Přírůstek hmotnosti a obezita u pacientů se schizofrenií jsou velmi časté. Obojí je spjato s rizikem onemocnění kardiovaskulárními chorobami, ale také diabetem mellitem II. typu, dále nonadherencí k farmakologické léčbě, nižší kvalitou života a častějšími rehospitalizacemi v psychiatrických zařízeních. Přírůstek hmotnosti i obezita jsou spjaty s medikací antipsychotiky, svoji roli však hrají i jiné faktory, jako genetická predispozice, nezdravý životní styl se zvýšeným příjmem kalorií a jejich sníženým výdejem a dále také socioekonomické faktory. Zásadní je monitorace přírůstku hmotnosti a dalších metabolických parametrů u pacientů se schizofrenií již od stanovení diagnózy a zahájení antipsychotické léčby. K tomu existují mezinárodní doporučení, která se však často nedodržují. Recentně existují i doporučení postupů, jak přírůstek hmotnosti a obezitu řešit. Způsoby řešení lze dělit na nefarmakologické a farmakologické. První by měly být užity ty nefarmakologické zahrnující edukaci o zdravém životním stylu. Nejsou-li dostatečně účinné, lze použít postupy farmakologické - čili nasazení medikace snižující tělesnou hmotnost. Jako nejefektivnější se jeví metformin (nejvíce důkazů) a topiramát nebo přikombinování aripiprazolu.

Weight gain and obesity in patients with schizophrenia are very frequent. Both are connected with cardiovascular disorders, but also with diabetes mellitus, non-adherence with pharmacological treatment, lower quality of life, and psychiatric readmissions. Weight gain is connected with adverse effects of antipsychotics, but also genetic vulnerability, unhealthy lifestyle with increased intake of calories and their decreased expenditure, and socioeconomic risk factors. Proper monitoring of weight gain and other metabolic parameters in patients with schizophrenia from the beginning of their treatment plays a key role. We have international guidelines for this monitoring which are poorly followed. Recently, we got also guidelines of weight gain and obesity management. The interventions can be divided into non-pharmacological and pharmacological ones. Non-pharmacological interventions including education about healthy lifestyle should be used firstly. If not efficient enough, it is possible to use pharmacological interventions - adjunctive medication inducing weight loss. Recent findings suggest that metformin (best evidence), topiramat, and add-on therapy with aripiprazole are the most effective ones.

• MeSH
• antipsychotika * farmakologie   škodlivé účinky   MeSH
• diabetes mellitus 2. typu prevence a kontrola   MeSH
• fruktosa analogy a deriváty   terapeutické užití   MeSH
• hmotnostní přírůstek účinky léků   MeSH
• kardiovaskulární nemoci prevence a kontrola   MeSH
• látky proti obezitě terapeutické užití   MeSH
• lidé MeSH
• metformin terapeutické užití   MeSH
• obezita * etiologie   chemicky indukované   terapie   MeSH
• schizofrenie * farmakoterapie   metabolismus   MeSH
• topiramat MeSH
• vzdělávání pacientů jako téma MeSH
• životní styl MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• práce podpořená grantem MeSH
• přehledy MeSH

PURPOSE: Signal transducer and activator of transcription 1 gain-of-function (STAT1 GOF) mutations are the most common cause of chronic mucocutaneous candidiasis (CMC). We aim to report the effect of oral ruxolitinib, the Janus kinase (JAK) family tyrosine kinase inhibitor, on clinical and immune status of a 12-year-old boy with severe CMC due to a novel STAT1 GOF mutation. METHODS: Clinical features and laboratory data were analyzed, particularly lymphocyte subsets, ex vivo IFNγ- and IFNα-induced STAT1, 3, 5 phosphorylation dynamics during the course of JAK1/2 inhibition therapy, and Th17-related, STAT1- and STAT3-inducible gene expression before and during the treatment. Sanger sequencing was used to detect the STAT1 mutation. Literature review of ruxolitinib in treatment of CMC is appended. RESULTS: A novel STAT1 GOF mutation (c.617T > C; p.L206P), detected in a child with recalcitrant CMC, was shown to be reversible in vitro with ruxolitinib. Major clinical improvement was achieved after 8 weeks of ruxolitinib treatment, while sustained suppression of IFNγ- and IFNα-induced phosphorylation of STAT1, STAT3, and STAT5, as well as increased STAT3-inducible and Th17-related gene expression, was demonstrated ex vivo. Clinical relapse and spike of all monitored phosphorylated STAT activity was registered shortly after unplanned withdrawal, decreasing again after ruxolitinib reintroduction. No increase of peripheral CD4+ IL17+ T cells was detected after 4 months of therapy. No adverse effects were noted. CONCLUSION: JAK1/2 inhibition with ruxolitinib represents a viable option for treatment of refractory CMC, if HSCT is not considered. However, long-term administration is necessary, as the effect is not sustained after treatment discontinuation.

• MeSH
• aktivační mutace * MeSH
• biologické markery MeSH
• CD4-pozitivní T-lymfocyty imunologie   metabolismus   MeSH
• cytokiny metabolismus   MeSH
• dítě MeSH
• fosforylace MeSH
• genetická predispozice k nemoci MeSH
• imunofenotypizace MeSH
• inhibitory proteinkinas aplikace a dávkování   terapeutické užití   MeSH
• Janus kinasy antagonisté a inhibitory   MeSH
• kandidóza chronická mukokutánní diagnóza   farmakoterapie   genetika   metabolismus   MeSH
• lidé MeSH
• mutace * MeSH
• mutační analýza DNA MeSH
• pyrazoly aplikace a dávkování   terapeutické užití   MeSH
• T-lymfocyty - podskupiny imunologie   metabolismus   MeSH
• transkripční faktor STAT1 genetika   metabolismus   MeSH
• výsledek terapie MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• mužské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH
• práce podpořená grantem MeSH

The prognostic significance of 1q21 gain, del(13)(q14), del(17)(p13), t(4;14)(p16.3;q32), and t(11;14)(q13;q32) detected by interphase fluorescein in situ hybridization (FISH) was studied in a cohort of 91 patients with newly diagnosed multiple myeloma (MM). 1q21 gain was detected in 37 of 91 patients (40.7%). In comparison with patients lacking 1q21 gain, patients with 1q21 gain had significantly shorter progression-free survival (PFS) (14.9 versus 27.4 months; P = .044) and worse 4-year overall survival (OS) (40.1% versus 76.2% of patients; P = <.001). PFS or OS were not influenced by the presence or absence of the other studied chromosomal abnormalities. Although the occurrence of 1q21 gain correlated with deletion of 13q14, the presence of 1q21 gain can be considered an independent prognostic factor, as no impact of del(13)(q14) as an isolated chromosomal abnormality on either PFS or OS has been observed. In comparison with patients lacking 1q21 gain, patients with 1q21 gain were significantly more likely to discontinue the preplanned treatment protocol because of disease progression or death. We conclude that 1q21 gain defines a prognostically unfavorable group of MM patients.

• MeSH
• analýza přežití MeSH
• chromozomální aberace MeSH
• dospělí MeSH
• hybridizace in situ fluorescenční MeSH
• kohortové studie MeSH
• lidé středního věku MeSH
• lidé MeSH
• lidské chromozomy, pár 1 MeSH
• mnohočetný myelom farmakoterapie   genetika   MeSH
• přežití bez známek nemoci MeSH
• prognóza MeSH
• protokoly protinádorové kombinované chemoterapie terapeutické užití   MeSH
• senioři MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze III MeSH
• práce podpořená grantem MeSH
• randomizované kontrolované studie MeSH

Calcium/calmodulin-dependent protein kinases (CaMKs) are key mediators of calcium signaling and underpin neuronal health. Although widely studied, the contribution of CaMKs to Mendelian disease is rather enigmatic. Here, we describe an unusual neurodevelopmental phenotype, characterized by milestone delay, intellectual disability, autism, ataxia, and mixed hyperkinetic movement disorder including severe generalized dystonia, in a proband who remained etiologically undiagnosed despite exhaustive testing. We performed trio whole-exome sequencing to identify a de novo essential splice-site variant (c.981+1G>A) in CAMK4, encoding CaMKIV. Through in silico evaluation and cDNA analyses, we demonstrated that c.981+1G>A alters CAMK4 pre-mRNA processing and results in a stable mRNA transcript containing a 77-nt out-of-frame deletion and a premature termination codon within the last exon. The expected protein, p.Lys303Serfs*28, exhibits selective loss of the carboxy-terminal regulatory domain of CaMKIV and bears striking structural resemblance to previously reported synthetic mutants that confer constitutive CaMKIV activity. Biochemical studies in proband-derived cells confirmed an activating effect of c.981+1G>A and indicated that variant-induced excessive CaMKIV signaling is sensitive to pharmacological manipulation. Additionally, we found that variants predicted to cause selective depletion of CaMKIV's regulatory domain are unobserved in diverse catalogs of human variation, thus revealing that c.981+1G>A is a unique molecular event. We propose that our proband's phenotype is explainable by a dominant CAMK4 splice-disrupting mutation that acts through a gain-of-function mechanism. Our findings highlight the importance of CAMK4 in human neurodevelopment, provide a foundation for future clinical research of CAMK4, and suggest the CaMKIV signaling pathway as a potential drug target in neurological disease.

• MeSH
• aktivační mutace genetika   MeSH
• cerebelární ataxie genetika   MeSH
• exom MeSH
• exony genetika   MeSH
• fenotyp MeSH
• hyperkineze genetika   MeSH
• lidé MeSH
• mentální retardace genetika   MeSH
• mutace MeSH
• nesmyslný kodon genetika   MeSH
• posunová mutace genetika   MeSH
• proteinkinasa závislá na vápníku a kalmodulinu typ 4 genetika   metabolismus   MeSH
• rodokmen MeSH
• sekvenování exomu MeSH
• sestřih RNA genetika   MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH
• práce podpořená grantem MeSH

INTRODUCTION: Height, body mass index (BMI), and weight gain are associated with breast cancer risk in the general population. It is unclear whether these associations also exist for carriers of pathogenic variants in the BRCA1 or BRCA2 genes. PATIENTS AND METHODS: An international pooled cohort of 8091 BRCA1/2 variant carriers was used for retrospective and prospective analyses separately for premenopausal and postmenopausal women. Cox regression was used to estimate breast cancer risk associations with height, BMI, and weight change. RESULTS: In the retrospective analysis, taller height was associated with risk of premenopausal breast cancer for BRCA2 variant carriers (HR 1.20 per 10 cm increase, 95% CI 1.04-1.38). Higher young-adult BMI was associated with lower premenopausal breast cancer risk for both BRCA1 (HR 0.75 per 5 kg/m2, 95% CI 0.66-0.84) and BRCA2 (HR 0.76, 95% CI 0.65-0.89) variant carriers in the retrospective analysis, with consistent, though not statistically significant, findings from the prospective analysis. In the prospective analysis, higher BMI and adult weight gain were associated with higher postmenopausal breast cancer risk for BRCA1 carriers (HR 1.20 per 5 kg/m2, 95% CI 1.02-1.42; and HR 1.10 per 5 kg weight gain, 95% CI 1.01-1.19, respectively). CONCLUSION: Anthropometric measures are associated with breast cancer risk for BRCA1 and BRCA2 variant carriers, with relative risk estimates that are generally consistent with those for women from the general population.

• MeSH
• dospělí MeSH
• genetická predispozice k nemoci MeSH
• geny BRCA2 * MeSH
• heterozygot MeSH
• hmotnostní přírůstek genetika   MeSH
• index tělesné hmotnosti MeSH
• lidé MeSH
• nádory prsu * epidemiologie   genetika   patologie   MeSH
• protein BRCA1 genetika   MeSH
• protein BRCA2 genetika   MeSH
• retrospektivní studie MeSH
• riziko MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH

Epileptic encephalopathies are a phenotypically and genetically heterogeneous group of severe epilepsies accompanied by intellectual disability and other neurodevelopmental features. Using next-generation sequencing, we identified four different de novo mutations in KCNA2, encoding the potassium channel KV1.2, in six isolated patients with epileptic encephalopathy (one mutation recurred three times independently). Four individuals presented with febrile and multiple afebrile, often focal seizure types, multifocal epileptiform discharges strongly activated by sleep, mild to moderate intellectual disability, delayed speech development and sometimes ataxia. Functional studies of the two mutations associated with this phenotype showed almost complete loss of function with a dominant-negative effect. Two further individuals presented with a different and more severe epileptic encephalopathy phenotype. They carried mutations inducing a drastic gain-of-function effect leading to permanently open channels. These results establish KCNA2 as a new gene involved in human neurodevelopmental disorders through two different mechanisms, predicting either hyperexcitability or electrical silencing of KV1.2-expressing neurons.

• MeSH
• dítě MeSH
• dospělí MeSH
• draslíkový kanál Kv1.2 genetika   MeSH
• epilepsie genetika   MeSH
• genetická predispozice k nemoci MeSH
• kohortové studie MeSH
• kojenec MeSH
• křeče u dětí genetika   MeSH
• lidé MeSH
• mladý dospělý MeSH
• mutace * MeSH
• předškolní dítě MeSH
• rodokmen MeSH
• sekvence aminokyselin MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• kojenec MeSH
• lidé MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH

UNLABELLED: Chromosomal aberrations are important prognostic factors in multiple myeloma diagnosis. We evaluated the effect common high-risk chromosomal aberrations in a cohort of 102 patients with relapsed disease treated with bortezomib or thalidomide. Our results showed that patients treated with thalidomide with a gain(1)(q21) had inferior survival compared with the bortezomib group. Therefore, bortezomib-based regiments are more effective for patients with relapsed multiple myeloma with an incidence of gain in the gain(1)(q21). BACKGROUND: Prognostic impact of specific chromosomal aberrations in patients with relapsed multiple myeloma (MM) treated with the novel agents is briefly described. PATIENTS AND METHODS: We analyzed the prognostic value of an extended panel of chromosomal aberrations [del(13)(q14), del(17)(p13), t(4;14)(p16;q32), gain(1)(q21), and hyperdiploidy] by using the technique of interphase fluorescence in situ hybridization in a cohort of 102 patients with relapsed MM treated with thalidomide- or bortezomib-based protocols. RESULTS: The gain(1)(q21) had a negative impact on overall survival for patients with MM treated with thalidomide (15.7 vs. 41.3 months; P = .004). Moreover, we confirmed the negative impact of the cumulative effect of 2 or more cytogenetic changes that occur simultaneously on the overall survival in the thalidomide group (20.3 months vs. not yet reached; P = .039). We did not find any significant impact of the aberrations studied on overall survival in the bortezomib cohort of patients. CONCLUSION: We conclude that bortezomib-based protocols are able to partially overcome the negative prognostic impact of the tested chromosomal abnormalities in patients with relapsed MM.

• MeSH
• chromozomální aberace MeSH
• dospělí MeSH
• incidence MeSH
• kyseliny boronové terapeutické užití   MeSH
• lidé středního věku MeSH
• lidé MeSH
• lidské chromozomy, pár 1 * MeSH
• mnohočetný myelom farmakoterapie   genetika   mortalita   patologie   MeSH
• prognóza MeSH
• protinádorové látky terapeutické užití   MeSH
• pyraziny terapeutické užití   MeSH
• recidiva MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• staging nádorů MeSH
• thalidomid terapeutické užití   MeSH
• trizomie * MeSH
• výsledek terapie MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

The DNA damage response (DDR) pathway and its core component tumor suppressor p53 block cell cycle progression after genotoxic stress and represent an intrinsic barrier preventing cancer development. The serine/threonine phosphatase PPM1D/Wip1 inactivates p53 and promotes termination of the DDR pathway. Wip1 has been suggested to act as an oncogene in a subset of tumors that retain wild-type p53. In this paper, we have identified novel gain-of-function mutations in exon 6 of PPM1D that result in expression of C-terminally truncated Wip1. Remarkably, mutations in PPM1D are present not only in the tumors but also in other tissues of breast and colorectal cancer patients, indicating that they arise early in development or affect the germline. We show that mutations in PPM1D affect the DDR pathway and propose that they could predispose to cancer.

• MeSH
• buněčný cyklus MeSH
• G1 fáze * MeSH
• genetická predispozice k nemoci MeSH
• HeLa buňky MeSH
• lidé MeSH
• MFC-7 buňky MeSH
• mutace * MeSH
• nádorové buněčné linie MeSH
• nádorový supresorový protein p53 genetika   MeSH
• nádory metabolismus   MeSH
• poškození DNA MeSH
• proteinfosfatasy genetika   fyziologie   MeSH
• regulace genové exprese u nádorů * MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Banana (Musa spp.) is an important crop in the African Great Lakes region in terms of income and food security, with the highest per capita consumption worldwide. Pests, diseases and climate change hamper sustainable production of bananas. New breeding tools with increased crossbreeding efficiency are being investigated to breed for resistant, high yielding hybrids of East African Highland banana (EAHB). These include genomic selection (GS), which will benefit breeding through increased genetic gain per unit time. Understanding trait variation and the correlation among economically important traits is an essential first step in the development and selection of suitable GS models for banana. In this study, we tested the hypothesis that trait variations in bananas are not affected by cross combination, cycle, field management and their interaction with genotype. A training population created using EAHB breeding material and its progeny was phenotyped in two contrasting conditions. A high level of correlation among vegetative and yield related traits was observed. Therefore, genomic selection models could be developed for traits that are easily measured. It is likely that the predictive ability of traits that are difficult to phenotype will be similar to less difficult traits they are highly correlated with. Genotype response to cycle and field management practices varied greatly with respect to traits. Yield related traits accounted for 31-35% of principal component variation under low and high input field management conditions. Resistance to Black Sigatoka was stable across cycles but varied under different field management depending on the genotype. The best cross combination was 1201K-1xSH3217 based on selection response (R) of hybrids. Genotyping using simple sequence repeat (SSR) markers revealed that the training population was genetically diverse, reflecting a complex pedigree background, which was mostly influenced by the male parents.

• MeSH
• banánovník genetika   MeSH
• fenotyp MeSH
• genetická variace * MeSH
• genom rostlinný MeSH
• genomika MeSH
• genotyp MeSH
• lokus kvantitativního znaku genetika   MeSH
• mikrosatelitní repetice genetika   MeSH
• populační genetika * MeSH
• selekce (genetika) * MeSH
• Publikační typ
• časopisecké články MeSH
• Geografické názvy
• Afrika MeSH

Array-based comparative genomic hybridization (arrayCGH) studies in chronic lymphocytic leukemia (CLL) have revealed novel recurrent chromosomal imbalances, such as a gain of chromosome 2p. However, a detailed cytogenetic analysis of the 2p gain region has not been elucidated. Here, we present cytogenetic and molecular cytogenetic analysis of 16 such cases selected from a group of 200 patients with CLL based on CGH and/or arrayCGH data. We revealed significant heterogeneity of the region of gain on 2p in CLL, including a new recurrent aberration: the dicentric chromosome, dic(2;18). In our cases, the region of gain involved three genes (MYCN, REL, and ALK) and was associated with an unmutated IgVH status in 14 out of 16 cases. We consider this aberration clinically important in CLL and suggest that an examination of the gene(s) located in region of gain should be included in the routine fluorescence in situ hybridization screening method used for patients with CLL.

• MeSH
• centromera genetika   MeSH
• chromozomální aberace MeSH
• chronická lymfatická leukemie genetika   patologie   MeSH
• dospělí MeSH
• genetická heterogenita MeSH
• hybridizace in situ fluorescenční MeSH
• karyotypizace MeSH
• lidé středního věku MeSH
• lidé MeSH
• lidské chromozomy, pár 2 genetika   MeSH
• senioři MeSH
• srovnávací genomová hybridizace MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH