Cystathionine β-synthase (CBS) deficiency has a wide clinical spectrum, ranging from neurodevelopmental problems, lens dislocation and marfanoid features in early childhood to adult onset disease with predominantly thromboembolic complications. We have analysed clinical and laboratory data at the time of diagnosis in 328 patients with CBS deficiency from the E-HOD (European network and registry for Homocystinurias and methylation Defects) registry. We developed comprehensive criteria to classify patients into four groups of pyridoxine responsivity: non-responders (NR), partial, full and extreme responders (PR, FR and ER, respectively). All groups showed overlapping concentrations of plasma total homocysteine while pyridoxine responsiveness inversely correlated with plasma/serum methionine concentrations. The FR and ER groups had a later age of onset and diagnosis and a longer diagnostic delay than NR and PR patients. Lens dislocation was common in all groups except ER but the age of dislocation increased with increasing responsiveness. Developmental delay was commonest in the NR group while no ER patient had cognitive impairment. Thromboembolism was the commonest presenting feature in ER patients, whereas it was least likely at presentation in the NR group. This probably is due to the differences in ages at presentation: all groups had a similar number of thromboembolic events per 1000 patient-years. Clinical severity of CBS deficiency depends on the degree of pyridoxine responsiveness. Therefore, a standardised pyridoxine-responsiveness test in newly diagnosed patients and a critical review of previous assessments is indispensable to ensure adequate therapy and to prevent or reduce long-term complications.
- MeSH
- cystathionin-beta-synthasa nedostatek MeSH
- dítě MeSH
- dospělí MeSH
- fenotyp MeSH
- homocystinurie diagnóza farmakoterapie enzymologie MeSH
- kojenec MeSH
- lidé středního věku MeSH
- lidé MeSH
- lineární modely MeSH
- methionin krev MeSH
- mladiství MeSH
- mladý dospělý MeSH
- opožděná diagnóza MeSH
- předškolní dítě MeSH
- pyridoxin terapeutické užití MeSH
- registrace MeSH
- senioři MeSH
- stupeň závažnosti nemoci MeSH
- Check Tag
- dítě MeSH
- dospělí MeSH
- kojenec MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- předškolní dítě MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Geografické názvy
- Evropa MeSH
Genetic discoveries of Alzheimer's disease are the drivers of our understanding, and together with polygenetic risk stratification can contribute towards planning of feasible and efficient preventive and curative clinical trials. We first perform a large genetic association study by merging all available case-control datasets and by-proxy study results (discovery n = 409,435 and validation size n = 58,190). Here, we add six variants associated with Alzheimer's disease risk (near APP, CHRNE, PRKD3/NDUFAF7, PLCG2 and two exonic variants in the SHARPIN gene). Assessment of the polygenic risk score and stratifying by APOE reveal a 4 to 5.5 years difference in median age at onset of Alzheimer's disease patients in APOE ɛ4 carriers. Because of this study, the underlying mechanisms of APP can be studied to refine the amyloid cascade and the polygenic risk score provides a tool to select individuals at high risk of Alzheimer's disease.
- MeSH
- Alzheimerova nemoc epidemiologie genetika patologie MeSH
- amyloidový prekurzorový protein beta genetika metabolismus MeSH
- apolipoproteiny E genetika MeSH
- celogenomová asociační studie MeSH
- datové soubory jako téma MeSH
- genetická predispozice k nemoci MeSH
- heterozygot MeSH
- hodnocení rizik metody MeSH
- jednonukleotidový polymorfismus MeSH
- kohortové studie MeSH
- lidé středního věku MeSH
- lidé MeSH
- multifaktoriální dědičnost * MeSH
- následné studie MeSH
- rizikové faktory MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- studie případů a kontrol MeSH
- věk při počátku nemoci MeSH
- Check Tag
- 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
- Research Support, N.I.H., Extramural MeSH
- validační studie MeSH
Diagnosis of salivary gland neoplasms is often challenging due to their high morphological diversity and overlaps. Several recurrent molecular alterations have been described recently, which can serve as powerful diagnostic tools and potential therapeutic targets (e.g. NTRK or RET fusions). However, current sequential molecular testing can be expensive and time consuming. In order to facilitate the diagnosis of salivary gland neoplasms, we designed an all-in-one RNA-based next generation sequencing panel suitable for the detection of mutations, fusions and gene expression levels (including NR4A3) of 27 genes involved in salivary gland neoplasms. Here we present the validation of the "SalvGlandDx" panel on FFPE histological specimen including fine needle aspiration (FNA) cell block material, against the standard methods currently used at our institution. In a second part we describe selected unique cases in which the SalvGlandDx panel allowed proper diagnosis and new insights into special molecular characteristics of selected salivary gland tumors. We characterize a unique salivary gland adenocarcinoma harboring a ZCCHC7-NTRK2 fusion, a highly uncommon spindle cell and pseudoangiomatoid adenoid-cystic carcinoma with MYBL1-NFIB fusion, and a purely oncocytic mucoepidermoid carcinoma, whereas diagnosis could be made by detection of a CRTC3-MAML2 rearrangement on the cell block specimen of the FNA. Further, a rare case of a SS18-ZBTB7A rearranged low-grade adenocarcinoma previously described as potential spectrum of microsecretory adenocarcinoma, is reported. In addition, features of six cases within the spectrum of polymorphous adenocarcinoma / cribriform adenocarcinoma of salivary gland including PRKD1 p.E710D mutations and novel fusions involving PRKAR2A-PRKD1, SNX9-PRKD1 and ATL2-PRKD3, are described.
- MeSH
- biopsie MeSH
- fúzní onkogenní proteiny genetika metabolismus MeSH
- hybridizace in situ fluorescenční MeSH
- imunohistochemie metody MeSH
- lidé MeSH
- mutace MeSH
- nádorové biomarkery * MeSH
- nádorové buněčné linie MeSH
- nádory slinných žláz diagnóza farmakoterapie genetika MeSH
- staging nádorů MeSH
- stanovení celkové genové exprese * metody MeSH
- stupeň nádoru MeSH
- vysoce účinné nukleotidové sekvenování * metody MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
Rye (Secale cereale L.) is an exceptionally climate-resilient cereal crop, used extensively to produce improved wheat varieties via introgressive hybridization and possessing the entire repertoire of genes necessary to enable hybrid breeding. Rye is allogamous and only recently domesticated, thus giving cultivated ryes access to a diverse and exploitable wild gene pool. To further enhance the agronomic potential of rye, we produced a chromosome-scale annotated assembly of the 7.9-gigabase rye genome and extensively validated its quality by using a suite of molecular genetic resources. We demonstrate applications of this resource with a broad range of investigations. We present findings on cultivated rye's incomplete genetic isolation from wild relatives, mechanisms of genome structural evolution, pathogen resistance, low-temperature tolerance, fertility control systems for hybrid breeding and the yield benefits of rye-wheat introgressions.
- MeSH
- fyziologická adaptace genetika MeSH
- fyziologický stres MeSH
- genom rostlinný * MeSH
- genová introgrese MeSH
- imunita rostlin genetika MeSH
- karyotyp MeSH
- mapování chromozomů metody MeSH
- pšenice genetika MeSH
- regulace genové exprese u rostlin MeSH
- rostlinné proteiny genetika metabolismus MeSH
- šlechtění rostlin metody MeSH
- zemědělské plodiny genetika imunologie MeSH
- žito genetika imunologie MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- MeSH
- autoimunitní hemolytická anemie farmakoterapie genetika MeSH
- beta-globiny genetika izolace a purifikace MeSH
- bronchiální astma genetika MeSH
- buněčná diferenciace MeSH
- chelátory železa terapeutické užití MeSH
- dítě MeSH
- erythropoetin metabolismus MeSH
- erytrocyty fyziologie MeSH
- erytropoéza genetika MeSH
- kultivované buňky MeSH
- lidé MeSH
- proliferace buněk MeSH
- receptory erythropoetinu metabolismus MeSH
- regulace genové exprese MeSH
- sekvenování exomu MeSH
- signální transdukce MeSH
- stupeň závažnosti nemoci MeSH
- transkripční faktor STAT3 genetika MeSH
- transkripční faktor STAT5 metabolismus MeSH
- zárodečné mutace genetika MeSH
- Check Tag
- dítě MeSH
- lidé MeSH
- Publikační typ
- dopisy MeSH
- práce podpořená grantem MeSH
Epithelial-myoepithelial carcinoma (EMC) can be a challenging diagnosis due to a lack of obvious invasion and bland cytology. We report an unusual case of a low-grade EMC with prominent fibrous stroma, an extensive solid-oncocytic differentiation and limited areas of morphological clearly identifiable characteristic biphasic (tubular) differentiation, clear cells and PAS-positive secretions/calcifications. Both areas were investigated by next generation sequencing (Oncomine comprehensive assay) and revealed a typical concordant HRAS p.Q61R mutation. An additional heterogeneous ARID1A (p.E672*) terminating mutation with loss of heterozygosity, which could be visualized predominantly in the solid-oncocytic differentiation by immunohistochemical loss of ARID1A protein expression, was found. This is the first case of an EMC of the salivary gland to be described with two separate tumor clones involving concordant HRAS and heterogeneous ARID1A mutations. The latter seem to be a "second hit" and was predominantly found in the solid-oncocytic differentiation, suggesting a potential morpho-molecular association.
- MeSH
- DNA vazebné proteiny genetika MeSH
- karcinom genetika patologie MeSH
- lidé MeSH
- mutace MeSH
- myoepiteliální nádor genetika patologie MeSH
- nádory glandulární a epitelové genetika patologie MeSH
- nádory příušní žlázy genetika patologie MeSH
- protoonkogenní proteiny p21(ras) genetika MeSH
- senioři MeSH
- transkripční faktory genetika MeSH
- Check Tag
- lidé MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- kazuistiky MeSH
PURPOSE: Minimal residual disease (MRD) helps to accurately assess when children with late bone marrow relapses of B-cell precursor (BCP) acute lymphoblastic leukemia (ALL) will benefit from allogeneic hematopoietic stem-cell transplantation (allo-HSCT). More detailed dissection of MRD response heterogeneity and the specific genetic aberrations could improve current practice. PATIENTS AND METHODS: MRD was assessed after induction treatment and at different times during relapse treatment until allo-HSCT (indicated in poor responders to induction; MRD ≥ 10-3) for patients being treated for late BCP-ALL bone marrow relapses (n = 413; median follow-up, 9.4 years) in the ALL-REZ BFM 2002 trial/registry (ClinicalTrials.gov identifier: NCT00114348). RESULTS: Patients with both good (MRD < 10-3) and poor responses to induction treatment reached excellent event-free survival (EFS; 72% v 65%) and overall survival (OS; 82% v 74%). Patients with MRD of 10-2 or greater after induction had reduced EFS (56%), and their MRD persisted until allo-HSCT more frequently than it did in patients with MRD of 10-3 or greater to less than 10-2 (P = .037). Patients with 25% or more leukemic blasts after induction (early nonresponders) had the poorest prognosis (EFS, 22%). Interestingly, patients with MRD of 10-3 or greater before allo-HSCT (late nonresponders) still had an EFS of 50% and OS of 63%, which in principle justifies allo-HSCT in these patients. From a panel of selected candidate genes, TP53 alterations (frequency, 8%) were the only genetic alteration with independent prognostic value in any MRD-based response subgroup. CONCLUSION: After induction treatment, MRD-based treatment stratification resulted in excellent survival in patients with late relapsed BCP-ALL. Prognosis could be further improved in very poor responders by intensifying treatment directly after induction. TP53 alterations can be defined as a novel genetic high-risk marker in all MRD response groups in late relapsed BCP-ALL. Here we identified early and late nonresponders to be considered as events in future trials.
- MeSH
- antitumorózní látky terapeutické užití MeSH
- dítě MeSH
- lidé MeSH
- lokální recidiva nádoru farmakoterapie MeSH
- mladiství MeSH
- pre-B-buněčná leukemie klasifikace patologie terapie MeSH
- přežití po terapii bez příznaků nemoci MeSH
- reziduální nádor genetika patologie MeSH
- transplantace hematopoetických kmenových buněk MeSH
- výběr pacientů MeSH
- Check Tag
- dítě MeSH
- lidé MeSH
- mladiství MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- klinické zkoušky MeSH
- práce podpořená grantem MeSH
BACKGROUND: Most patients with multiple sclerosis without previous optic neuritis have thinner retinal layers than healthy controls. We assessed the role of peripapillary retinal nerve fibre layer (pRNFL) thickness and macular volume in eyes with no history of optic neuritis as a biomarker of disability worsening in a cohort of patients with multiple sclerosis who had at least one eye without optic neuritis available. METHODS: In this multicentre, cohort study, we collected data about patients (age ≥16 years old) with clinically isolated syndrome, relapsing-remitting multiple sclerosis, and progressive multiple sclerosis. Patients were recruited from centres in Spain, Italy, France, Germany, Czech Republic, Netherlands, Canada, and the USA, with the first cohort starting in 2008 and the latest cohort starting in 2013. We assessed disability worsening using the Expanded Disability Status Scale (EDSS). The pRNFL thickness and macular volume were assessed once at study entry (baseline) by optical coherence tomography (OCT) and was calculated as the mean value of both eyes without optic neuritis for patients without a history of optic neuritis or the value of the non-optic neuritis eye for patients with previous unilateral optic neuritis. Researchers who did the OCT at baseline were masked to EDSS results and the researchers assessing disability with EDSS were masked to OCT results. We estimated the association of pRNFL thickness or macular volume at baseline in eyes without optic neuritis with the risk of subsequent disability worsening by use of proportional hazards models that included OCT metrics and age, disease duration, disability, presence of previous unilateral optic neuritis, and use of disease-modifying therapies as covariates. FINDINGS: 879 patients with clinically isolated syndrome (n=74), relapsing-remitting multiple sclerosis (n=664), or progressive multiple sclerosis (n=141) were included in the primary analyses. Disability worsening occurred in 252 (29%) of 879 patients with multiple sclerosis after a median follow-up of 2·0 years (range 0·5-5 years). Patients with a pRNFL of less than or equal to 87 μm or less than or equal to 88 μm (measured with Spectralis or Cirrus OCT devices) had double the risk of disability worsening at any time after the first and up to the third years of follow-up (hazard ratio 2·06, 95% CI 1·36-3·11; p=0·001), and the risk was increased by nearly four times after the third and up to the fifth years of follow-up (3·81, 1·63-8·91; p=0·002). We did not identify meaningful associations for macular volume. INTERPRETATION: Our results provide evidence of the usefulness of monitoring pRNFL thickness by OCT for prediction of the risk of disability worsening with time in patients with multiple sclerosis. FUNDING: Instituto de Salud Carlos III.
- MeSH
- dospělí MeSH
- kohortové studie MeSH
- lidé středního věku MeSH
- lidé MeSH
- macula lutea diagnostické zobrazování MeSH
- následné studie MeSH
- nemoci retiny diagnostické zobrazování etiologie MeSH
- neurony sítnice patologie MeSH
- optická koherentní tomografie metody MeSH
- prognóza MeSH
- progrese nemoci * MeSH
- roztroušená skleróza komplikace patofyziologie MeSH
- stupeň závažnosti nemoci 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
Psychiatry is that branch of the medical profession, which deals with the origin, diagnosis, prevention, and management of mental disorders or mental illness, emotional and behavioural disturbances. Thus, a psychiatrist is a trained doctor who has received further training in the field of diagnosing and managing mental illnesses, mental disorders and emotional and behavioural disturbances. This EPA Guidance document was developed following consultation and literature searches as well as grey literature and was approved by the EPA Guidance Committee. The role and responsibilities of the psychiatrist include planning and delivering high quality services within the resources available and to advocate for the patients and the services. The European Psychiatric Association seeks to rise to the challenge of articulating these roles and responsibilities. This EPA Guidance is directed towards psychiatrists and the medical profession as a whole, towards other members of the multidisciplinary teams as well as to employers and other stakeholders such as policy makers and patients and their families.
- MeSH
- duševní poruchy diagnóza terapie MeSH
- hodnocení rizik MeSH
- lidé MeSH
- odborná způsobilost * MeSH
- postoj ke zdraví MeSH
- psychiatrické posuzovací škály MeSH
- psychiatrie normy MeSH
- role odborníka * MeSH
- služby péče o duševní zdraví normy MeSH
- směrnice pro lékařskou praxi jako téma MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
