Real-time quaking-induced conversion assay (RT-QuIC) exploits templating activity of pathogenic prion protein for ultrasensitive detection of prions. We have utilized second generation RT-QuIC assay to analyze matching post-mortem cerebrospinal fluid and skin samples of 38 prion disease patients and of 30 deceased neurological controls. The analysis of cerebrospinal fluid samples led to 100% sensitivity and 100% specificity, but some samples had to be diluted before the analysis to alleviate the effect of present RT-QuIC inhibitors. The analysis of the corresponding skin samples provided 89.5% sensitivity and 100% specificity. The median seeding dose present in the skin was one order of magnitude higher than in the cerebrospinal fluid, despite the overall fluorescent signal of the skin samples was comparatively lower. Our data support the use of post-mortem cerebrospinal fluid for confirmation of prion disease diagnosis and encourage further studies of the potential of skin biopsy samples for intra-vitam prion diseases ́ diagnostics.
- MeSH
- biotest MeSH
- Creutzfeldtova-Jakobova nemoc * diagnóza mozkomíšní mok MeSH
- kůže metabolismus MeSH
- lidé MeSH
- prionová bílkovina MeSH
- prionové nemoci * diagnóza MeSH
- priony * metabolismus MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
Birds represent important hosts for numerous viruses, including zoonotic viruses and pathogens with the potential to cause major economic losses to the poultry industry. Viral replication and transmission can be inhibited or blocked by the action of antiviral restriction factors (RFs) encoded by the host. One well-characterized RF is tetherin, a protein that directly blocks the release of newly formed viral particles from infected cells. Here, we describe the evolutionary loss of a functional tetherin gene in two galliform birds, turkey (Meleagris gallopavo) and Mikado pheasant (Syrmaticus mikado). Moreover, we demonstrate that the structurally related protein TMCC(aT) exerts antiviral activity in several birds, albeit by a mechanism different from that of tetherin. The evolutionary scenario described here represents the first documented loss-of-tetherin cases in vertebrates.
- MeSH
- antigen stromálních buněk kostní dřeně * genetika MeSH
- biologická evoluce MeSH
- CD antigeny * genetika metabolismus MeSH
- GPI-vázané proteiny genetika MeSH
- ptáci MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Sepsis has evolved as an enormous health issue amongst critically ill patients. It is a major risk factor that results in multiple organ failure and shock. Acute kidney injury (AKI) is one of the most frequent complications underlying sepsis, which portends a heavy burden of mortality and morbidity. Thus, the present review is aimed to provide an insight into the recent progression in the molecular mechanisms targeting dysregulated immune response and cellular dysfunction involved in the development of sepsis-associated AKI, accentuating the phytoconstituents as eligible candidates for attenuating the onset and progression of sepsis-associated AKI. The pathogenesis of sepsis-mediated AKI entails a complicated mechanism and is likely to involve a distinct constellation of hemodynamic, inflammatory, and immune mechanisms. Novel biomarkers like neutrophil gelatinase-associated lipocalin, soluble triggering receptor expressed on myeloid cells 1, procalcitonin, alpha-1-microglobulin, and presepsin can help in a more sensitive diagnosis of sepsis-associated AKI. Many bioactive compounds like curcumin, resveratrol, baicalin, quercetin, and polydatin are reported to play an important role in the prevention and management of sepsis-associated AKI by decreasing serum creatinine, blood urea nitrogen, cystatin C, lipid peroxidation, oxidative stress, IL-1β, TNF-α, NF-κB, and increasing the activity of antioxidant enzymes and level of PPARγ. The plant bioactive compounds could be developed into a drug-developing candidate in managing sepsis-mediated acute kidney injury after detailed follow-up studies. Lastly, the gut-kidney axis may be a more promising therapeutic target against the onset of septic AKI, but a deeper understanding of the molecular pathways is still required.
- MeSH
- akutní poškození ledvin * farmakoterapie etiologie diagnóza MeSH
- antigeny CD14 metabolismus MeSH
- biologické markery MeSH
- lidé MeSH
- lipokaliny terapeutické užití MeSH
- peptidové fragmenty metabolismus MeSH
- proteiny akutní fáze analýza metabolismus terapeutické užití MeSH
- sepse * komplikace farmakoterapie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
OBJECTIVES: Malignant pleural mesothelioma (MPM) is an aggressive disease with grim prognosis due to lack of effective treatment options. Disease prediction in association with early diagnosis may both contribute to improved MPM survival. Inflammation and autophagy are two processes associated with asbestos-induced transformation. We evaluated the level of two autophagic factors ATG5 and HMGB1, microRNAs (miRNAs) such as miR-126 and miR-222, and the specific biomarker of MPM, soluble mesothelin related proteins (Mesothelin) in asbestos-exposed individuals, MPM patients, and healthy subjects. The performance of these markers in detecting MPM was investigated in pre-diagnostic samples of asbestos-subjects who developed MPM during the follow-up and compared for the three groups. RESULTS: The ATG5 best distinguished the asbestos-exposed subjects with and without MPM, while miR-126 and Mesothelin were found as a significant prognostic biomarker for MPM. ATG5 has been identified as an asbestos-related biomarker that can help to detect MPM with high sensitivity and specificity in pre-diagnostic samples for up to two years before diagnosis. To utilize this approach practically, higher number of cases has to be tested in order to give the combination of the two markers sufficient statistical power. Performance of the biomarkers should be confirmed by testing their combination in an independent cohort with pre-diagnostic samples.
- MeSH
- Atg5 MeSH
- azbest * škodlivé účinky MeSH
- časná diagnóza MeSH
- GPI-vázané proteiny škodlivé účinky MeSH
- lidé MeSH
- maligní mezoteliom * MeSH
- mezotelin MeSH
- mezoteliom * diagnóza MeSH
- mikro RNA * MeSH
- nádorové biomarkery metabolismus MeSH
- nádory pleury * diagnóza MeSH
- nádory plic * diagnóza MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
Myelin oligodendrocyte glycoprotein antibody-positive disease (MOGAD) is a relatively new diagnostic entity that has emerged from the spectrum of neuromyelitis optica disorder (NMOSD), formerly also known as Devic's disease. This inflammatory autoimmune demyelinating disease affects the optic nerve, spinal cord and some other structures of the central nervous system. One of the cardinal manifestations in adult patients is optic neuritis. In children, the disease manifests as acute demyelinating encephalomyelitis (ADEM). The main diagnostic criteria are visible signs of CNS demyelination and detection of serum MOG-IgG antibodies. An attack of optic neuritis is accompanied by a severe visual deficit, which in most cases is at the level of counting fingers. A relatively good adjustment of visual functions is typical. We can quantify the severity of the eye impairment using OCT (optical coherence tomography), where, despite the good adjustment of visual functions, we find a significant loss of nerve fibers. Changes are seen in the optic nerve (pRNFL - peripapillary retinal nerve fiber layer) and macular area - ganglion cells (GCL - ganglion cell layer) and inner plexiform layer (IPL - inner plexiform layer). As a result of an attack of optic neuritis, there is a varying degree of impairment of visual functions and the optic nerve. The severity of the disability is dependent on the timely initiation of therapy and the setting of chronic therapy to prevent further attacks of the disease. Interdisciplinary cooperation between a neurologist and an ophthalmologist is very important in the diagnosis of optic neuritis.
Onemocnění s pozitivitou protilátek proti myelinovému oligodendrocytárnímu glykoproteinu (MOGAD) je relativně nová diagnostická jednotka, která se vyčlenila ze spektra onemocnění neuromyelitis optica (NMOSD), dříve nazýváného také Morbus Devic. Toto zánětlivé autoimunitní demyelinizační onemocnění postihuje zrakový nerv, míchu a některé další struktury centrální nervové soustavy. Jeden z kardinálních projevů u dospělých pacientů je optická neuritida (ON). U dětí se onemocnění manifestuje jako akutní demyelinizační encefalomyelitida (ADEM). Hlavní diagnostická kritéria jsou patrné známky demyelinizace CNS a průkaz sérových protilátek MOG‐IgG. Ataku optické neuritidy doprovází těžký zrakový deficit, který je ve většině případů až na úrovni počítání prstů. Typická je relativně dobrá úprava zrakových funkcí. Tíži očního postižení můžeme kvantifikovat pomocí OCT (optická koherenční tomografie), kde i přes dobrou úpravu zrakových funkcí nacházíme výrazný úbytek nervových vláken. Změny jsou patrné v oblasti zrakového nervu (pRNFL – peripapillary retinal nerve fiber layer) a makulární oblasti – gangliové buňky (GCL – ganglion cell layer) a vnitřní plexifomní vrstva (IPL – inner plexiform layer). Následkem proběhlé ataky optické neuritidy je různá míra postižení zrakových funkcí a optického nervu. Míra postižení je závislá na včasném zahájení léčby a nastavení terapie chronické, aby se předešlo dalším atakám onemocnění. Mezioborová spolupráce neurologa a oftalmologa je při diagnostice optických neuritid velmi důležitá.
- MeSH
- lidé MeSH
- myelinový oligodendrocytární glykoprotein * imunologie MeSH
- neuromyelitis optica * diagnostické zobrazování farmakoterapie patofyziologie patologie terapie MeSH
- oči diagnostické zobrazování MeSH
- optická koherentní tomografie MeSH
- roztroušená skleróza diagnostické zobrazování komplikace MeSH
- zánět zrakového nervu diagnostické zobrazování farmakoterapie patofyziologie patologie terapie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- přehledy MeSH
BACKGROUND: Mirvetuximab soravtansine-gynx (MIRV), a first-in-class antibody-drug conjugate targeting folate receptor α (FRα), is approved for the treatment of platinum-resistant ovarian cancer in the United States. METHODS: We conducted a phase 3, global, confirmatory, open-label, randomized, controlled trial to compare the efficacy and safety of MIRV with the investigator's choice of chemotherapy in the treatment of platinum-resistant, high-grade serous ovarian cancer. Participants who had previously received one to three lines of therapy and had high FRα tumor expression (≥75% of cells with ≥2+ staining intensity) were randomly assigned in a 1:1 ratio to receive MIRV (6 mg per kilogram of adjusted ideal body weight every 3 weeks) or chemotherapy (paclitaxel, pegylated liposomal doxorubicin, or topotecan). The primary end point was investigator-assessed progression-free survival; key secondary analytic end points included objective response, overall survival, and participant-reported outcomes. RESULTS: A total of 453 participants underwent randomization; 227 were assigned to the MIRV group and 226 to the chemotherapy group. The median progression-free survival was 5.62 months (95% confidence interval [CI], 4.34 to 5.95) with MIRV and 3.98 months (95% CI, 2.86 to 4.47) with chemotherapy (P<0.001). An objective response occurred in 42.3% of the participants in the MIRV group and in 15.9% of those in the chemotherapy group (odds ratio, 3.81; 95% CI, 2.44 to 5.94; P<0.001). Overall survival was significantly longer with MIRV than with chemotherapy (median, 16.46 months vs. 12.75 months; hazard ratio for death, 0.67; 95% CI, 0.50 to 0.89; P = 0.005). During the treatment period, fewer adverse events of grade 3 or higher occurred with MIRV than with chemotherapy (41.7% vs. 54.1%), as did serious adverse events of any grade (23.9% vs. 32.9%) and events leading to discontinuation (9.2% vs. 15.9%). CONCLUSIONS: Among participants with platinum-resistant, FRα-positive ovarian cancer, treatment with MIRV showed a significant benefit over chemotherapy with respect to progression-free and overall survival and objective response. (Funded by ImmunoGen; MIRASOL ClinicalTrials.gov number, NCT04209855.).
- MeSH
- chemorezistence genetika MeSH
- epiteliální ovariální karcinom * farmakoterapie genetika MeSH
- folátový receptor 1 antagonisté a inhibitory genetika MeSH
- humanizované monoklonální protilátky aplikace a dávkování škodlivé účinky terapeutické užití MeSH
- imunokonjugáty aplikace a dávkování škodlivé účinky terapeutické užití MeSH
- lidé MeSH
- maytansin * aplikace a dávkování škodlivé účinky analogy a deriváty terapeutické užití MeSH
- nádory vaječníků * farmakoterapie genetika MeSH
- sloučeniny platiny farmakologie MeSH
- Check Tag
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- klinické zkoušky, fáze III MeSH
- randomizované kontrolované studie MeSH
- srovnávací studie MeSH
The clinical characteristics of autosomal dominant tubulointerstitial kidney disease (ADTKD) include bland urinary sediment, slowly progressive chronic kidney disease (CKD) with many patients reaching end stage renal disease (ESRD) between age 20 and 70 years, and autosomal dominant inheritance. Due to advances in genetic diagnosis, ADTKD is becoming increasingly recognized as a cause of CKD. Pathogenic variants in UMOD, MUC1, and REN are the most common causes of ADTKD. ADTKD-UMOD is also associated with hyperuricemia and gout. ADTKD-REN often presents in childhood with mild hypotension, CKD, hyperkalemia, acidosis, and anemia. ADTKD-MUC1 patients present only with CKD. This review describes the pathophysiology, genetics, clinical manifestation, and diagnosis for ADTKD, with an emphasis on genetic testing and genetic counseling suggestions for patients.
- MeSH
- chronická renální insuficience * MeSH
- dospělí MeSH
- genetické testování * MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladý dospělý MeSH
- mutace MeSH
- senioři MeSH
- uromodulin genetika MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladý dospělý MeSH
- senioři MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
Neuromyelitis optica (NMO) a spektrum ochorení NMO (neuromyelitis optica spectrum disorders – NMOSD) sa na základe klinických a paraklinických kritérií, predovšetkým MR a prítomnosti protilátok proti akvaporínu 4 (AQP4), jasne odčlenili od sclerosis multiplex (SM) ako samostatná nozologická jednotka. Možnosti MR spolu so sérologickým testovaním protilátok proti AQP4 a myelínovému oligodendrocytovému glykoproteínu (MOG), zohrávajú dôležitú úlohu v diagnostike a diferenciálnej diagnostike NMOSD od SM a MOGAD – myelin ologodendrocyte glycoprotein associated disease.
Neuromyelitis optica (NMO) and neuromyelitis optica spectrum disorders (NMOSD) have been clearly separated from sclerosis multiplex (SM) as a distinct nosological entity based on clinical and paraclinical criteria, particularly MRI and the presence of antibodies to aquaporin-4 (AQP4). The capabilities of MRI, together with serological testing for antibodies to AQP4 and myelin oligodendrocyte glycoprotein (MOG), play an important role in the diagnosis and differential diagnosis of NMOSD from SM and MOGAD-myelin oligodendrocyte glycoprotein associated disease.
- MeSH
- akvaporin 4 imunologie MeSH
- centrální nervový systém diagnostické zobrazování patologie MeSH
- diferenciální diagnóza MeSH
- lidé MeSH
- magnetická rezonanční tomografie * MeSH
- mozek diagnostické zobrazování patologie MeSH
- myelinový oligodendrocytární glykoprotein MeSH
- neuromyelitis optica * diagnostické zobrazování klasifikace patologie MeSH
- senioři MeSH
- transverzální myelitida diagnostické zobrazování klasifikace patologie MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- Publikační typ
- kazuistiky MeSH
OBJECTIVE: The use of thiazolidinediones (TZDs) as insulin sensitizers has been shown to have side effects including increased accumulation of bone marrow adipocytes (BMAds) associated with a higher fracture risk and bone loss. A novel TZD analog MSDC-0602K with low affinity to PPARγ has been developed to reduce adverse effects of TZD therapy. However, the effect of MSDC-0602K on bone phenotype and bone marrow mesenchymal stem cells (BM-MSCs) in relation to obesity has not been intensively studied yet. METHODS: Here, we investigated whether 8-week treatment with MSDC-0602K has a less detrimental effect on bone loss and BM-MSC properties in obese mice in comparison to first generation of TZDs, pioglitazone. Bone parameters (bone microstructure, bone marrow adiposity, bone strength) were examined by μCT and 3-point bending test. Primary BM-MSCs were isolated and measured for osteoblast and adipocyte differentiation. Cellular senescence, bioenergetic profiling, nutrient consumption and insulin signaling were also determined. RESULTS: The findings demonstrate that MSDC-0602K improved bone parameters along with increased proportion of smaller BMAds in tibia of obese mice when compared to pioglitazone. Further, primary BM-MSCs isolated from treated mice and human BM-MSCs revealed decreased adipocyte and higher osteoblast differentiation accompanied with less inflammatory and senescent phenotype induced by MSDC-0602K vs. pioglitazone. These changes were further reflected by increased glycolytic activity differently affecting glutamine and glucose cellular metabolism in MSDC-0602K-treated cells compared to pioglitazone, associated with higher osteogenesis. CONCLUSION: Our study provides novel insights into the action of MSDC-0602K in obese mice, characterized by the absence of detrimental effects on bone quality and BM-MSC metabolism when compared to classical TZDs and thus suggesting a potential therapeutical use of MSDC-0602K in both metabolic and bone diseases.
- MeSH
- antigen stromálních buněk kostní dřeně metabolismus farmakologie MeSH
- glukosa metabolismus MeSH
- glutamin metabolismus MeSH
- hypoglykemika farmakologie MeSH
- inzulin metabolismus MeSH
- lidé MeSH
- mezenchymální kmenové buňky * metabolismus MeSH
- myši obézní MeSH
- myši MeSH
- obezita farmakoterapie metabolismus MeSH
- pioglitazon metabolismus farmakologie MeSH
- PPAR gama metabolismus MeSH
- spirosloučeniny MeSH
- thiazolidindiony * farmakologie MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
The kidney-specific gene UMOD encodes for uromodulin, the most abundant protein excreted in normal urine. Rare large-effect variants in UMOD cause autosomal dominant tubulointerstitial kidney disease (ADTKD), while common low-impact variants strongly associate with kidney function and the risk of chronic kidney disease (CKD) in the general population. It is unknown whether intermediate-effect variants in UMOD contribute to CKD. Here, candidate intermediate-effect UMOD variants were identified using large-population and ADTKD cohorts. Biological and phenotypical effects were investigated using cell models, in silico simulations, patient samples, and international databases and biobanks. Eight UMOD missense variants reported in ADTKD are present in the Genome Aggregation Database (gnomAD), with minor allele frequency (MAF) ranging from 10-5 to 10-3. Among them, the missense variant p.Thr62Pro is detected in ∼1/1,000 individuals of European ancestry, shows incomplete penetrance but a high genetic load in familial clusters of CKD, and is associated with kidney failure in the 100,000 Genomes Project (odds ratio [OR] = 3.99 [1.84 to 8.98]) and the UK Biobank (OR = 4.12 [1.32 to 12.85). Compared with canonical ADTKD mutations, the p.Thr62Pro carriers displayed reduced disease severity, with slower progression of CKD and an intermediate reduction of urinary uromodulin levels, in line with an intermediate trafficking defect in vitro and modest induction of endoplasmic reticulum (ER) stress. Identification of an intermediate-effect UMOD variant completes the spectrum of UMOD-associated kidney diseases and provides insights into the mechanisms of ADTKD and the genetic architecture of CKD.
- MeSH
- chronická renální insuficience * genetika MeSH
- heterozygot MeSH
- lidé MeSH
- mutace MeSH
- uromodulin * genetika MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH