Efeito da dexmedetomidina sobre a arritmia cardíaca induzida pela adrenalina em cães anestesiados pelo sevofluorano Effect of dexmedetomidine on the heart arrhythmia induced by the adrenaline in dogs anesthetized by sevoflurane

Avaliou-se o efeito da dexmedetomidina sobre o ritmo cardíaco em 20 cães, sem raça definida, de ambos os sexos e considerados sadios, anestesiados pelo sevofluorano e submetidos a doses crescentes de adrenalina. Os animais foram, aleatoriamente, distribuídos em dois grupos (placebo e dexmedetomidina). No grupo placebo, os animais receberam, por via intravenosa, solução de NaCl a 0,9%, na dose de 0,3ml/kg. Foram considerados dois momentos, M0 e M1, imediatamente antes e após a aplicação, respectivamente. Após 10 minutos, realizou-se a indução anestésica com sevofluorano, por meio de máscara facial vedada, até a perda do reflexo laringotraqueal. Em seguida, procedeu-se à intubação orotraqueal e a manutenção da anestesia foi realizada com a administração de sevofluorano na concentração de 1,5CAM, em circuito anestésico com reinalação parcial de gases. Decorridos 20 minutos da indução anestésica, iniciou-se a administração intravenosa contínua de solução de adrenalina a 2% em doses crescentes de 1, 2, 3, 4 e 5mg/kg/min, por meio de bomba de infusão, com aumento da dose em intervalos de 10 minutos. Imediatamente antes desse acréscimo eram feitas as mensurações (M2 a M6). No grupo dexmedetomidina empregou-se a mesma metodologia substituindo-se a solução de NaCl a 0,9% por hidrocloridrato de dexmedetomidina, na dose de 1µg/kg. Foram registradas as pressões arteriais, em M0 e em M2 a M6, e o traçado eletrocardiográfico, na derivação DII (M2 a M6), considerando-se para efeito estatístico o número total de bloqueios atrioventriculares (BAV) de primeiro e segundo graus e de complexos ventriculares prematuros (ESV), coincidentes com cada dose de adrenalina. Os dados foram submetidos à análise de variância seguida pelo teste de Tukey (P<0,05). Verificou-se que a dexmedetomidina interfere significativamente na condução atrioventricular levando a maior ocorrência de BAV e reduz o número de ESV nas doses infundidas de 2 e 3mg/kg/min de adrenalina. Logo após a aplicação de dexmedetomidina, observaram-se redução da freqüência cardíaca e da pressão arterial, cuja diminuição persistiu por até uma hora.<br>The effect of dexmedetomidine on the cardiac rhythm in twenty healthy mongrel dogs of both sexes anesthetized with sevofluorane and submitted to increasing doses of adrenaline was evaluated. The animals were randomly allotted to different treatment groups. Animals of placebo group were intravenous injected with 0.9% NaCl solution at 0.3ml/kg/IV. Two moments were considered, M0 and M1, the moments immediately before and after application, respectively. Ten minutes later, the dogs were anesthetized using sevofluorane via face mask until lost of their laringotracheal reflex. Then, orotracheal intubation was performed and maintenance of anesthesia was kept with 1,5MAC sevofluorane using an anesthetic circuit with a rebreathing system. Twenty minutes after anesthesia induction, continuous IV administration of 2% adrenaline solution was given at increasing doses of 1,2,3,4 and 5mg/kg/min., every ten minutes, respectively. The moments M2 to M6 were measured immediately before the next increase of dose. In dexmedetomidine group, the same technique was used replacing 0.9% NaCl by dexmedetomidine hydrochloride at 1mg/kg. Blood pressures were recorded at M0 and M2 to M6. Electrocardiography line in the derivation DII (M2 to M6) was used to observe the number of atrioventricular blocks (AVB) of first and second degrees and ventricular premature complexes (VPC). Statistic evaluation was performed by analysis of variance followed by Tukey's test (P<0.05). Dexmedetomidine significantly altered the atrioventricular conduction resulting in a higher occurrence of AVB. This drug reduced the number of VPC at 2 and 3mg/kg/min of adrenaline. After administration of dexmedetomidine, reduction of arterial blood pressure up to one hour and reduction of cardiac rate were observed

PIGN encephalopathy: Characterizing the epileptology.

Epilepsy is common in patients with PIGN diseases due to biallelic variants; however, limited epilepsy phenotyping data have been reported. We describe the epileptology of PIGN encephalopathy. We recruited patients with epilepsy due to biallelic PIGN variants and obtained clinical data regarding age at seizure onset/offset and semiology, development, medical history, examination, electroencephalogram, neuroimaging, and treatment. Seizure and epilepsy types were classified. Twenty six patients (13 female) from 26 families were identified, with mean age 7 years (range = 1 month to 21 years; three deceased). Abnormal development at seizure onset was present in 25 of 26. Developmental outcome was most frequently profound (14/26) or severe (11/26). Patients presented with focal motor (12/26), unknown onset motor (5/26), focal impaired awareness (1/26), absence (2/26), myoclonic (2/26), myoclonic-atonic (1/26), and generalized tonic-clonic (2/26) seizures. Twenty of 26 were classified as developmental and epileptic encephalopathy (DEE): 55% (11/20) focal DEE, 30% (6/20) generalized DEE, and 15% (3/20) combined DEE. Six had intellectual disability and epilepsy (ID+E): two generalized and four focal epilepsy. Mean age at seizure onset was 13 months (birth to 10 years), with a lower mean onset in DEE (7 months) compared with ID+E (33 months). Patients with DEE had drug-resistant epilepsy, compared to 4/6 ID+E patients, who were seizure-free. Hyperkinetic movement disorder occurred in 13 of 26 patients. Twenty-seven of 34 variants were novel. Variants were truncating (n = 7), intronic and predicted to affect splicing (n = 7), and missense or inframe indels (n = 20, of which 11 were predicted to affect splicing). Seven variants were recurrent, including p.Leu311Trp in 10 unrelated patients, nine with generalized seizures, accounting for nine of the 11 patients in this cohort with generalized seizures. PIGN encephalopathy is a complex autosomal recessive disorder associated with a wide spectrum of epilepsy phenotypes, typically with substantial profound to severe developmental impairment

<em>GRIN2B</em> encephalopathy: Novel findings on phenotype, variant clustering, functional consequences and treatment aspects.

BACKGROUND: We aimed for a comprehensive delineation of genetic, functional and phenotypic aspects of GRIN2B encephalopathy and explored potential prospects of personalised medicine. METHODS: Data of 48 individuals with de novo GRIN2B variants were collected from several diagnostic and research cohorts, as well as from 43 patients from the literature. Functional consequences and response to memantine treatment were investigated in vitro and eventually translated into patient care. RESULTS: Overall, de novo variants in 86 patients were classified as pathogenic/likely pathogenic. Patients presented with neurodevelopmental disorders and a spectrum of hypotonia, movement disorder, cortical visual impairment, cerebral volume loss and epilepsy. Six patients presented with a consistent malformation of cortical development (MCD) intermediate between tubulinopathies and polymicrogyria. Missense variants cluster in transmembrane segments and ligand-binding sites. Functional consequences of variants were diverse, revealing various potential gain-of-function and loss-of-function mechanisms and a retained sensitivity to the use-dependent blocker memantine. However, an objectifiable beneficial treatment response in the respective patients still remains to be demonstrated. CONCLUSIONS: In addition to previously known features of intellectual disability, epilepsy and autism, we found evidence that GRIN2B encephalopathy is also frequently associated with movement disorder, cortical visual impairment and MCD revealing novel phenotypic consequences of channelopathies

New developments in small molecular compounds for anti-hepatitis C virus (HCV) therapy*

Infection with hepatitis C virus (HCV) affects approximately 170 million people worldwide. However, no vaccine or immunoglobulin is currently available for the prevention of HCV infection. The standard of care (SOC) involving pegylated interferon-α (PEG-IFN α) plus ribavirin (RBV) for 48 weeks results in a sustained virologic response in less than 50% of patients with chronic hepatitis C genotype 1, the most prevalent type of HCV in North America and Europe. Recently, reliable in vitro culture systems have been developed for accelerating antiviral therapy research, and many new specifically targeted antiviral therapies for hepatitis C (STAT-C) and treatment strategies are being evaluated in clinical trials. These new antiviral agents are expected to improve present treatment significantly and may potentially shorten treatment duration. The aim of this review is to summarize the current developments in new anti-HCV drugs