Emeryho­‐Dreifussova svalová dystrofie (EDMD) patří k vzácným genetickým onemocněním, kde je hlavní příčinou porucha genů kódujících jaderné membránové proteiny. Neurologické příznaky bývají méně vyjádřené a jsou i pro pacienty méně limitující. Naopak dominující jsou kardiální příznaky s poruchami tvorby a převodu vzruchu (sick sinus syndrom, AV blokády, síňové arytmie) či výskytem dilatační kardiomyopatie. Tyto projevy jsou klinicky závažnější a je nutné na ně u pacientů s EDMD myslet. V článku uvádíme soubor deseti nemocných s EDMD, kde poukazujeme na různorodost a závažnost kardiálních obtíží včetně nutnosti dlouhodobé dispenzarizace v rámci multidisciplinárního týmu.

Emery-Dreifuss muscular dystrophy (EDMD) belongs to a rare genetic diseases with disturbances of the genes encoding nuclear membrane proteins. Neurological symptoms are less pronounced and not too limiting for EDMD patients; however, dominant cardiac symptoms with conduction impairment (AV block, atrial arrhythmias) and/or cardiomyopathy are the most serious manifestations of EDMD. We present 10 patients with EDMD, pointing out the variability and severity of cardiac problems, including long-term medical care within the approach of the multidisciplinary medical team.

• MeSH
• kardiomyopatie etiologie   genetika   MeSH
• klinická studie jako téma metody   MeSH
• kontraktura etiologie   MeSH
• lidé MeSH
• nemoci srdce * etiologie   genetika   MeSH
• srdeční arytmie etiologie   genetika   MeSH
• svalová dystrofie Emeryho-Dreifussova * komplikace   terapie   MeSH
• Check Tag
• lidé MeSH

• Publikační typ
• abstrakt z konference MeSH

• Klíčová slova
• efgartigimod,
• MeSH
• injekce subkutánní MeSH
• klinická studie jako téma MeSH
• látky ovlivňující centrální nervový systém * farmakologie   terapeutické užití   MeSH
• lidé středního věku MeSH
• lidé MeSH
• myasthenia gravis * farmakoterapie   psychologie   MeSH
• telemedicína metody   MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• Publikační typ
• kazuistiky MeSH

In recent years, numerous evidence has been accumulated about the extent of A-to-I editing in human RNAs and the key role ADAR1 plays in the cellular editing machinery. It has been shown that A-to-I editing occurrence and frequency are tissue-specific and essential for some tissue development, such as the liver. To study the effect of ADAR1 function in hepatocytes, we have created Huh7.5 ADAR1 KO cell lines. Upon IFN treatment, the Huh7.5 ADAR1 KO cells show rapid arrest of growth and translation, from which they do not recover. We analyzed translatome changes by using a method based on sequencing of separate polysome profile RNA fractions. We found significant changes in the transcriptome and translatome of the Huh7.5 ADAR1 KO cells. The most prominent changes include negatively affected transcription by RNA polymerase III and the deregulation of snoRNA and Y RNA levels. Furthermore, we observed that ADAR1 KO polysomes are enriched in mRNAs coding for proteins pivotal in a wide range of biological processes such as RNA localization and RNA processing, whereas the unbound fraction is enriched mainly in mRNAs coding for ribosomal proteins and translational factors. This indicates that ADAR1 plays a more relevant role in small RNA metabolism and ribosome biogenesis.

• MeSH
• adenosindeaminasa * genetika   metabolismus   MeSH
• buněčné linie MeSH
• editace RNA * MeSH
• genový knockout MeSH
• hepatocyty * metabolismus   MeSH
• lidé MeSH
• messenger RNA genetika   metabolismus   MeSH
• polyribozomy metabolismus   genetika   MeSH
• proteiny vázající RNA * genetika   metabolismus   MeSH
• proteosyntéza MeSH
• transkriptom MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

INTRODUCTION: Up to 50% of diabetic patients with neuropathy suffer from chronic pain, namely painful diabetic neuropathy (PDN), an unmet medical need with significant impact on quality of life. Gabapentin is widely used for PDN, albeit with frequent dose-limiting effects. Trazodone, an antidepressant with multi-modal action, has shown promising results when given at low doses as an add-on to gabapentin. Upon previous clinical trials and experimental evidence, a fixed-dose combination (FDC) of both compounds, at low doses, was developed for neuropathic pain. METHODS: This was a phase II, randomized, double-blind, placebo and reference controlled, dose-finding, multicenter, international, prospective study. Male and female diabetic patients aged 18-75 years and affected by PDN were eligible for enrolment. Patients were randomized (1:1:1:1:2 ratio) to trazodone and gabapentin (Trazo/Gaba) 2.5/25 mg t.i.d. for 8 weeks, Trazo/Gaba 5/50 mg t.i.d. for 8 weeks, Trazo/Gaba 10/100 mg t.i.d. for 8 weeks, gabapentin (Gaba), or placebo (PLB). The aim of the study was to collect preliminary information on the effect of the 3 different FDCs of Trazo/Gaba on pain intensity based on the 11-point numeric rating score (NRS) after 8 weeks of treatment. The secondary objectives were the evaluation of the percentage of responders, neuropathic pain symptoms, anxiety, sleep, quality of life, safety, and tolerability. The primary efficacy endpoint was evaluated with last observation carried out forward (LOCF), using an analysis of covariance (ANCOVA), including treatment and centers as factors and baseline as covariate and applying linear contrast test, excluding the active treatment. Only if the linear contrast test was significant (p < 0.05), the step-down Dunnett test would be used to determine the minimum effective dose significantly different from PLB. If linearity was not verified, an adjusted ANCOVA model and comparisons with Dunnett test were performed. Before the application of the ANCOVA model, the non-significance of interaction treatment per baseline was verified. RESULTS: A total of 240 patients were included in the modified intention-to-treat (m-ITT) population: 39 in Trazo/Gaba 2.5/25 mg, 38 in Trazo/Gaba 5/50 mg, 37 in Trazo/Gaba 10/100 mg, 83 in PLB, and 43 in Gaba. After 8 weeks of treatment, changes of the average daily pain score based on the 11-point NRS from baseline were - 2.52 ± 2.31 in Trazo/Gaba 2.5/25 mg group, - 2.24 ± 1.96 in Trazo/Gaba 5/50 mg group, - 2.46 ± 2.12 in Trazo/Gaba 10/100 mg group, - 1.92 ± 2.21 in Gaba group, and - 2.02 ± 1.95 in the PLB group. The linear contrast test did not result in significant differences (p > 0.05) among treatment groups. Consequently, the minimum effective dose against PLB was not determined. The multiple comparison with Dunnett adjustment did not show any statistically significant differences vs. PLB after 8 weeks of treatment: Trazo/Gaba 2.5/25 mg (95% confidence interval (CI) - 1.2739, 0.2026; p = 0.1539); Trazo/Gaba 5/50 mg (95% CI - 0.9401, 0.5390; p = 0.5931); Trazo/Gaba 10/100 mg (95% CI - 1.0342, 0.4582; p = 0.4471). However, patients receiving the lowest dose of Trazo/Gaba 2.5/25 mg showed a statistically significant difference to PLB after 6 weeks of treatment (95% CI - 1.6648, - 0.2126; p = 0.0116). Positive results were also found for responder patients, other items related to the pain, anxiety, depression, sleep, and quality of life, consistently in favor to the lowest Trazo/Gaba FDC. Two serious adverse events (SAEs) occurred but were judged unrelated to the study treatment. Treatment-emergent adverse events (TEAEs) were mainly mild-to-moderate in intensity and involved primarily nervous system, gastrointestinal disorders, and investigations. CONCLUSIONS: The primary end point of the study was the change from baseline of the average daily pain score based on the 11-point NRS after 8 weeks of treatment. While the primary endpoint was not reached, patients treated with Trazo/Gaba 2.5/25 mg t.i.d. showed statistically significant improvement of pain and other scores after 6 weeks and reported consistent better results in comparison to PLB on primary and secondary endpoints for the overall study duration. According to these results, the lowest dose of Trazo/Gaba FDC may be the best candidate for further clinical development to confirm the potential benefits of the FDC drug for this condition. CLINICAL TRIAL REGISTRATION: NCT03749642.

• Publikační typ
• časopisecké články MeSH

BACKGROUND AND OBJECTIVES: ASPEN-1 was a phase 3, randomized, double-blind, placebo-controlled study to evaluate the efficacy, duration of response, and safety of 2 doses of DaxibotulinumtoxinA for Injection (DAXI), a novel botulinum toxin type A formulation in participants with cervical dystonia (CD). METHODS: Adults (aged 18-80 years) with moderate-to-severe CD (Toronto Western Spasmodic Torticollis Rating Scale [TWSTRS] total score ≥20) were enrolled at 60 sites across 9 countries in Europe and North America. Participants were randomized (3:3:1) to single-dose intramuscular DAXI 125U, 250U, or placebo and followed for up to 36 weeks after injection. The primary end point was change from baseline in TWSTRS total score averaged across weeks 4 and 6. Key secondary end points included duration of effect, Clinical and Patient Global Impression of Change (CGIC, PGIC), TWSTRS subscale scores, and safety. Multiplicity-adjusted intent-to-treat hypothesis tests with multiple imputation were performed using ANCOVA and Cochran-Mantel-Haenszel analyses. RESULTS: Of 444 individuals screened, 301 were randomized to DAXI 125U (n = 125) or 250U (n = 130) or placebo (n = 46). DAXI 125U and 250U significantly improved the mean TWSTRS total score vs placebo (least squares mean [standard error] difference vs placebo: DAXI 125U, -8.5 [1.93], p < 0.0001; DAXI 250U, -6.6 [1.92], p = 0.0006). The median duration of effect (time from treatment until loss of ≥80% of the peak improvement in average TWSTRS total score achieved at weeks 4 and 6) was 24.0 (95% confidence interval 20.3-29.1) weeks with DAXI 125U and 20.3 (16.7-24.0) weeks with DAXI 250U. Significant improvements were also observed with DAXI in CGIC and PGIC responder rates and TWSTRS subscales. Treatment-related treatment-emergent adverse events (TEAEs) were reported by 29.6% of participants with DAXI 125U, 23.8% with DAXI 250U, and 17.4% with placebo, with injection site pain being the most common overall. The most frequently reported treatment-related TEAEs of interest in DAXI 125U, DAXI 250U, and placebo, respectively, were muscular weakness (4.8%, 2.3%, 0%), musculoskeletal pain (2.4%, 3.1%, 0%), and dysphagia (1.6%, 3.8%, 0%). DISCUSSION: This study demonstrated that DAXI, at doses of 125U and 250U, is an effective, safe, long-acting, and well-tolerated treatment for CD. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov identifier (NCT03608397, submitted July 11, 2018) and EU Clinical Trials Register (ClinicalTrialsRegister.eu EudraCT identifier 2018-000446-19, submitted September 13, 2018). First participant enrolled on June 11, 2018. Trial registration was performed in accordance with the Food and Drug Administration Amendments Act (FDAAA 801), which stipulates that the responsible party register an applicable clinical trial not later than 21 calendar days after enrolling the first human participant (42 CFR 11.24). CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that in adults with moderate-to-severe idiopathic cervical dystonia, DAXI reduces dystonia more effectively than placebo.

• MeSH
• botulotoxiny typ A * škodlivé účinky   MeSH
• dospělí MeSH
• dvojitá slepá metoda MeSH
• dystonické poruchy * farmakoterapie   MeSH
• injekce intramuskulární MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• nervosvalové látky * škodlivé účinky   MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• tortikolis * farmakoterapie   chemicky indukované   MeSH
• výsledek terapie MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze III MeSH
• randomizované kontrolované studie MeSH

Mnoho neurologických nemocí je spojeno s výskytem různě intenzivní bolesti vyskytující se v různých lokalizacích. Jedná se nejen o bolest nocicepční, při poškození tkání, ale rovněž o neuropatickou bolest, a to periferní i centrální. U neurologických nemocí z povolání je bolest charakteristickým a častým projevem. Bolest v zádech jako nemoc z povolání se projevuje jak radikulární bolestí, tak i nocicepční. U neuropatií a úžinových syndromů převládá neuropatická bolest často s dalšími senzitivními projevy. Fokální dystonie se vyznačují bolestí vyzařující ze svalů a dalších páteřních a kloubních struktur. Zánětlivé profesionální nemoci jsou provázeny různými typy bolesti, a to včetně neuropatické.

Many neurologic diseases are associated with occurence of pain of various intensity and various localizations. There is not only nociceptive pain, developed in tissue damage, but also neuropathic pain, peripheral and central. In neurologic occupational diseases pain is a characteristic and frequent feature. Low back pain as an occupational disease is charaterized not only as radicu­lar pain but also as nociceptive pain. In neuropathies and entrapment syndromes neuropathic pain prevailes, often with other sensory symptoms. Focal dystonias are associated with pain irradiated from muscles and other vertebral and articular structures. Inflammatory occupational diseases are accompanied by various types of pain, including neuropathic pain.

• MeSH
• bolesti zad * etiologie   patologie   MeSH
• infekční nemoci patologie   MeSH
• lidé MeSH
• nemoci z povolání * patologie   MeSH
• neuralgie etiologie   farmakoterapie   patologie   MeSH
• úžinové syndromy etiologie   patologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• přehledy MeSH

Mnoho neurologických nemocí je spojeno s výskytem různě intenzivní bolesti vyskytující se v různých lokalizacích. Jedná se nejen o bolest nocicepční, při poškození tkání, ale rovněž o neuropatickou bolest, a to periferní i centrální. U neurologických nemocí z povolání je bolest charakteristickým a častým projevem. Bolest v zádech jako nemoc z povolání se projevuje jak radikulární bolestí, tak i nocicepční. U neuropatií a úžinových syndromů převládá neuropatická bolest často s dalšími senzitivními projevy. Fokální dystonie se vyznačují bolestí vyzařující ze svalů a dalších páteřních a kloubních struktur. Zánětlivé profesionální nemoci jsou provázeny různými typy bolesti, a to včetně neuropatické.

Many neurologic diseases are associated with occurence of pain of various intensity and various localizations. There is not only nociceptive pain, developed in tissue damage, but also neuropathic pain, peripheral and central. In neurologic occupational diseases pain is a characteristic and frequent feature. Low back pain as an occupational disease is charaterized not only as radicular pain but also as nociceptive pain. In neuropathies and entrapment syndromes neuropathic pain prevailes, often with other sensory symptoms. Focal dystonias are associated with pain irradiated from muscles and other vertebral and articular structures. Inflammatory occupational diseases are accompanied by various types of pain, including neuropathic pain.

Při zásahu elektrickým proudem záleží na napětí, délce průchodu proudu, typu proudu a na tělesné lokalizaci. Zásah bleskem je vždy nebezpečný a je spojen s vysokou mortalitou. Může se jednat o přímý zásah, nepřímý zásah svedený z okolních struktur, či zásah zemními proudy. Ze struktur nervového systému bývají často poškozeny periferní nervy, ale také mozek, mícha, svaly. Poškození elektrickým výbojem jsou často těžšího stupně, jejich léčba je zdlouhavá, výsledná úprava poškozeného nervového systému nebývá dokonalá. Důležitá je proto prevence, a to u úrazů elektrickým proudem i úrazů způsobených bleskem.

When an electric shock occurs, it depends on the voltage, the length of the current, the type of current and where is the localization on the human body. A lightning strike is always very dangerous and connecting with a high mortality. A person can be affected by a direct hit, an indirect hit from surrounding structures, or a hit by ground currents. Nervous system can be damaged at the periphery (peripheral nerves), but also the brain, spinal cord, and muscles. Electric shock injuries are often of a more severe degree. The treatment is usually long-lasting. The final clinical outcome of the damaged nervous system is usually not perfect and may be incomplete. Prevention is therefore important, both for electric shocks and lightning injuries.

• MeSH
• kognitivní poruchy etiologie   MeSH
• lidé MeSH
• nervová tkáň zranění   MeSH
• paralýza etiologie   MeSH
• poranění bleskem MeSH
• poranění elektrickým proudem * MeSH
• poranění nervového systému terapie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• přehledy MeSH

Na podkladě fyzikálních příčin vznikají v pracovní zátěži mononeuropatie (úžinové syndromy i komprese periferních nervů) i polyneuropatie. Nejčastějším fyzikální vlivem je přetížení, dále následuje expozice vibracím přenášeným na horní končetiny, ale také chlad, vlhko, nepříznivá pracovní poloha, tlak na nerv proti tvrdé podložce. Úžinové syndromy i zevní komprese periferního nervu vedou k ischemii fasciklů i jednotlivých axonů, k rozvoji edému, k poruše venózního odtoku, k vzestupu tlaku v úžině a nakonec i k fokální demyelinizaci či axonální lézi. Nadlimitní vibrace přenášené na horní končetinu vedou ke spazmům arteriol, k ischemii tkáně na akru HK, k poškození senzitivních a pak i motorických vláken a k rozvoji vibrační neuropatie. Důležité je klinické a elektrofyziologické zhodnocení. Následuje léčba a komplexní preventivní opatření.

Mononeuropathies (entrapment syndromes and compressions of peripheral nerves) and polyneuropathies develop during occupational exposition on the ground of physical reasons. The most common physical impact is overload, followed by exposition to vibrations transmitted to upper extremities, then cold, humidity, unfavorable position in work, and pressure on the nerve against a hard structure. Entrapment syndromes and outer compressions of peripheral nerves lead to the ischemic changes of fascicles and single axons, to development of oedema, to failure of the venous outflow, to the increase of pressure in entrapment and lastly to the focal demyelinization or axonal lesion. Over-limit vibration transferred via the upper extremity cause spasms of arteriols, leading to the tissue ischemia at the terminal structures of hand and fingers, to lesion of sensitive and later of motor nerve fibres and to the development of vibration neuropathy. Clinical and electrophysiological evaluation of these disorders is important. Treatment and the complex prophylactic measures follow.

• MeSH
• elektrodiagnostika metody   MeSH
• lidé MeSH
• magnetická rezonanční tomografie metody   MeSH
• nemoci z povolání diagnóza   prevence a kontrola   MeSH
• polyneuropatie MeSH
• syndrom karpálního tunelu diagnóza   etiologie   terapie   MeSH
• úžinové syndromy * diagnóza   etiologie   terapie   MeSH
• úžinový syndrom MeSH
• Check Tag
• lidé MeSH