"00064165" Dotaz Zobrazit nápovědu
Dynamic changes in maternal‒zygotic transition (MZT) require complex regulation of zygote formation, maternal transcript decay, embryonic genome activation (EGA), and cell cycle progression. Although these changes are well described, some key regulatory factors are still elusive. Sirtuin-1 (SIRT1), an NAD+-dependent histone deacetylase, is a versatile driver of MZT via its epigenetic and nonepigenetic substrates. This study focused on the dynamics of SIRT1 in early embryos and its contribution to MZT. A conditional SIRT1-deficient knockout mouse model was used, accompanied by porcine and human embryos. Embryos across mammalian species showed the prominent localization of SIRT1 in the nucleus throughout early embryonic development. Accordingly, SIRT1 interacts with histone H4 on lysine K16 (H4K16) in both mouse and human blastocysts. While maternal SIRT1 is dispensable for MZT, at least one allele of embryonic Sirt1 is required for early embryonic development around the time of EGA. This role of SIRT1 is surprisingly mediated via a transcription-independent mode of action.
- MeSH
- blastocysta metabolismus MeSH
- embryo savčí metabolismus MeSH
- embryonální vývoj * genetika MeSH
- histony metabolismus MeSH
- lidé MeSH
- myši knockoutované * MeSH
- myši MeSH
- prasata MeSH
- sirtuin 1 * metabolismus genetika MeSH
- vývojová regulace genové exprese MeSH
- zvířata MeSH
- zygota * metabolismus MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- myši MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
The amyloid cascade hypothesis postulates that extracellular deposits of amyloid β (Aβ) are the primary and initial cause leading to the full development of Alzheimer's disease (AD) with intracellular neurofibrillary tangles; however, the details of this mechanism have not been fully described until now. Our preliminary data, coming from our day-to-day neuropathology practice, show that the primary location of the hyperphosphorylated tau protein is in the vicinity of the cell membrane of dystrophic neurites. This observation inspired us to formulate a hypothesis that presumes an interaction between low-density lipoprotein receptor-related protein 1 (LRP1) and fibrillar aggregates of, particularly, Aβ42 anchored at the periphery of neuritic plaques, making internalization of the LRP1-Aβ42 complex infeasible and, thus, causing membrane dysfunction, leading to the tauopathy characterized by intracellular accumulation and hyperphosphorylation of the tau protein. Understanding AD as a membrane dysfunction tauopathy may draw attention to new treatment approaches not only targeting Aβ42 production but also, perhaps paradoxically, preventing the formation of LRP1-Aβ42.
- MeSH
- Alzheimerova nemoc * metabolismus patologie etiologie MeSH
- amyloidní beta-protein * metabolismus MeSH
- buněčná membrána metabolismus MeSH
- fosforylace MeSH
- lidé MeSH
- peptidové fragmenty metabolismus MeSH
- protein 1 související s LDL-receptory * metabolismus MeSH
- proteiny tau * metabolismus MeSH
- tauopatie * metabolismus patologie etiologie MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
OBJECTIVES: To assess the diagnostic performance and interobserver agreement of CT pulmonary angiography (CTPA) in the detection of chronic thromboembolic pulmonary hypertension (CTEPH) and its features among radiologists of different levels of experience. MATERIALS AND METHODS: In this retrospective, single-center, single-blinded study, three radiologists with different levels of experience in CT imaging (R1:15 years, R2:6 years, and R3:3 years) evaluated CTPA of 51 patients ultimately diagnosed with CTEPH (European Society of Cardiology guidelines) and 49 patients without CTEPH in random order to assess the presence of CTEPH, its features in the pulmonary artery tree, proximal level of involvement, bronchial artery hypertrophy, mosaic perfusion, and right heart overload. RESULTS: CTPAs of 51 patients with CTEPH (median age, 66 years (IQR 56-72), 28 men) and 49 patients without CTEPH (median age, 65 years (IQR 50-74), 25 men) were evaluated. The sensitivity and specificity for the detection of CTEPH was 100% (all radiologists) and 100% (R1), 96% (R2), and 96% (R3) with almost perfect agreement (κ = 0.95). The sensitivity and specificity for detecting CTEPH by mosaic perfusion would be 89% (95%CI 83-93%) and 81% (74-87%). The level of pulmonary artery involvement was reported with moderate agreement (κ = 0.54, 95%CI 0.40-0.65). Substantial agreement was found in the evaluation of mosaic attenuation (κ = 0.75, 95%CI 0.64-0.84), right heart overload (κ = 0.68, 95%CI 0.56-0.79), and bronchial artery hypertrophy (0.71, 95%CI 0.59-0.82) which were the best predictors of CTEPH (p < 0.0001). CONCLUSIONS: CTPA has high sensitivity and specificity in detecting CTEPH and almost perfect agreement among radiologists of different levels of expertise. CLINICAL RELEVANCE: CT pulmonary angiography can be used as a first-line imaging modality in patients with suspected chronic thromboembolic pulmonary hypertension (CTEPH) even when interpreted by non-CTEPH experts. KEY POINTS: • CT pulmonary angiography has high sensitivity and specificity in detecting chronic thromboembolic pulmonary hypertension (CTEPH) and almost perfect interobserver agreement among radiologists of different levels of expertise. • Substantial agreement exists in the assessment of mosaic attenuation, right heart overload, and bronchial artery hypertrophy, which are the best predictors of CTEPH.
- MeSH
- angiografie metody MeSH
- chronická nemoc MeSH
- hypertrofie MeSH
- jednoduchá slepá metoda MeSH
- lidé středního věku MeSH
- lidé MeSH
- plicní embolie * komplikace diagnostické zobrazování MeSH
- plicní hypertenze * komplikace diagnostické zobrazování MeSH
- počítačová rentgenová tomografie metody MeSH
- retrospektivní 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
PURPOSE: Male breast cancer (MBC) is a rare, but increasingly common disease, and lacks prospective studies. Collaborative efforts are needed to understand and address MBC, including its prognosis, in different countries. METHODS: We retrospectively reviewed the clinical, histopathological, and molecular-genetic characteristics, treatments, and survival outcomes of MBC diagnosed between 2007 and 2017 in the Czech Republic. Prognostic factors of overall survival (OS), recurrence-free interval (RFi), and breast cancer-specific mortality (BCSM) were analyzed and indirectly compared to international data. RESULTS: We analyzed 256 patients with MBC (median age 66 years), including 12% with de novo metastatic (M1). Of 201 non-metastatic (M0) patients, 6% were <40 years old, 29% had stage I, 55% were cN0, and 54% underwent genetic testing. Overall, 97% of tumors had estrogen receptor expression ≥10%, 61% had high Ki67 index, 40% were high-grade (G3), and 68% were luminal B-like (HER2-negative). Systemic therapies included endocrine therapy (90%) and chemotherapy (53%). Few (5%) patients discontinued adjuvant endocrine therapy for reasons other than disease relapse or death. Patients treated with aromatase inhibitors alone had significantly shorter RFi (P < .001). OS, RFi, and BCSM were associated with disease stage, T stage, N stage, progesterone receptor expression, grade, and Ki67 index. Median OS reached 122 and 42 months in M0 and de novo M1 patients, respectively. CONCLUSION: Due to the rarity of MBC, this study highlights important findings from real clinical practice. Although the number of patients with MBC with unfavorable features was higher in this Czech dataset than in international studies, the prognosis remains consistent with real-world evidence.
- MeSH
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- nádory prsu u mužů * patologie mortalita terapie farmakoterapie MeSH
- prognóza MeSH
- retrospektivní studie MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- Publikační typ
- časopisecké články MeSH
- multicentrická studie MeSH
- Geografické názvy
- Česká republika MeSH
- MeSH
- arteriovenózní píštěl patofyziologie diagnóza komplikace MeSH
- arteriovenózní zkrat metody MeSH
- dialýza ledvin MeSH
- hemodynamika * fyziologie MeSH
- lidé středního věku MeSH
- lidé MeSH
- senioři MeSH
- srdeční selhání * patofyziologie diagnóza MeSH
- vysoký srdeční výdej patofyziologie etiologie diagnóza MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- dopisy MeSH
OBJECTIVES: To quantify extraprostatic findings (EPFs) on prostate MRI, estimate the proportion of reported and unreported EPFs, assess their clinical importance, and propose standardized reporting of EPFs. MATERIALS AND METHODS: Prostate 3-T MRI studies, reports, and clinical data from 623 patients (age 67.9 ± 8.2 years) were retrospectively analyzed and re-evaluated for the presence of EPFs and their clinical significance: E1-no finding or findings that have no clinical significance; E2-potentially significant findings; and E3-significant findings. RESULTS: Secondary reading identified 1236 EPFs in 593 patients (1.98 ± 1.13 EPFs per patient, no EPFs in 30 patients), from which 468 (37.8%) were mentioned in the original report. The most common findings included diverticulosis (44% of patients), hydrocele (34%), inguinal fat hernia (16%), and bladder wall trabecular hypertrophy (15%). There were 80 (6.5%) E2 EPFs and 30 (2.4%) E3 EPFs. From E3 EPFs, 10 (33%) were not originally reported. A workup was suggested in 35 (52%) of the 67 originally reported E2 and E3 findings with follow-up and performed in 20 (30%). Fourteen (21%) EPFs in 11 patients influenced their management. Four experienced radiologists originally reported 1.8 to 2.5 findings per patient (p < 0.0001). CONCLUSIONS: EPFs on prostate MRI are frequent, but only 2.4% are clinically significant (E3), and 33% of these are not reported. Only 30% of E2 and E3 findings are further explored, and 21% influence patient management. We suggest that an "E" category should be attached to the PI-RADS system to identify the presence of EPFs that require further workup. CRITICAL RELEVANCE STATEMENT: Extraprostatic findings on prostate MRI are frequent, but only 2.4% are clinically significant (E3), and 33% of these are not reported. We advocate standardized reporting of extraprostatic findings indicating their clinical significance. KEY POINTS: • Extraprostatic findings on prostate MRI are frequent with an average of two findings per patient. • 2.4% of extraprostatic findings are significant, and 33% of these are not reported. • There is a significant variability among experienced radiologists in reporting extraprostatic findings.
- Publikační typ
- časopisecké články MeSH
INTRODUCTION: Our study (part of multicentric "MindCOVID") investigates risk factors for anxiety and depression among pregnant women during the COVID-19 pandemic in the Czech Republic. MATERIAL AND METHODS: The study used a prospective cross-sectional design. Data was collected using an online self-administered questionnaire. Standardized scales, general anxiety disorder (GAD)-7 and patient health questionnaire (PHQ)-9 were administered online. Multivariate regression analysis was employed to evaluate the relationship between sociodemographic, medical and psychological variables. RESULTS: The Czech sample included 1830 pregnant women. An increase of depressive and anxiety symptoms measured by PHQ-9 and GAD-7 in pregnant women during the COVID-19 pandemic was associated with unfavorable financial situation, low social and family support, psychological and medical problems before and during pregnancy and infertility treatment. Fear of being infected and adverse effect of COVID-19, feeling of burden related to restrictions during delivery and organization of delivery and feeling of burden related to finances were associated with worse anxiety and depressive symptoms. CONCLUSIONS: Social and emotional support and lack of financial worries are protective factors against mood disorders in pregnant women in relation to COVID-19 pandemic. In addition, adequate information about organization of delivery and additional support from healthcare professionals during the delivery are needed. Our findings can be used for preventive interventions, given that repeated pandemics in the future are anticipated.
- MeSH
- COVID-19 * epidemiologie psychologie MeSH
- deprese diagnóza MeSH
- lidé MeSH
- pandemie prevence a kontrola MeSH
- prospektivní studie MeSH
- průřezové studie MeSH
- SARS-CoV-2 MeSH
- těhotenství MeSH
- těhotné ženy psychologie MeSH
- úzkost diagnóza MeSH
- Check Tag
- lidé MeSH
- těhotenství MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- Geografické názvy
- Česká republika MeSH
Many breast cancer (BC) predisposition genes encode proteins involved in DNA damage repair (DDR). Identification of germline pathogenic va-riants (PV) in DDR genes raises the question whether their presence can influence the treatment outcomes and potential radiation-induced toxicity in their carriers treated by adjuvant radiotherapy, which has not yet been answered conclusively. We retrospectively examined records of 213 BC patients treated by adjuvant radiotherapy, including 39 (18.3 %) BRCA1/2 PV carriers, 25 carriers (11.7 %) of PV in other breast cancer-predisposing genes, and 149 (70 %) non-carriers. Our goal was to examine 5-year disease-free survival (5y DFS) rates among the study groups and determine the impact of radiotherapy-induced lymphopoenia (RIL) on this outcome. While we found no significant difference in 5y DFS between non-carriers and carriers of BRCA mutations (86.4 % vs 78.4 % P = 0.24) or between non-carriers and other studied mutations (86.4 % vs 93.3 %; P = 0.27), respectively, we observed that the entire group of PV carriers had a significantly lower proportion of patients without RIL (P = 0.04) than the non-carriers. In contrast, subsequent analyses indicated a non-significant trend toward an increased 5y DFS in PV carriers with RIL. Our single-centre study indicated that the presence of PV in BC patients has an insignificant impact on DFS but can reduce the risk of RIL associated with adjuvant radiotherapy. It remains unclear whether this may result from the paradoxical activation of anti-tumour immunity in PV carriers with higher lymphocyte consumption resulting from higher immune effectiveness.
Creutzfeldt-Jakob disease (CJD), the most common human prion disorder, may occur as "pure" neurodegeneration with isolated prion deposits in the brain tissue; however, comorbid cases with different concomitant neurodegenerative diseases have been reported. This retrospective study examined correlations of clinical, neuropathological, molecular-genetic, immunological, and neuroimaging biomarkers in pure and comorbid CJD. A total of 215 patients have been diagnosed with CJD during the last ten years by the Czech National Center for Prion Disorder Surveillance. Data were collected from all patients with respect to diagnostic criteria for probable CJD, including clinical description, EEG, MRI, and CSF findings. A detailed neuropathological analysis uncovered that only 11.16% were "pure" CJD, while 62.79% had comorbid tauopathy, 20.47% had Alzheimer's disease, 3.26% had frontotemporal lobar degeneration, and 2.33% had synucleinopathy. The comorbid subgroup analysis revealed that tauopathy was linked to putaminal hyperintensity on MRIs, and AD mainly impacted the age of onset, hippocampal atrophy on MRIs, and beta-amyloid levels in the CSF. The retrospective data analysis found a surprisingly high proportion of comorbid neuropathologies; only 11% of cases were verified as "pure" CJD, i.e., lacking hallmarks of other neurodegenerations. Comorbid neuropathologies can impact disease manifestation and can complicate the clinical diagnosis of CJD.
- Publikační typ
- časopisecké články MeSH
Gerstmann-Sträussler-Scheinker syndrome (GSS) is a hereditary neurodegenerative disease characterized by extracellular aggregations of pathological prion protein (PrP) forming characteristic plaques. Our study aimed to evaluate the micromorphology and protein composition of these plaques in relation to age, disease duration, and co-expression of other pathogenic proteins related to other neurodegenerations. Hippocampal regions of nine clinically, neuropathologically, and genetically confirmed GSS subjects were investigated using immunohistochemistry and multichannel confocal fluorescent microscopy. Most pathognomic prion protein plaques were small (2-10 μm), condensed, globous, and did not contain any of the other investigated proteinaceous components, particularly dystrophic neurites. Equally rare (in two cases out of nine) were plaques over 50 μm having predominantly fibrillar structure and exhibit the presence of dystrophic neuritic structures; in one case, the plaques also included bulbous dystrophic neurites. Co-expression with hyperphosphorylated protein tau protein or amyloid beta-peptide (Aβ) in GSS PrP plaques is generally a rare observation, even in cases with comorbid neuropathology. The dominant picture of the GSS brain is small, condensed plaques, often multicentric, while presence of dystrophic neuritic changes accumulating hyperphosphorylated protein tau or Aβ in the PrP plaques are rare and, thus, their presence probably constitutes a trivial observation without any relationship to GSS development and progression.
- MeSH
- dospělí MeSH
- Gerstmannova-Strausslerova-Scheinkerova nemoc * genetika metabolismus patologie MeSH
- lidé středního věku MeSH
- lidé MeSH
- missense mutace * MeSH
- patologická konformace proteinů * genetika metabolismus patologie MeSH
- prionová bílkovina * genetika metabolismus 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
- srovnávací studie MeSH
