BACKGROUND AND OBJECTIVES: KCNH5 encodes the voltage-gated potassium channel EAG2/Kv10.2. We aimed to delineate the neurodevelopmental and epilepsy phenotypic spectrum associated with de novo KCNH5 variants. METHODS: We screened 893 individuals with developmental and epileptic encephalopathies for KCNH5 variants using targeted or exome sequencing. Additional individuals with KCNH5 variants were identified through an international collaboration. Clinical history, EEG, and imaging data were analyzed; seizure types and epilepsy syndromes were classified. We included 3 previously published individuals including additional phenotypic details. RESULTS: We report a cohort of 17 patients, including 9 with a recurrent de novo missense variant p.Arg327His, 4 with a recurrent missense variant p.Arg333His, and 4 additional novel missense variants. All variants were located in or near the functionally critical voltage-sensing or pore domains, absent in the general population, and classified as pathogenic or likely pathogenic using the American College of Medical Genetics and Genomics criteria. All individuals presented with epilepsy with a median seizure onset at 6 months. They had a wide range of seizure types, including focal and generalized seizures. Cognitive outcomes ranged from normal intellect to profound impairment. Individuals with the recurrent p.Arg333His variant had a self-limited drug-responsive focal or generalized epilepsy and normal intellect, whereas the recurrent p.Arg327His variant was associated with infantile-onset DEE. Two individuals with variants in the pore domain were more severely affected, with a neonatal-onset movement disorder, early-infantile DEE, profound disability, and childhood death. DISCUSSION: We describe a cohort of 17 individuals with pathogenic or likely pathogenic missense variants in the voltage-sensing and pore domains of Kv10.2, including 14 previously unreported individuals. We present evidence for a putative emerging genotype-phenotype correlation with a spectrum of epilepsy and cognitive outcomes. Overall, we expand the role of EAG proteins in human disease and establish KCNH5 as implicated in a spectrum of neurodevelopmental disorders and epilepsy.

• MeSH
• Child MeSH
• Ether-A-Go-Go Potassium Channels * genetics   MeSH
• Epilepsy, Generalized * genetics   MeSH
• Epilepsy * genetics   MeSH
• Phenotype MeSH
• Humans MeSH
• Mutation MeSH
• Infant, Newborn MeSH
• Seizures genetics   MeSH
• Check Tag
• Child MeSH
• Humans MeSH
• Infant, Newborn MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Research Support, N.I.H., Extramural MeSH

IMPORTANCE: Corticosteroidal anti-inflammatory drugs are widely prescribed but long-term use shows adverse effects that detract from patient quality of life. OBJECTIVE: To determine if vamorolone, a structurally unique dissociative steroidal anti-inflammatory drug, is able to retain efficacy while reducing safety concerns with use in Duchenne muscular dystrophy (DMD). DESIGN, SETTING, AND PARTICIPANTS: Randomized, double-blind, placebo- and prednisone-controlled 24-week clinical trial, conducted from June 29, 2018, to February 24, 2021, with 24 weeks of follow-up. This was a multicenter study (33 referral centers in 11 countries) and included boys 4 to younger than 7 years of age with genetically confirmed DMD not previously treated with corticosteroids. INTERVENTIONS: The study included 4 groups: placebo; prednisone, 0.75 mg/kg per day; vamorolone, 2 mg/kg per day; and vamorolone, 6 mg/kg per day. MAIN OUTCOMES AND MEASURES: Study outcomes monitored (1) efficacy, which included motor outcomes (primary: time to stand from supine velocity in the vamorolone, 6 mg/kg per day, group vs placebo; secondary: time to stand from supine velocity [vamorolone, 2 mg/kg per day], 6-minute walk distance, time to run/walk 10 m [vamorolone, 2 and 6 mg/kg per day]; exploratory: NorthStar Ambulatory Assessment, time to climb 4 stairs) and (2) safety, which included growth, bone biomarkers, and a corticotropin (ACTH)-challenge test. RESULTS: Among the 133 boys with DMD enrolled in the study (mean [SD] age, 5.4 [0.9] years), 121 were randomly assigned to treatment groups, and 114 completed the 24-week treatment period. The trial met the primary end point for change from baseline to week 24 time to stand velocity for vamorolone, 6 mg/kg per day (least-squares mean [SE] velocity, 0.05 [0.01] m/s vs placebo -0.01 [0.01] m/s; 95% CI, 0.02-0.10; P = .002) and the first 4 sequential secondary end points: time to stand velocity, vamorolone, 2 mg/kg per day, vs placebo; 6-minute walk test, vamorolone, 6 mg/kg per day, vs placebo; 6-minute walk test, vamorolone, 2 mg/kg per day, vs placebo; and time to run/walk 10 m velocity, vamorolone, 6 mg/kg per day, vs placebo. Height percentile declined in prednisone-treated (not vamorolone-treated) participants (change from baseline [SD]: prednisone, -1.88 [8.81] percentile vs vamorolone, 6 mg/kg per day, +3.86 [6.16] percentile; P = .02). Bone turnover markers declined with prednisone but not with vamorolone. Boys with DMD at baseline showed low ACTH-stimulated cortisol and high incidence of adrenal insufficiency. All 3 treatment groups led to increased adrenal insufficiency. CONCLUSIONS AND RELEVANCE: In this pivotal randomized clinical trial, vamorolone was shown to be effective and safe in the treatment of boys with DMD over a 24-week treatment period. Vamorolone may be a safer alternative than prednisone in this disease, in which long-term corticosteroid use is the standard of care. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03439670.

• MeSH
• Adrenal Insufficiency * chemically induced   drug therapy   MeSH
• Adrenocorticotropic Hormone therapeutic use   MeSH
• Anti-Inflammatory Agents adverse effects   MeSH
• Biomarkers MeSH
• Muscular Dystrophy, Duchenne * drug therapy   MeSH
• Double-Blind Method MeSH
• Adrenal Cortex Hormones MeSH
• Hydrocortisone therapeutic use   MeSH
• Quality of Life MeSH
• Humans MeSH
• Prednisone therapeutic use   MeSH
• Child, Preschool MeSH
• Treatment Outcome MeSH
• Check Tag
• Humans MeSH
• Male MeSH
• Child, Preschool MeSH
• Publication type
• Journal Article MeSH
• Multicenter Study MeSH
• Research Support, Non-U.S. Gov't MeSH
• Randomized Controlled Trial MeSH
• Research Support, N.I.H., Extramural MeSH

Kniha vás naučí přát si správným způsobem, tak, aby se vám splnily všechny vaše sny. Každý má v sobě přirozenou schopnost lidské mysli dosáhnout svých cílů pomocí tvůrčí představivosti, která vám pomůže dosáhnout skutečně přelomové a pozitivní změny ve vašem životě. Zkušený autor vám představí efektivní systém, jak si plnit sny, a také účinné metody, jak se vypořádat s těžkostmi, které na své cestě potkáváme.Pomocí tvůrčí představivosti můžete například:· zlepšit své zdraví· najít a vybudovat naplňující vztah· vylepšit svou kariéru a vydělat více peněz· rozšířit své možnosti a kreativitu· zbavit se depresí a špatných nálad

Záleží jenom na vás, jestli si vytvoříte příznivé životní prostředí, kde bude proudit hojnost čchi, univerzální životní energie, a díky ní získáte štěstí, prosperitu a zdraví. Rady obsažené v této knížce se vám osvědčí v každém případě, ať bydlíte v domě se zahrádkou nebo třeba v pronajatém bytě, kde máte jenom pár květináčů. Mimořádná kniha Richarda Webstera Feng-šuej pro zahradu vám poskytne výborné rady.

• Keywords
• feng šuej,
• MeSH
• Medicine, Chinese Traditional MeSH
• Gardening methods   MeSH
• Publication type
• Handbook MeSH

• Conspectus
• Plánování krajiny. Parky. Zahrady
• NML Fields
• zájmy a záliby

Když nastane ta pravá chvíle, mohou být vzpomínky na minulé životy prospěšné. Mohou nám pomoci odhalit smysl našeho života i hojit rány, které nám přinesl. Vědomé vzpomínání na minulý život nám může zároveň pomoci odstranit nevyváženost karmy a odhalit skryté schopnosti a vlohy, které si přinášíme z minulých životů.

• Keywords
• reinkarnace, reinkarnační terapie,
• MeSH
• Psychotherapy methods   MeSH
• Publication type
• Handbook MeSH

• Conspectus
• Fyzioterapie. Psychoterapie. Alternativní lékařství
• NML Fields
• alternativní lékařství
• psychoterapie

Rozviňte své duchovní vědomí pro zdraví a úspěch Schopnost vidět auru a rozumět jí má v sobě každý, jenom není rozvinutá. Každý se to může poměrně jednoduše naučit, když ví jak na to. A právě pro ně je určená tato kniha. Naučíte se jak: vidět auru a interpretovat význam jejích barev si svoji auru chránit správně komunikovat s lidmi v závislosti na barvě jejich aury zjistit oblasti života, nad kterými byste se měli zamyslet a pracovat na jejich změně nebo zlepšení vtisknout do aury svá přání.

• MeSH
• Complementary Therapies MeSH
• Mind-Body Relations, Metaphysical MeSH
• Publication type
• Popular Work MeSH

• Conspectus
• Patologie. Klinická medicína
• NML Fields
• terapie

• MeSH
• Physiognomy MeSH
• Yin-Yang MeSH
• Mind-Body Relations, Metaphysical MeSH
• Face MeSH
• Personality MeSH
• Facial Expression MeSH
• Publication type
• Popular Work MeSH
• Handbook MeSH

• Conspectus
• Okultismus
• NML Fields
• okultní vědy
• psychologie, klinická psychologie

Staré čínské učení radí, jak pracovat s duchovními silami, aby v domově a životě zavládla láska.

• Keywords
• feng šuej,
• MeSH
• Housing MeSH
• Interpersonal Relations MeSH
• Marriage MeSH
• Life Style MeSH
• Publication type
• Popular Work MeSH
• Handbook MeSH
• Geographicals
• China MeSH

• Conspectus
• Orientální filozofie
• NML Fields
• humanitní vědy a umění

• MeSH
• Hemagglutinins physiology   MeSH
• Humans MeSH
• Influenza A virus MeSH
• Check Tag
• Humans MeSH

• MeSH
• Hemagglutinins physiology   MeSH
• Humans MeSH
• Influenza A virus MeSH
• Check Tag
• Humans MeSH