interleukin-23 MeSH

We present a case of a 42-year-old woman with Mendelian susceptibility to mycobacterial disease. The disease was diagnosed at an adult age with relatively typical clinical manifestations; the skeleton, joints, and soft tissues were affected by nontuberculous mycobacteria: Mycobacterium lentiflavum, M. kansasii, and M. avium. A previously published loss-of-function and functionally validated variant NM_000416.2:c.819_822delTAAT in IFNGR1 in a heterozygous state was detected using whole-exome sequencing. After interferon-γ therapy was started at a dose of 200 µg/m2 three times a week, there was significant clinical improvement, with the need to continue the macrolide-based combination regimen. In the last 4 months, she has been in this therapy without the need for antibiotic treatment.

• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH

Objectives: Development of right ventricular failure (RVF) after left ventricular assist device (LVAD) implantation remains a leading cause of perioperative morbidity, end-organ dysfunction and mortality. The objective of this study was to investigate whether the etiology of HF (ischemic HF versus non-ischemic HF) affects the risk of RVF within admission for LVAD implantation and during long-term follow-up. Methods: Between January 2011 and June 27, 2018, 3536 patients were prospectively enrolled into EUROMACS registry. Adult patients (>18 years) who received a first time LVAD were included. When excluding patients with congenital, restrictive, hypertrophic, valvular cardiomyopathies, and myocarditis the total population consisted of 2404 patients. Results: The total cohort consists of 2404 patients. Mean age were 55 years and predominantly male sex [2024 (84.2%)]. At the time of LVAD implantation 1355 (56.4%) patients had ischemic HF and 1049 (43.6%) patients had non-ischemic HF. The incidence of RVF was significantly increased in the non-ischemic HF group in the adjusted model (p = .026). The relative risk difference for RVF in patients with non-ischemic HF was in the adjusted model increased by an absolute value of 5.1% (95% CI: 0.61-9.6). In the ischemic HF group 76 patients (13.4%) developed late RVF and 62 patients (14.8%) in the non-ischemic HF group (p = .56). No differences in occurrence of RVF between HF etiology was observed after 2 and 4 years of follow-up, respectively (crude: p = .25, adjusted (sex and age) p = .2 and crude: p = .59, adjusted (sex and age) p = .44). Conclusions: Patients with non-ischemic HF undergoing LVAD had an increased incidence of early RVF compared to patients with ischemic HF in a large European population. During follow-up after discharge 14% patients developed RVF. We recommend HF etiology to be considered in identifying patients who are at risk for postoperative RVF after LVAD implantation.

• Klíčová slova
• Left ventricular assist device, ischemic heart failure, non-ischemic heart failure, right ventricular failure,
• MeSH
• časové faktory MeSH
• dospělí MeSH
• dysfunkce pravé srdeční komory diagnostické zobrazování   epidemiologie   patofyziologie   MeSH
• funkce levé komory srdeční * MeSH
• funkce pravé komory srdeční * MeSH
• hodnocení rizik MeSH
• implantace protézy škodlivé účinky   přístrojové vybavení   MeSH
• incidence MeSH
• lidé středního věku MeSH
• lidé MeSH
• podpůrné srdeční systémy * MeSH
• registrace MeSH
• rizikové faktory MeSH
• srdeční selhání diagnostické zobrazování   epidemiologie   patofyziologie   terapie   MeSH
• výsledek terapie MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• multicentrická studie MeSH
• srovnávací studie MeSH
• Geografické názvy
• Evropa epidemiologie   MeSH

PURPOSE: Hereditary angioedema (HAE) is a rare autosomal dominant life-threatening disease characterized by low levels of C1 inhibitor (type I HAE) or normal levels of ineffective C1 inhibitor (type II HAE), typically occurring as a consequence of a SERPING1 mutation. In some cases, a causal mutation remains undetected after using a standard molecular genetic analysis. RESULTS: Here we show a long methodological way to the final discovery of c.1029 + 384A > G, a novel deep intronic mutation in intron 6 which is responsible for HAE type I in a large family and has not been identified by a conventional diagnostic approach. This mutation results in de novo donor splice site creation and subsequent pseudoexon inclusion, the mechanism firstly described to occur in SERPING1 in this study. We additionally discovered that the proximal part of intron 6 is a region potentially prone to pseudoexon-activating mutations, since natural alternative exons and additional cryptic sites occur therein. Indeed, we confirmed the existence of at least two different alternative exons in this region not described previously. CONCLUSIONS: In conclusion, our results suggest that detecting aberrant transcripts, which are often low abundant because of nonsense-mediated decay, requires a modified methodological approach. We suggest SERPING1 intron 6 sequencing and/or tailored mRNA analysis to be routinely used in HAE patients with no mutation identified in the coding sequence.

• Klíčová slova
• Hereditary angioedema, SERPING1, donor splice site, pre-mRNA splicing, pseudoexon activation,
• MeSH
• dítě MeSH
• dospělí MeSH
• exony genetika   MeSH
• hereditární angioedém, typy I a II genetika   MeSH
• inhibiční protein komplementu C1 genetika   MeSH
• introny genetika   MeSH
• lidé středního věku MeSH
• lidé MeSH
• místa sestřihu RNA genetika   MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mutace genetika   MeSH
• mutační analýza DNA metody   MeSH
• rodokmen MeSH
• senioři MeSH
• splicing proteinů genetika   MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• inhibiční protein komplementu C1 MeSH
• místa sestřihu RNA MeSH

IMPORTANCE: Familial hypercholesterolemia (FH) is an underdiagnosed and undertreated genetic disorder that leads to premature morbidity and mortality due to atherosclerotic cardiovascular disease. Familial hypercholesterolemia affects 1 in 200 to 250 people around the world of every race and ethnicity. The lack of general awareness of FH among the public and medical community has resulted in only 10% of the FH population being diagnosed and adequately treated. The World Health Organization recognized FH as a public health priority in 1998 during a consultation meeting in Geneva, Switzerland. The World Health Organization report highlighted 11 recommendations to address FH worldwide, from diagnosis and treatment to family screening and education. Research since the 1998 report has increased understanding and awareness of FH, particularly in specialty areas, such as cardiology and lipidology. However, in the past 20 years, there has been little progress in implementing the 11 recommendations to prevent premature atherosclerotic cardiovascular disease in an entire generation of families with FH. OBSERVATIONS: In 2018, the Familial Hypercholesterolemia Foundation and the World Heart Federation convened the international FH community to update the 11 recommendations. Two meetings were held: one at the 2018 FH Foundation Global Summit and the other during the 2018 World Congress of Cardiology and Cardiovascular Health. Each meeting served as a platform for the FH community to examine the original recommendations, assess the gaps, and provide commentary on the revised recommendations. The Global Call to Action on Familial Hypercholesterolemia thus represents individuals with FH, advocacy leaders, scientific experts, policy makers, and the original authors of the 1998 World Health Organization report. Attendees from 40 countries brought perspectives on FH from low-, middle-, and high-income regions. Tables listing country-specific government support for FH care, existing country-specific and international FH scientific statements and guidelines, country-specific and international FH registries, and known FH advocacy organizations around the world were created. CONCLUSIONS AND RELEVANCE: By adopting the 9 updated public policy recommendations created for this document, covering awareness; advocacy; screening, testing, and diagnosis; treatment; family-based care; registries; research; and cost and value, individual countries have the opportunity to prevent atherosclerotic heart disease in their citizens carrying a gene associated with FH and, likely, all those with severe hypercholesterolemia as well.

• MeSH
• celosvětové zdraví MeSH
• hyperlipoproteinemie typ II diagnóza   prevence a kontrola   terapie   MeSH
• lidé MeSH
• osobní újma zaviněná nemocí MeSH
• směrnice pro lékařskou praxi jako téma MeSH
• veřejné zdravotnictví MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

AIMS: In left-sided infective endocarditis (IE), a large vegetation >10 mm is associated with higher mortality, yet it is unknown whether surgery during the acute phase opposed to medical therapy is associated with improved survival. We assessed the association between surgery and 6-month mortality as related to vegetation size. METHODS AND RESULTS: Patients with definite, left-sided IE (2008-2012) from The International Collaboration on Endocarditis prospective, multinational registry were included. We compared clinical characteristics and 6-month mortality (by Cox regression with inverse propensity of treatment weighting) between patients with vegetation size ≤10 mm vs. >10 mm in maximum length by surgical treatment strategy. A total of 1006 patients with left sided IE were included; 422 with a vegetation size ≤10 mm (median age 66.0 years, 33% women) and 584 (median age 58.4 years, 34% women) patients with a large vegetation >10 mm. Operative risk by STS-IE score was similar between groups. Embolic events occurred in 28.4% vs. 44.3% (P < 0.001), respectively. Patients with a vegetation >10 mm was associated with higher 6-month mortality (25.1% vs. 19.4% for small vegetation, P = 0.035). However, after propensity adjustment, the association with higher mortality persisted only in patients with a large vegetation >10 mm vs. ≤10 mm: hazard ratio (HR) 1.55 (1.27-1.90); but only in patients with large vegetation managed medically [HR 1.86 (1.48-2.34)] rather than surgically [HR 1.01 (0.69-1.49)]. CONCLUSION: Left-sided IE with vegetation size >10 mm was associated with an increased mortality at 6 months in this observational study but was dependent on treatment strategy. For patients with large vegetation undergoing surgical treatment, survival was similar to patients with smaller vegetation size.

• Klíčová slova
• Antibiotics, Infective endocarditis, Outcomes, Surgery, Vegetation size,
• MeSH
• analýza přežití MeSH
• bakteriální endokarditida mikrobiologie   mortalita   chirurgie   MeSH
• časové faktory MeSH
• lidé středního věku MeSH
• lidé MeSH
• prospektivní studie MeSH
• senioři MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• multicentrická studie MeSH
• práce podpořená grantem MeSH

PURPOSE OF REVIEW: Familial hypercholesterolemia (FH) is often perceived and described as underdiagnosed and undertreated, though effective treatment of FH is available. Owing to the mentioned facts, it is ever more imperative to screen and treat FH patients. Subsequent to the identification of patients, the project focuses on the improvement of their prognoses. The ScreenPro FH project was established as a functional international network for the diagnosis, screening, and treatment of FH. Individual countries were assigned goals, e.g., to define the actual situation and available treatment. With "central support," more centers and countries participated in the project. Subsequently, individual countries reported the results at the beginning and end of the project. Collected data were statistically evaluated. RECENT FINDINGS: The increasing number of patients in databases, from 7500 in 2014 to 25,347 in 2018, demonstrates the improvement in overall effectiveness, as well as an increase in the number of centers from 70 to 252. Before all, LDL-C decreased by 41.5% and total cholesterol by 32.3%. As data from all countries and patients were not available at the time of the analysis, only those results from 10 countries and 5585 patients at the beginning of the project and at the time of writing are included. Our data are quite positive. However, our results have only limited validity. Our patients are far from the target levels of LDL-C. The situation can be improved with the introduction of new therapy, PCSK9-i, evolocumab, and alirocumab. International cooperation improved the screening of FH and finally led to an improvement in cardiovascular risk.

• Klíčová slova
• Alirocumab, Evolocumab, FH, Familial hypercholesterolemia, LDL-C, ScreenPro FH,
• MeSH
• anticholesteremika terapeutické užití   MeSH
• humanizované monoklonální protilátky terapeutické užití   MeSH
• hyperlipoproteinemie typ II diagnóza   farmakoterapie   epidemiologie   MeSH
• incidence MeSH
• lidé MeSH
• mezinárodní spolupráce * MeSH
• PCSK9 inhibitory MeSH
• plošný screening metody   MeSH
• poskytování zdravotní péče normy   MeSH
• proproteinkonvertasa subtilisin/kexin typu 9 imunologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Geografické názvy
• Evropa epidemiologie   MeSH
• Názvy látek
• alirocumab MeSH Prohlížeč
• anticholesteremika MeSH
• evolocumab MeSH Prohlížeč
• humanizované monoklonální protilátky MeSH
• PCSK9 inhibitory MeSH
• PCSK9 protein, human MeSH Prohlížeč
• proproteinkonvertasa subtilisin/kexin typu 9 MeSH

Neutrophils impact on processes preceding the formation of bradykinin, a major swelling mediator in hereditary angioedema (HAE), yet their potential role in HAE pathogenesis has not been sufficiently studied. We assessed the relative mRNA expression of 10 genes related to neutrophil activation using RNA extracted from the peripheral blood neutrophils of 23 HAE patients in a symptom-free period and 39 healthy donors. Increased relative mRNA expression levels of CD274, IL1B, IL1RN, IL8, MMP9, and TLR4, together with a lack in their mutual correlations detected in HAE patients compared to healthy controls, suggested a preactivated state and dysregulation of patients' neutrophils. Patients' neutrophil-alerted state was further supported by increased CD11b, decreased CD16 plasma membrane deposition, and increased relative CD274+ and CD87+ neutrophil counts, but not by increased neutrophil elastase or myeloperoxidase plasma levels. As CD274 mediates inhibitory signals to different immune cells, neutrophils were cocultured with T-cells/PBMC. The decrease in CD25+ and IFN-γ + T-cell/PBMC ratio in patients indicated the patients' neutrophil suppressive functions. In summary, the results showed neutrophils' alerted state and dysregulation at the transcript level in patients with HAE types I and II even in a symptom-free period, which might make them more susceptible to edema formation. Neutrophils' T-cell suppressive capacity in HAE patients needs to be further investigated.

• MeSH
• antagonista receptoru pro interleukin 1 metabolismus   MeSH
• antigeny CD11b metabolismus   MeSH
• antigeny CD274 metabolismus   MeSH
• dítě MeSH
• dospělí MeSH
• ELISA MeSH
• hereditární angioedém, typy I a II metabolismus   MeSH
• interleukin-1beta metabolismus   MeSH
• interleukin-8 metabolismus   MeSH
• kultivované buňky MeSH
• leukocyty mononukleární metabolismus   MeSH
• lidé MeSH
• matrixová metaloproteinasa 9 metabolismus   MeSH
• messenger RNA MeSH
• mladiství MeSH
• mladý dospělý MeSH
• neutrofily metabolismus   MeSH
• pankreatická elastasa krev   MeSH
• peroxidasa krev   MeSH
• průtoková cytometrie MeSH
• receptory IgG metabolismus   MeSH
• receptory urokinázového aktivátoru plazminogenu metabolismus   MeSH
• toll-like receptor 4 metabolismus   MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• antagonista receptoru pro interleukin 1 MeSH
• antigeny CD11b MeSH
• antigeny CD274 MeSH
• IL1B protein, human MeSH Prohlížeč
• IL1RN protein, human MeSH Prohlížeč
• interleukin-1beta MeSH
• interleukin-8 MeSH
• matrixová metaloproteinasa 9 MeSH
• messenger RNA MeSH
• pankreatická elastasa MeSH
• peroxidasa MeSH
• receptory IgG MeSH
• receptory urokinázového aktivátoru plazminogenu MeSH
• toll-like receptor 4 MeSH