BACKGROUND: The emergence of new SARS-CoV-2 variants of concern B.1.1.7 (Alpha), B.1.351 (Beta), P.1 (Gamma) and B.1.617.2 (Delta) that harbor mutations in the viral S protein raised concern about activity of current vaccines and therapeutic antibodies. Independent studies have shown that mutant variants are partially or completely resistant against some of the therapeutic antibodies authorized for emergency use. METHODS: We employed hybridoma technology, ELISA-based and cell-based S-ACE2 interaction assays combined with authentic virus neutralization assays to develop second-generation antibodies, which were specifically selected for their ability to neutralize the new variants of SARS-CoV-2. FINDINGS: AX290 and AX677, two monoclonal antibodies with non-overlapping epitopes, exhibit subnanomolar or nanomolar affinities to the receptor binding domain of the viral Spike protein carrying amino acid substitutions N501Y, N439K, E484K, K417N, and a combination N501Y/E484K/K417N found in the circulating virus variants. The antibodies showed excellent neutralization of an authentic SARS-CoV-2 virus representing strains circulating in Europe in spring 2020 and also the variants of concern B.1.1.7 (Alpha), B.1.351 (Beta) and B.1.617.2 (Delta). In addition, AX677 is able to bind Omicron Spike protein just like the wild type Spike. The combination of the two antibodies prevented the appearance of escape mutations of the authentic SARS-CoV-2 virus. Prophylactic administration of AX290 and AX677, either individually or in combination, effectively reduced viral burden and inflammation in the lungs, and prevented disease in a mouse model of SARS-CoV-2 infection. INTERPRETATION: The virus-neutralizing properties were fully reproduced in chimeric mouse-human versions of the antibodies, which may represent a promising tool for COVID-19 therapy. FUNDING: The study was funded by AXON Neuroscience SE and AXON COVIDAX a.s.
- MeSH
- angiotensin konvertující enzym 2 chemie genetika metabolismus MeSH
- antigenní drift a shift MeSH
- COVID-19 virologie MeSH
- farmakoterapie COVID-19 MeSH
- glykoprotein S, koronavirus genetika imunologie metabolismus MeSH
- imunodominantní epitopy imunologie MeSH
- kinetika MeSH
- lidé MeSH
- modely nemocí na zvířatech MeSH
- monoklonální protilátky imunologie terapeutické užití MeSH
- mutace MeSH
- myši MeSH
- neutralizační testy MeSH
- plíce patologie MeSH
- protinádorové látky imunologicky aktivní imunologie terapeutické užití MeSH
- SARS-CoV-2 genetika imunologie izolace a purifikace MeSH
- vazba proteinů MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Psychoterapie zaměřená na přenos (Transference-focused psychotherapy, TFP) je strukturovaná, manualizovaná, evidence-based metoda vytvořená speciálně pro léčbu lidí s hraniční a dalšími vážnými poruchami osobnosti. Metoda vychází z psychoanalytické teorie objektních vztahů a je vyvíjena skupinou kolem Otto F. Kernberga. TFP cílí na konsolidaci identity, lepší emoční regulaci a zvýšení kvality mezilidských vztahů. Příspěvek představuje jednotlivé fáze léčby, vysvětluje funkci konkrétních intervencí TFP v terapeutickém procesu a pomocí kazuistických vinět případu ilustruje jejich aplikaci v praxi.
Transference-Focused Psychotherapy (TFP) is a structured, manualized, evidence-based treatment designed specifically for patients with borderline and other severe personality disorders. The method is based on the psychoanalytic object relations theory and it has been developed by Otto F. Kernberg and his colleagues. TFP focuses on consolidating identity, improving emotion regulation and increasing the quality of interpersonal relationships. This article presents individual phases of the treatment, explains the function of the specific TFP interventions in the therapeutic process and their application is illustrated by a clinical vignettes in practice.
OBJECTIVE: To investigate whether tau phosphorylated at Thr217 (p-tau T217) assay in CSF can distinguish patients with Alzheimer disease (AD) from patients with other dementias and healthy controls. METHODS: We developed and validated a novel Simoa immunoassay to detect p-tau T217 in CSF. There was a total of 190 participants from 3 cohorts with AD (n = 77) and other neurodegenerative diseases (n = 69) as well as healthy participants (n = 44). RESULTS: The p-tau T217 assay (cutoff 242 pg/mL) identified patients with AD with accuracy of 90%, with 78% positive predictive value (PPV), 97% negative predictive value (NPV), 93% sensitivity, and 88% specificity, compared favorably with p-tau T181 ELISA (52 pg/mL), showing 78% accuracy, 58% PPV, 98% NPV, 71% specificity, and 97% sensitivity. The assay distinguished patients with AD from age-matched healthy controls (cutoff 163 pg/mL, 98% sensitivity, 93% specificity), similarly to p-tau T181 ELISA (cutoff 60 pg/mL, 96% sensitivity, 86% specificity). In patients with AD, we found a strong correlation between p-tau T217 and p-tau T181, total tau and β-amyloid 40, but not β-amyloid 42. CONCLUSIONS: This study demonstrates that p-tau T217 displayed better diagnostic accuracy than p-tau T181. The data suggest that the new p-tau T217 assay has potential as an AD diagnostic test in clinical evaluation. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that a CSF immunoassay for p-tau T217 distinguishes patients with AD from patients with other dementias and healthy controls.
- MeSH
- Alzheimerova nemoc mozkomíšní mok diagnóza MeSH
- amyloidní beta-protein mozkomíšní mok MeSH
- diferenciální diagnóza MeSH
- frontotemporální demence mozkomíšní mok diagnóza MeSH
- imunoanalýza metody normy MeSH
- kohortové studie MeSH
- lidé středního věku MeSH
- lidé MeSH
- neurodegenerativní nemoci mozkomíšní mok diagnóza MeSH
- peptidové fragmenty mozkomíšní mok MeSH
- prediktivní hodnota testů MeSH
- primární progresivní afázie mozkomíšní mok diagnóza MeSH
- progresivní supranukleární obrna mozkomíšní mok diagnóza MeSH
- proteiny tau mozkomíšní mok MeSH
- reprodukovatelnost výsledků MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- senzitivita a specificita MeSH
- tauopatie mozkomíšní mok diagnóza 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
- hodnotící studie MeSH
- práce podpořená grantem MeSH
Alzheimer's disease (AD) and progressive supranuclear palsy are two common neurodegenerative tauopathies, and the most common cause of progressive brain dementia in elderly affecting more than 35 million people. The tauopathies are characterized by abnormal deposition of microtubule associated protein tau into intracellular neurofibrillary tangles composed mainly of the hyperphosphorylated form of the protein. The diagnosis of tauopathies is based on the presence of clinical features and pathological changes. Over the last decade, there has been an intensive search for novel biochemical markers for clinical diagnosis of AD and other tauopathies. In the present study, we used transgenic rat model for tauopathy expressing human truncated tau protein (aa 151-391/4R) to analyze the cerebrospinal fluid (CSF) peptidome using liquid chromatography - matrix assisted laser desorption/ionization mass spectrometry (LC-MALDI TOF/TOF). From 345 peptides, we identified a total of 175 proteins. Among them, 17 proteins were significantly altered in the CSF of transgenic rats. The following proteins were elevated in the CSF of transgenic rats when compared to the control animals: neurofilament light and medium chain, apolipoprotein E, gamma-synuclein, chromogranin A, reticulon-4, secretogranin-2, calsyntein-1 and -3, endothelin-3, neuroendocrine protein B72A, alpha-1-macroglobulin, and augurin. Interestingly most of the identified proteins were previously linked to AD and other tauopathies, indicating the significance of transgenic animals in biomarker validation.
- MeSH
- chromatografie kapalinová MeSH
- krysa rodu rattus MeSH
- lidé MeSH
- modely nemocí na zvířatech MeSH
- peptidy MeSH
- potkani transgenní MeSH
- proteiny tau genetika MeSH
- spektrometrie hmotnostní - ionizace laserem za účasti matrice MeSH
- tauopatie genetika MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- MeSH
- emigrace a imigrace * MeSH
- lidé MeSH
- obranné mechanismy MeSH
- politické systémy MeSH
- politika MeSH
- postoj * MeSH
- úzkost * psychologie MeSH
- Check Tag
- lidé MeSH
- Geografické názvy
- Evropa MeSH
BACKGROUND: Increasing prevalence of cognitive impairment in an aging canine population poses a serious health problem. Identifying risk factors, which may influence the onset of cognitive decline, is becoming increasingly important. Here we investigated whether age, sex, weight, nutrition, dogs' housing and reproductive state were associated with increased risk of canine cognitive dysfunction syndrome (CCDS) in Slovakia. RESULTS: Age was associated with cognitive decline and nutrition emerged as a significant predictor variable. Dogs fed controlled diets had 2.8 times lower odds of developing CCDS when compared with dogs fed uncontrolled diets. Sex, weight, reproductive state and dogs' housing were not significantly associated with cognitive decline. Further, the prevalence of CCDS was similar in both small and medium/large sized dogs aged 8-11 years, but differed in dogs at an age of 11-13 years. CONCLUSION: Age was found to be the most prominent risk factors of CCDS. Nutrition may influence the cognitive state of dogs. This finding suggests that nutritional interventions may modify canine cognitive functions.
- MeSH
- incidence MeSH
- kognice * MeSH
- kognitivní poruchy epidemiologie etiologie MeSH
- nemoci psů epidemiologie etiologie MeSH
- prevalence MeSH
- psi MeSH
- rizikové faktory MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- psi MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Geografické názvy
- Slovenská republika epidemiologie MeSH
Hyperhomocysteinemia is a common occurrence in many neurodegenerative diseases, including tauopathies. We developed and validated a simple and sensitive liquid chromatography-tandem mass spectrometry method for the analysis of homocysteine (Hcy) in rat plasma. Hcy was analyzed using ultra-performance liquid chromatography on a C8 column with detection by positive ESI tandem mass spectrometry. For optimal retention and separation, we used ion-pair reagent-heptafluorobutyric acid. The method utilizes heavy labeled internal standard and does not require any derivatization or extraction step. The procedure was validated in compliance with the European Medicines Agency guideline. The limit of detection was 0.15 µmol/L and the limit of quantification was 0.5 µmol/L. The method showed excellent linearity with regression coefficients higher than 0.99. The accuracy was in the range of 93-98%. The inter-day precision (n = 5 days), expressed as % relative standard deviation, was in the range 3-8%. Using this method, we analyzed plasma samples from two transgenic lines of the rat model for tauopathies.
- MeSH
- chromatografie kapalinová metody MeSH
- homocystein krev MeSH
- krysa rodu rattus MeSH
- limita detekce MeSH
- lineární modely MeSH
- potkani inbrední SHR MeSH
- potkani transgenní MeSH
- potkani Wistar MeSH
- reprodukovatelnost výsledků MeSH
- stabilita léku MeSH
- studie případů a kontrol MeSH
- tandemová hmotnostní spektrometrie metody MeSH
- tauopatie krev MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Synaptic failure and neurofibrillary degeneration are two major neuropathological substrates of cognitive dysfunction in Alzheimer's disease (AD). Only a few studies have demonstrated a direct relationship between these two AD hallmarks. To investigate tau mediated synaptic injury we used rat model of tauopathy that develops extensive neurofibrillary pathology in the cortex. Using fractionation of cortical synapses, we identified an increase in endogenous rat tau isoforms in presynaptic compartment, and their mis-sorting to the postsynaptic density (PSD). Truncated transgenic tau was distributed in both compartments exhibiting specific phospho-pattern that was characteristic for each synaptic compartment. In the presynaptic compartment, truncated tau was associated with impairment of dynamic stability of microtubules which could be responsible for reduction of synaptic vesicles. In the PSD, truncated tau lowered the levels of neurofilaments. Truncated tau also significantly decreased the synaptic levels of Aβ40 but not Aβ42. These data show that truncated tau differentially deregulates synaptic proteome in pre- and postsynaptic compartments. Importantly, we show that alteration of Aβ can arise downstream of truncated tau pathology.
- Publikační typ
- časopisecké články MeSH
