Around 180 genes have been associated with congenital anomalies of the kidney and urinary tract (CAKUT) in mice, and represent promising novel candidate genes for human CAKUT. In whole-exome sequencing data of two siblings with genetically unresolved multicystic dysplastic kidneys (MCDK), prioritizing variants in murine CAKUT-associated genes yielded a rare variant in the teashirt zinc finger homeobox 3 (TSHZ3) gene. Therefore, the role of TSHZ3 in human CAKUT was assessed. Twelve CAKUT patients from 9/301 (3%) families carried five different rare heterozygous TSHZ3 missense variants predicted to be deleterious. CAKUT patients with versus without TSHZ3 variants were more likely to present with hydronephrosis, hydroureter, ureteropelvic junction obstruction, MCDK, and with genital anomalies, developmental delay, overlapping with the previously described phenotypes in Tshz3-mutant mice and patients with heterozygous 19q12-q13.11 deletions encompassing the TSHZ3 locus. Comparable with Tshz3-mutant mice, the smooth muscle layer was disorganized in the renal pelvis and thinner in the proximal ureter of the nephrectomy specimen of a TSHZ3 variant carrier compared to controls. TSHZ3 was expressed in the human fetal kidney, and strongly at embryonic day 11.5-14.5 in mesenchymal compartments of the murine ureter, kidney, and bladder. TSHZ3 variants in a 5' region were more frequent in CAKUT patients than in gnomAD samples (p < 0.001). Mutant TSHZ3 harboring N-terminal variants showed significantly altered SOX9 and/or myocardin binding, possibly adversely affecting smooth muscle differentiation. Our results provide evidence that heterozygous TSHZ3 variants are associated with human CAKUT, particularly MCDK, hydronephrosis, and hydroureter, and, inconsistently, with specific extrarenal features, including genital anomalies.

• MeSH
• dítě MeSH
• heterozygot * MeSH
• homeodoménové proteiny genetika   MeSH
• kojenec MeSH
• ledviny abnormality   metabolismus   MeSH
• lidé MeSH
• missense mutace MeSH
• močové ústrojí abnormality   metabolismus   MeSH
• multicystické dysplastické ledviny genetika   MeSH
• myši MeSH
• předškolní dítě MeSH
• transkripční faktory genetika   MeSH
• urogenitální abnormality genetika   patologie   MeSH
• vezikoureterální reflux MeSH
• zvířata MeSH
• Check Tag
• dítě MeSH
• kojenec MeSH
• lidé MeSH
• mužské pohlaví MeSH
• myši MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

BACKGROUND: There exist multiple extraintestinal manifestations of inflammatory bowel disease. The most common are arthritis, aphthous stomatitis, or uveitis. Aseptic abscess syndrome is not usually included among these extraintestinal manifestations. In our case report, we present a rare case of aseptic abscess syndrome as the first manifestation of inflammatory bowel disease. CASE PRESENTATION: We present the case of a 10-year-old girl whose only initial medical issue was recurrent submandibular lymphadenitis unresponsive to standard antibiotic therapy. A broad differential diagnosis was initiated to exclude an infectious etiology. Eventually, it was necessary to proceed with extirpation of the suspected lymph node. Histological examination showed suppurative granulomatous inflammation, so it was further examined for noninfectious cause. Blood tests revealed positivity of ASCA antibodies (Anti-Saccharomyces cerevisiae) in both IgA and IgG classes. Despite absence of typical gastrointestinal symptoms, bowel ultrasound was performed, followed by magnetic resonance enterography. Both showed inflammatory changes in the terminal ileum. Subsequent endoscopy of the gastrointestinal tract and histological examination of biopsy specimens confirmed a diagnosis of Crohn's disease with terminal ileum and rectum involvement. A standard treatment based on current guidelines led to remission without recurrence of lymphadenitis. CONCLUSIONS: In cases of lymphadenitis that does not respond to standard antibiotic treatment, diagnosis of aseptic abscess syndrome should be considered as a potential etiology and, subsequently, inflammatory bowel disease should be investigated, given that this syndrome is associated with inflammatory bowel disease in as many as 70% of cases. To our knowledge, this is the first published case report describing aseptic abscess syndrome affecting cervical lymph nodes as an extraintestinal manifestation of pediatric Crohn's disease.

• MeSH
• absces * etiologie   diagnóza   MeSH
• Crohnova nemoc * komplikace   diagnóza   MeSH
• diferenciální diagnóza MeSH
• dítě MeSH
• lidé MeSH
• lymfadenitida * etiologie   diagnóza   MeSH
• syndrom MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH

Stanovení koncentrace natriuretických peptidů patří k hlavním pomocným laboratorním metodám diagnostiky srdečního selhání. V současné době se doporučuje stanovení koncentrace N-terminálního fragmentu prohormonu natriuretického peptidu typu B (NT-proBNP) v krvi. Vyšetření NT-proBNP slouží k diagnostice a prognostické stratifikaci pacientů s akutním a chronickým srdečním selháním a v diferenciální diagnostice akutní dušnosti na pohotovosti. Patří mezi významné metody hodnocení rizika u pacientů s akutním infarktem myokardu (IM) a u plicní embolie. V poslední době se objevují důkazy pro to, že stanovení NT-proBNP může vést k předpovědi srdečního selhání u osob s vysokým rizikem kardiovaskulárních onemocnění.

Examination of natriuretic peptides concentration belongs to the main auxiliary methods of the heart failure diagnosis. I tis currently recommend the determination of the N-terminal fragment of the B-type natriuretic peptide in the blood. The determination of NT-proBNP is used for diagnosis and prognostic stratification of the patients with acute and chronic heart failure and in the differential diagnosis in acute dyspnea at an emergency department. It belongs to important methods of risk assessment in patients with acute myocardial infarction and pulmonary emboly. Recently there is emerging evidence that the determination of NT-proBNP may predict heart failure in patients at high cardiovascular risk.

• Klíčová slova
• NT-proBNP,
• MeSH
• diferenciální diagnóza MeSH
• dyspnoe diagnóza   etiologie   MeSH
• lidé MeSH
• natriuretické peptidy * analýza   fyziologie   krev   MeSH
• natriuretický peptid typu B analýza   krev   MeSH
• rizikové faktory kardiovaskulárních chorob MeSH
• srdeční selhání * diagnóza   krev   prevence a kontrola   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• práce podpořená grantem MeSH
• přehledy MeSH

BACKGROUND: Tick-borne encephalitis (TBE) is the most common tick-borne viral infection in Eurasia. Outcomes range from asymptomatic infection to fatal encephalitis, with host genetics likely playing a role. BALB/c mice have intermediate susceptibility to TBE virus (TBEV) and STS mice are highly resistant, whereas the recombinant congenic strain CcS-11, which carries 12.5% of the STS genome on the BALB/c background, is more susceptible than BALB/c mice. In the present study, we employed these genetically distinct mouse models to investigate the host response to TBEV infection in both peripheral macrophages, one of the initial target cell populations, and the brain, the terminal target organ of the virus. METHODS: TBEV growth and the production of key cytokines and chemokines were measured and compared in macrophages derived from BALB/c, CcS-11, and STS mice. In addition, brains from these TBEV-infected mouse strains underwent in-depth transcriptomic analysis. RESULTS: Virus production in BALB/c and CcS-11 macrophages exhibited similar kinetics 24 and 48 h post-infection (hpi), but CcS-11 macrophages yielded significantly higher titers 72 hpi. Macrophages from both sensitive strains demonstrated elevated chemokine and proinflammatory cytokine production upon infection, whereas the resistant strain, STS, showed no cytokine/chemokine activation. Transcriptomic analysis of brain tissue demonstrated that the genetic background of the mouse strains dictated their transcriptional response to infection. The resistant strain exhibited a more robust cell-mediated immune response, whereas both sensitive strains showed a less effective cell-mediated response but increased cytokine signaling and signs of demyelination, with loss of oligodendrocytes. CONCLUSIONS: Our findings suggest that variations in susceptibility linked to host genetic background correspond with distinct host responses, both in the periphery upon virus entry into the organism and in the brain, the target organ of the virus. These results provide insights into the influence of host genetics on the clinical trajectory of TBE.

• MeSH
• cytokiny * metabolismus   genetika   MeSH
• genotyp MeSH
• klíšťová encefalitida * imunologie   virologie   genetika   MeSH
• makrofágy * imunologie   virologie   MeSH
• mozek * virologie   imunologie   MeSH
• myši inbrední BALB C * MeSH
• myši MeSH
• viry klíšťové encefalitidy * genetika   fyziologie   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

TP73 is a member of the TP53 gene family and produces N- and C-terminal protein isoforms through alternative promoters, alternative translation initiation and alternative splicing. Most notably, p73 protein isoforms may either contain a p53-like transactivation domain (TAp73 isoforms) or lack this domain (ΔTAp73 isoforms) and these variants have opposing or independent functions. To date, there is a lack of well-characterised isoform-specific p73 antibodies. Here, we produced polyclonal and monoclonal antibodies to N-terminal p73 variants and the C-terminal p73α isoform, the most common variant in human tissues. These reagents show that TAp73 is a marker of multiciliated epithelial cells, while ΔTAp73 is a marker of non-proliferative basal/reserve cells in squamous epithelium. We were unable to detect ΔNp73 variant proteins, in keeping with recent data that this is a minor form in human tissues. Most cervical squamous cell carcinomas (79%) express p73α, and the distribution of staining in basal cells correlated with lower tumour grade. TAp73 was found in 17% of these tumours, with a random distribution and no association with clinicopathological features. These data indicate roles for ΔTAp73 in maintaining a non-proliferative state of undifferentiated squamous epithelial cells and for TAp73 in the production of differentiated multiciliated cells.

• MeSH
• epitelové buňky metabolismus   MeSH
• lidé MeSH
• monoklonální protilátky MeSH
• nádorové buněčné linie MeSH
• nádory děložního čípku metabolismus   patologie   genetika   MeSH
• nádory metabolismus   patologie   genetika   MeSH
• protein - isoformy * metabolismus   genetika   MeSH
• protein p73 * metabolismus   genetika   MeSH
• spinocelulární karcinom metabolismus   patologie   genetika   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Recently, we have identified a recessive mutation, an abnormal coat appearance in the BXH6 strain, a member of the HXB/BXH set of recombinant inbred (RI) strains. The RI strains were derived from the spontaneously hypertensive rat (SHR) and Brown Norway rat (BN-Lx) progenitors. Whole genome sequencing of the mutant rats identified the 195875980 G/A mutation in the tuftelin 1 (Tuft1) gene on chromosome 2, which resulted in a premature stop codon. Compared with wild-type BXH6 rats, BXH6-Tuft1 mutant rats exhibited lower body weight due to reduced visceral fat and ectopic fat accumulation in the liver and heart. Reduced adiposity was associated with decreased serum glucose and insulin and increased insulin-stimulated glycogenesis in skeletal muscle. In addition, mutant rats had lower serum monocyte chemoattractant protein-1 and leptin levels, indicative of reduced inflammation. Analysis of the liver proteome identified differentially expressed proteins from fatty acid metabolism and β-oxidation, peroxisomes, carbohydrate metabolism, inflammation, and proteasome pathways. These results provide evidence for the important role of the Tuft1 gene in the regulation of lipid and glucose metabolism and suggest underlying molecular mechanisms.NEW & NOTEWORTHY A new spontaneous mutation, abnormal hair appearance in the rat, has been identified as a nonfunctional tuftelin 1 (Tuft1) gene. The pleiotropic effects of this mutation regulate glucose and lipid metabolism. Analysis of the liver proteome revealed possible molecular mechanisms for the metabolic effects of the Tuft1 gene.

• MeSH
• glukosa * metabolismus   MeSH
• inzulin metabolismus   MeSH
• krysa rodu rattus MeSH
• metabolismus lipidů genetika   MeSH
• nesmyslný kodon * genetika   MeSH
• potkani inbrední BN MeSH
• potkani inbrední SHR MeSH
• proteom metabolismus   MeSH
• zánět MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Atypický (komplementem mediovaný) hemolyticko-uremický syndrom (aHUS) je vzácné onemocnění s vysokým rizikem závažného orgánového postižení a smrti. Řadí se mezi trombotické mikroangiopatie a je charakterizován kombinací neimunitní hemolytické anemie, konsumpční trombocytopenie a poškození endotelu s následnou poruchou mikrocirkulace vedoucí k ischemickému poškození cílových orgánů, zejména ledvin. Laboratorní a klinické charakteristiky trombotických mikroangiopatií však splňuje celá řada stavů různé etiologie, což značně ztěžuje diferenciální diagnostiku tohoto onemocnění. Příčinou aHUS je geneticky podmíněné či získané narušení rovnováhy mezi aktivátory a regulátory alternativní dráhy komplementu, vedoucí k její trvalé aktivaci, tvorbě terminálních lytických komplexů a orgánovému postižení. U více než 50 % nemocných s aHUS je možné identifikovat mutaci v genech pro komplementární faktory, asi u 5–10 % pak nacházíme protilátky proti složkám komplementu (resp. faktoru H). U nositelů mutací může díky inkompletní genetické penetranci klinické onemocnění propuknout až v přítomnosti spouštěčů amplifikace komplementu, jako jsou např. infekce, operace či těhotenství. Identifikace kauzální mutace není pro diagnózu aHUS nezbytná, je ale důležitá pro stanovení prognózy, rizika relapsu při přerušení léčby či po transplantaci ledviny. Prognóza tohoto onemocnění se v posledních letech dramaticky zlepšila díky možnosti specifické léčby spočívající v podávání inhibitorů C5 složky komplementu, přesto zůstává limitována zejména rychlou a správnou diagnostikou a včasným zahájením léčby. Dosud nevyřešenými otázkami jsou také délka léčby, podmínky jejího ukončení či přerušení a také další sledování pacientů po prodělané atace tohoto vzácného onemocnění.

Atypical (or complement-mediated) haemolytic uremic syndrome (aHUS) is a rare disease with a high risk of severe organ damage and death. As a representative of thrombotic microangiopathies, it is defined by microangiopathic haemolytic anaemia, thrombocytopenia and endothelial cell damage resulting in ischemic target organ injury, especially kidney failure. A variety of clinical scenarios can have the features of thrombotic microangiopathies thus impeding the differential diagnosis of the underlying condition. aHUS is caused by a genetic or acquired defect in the regulation of the alternative complement pathway resulting in its persistent activation, formation of terminal membrane attacking complexes, microvascular endothelial damage and ischemic organ injury. Roughly 50% of patients have rare germline variants in complement genes, detection of antibodies against complement factors (CFH) is much less common. In carriers of these genetic mutations, due to the incomplete genetic penetrance of aHUS, a clinically significant disease often requires a complement-amplifying trigger such as infection, surgery or pregnancy. Identification of germline variants is not necessary for the diagnosis of aHUS; however, it is important for the estimation of prognosis and risk of relapse after treatment termination or kidney transplant. Thanks to new specific treatment options represented by complement inhibitors, the prognosis of patients with aHUS has improved rapidly, however, it remains dependent on rapid and correct diagnostics and early treatment initiation. Further discussed and unsolved questions relate to treatment duration and the possibility of its termination as well as further management and follow-up of patients after the episode of aHUS.

• Klíčová slova
• eculizumab,
• MeSH
• atypický hemolyticko-uremický syndrom * diagnóza   patofyziologie   terapie   MeSH
• diferenciální diagnóza MeSH
• humanizované monoklonální protilátky aplikace a dávkování   škodlivé účinky   terapeutické užití   MeSH
• inhibitory komplementu terapeutické užití   MeSH
• lidé MeSH
• mutace genetika   MeSH
• plazmaferéza MeSH
• renální insuficience etiologie   MeSH
• trombotické mikroangiopatie klasifikace   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• přehledy MeSH

Ganglioneurom je vzácný, benigní, terminálně diferencovaný a pomalu rostoucí nádor autonomního nervového systému, který obvykle vzniká ze sympatických gangliových buněk. Většina z nich je asymptomatická a nachází se náhodně. Uvádíme poměrně vzácný případ ganglioneuromu zadního mediastina, který byl souběžně diagnostikován při vstupním zobrazovacím vyšetření 11leté dívky s akutní lymfoblastickou leukemií (ALL). Histopatologické a histochemické vyšetření bioptických vzorků potvrdily diagnózu ganglioneuromu. Vzhledem k asymptomatickému průběhu, bez propagace nádoru do páteřního kanálu byl zvolen neoperativní management sledováním pomocí zobrazovacích metod. Dívka s akutní leukemií je v celkové remisi, na udržovací léčbě podle protokolu AIEOP-BFM ALL 2017. Kontrolní vyšetření MR hrudníku po 10 měsících potvrdilo stacionární charakter GN bez progrese.

Ganglioneuroma is a rare, benign, terminally differentiated and slow-growing tumour of the autonomic nervous system, usually arising from sympathetic ganglion cells. Most are asymptomatic and found incidentally. We report a relatively rare case of a ganglioneuroma of the posterior mediastinum that was diagnosed simultaneously on initial imaging in an 11-year-old girl with acute lymphoblastic leukemia (ALL). Histopathological and histochemical examination of biopsy speci­mens confirmed the diagnosis of ganglioneuroma. Because of an asymptomatic course, without tumor propagation into the spinal canal, a non-operative mana­gement by imaging follow-up was chosen. The girl with acute leukemia is in complete remission, on maintenance treatment according to the AIEOP-BFM ALL 2017 protocol. The control chest MRI after 10 months confirmed the stationary character of GN without progression.

• MeSH
• akutní lymfatická leukemie * diagnóza   farmakoterapie   MeSH
• diagnostické zobrazování metody   MeSH
• dítě MeSH
• ganglioneurom * diagnostické zobrazování   diagnóza   klasifikace   patologie   MeSH
• lidé MeSH
• magnetická rezonanční tomografie metody   MeSH
• management nemoci MeSH
• nádory mediastina diagnóza   klasifikace   MeSH
• souběh chronických nemocí klasifikace   MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• kazuistiky MeSH
• práce podpořená grantem MeSH

The present study was undertaken to provide more information on the peripheral RNA containing ring of ringshaped nucleoli (RSNo). Human lymphocytes of blood donors and patients suffering from B chronic lymphocytic leukemia mostly characterized by RSNo represented very convenient cell models for such study. According to the light microscopy the peripheral RNA ring possessed several highly condensed foci. Such regions represented accumulated dense RNA fibrillar components (DFCs) seen by the electron microscopy. In contrary, the incidence of dense granular RNA-containing components (GCs) in surrounding portions of the RNA ring was small. Thus, the structural and morphological organization of the peripheral RNA ring of RSNo apparently reflects sites of micro-segregated foci of DFCs and a small incidence of GCs. That structural organization of the peripheral RNA ring of RSNo appeared to be a prerequisite for further regressive nucleolar changes resulting in the development of micronucleoli in terminal lymphocytes.

• MeSH
• buněčné jadérko * ultrastruktura   patologie   MeSH
• chronická lymfatická leukemie * patologie   MeSH
• dárci krve * MeSH
• lidé MeSH
• lymfocyty * patologie   MeSH
• RNA MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

INTRODUCTION: Chronic effects of noninvasive ventilation on myocardial function in patients with obesity hypoventilation syndrome (OHS) are scarcely understood. The aim of the present study was to evaluate the long-term effects of volume-targeted bilevel positive airway pressure ventilation (BiPAP) on cardiac parameters and myocardial biomarkers in patients with OHS. METHODS: Clinically stable patients with OHS referred to the tertiary center for the initiation of long-term BiPAP therapy were consecutively enrolled. At baseline, all participants underwent overnight cardiorespiratory polygraphy. BiPAP therapy using volume-targeted spontaneous/timed mode delivered via an oro-nasal mask was initiated. Beat-to-beat noninvasive monitoring by impedance cardiography was used to assess heart function at baseline and after 3 and 12 months of BiPAP use. Serum troponin 1, N-Terminal Pro-B-Type Natriuretic Peptide (NT-ProBNP), tumor necrosis factor-alpha (TNF-α), and interleukin-6 (IL-6) were monitored. RESULTS: Thirteen patients (10 men; mean age, 55.8 ± 9.8 years; mean body mass index of 47.8 ± 5.9 kg/m2) were recruited. From baseline to 3, and to 12 months of BiPAP use, left ventricular stroke volume (SV), ejection time (LVET), and ejection time index significantly increased (P = 0.030; P < 0.001; P = 0.003, respectively), while heart rate and systolic time ratio significantly decreased (P = 0.004; P = 0.034, respectively). Reductions in serum NT-proBNP, IL-6 and TNF-α were observed (P = 0.045; P = 0.018; P = 0.003, respectively). No significant changes in serum troponin were detected throughout the study. CONCLUSIONS: The present findings of increased SV, in association with lengthening of LVET, reductions of NT-proBNP and reductions in circulatory inflammatory markers in patients with stable OHS and chronic moderate-to-severe daytime hypercapnia treated with BiPAP over 1 year support the role of this therapeutic mode in such patients.

• MeSH
• biologické markery * krev   MeSH
• časové faktory MeSH
• hypoventilační syndrom při obezitě * terapie   patofyziologie   MeSH
• interleukin-6 * krev   MeSH
• kardiografie impedanční MeSH
• lidé středního věku MeSH
• lidé MeSH
• natriuretický peptid typu B * krev   MeSH
• neinvazivní ventilace * metody   MeSH
• peptidové fragmenty * krev   MeSH
• senioři MeSH
• TNF-alfa krev   MeSH
• troponin I krev   MeSH
• ventilace umělá s výdechovým přetlakem metody   MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH