BACKGROUND: Adenosine-to-inosine RNA editing is a co-transcriptional/post-transcriptional modification of double-stranded RNA, catalysed by one of two active adenosine deaminases acting on RNA (ADARs), ADAR1 and ADAR2. ADARB1 encodes the enzyme ADAR2 that is highly expressed in the brain and essential to modulate the function of glutamate and serotonin receptors. Impaired ADAR2 editing causes early onset progressive epilepsy and premature death in mice. In humans, ADAR2 dysfunction has been very recently linked to a neurodevelopmental disorder with microcephaly and epilepsy in four unrelated subjects. METHODS: We studied three children from two consanguineous families with severe developmental and epileptic encephalopathy (DEE) through detailed physical and instrumental examinations. Exome sequencing (ES) was used to identify ADARB1 mutations as the underlying genetic cause and in vitro assays with transiently transfected cells were performed to ascertain the impact on ADAR2 enzymatic activity and splicing. RESULTS: All patients showed global developmental delay, intractable early infantile-onset seizures, microcephaly, severe-to-profound intellectual disability, axial hypotonia and progressive appendicular spasticity. ES revealed the novel missense c.1889G>A, p.(Arg630Gln) and deletion c.1245_1247+1 del, p.(Leu415PhefsTer14) variants in ADARB1 (NM_015833.4). The p.(Leu415PhefsTer14) variant leads to incorrect splicing resulting in frameshift with a premature stop codon and loss of enzyme function. In vitro RNA editing assays showed that the p.(Arg630Gln) variant resulted in a severe impairment of ADAR2 enzymatic activity. CONCLUSION: In conclusion, these data support the pathogenic role of biallelic ADARB1 variants as the cause of a distinctive form of DEE, reinforcing the importance of RNA editing in brain function and development.

• MeSH
• adenosindeaminasa genetika   metabolismus   MeSH
• alely MeSH
• dítě MeSH
• dvouvláknová RNA metabolismus   MeSH
• editace RNA MeSH
• epilepsie enzymologie   genetika   MeSH
• HEK293 buňky MeSH
• lidé MeSH
• mutace MeSH
• nemoci mozku enzymologie   genetika   metabolismus   MeSH
• neurovývojové poruchy enzymologie   genetika   MeSH
• pokrevní příbuzenství MeSH
• předškolní dítě MeSH
• proteiny vázající RNA genetika   metabolismus   MeSH
• rodokmen MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH
• práce podpořená grantem MeSH

The metabolism of sulfur-containing amino acids (SAAs) requires an orchestrated interplay among several dozen enzymes and transporters, and an adequate dietary intake of methionine (Met), cysteine (Cys), and B vitamins. Known human genetic disorders are due to defects in Met demethylation, homocysteine (Hcy) remethylation, or cobalamin and folate metabolism, in Hcy transsulfuration, and Cys and hydrogen sulfide (H2S) catabolism. These disorders may manifest between the newborn period and late adulthood by a combination of neuropsychiatric abnormalities, thromboembolism, megaloblastic anemia, hepatopathy, myopathy, and bone and connective tissue abnormalities. Biochemical features include metabolite deficiencies (e.g. Met, S-adenosylmethionine (AdoMet), intermediates in 1-carbon metabolism, Cys, or glutathione) and/or their accumulation (e.g. S-adenosylhomocysteine, Hcy, H2S, or sulfite). Treatment should be started as early as possible and may include a low-protein/low-Met diet with Cys-enriched amino acid supplements, pharmacological doses of B vitamins, betaine to stimulate Hcy remethylation, the provision of N-acetylcysteine or AdoMet, or experimental approaches such as liver transplantation or enzyme replacement therapy. In several disorders, patients are exposed to long-term markedly elevated Met concentrations. Although these conditions may inform on Met toxicity, interpretation is difficult due to the presence of additional metabolic changes. Two disorders seem to exhibit Met-associated toxicity in the brain. An increased risk of demyelination in patients with Met adenosyltransferase I/III (MATI/III) deficiency due to biallelic mutations in the MATIA gene has been attributed to very high blood Met concentrations (typically >800 μmol/L) and possibly also to decreased liver AdoMet synthesis. An excessively high Met concentration in some patients with cystathionine β-synthase deficiency has been associated with encephalopathy and brain edema, and direct toxicity of Met has been postulated. In summary, studies in patients with various disorders of SAA metabolism showed complex metabolic changes with distant cellular consequences, most of which are not attributable to direct Met toxicity.

• MeSH
• aminokyseliny sírové metabolismus   MeSH
• cystein metabolismus   MeSH
• glutathion metabolismus   MeSH
• homocystein metabolismus   MeSH
• homocystinurie etiologie   metabolismus   MeSH
• játra metabolismus   MeSH
• lidé MeSH
• metabolické nemoci genetika   metabolismus   patologie   terapie   MeSH
• methionin metabolismus   MeSH
• methioninadenosyltransferasa metabolismus   MeSH
• metylace MeSH
• nemoci mozku etiologie   metabolismus   MeSH
• S-adenosylmethionin metabolismus   MeSH
• síra metabolismus   MeSH
• siřičitany metabolismus   MeSH
• sloučeniny síry metabolismus   MeSH
• sulfan metabolismus   MeSH
• vrozené poruchy metabolismu patologie   terapie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH

• MeSH
• diethylentriaminpentaacetát gadolinia aplikace a dávkování   škodlivé účinky   MeSH
• gadolinium * aplikace a dávkování   škodlivé účinky   MeSH
• kontrastní látky * aplikace a dávkování   škodlivé účinky   MeSH
• lidé MeSH
• magnetická rezonanční tomografie škodlivé účinky   MeSH
• nefrogenní systémová fibróza * chemicky indukované   MeSH
• nemoci mozku metabolismus   patologie   MeSH
• renální insuficience komplikace   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• dopisy MeSH

Prion and other amyloid-forming diseases represent a group of neurodegenerative disorders that affect both animals and humans. The role of metal ions, especially copper and zinc is studied intensively in connection with these diseases. Their involvement in protein misfolding and aggregation and their role in creation of reactive oxygen species have been shown. Recent data also show that metal ions not only bind the proteins with high affinity, but also modify their biochemical properties, making them important players in prion-related diseases. In particular, the level of zinc ions is tightly regulated by several mechanisms, including transporter proteins and the low molecular mass thiol-rich metallothioneins. From four metallothionein isoforms, metallothionein-3, a unique brain-specific metalloprotein, plays a crucial role only in this regulation. This review critically evaluates the involvement of metallothioneins in prion- and amyloid-related diseases in connection with the relationship between metallothionein isoforms and metal ion regulation of their homeostasis.

• MeSH
• amyloidóza metabolismus   MeSH
• lidé MeSH
• metalothionein metabolismus   MeSH
• nemoci mozku metabolismus   MeSH
• prionové nemoci metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH

• Klíčová slova
• Zaostřený ultrazvuk,
• MeSH
• Alzheimerova nemoc farmakoterapie   MeSH
• biomedicínský výzkum * metody   trendy   MeSH
• hematoencefalická bariéra * metabolismus   účinky léků   ultrasonografie   MeSH
• lidé MeSH
• nádory mozku * farmakoterapie   krevní zásobení   metabolismus   MeSH
• nemoci mozku farmakoterapie   krev   metabolismus   MeSH
• neurochirurgické výkony metody   trendy   využití   MeSH
• statistika jako téma MeSH
• Check Tag
• lidé MeSH
• Geografické názvy
• Kanada MeSH

NMDA receptors have received much attention over the last few decades, due to their role in many types of neural plasticity on the one hand, and their involvement in excitotoxicity on the other hand. There is great interest in developing clinically relevant NMDA receptor antagonists that would block excitotoxic NMDA receptor activation, without interfering with NMDA receptor function needed for normal synaptic transmission and plasticity. This review summarizes current understanding of the structure of NMDA receptors and the mechanisms of NMDA receptor activation and modulation, with special attention given to data describing the properties of various types of NMDA receptor inhibition. Our recent analyses point to certain neurosteroids as NMDA receptor inhibitors with desirable properties. Specifically, these compounds show use-dependent but voltage-independent block, that is predicted to preferentially target excessive tonic NMDA receptor activation. Importantly, neurosteroids are also characterized by use-independent unblock, compatible with minimal disruption of normal synaptic transmission. Thus, neurosteroids are a promising class of NMDA receptor modulators that may lead to the development of neuroprotective drugs with optimal therapeutic profiles.

• MeSH
• gating iontového kanálu účinky léků   MeSH
• konformace proteinů MeSH
• lidé MeSH
• mozek účinky léků   metabolismus   MeSH
• nemoci mozku farmakoterapie   metabolismus   MeSH
• nervový přenos účinky léků   MeSH
• neurony účinky léků   metabolismus   MeSH
• neuroprotektivní látky terapeutické užití   MeSH
• receptory N-methyl-D-aspartátu chemie   účinky léků   metabolismus   ultrastruktura   MeSH
• vztahy mezi strukturou a aktivitou MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH

Vďaka zobrazovaciemu pokroku (PET, fMR) a neuropsychofarmakologickým poznatkom dochádza k posunu pochopenia pradávnych fenoménov „placeba a noceba“ z empirickej do vedecky exaktnejšej roviny s prekvapujúcimi odhaleniami. Oba fenomény majú neurotopicky rozložené teritóriá, neurotrasmiterové krytie (najmä opioidným, dopamínovým, cholecystokinínovým systémom). Placebo efekt možno zrušiť naloxonom, nocebo jav zasa progludidom. Akceptovanými mechanizmami týchto reakcií sú procesy očakávania (odmeny), ako aj komplikované „pavlovovské“ princípy podmieňovania. Naďalej zostáva rad nevysvetlených či roztvorených problémov (napr. responzibilita k týmto javom, neštandardnosť a prchavosť ich prejavov). Placebo/nocebo javy sa najmarkantnejšie uplatňujú v palete neuropsychiatrických afekcií. Súčasný stav poznania potvrdzuje nenahraditeľnosť využitia placeba pri objektivizácii účinku nových liečebných molekúl v randomizovanom dvojito zaslepenom pokuse. Turbulentný nárast informácií v tejto sfére nevylučuje etablovanie samostatného pododboru – „placebológie“.

Due to advances in imaging technology (PET, fMRI) and neuropsychopharmacological knowledge, there has been a shift in the understanding of the ancient phenomena of "placebo and nocebo" from empirical to a more scientifically exact level with surprising findings. Both the phenomena have neurotopically distributed territories, neurotransmitter coverage (particularly with the opioid, dopamine, and cholecystokinin systems). The placebo effect may be inhibited by naloxone while the nocebo phenomenon by using proglumide. The mechanisms accepted in these reactions are the processes of expectation (of a reward) as well as complicated Pavlov's principles of conditioning. There still remain a number of unexplained or unresolved problems (e.g. responsiveness to these phenomena, nonstandard nature and transience of their manifestations). The placebo/nocebo phenomena are most significantly involved in a range of neuropsychiatric affections. The current state of knowledge confirms the irreplaceability of placebo use in objectification of the effect of novel therapeutic molecules in a randomized double-blind trial. A dramatic increase in information in this field might even result in the establishment of a separate subspeciality – "placebology". of reward and conditioning, "placebology".

• MeSH
• cholecystokinin metabolismus   MeSH
• depresivní poruchy farmakoterapie   MeSH
• lidé * MeSH
• mozek metabolismus   patofyziologie   účinky léků   MeSH
• nemoci mozku farmakoterapie   metabolismus   psychologie   MeSH
• neuropsychiatrie * trendy   MeSH
• nevědomí (psychologie) MeSH
• odměna MeSH
• Parkinsonova nemoc farmakoterapie   psychologie   MeSH
• placeba farmakologie   terapeutické užití   MeSH
• placebo efekt * MeSH
• podmiňování (psychologie) fyziologie   MeSH
• vědomí fyziologie   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• Check Tag
• lidé * MeSH
• Publikační typ
• přehledy MeSH

• MeSH
• albuminy fyziologie   metabolismus   nedostatek   MeSH
• diabetes insipidus etiologie   terapie   MeSH
• hyperkalcemie etiologie   patofyziologie   terapie   MeSH
• hyperkalemie etiologie   metabolismus   terapie   MeSH
• hypernatremie etiologie   metabolismus   terapie   MeSH
• hypokalcemie etiologie   patofyziologie   terapie   MeSH
• hypokalemie etiologie   metabolismus   terapie   MeSH
• hyponatremie etiologie   metabolismus   terapie   MeSH
• ledviny fyziologie   metabolismus   sekrece   MeSH
• lidé MeSH
• nedostatek hořčíku etiologie   patofyziologie   terapie   MeSH
• nemoci mozku komplikace   metabolismus   MeSH
• osmolární koncentrace MeSH
• poruchy metabolismu fosforu etiologie   patofyziologie   terapie   MeSH
• syndrom nepřiměřené sekrece ADH diagnóza   metabolismus   MeSH
• tělesné tekutiny * fyziologie   chemie   sekrece   MeSH
• vodní a elektrolytová nerovnováha * etiologie   patofyziologie   terapie   MeSH
• Check Tag
• lidé MeSH

Focal cortical dysplasias (FCDs) of the brain are recognized as a frequent cause of intractable epilepsy. To contribute to the current understanding of the mechanisms of epileptogenesis in FCD, our study provides evidence that not only cellular alterations and synaptic transmission, but also changed diffusion properties of the extracellular space (ECS), induced by modified extracellular matrix (ECM) composition and astrogliosis, might be involved in the generation or spread of seizures in FCD. The composition of the ECM in FCD and non-malformed cortex (in 163 samples from 62 patients) was analyzed immunohistochemically and correlated with the corresponding ECS diffusion parameter values determined with the real-time iontophoretic method in freshly resected cortex (i.e. the ECS volume fraction and the geometrical factor tortuosity, describing the hindrances to diffusion in the ECS). The ECS in FCD was shown to differ from that in non-malformed cortex, mainly by the increased accumulation of certain ECM molecules (tenascin R, tenascin C, and versican) or by their reduced expression (brevican), and by the presence of an increased number of astrocytic processes. The consequent increase of ECS diffusion barriers observed in both FCD type I and II (and, at the same time, the enlargement of the ECS volume in FCD type II) may alter the diffusion of neuroactive substances through the ECS, which mediates one of the important modes of intercellular communication in the brain - extrasynaptic volume transmission. Thus, the changed ECM composition and altered ECS diffusion properties might represent additional factors contributing to epileptogenicity in FCD.

• MeSH
• astrocyty metabolismus   MeSH
• brevican analýza   MeSH
• difuze MeSH
• dítě MeSH
• dospělí MeSH
• extracelulární matrix chemie   metabolismus   MeSH
• extracelulární prostor chemie   metabolismus   MeSH
• iontoforéza metody   MeSH
• lidé středního věku MeSH
• lidé MeSH
• malformace mozkové kůry metabolismus   patologie   MeSH
• mladiství MeSH
• mladý dospělý MeSH
• nemoci mozku metabolismus   patologie   MeSH
• neokortex patologie   MeSH
• předškolní dítě MeSH
• tenascin analýza   MeSH
• versikany analýza   MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

An increasing number of patients with nuclear genetic defects of mitochondrial ATP synthase have been identified in recent years. They are characterized by early onset, lactic acidosis, 3-methylglutaconic aciduria, hypertrophic cardiomyopathy and encephalopathy and most cases have a fatal outcome. Patient tissues show isolated defect of the ATP synthase complex and its content decreases to > or =30% of normal due to altered enzyme biosynthesis and assembly. Gene mapping and complementation studies have identified mutations in TMEM70 gene encoding a 30kD mitochondrial protein of unknown function as the cause of the disease. An altered synthesis of this new ancillary factor in ATP synthase biogenesis was found in most of the known patients with decreased ATP synthase content. As revealed by phylogenetic analysis, TMEM70 is specific for higher eukaryotes.

• MeSH
• buněčné jádro genetika   patologie   MeSH
• druhová specificita MeSH
• familiární hypertrofická kardiomyopatie genetika   metabolismus   MeSH
• fylogeneze MeSH
• lidé MeSH
• membránové proteiny * genetika   MeSH
• mitochondriální proteiny * genetika   MeSH
• mitochondriální protonové ATPasy genetika   metabolismus   MeSH
• mitochondrie genetika   metabolismus   MeSH
• mutace MeSH
• nemoci mozku genetika   metabolismus   MeSH
• oxidativní fosforylace MeSH
• respirační komplex IV genetika   metabolismus   MeSH
• savci MeSH
• testy genetické komplementace MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• práce podpořená grantem MeSH