Short-term treatment with Uncaria tomentosa aggravates the injury phenotype in mdx mice

Introduction: Uncaria tomentosa (Willd. ex Roem. & Schult.) DC. (Rubiaceae) or UT is a medicinal plant with antiviral, antimutagenic, anti-inflammatory and antioxidant properties. Duchenne muscular dystrophy (DMD) is a severe muscle wasting disease caused by mutations in the dystrophin gene; this deficiency leads to sarcolemma instability, inflammation, muscle degeneration and fibrosis. Objective: Considering the importance of inflammation to dystrophy progression and the anti-inflammatory activity of UT, in the present study we evaluated whether oral administration of UT extract would ameliorate dystrophy in the mdx mice, a DMD model. Methods: Eight-week-old male mdx mice were submitted to 200 mg/kg body weight daily UT oral administration for 6 weeks. General histopathology was analysed, and muscle tumor necrosis factor α, transforming growth factor-ß, myostatin and osteopontin transcript levels were assessed. The ability of mice to sustain limb tension to oppose their gravitational force was measured. Data were analysed with the unpaired Student's t-test. Results: Morphologically, both untreated and UT-treated animals exhibited internalised nuclei, increased endomysial connective tissue and variations in muscle fibre diameters. Body weight and muscle strength were significantly reduced in the UT-treated animals. Blood creatine kinase was higher in UT-treated compared to untreated animals. In tibialis anterior, myostatin, transcript was more highly expressed in the UT-treated while in the diaphragm muscle, transforming growth factor-ß transcripts were less expressed in the UT-treated. Conclusion: While previous studies identified anti-inflammatory, antiproliferative and anticarcinogenic UT effects, the extract indicates worsening of dystrophic muscles phenotype after short-term treatment in mdx mice.

Perfis clínicos e genéticos de pacientes com amiloidose transtiretina hereditária e do tipo selvagem: o registro de amiloidose cardíaca transtiretina no Estado de São Paulo, Brasil (REACT-SP) / Clinical and genetic profiles of patients with hereditary and wild-type transthyretin amyloidosis: the transthyretin cardiac amyloidosis registry in the State of São Paulo, Brazil (REACT-SP)

INTRODUÇÃO: A amiloidose transtiretina (ATTR) é uma doença multissistêmica causada pela deposição de proteína fibrilar em órgãos e tecidos. Os genótipos e fenótipos da ATTR são altamente heterogêneos. MÉTODOS: Apresentamos dados sobre sinais e sintomas físicos, avaliações cardíacas e neurológicas, e genética em pacientes incluídos no Registro de Amiloidose Cardíaca Transtiretina no Estado de São Paulo (REACT-SP), Brasil. RESULTADOS: Foram incluídos 644 pacientes, sendo 505 com a forma variante (ATTRv) e 139 com a forma selvagem (ATTRwt). Dezesseis mutações diferentes foram detectadas, sendo as mais comuns Val50Met (48,3%) e V142Ile (40,8%). No geral, mais da metade dos pacientes apresentou envolvimento cardíaco, e a diferença nessa proporção entre os grupos ATTRv e ATTRwt foi significativa (43,9 vs. 89,9%; p<0,001). O fenótipo neurológico também diferiu entre ATTRv e ATTRwt (56,8 vs. 31,7%; p<0,001). O fenótipo misto foi encontrado em 25,6% da população, sem diferença significativa entre as formas de amiloidose. Um grupo de pacientes permaneceu assintomático (10,4%), com uma proporção menor de pacientes assintomáticos no grupo ATTRwt. CONCLUSÕES: Este estudo detalha o espectro clínico e genético de pacientes com ATTR em São Paulo, Brasil. Esta análise preliminar destaca a considerável heterogeneidade fenotípica das manifestações neurológicas e cardíacas em pacientes com ATTR variante e ATTR do tipo selvagem.

Trilobatin contributes to the improvement of myopathy in a mouse model of Duchenne muscular dystrophy.

Duchenne muscular dystrophy (DMD) occurs due to genetic mutations that lead to a deficiency in dystrophin production and consequent progressive degeneration of skeletal muscle fibres, through oxidative stress and an exacerbated inflammatory process. The flavonoid trilobatin (TLB) demonstrates antioxidant and anti-inflammatory potential. Its high safety profile and effective action make it a potent therapy for the process of dystrophic muscle myonecrosis. Thus, we sought to investigate the action of TLB on damage in a DMD model, the mdx mouse. Eight-week-old male animals were treated with 160 mg/kg/day of trilobatin for 8 weeks. Control animals were treated with saline. Following treatment, muscle strength, serum creatine kinase (CK) levels, histopathology (necrotic myofibres, regenerated fibres/central nuclei, Feret's diameter and inflammatory area) and the levels of catalase and NF-κB (western blotting) of the quadriceps (QUA), diaphragm (DIA) and tibialis anterior (TA) muscles were measured. TLB was able to significantly increase muscle strength and reduce serum CK levels in dystrophic animals. The QUA of mdx mice showed a reduction in catalase and the number of fibres with a centralized nucleus after treatment with TLB. In the DIA of dystrophic animals, TLB reduced the necrotic myofibres, inflammatory area and NF-κB and increased the number of regenerated fibres and the total fibre diameter. In TA, TLB increased the number of regenerated fibres and reduced catalase levels in these animals. It is concluded that in the mdx experimental model, treatment with TLB was beneficial in the treatment of DMD.

Newborn screening for spinal muscular atrophy - what have we learned?

INTRODUCTION: Over the last decade, the treatment of spinal muscular atrophy (SMA) has become a paradigm of the importance of early and accurate diagnosis and prompt treatment. Three different therapeutic approaches that aims to increase SMN protein are approved now by Food and Drug Administration (FDA) and European Medicines Agency (EMA) for treatment of SMA; their efficacies have been demonstrated in pivotal trials. AREAS COVERED: The authors report on the two controlled studies and real-world evidence that have demonstrated that the treatment of patients pre-symptomatically ensures normal or only slightly sub-normal motor development in children who would otherwise develop a severe form of the disease. Furthermore, the authors highlight the several newborn screening (NBS) methods that are now available, all of which are based on real-time PCR, that reliably and robustly diagnose SMA except in subjects with disease caused by a point mutation. EXPERT OPINION: Pre-symptomatic treatment of SMA has been clearly demonstrated to prevent the most severe forms of the disease. NBS constitutes more than a simple test and should be considered as a global process to accelerate treatment access and provide global management of patients and parents. Even though the cost of NBS is low and health economics studies have clearly demonstrated its value, the fear of identifying more patients than the system can treat is often reported in large middle-income countries.

Update of the Brazilian consensus recommendations on Duchenne muscular dystrophy.

In the last few decades, there have been considerable improvements in the diagnosis and care of Duchenne muscular dystrophy (DMD), the most common childhood muscular dystrophy. International guidelines have been published and recently reviewed. A group of Brazilian experts has developed a standard of care based on a literature review with evidence-based graded recommendations in a two-part publication. Implementing best practice management has helped change the natural history of this chronic progressive disorder, in which the life expectancy for children of the male sex in the past used to be very limited. Since the previous publication, diagnosis, steroid treatment, rehabilitation, and systemic care have gained more significant insights with new original work in certain fields. Furthermore, the development of new drugs is ongoing, and some interventions have been approved for use in certain countries. Therefore, we have identified the need to review the previous care recommendations for Brazilian patients with DMD. Our objective was to create an evidence-based document that is an update on our previous consensus on those topics.

Nas últimas décadas, houve progressos significativos no diagnóstico e no tratamento da distrofia muscular de Duchenne (DMD), considerada a distrofia muscular mais comum na infância. Diretrizes internacionais foram publicadas e revisadas recentemente. Um grupo de especialistas brasileiros desenvolveu um padrão de atendimento baseado em revisão de literatura, com recomendações graduadas pautadas em evidências compiladas em uma publicação dividida em duas partes. A implementação de melhores práticas de manejo ajudou a modificar a história natural desta doença crônica, progressiva, que, no passado, oferecia uma expectativa de vida muito limitada para crianças do sexo masculino. Desde a publicação desse consenso anterior, o diagnóstico, o tratamento com esteroides, a reabilitação e os cuidados sistêmicos ganharam novas possibilidades a partir da divulgação dos resultados de trabalhos originais em algumas dessas áreas. Além disso, as pesquisas e o desenvolvimento de novos fármacos estão em andamento, e algumas intervenções já foram aprovadas para uso em determinados países. Nesse contexto, identificamos a necessidade de rever as recomendações anteriores sobre o manejo dos pacientes brasileiros com DMD. Nosso objetivo principal foi elaborar uma atualização baseada em evidências sobre esses tópicos do consenso.

Three years of COVID-19 pandemic: comparative analysis of incidence, lethality and mortality among the States of the south region of Brazil / Três anos de pandemia da COVID-19: análise comparativa da incidência, letalidade e mortalidade entre os Estados da região sul do Brasi

Introduction: the first COVID-19 case in Brazil was confirmed on February 26, 2020. As of March 17, 2023, the Ministry of Health reported 699,634 deaths from COVID-19, with a case fatality rate of 1.9%. The impact of the COVID-19 pandemic in Brazil extends to socioeconomic and healthcare systems, reflecting significant regional disparities. Objective: To analyze mortality, incidence, and case fatality rates for COVID-19 in the states of Paraná and Santa Catarina, in the southern region of Brazil. Methods: This is an ecological time-series study using official Brazilian secondary data for COVID-19 cases and deaths. Data were extracted from the dashboard of the State Health Department of Santa Catarina and Paraná. Temporal series were developed for trend analysis using the Prais-Winsten regression model. Statistical analyses were performed using STATA 14.0 software (College Station, TX, USA, 2013). Results: In the analysis of rates over the entire period, trends for mortality, case fatality, and incidence in the state of Santa Catarina are decreasing, decreasing, and stationary, respectively. In Paraná, rates over the entire period showed a stationary trend for mortality, decreasing for case fatality, and increasing for incidence. Conclusion: COVID-19 had a devastating effect on the states of Santa Catarina and Paraná. Both states experienced the progression of the COVID-19 pandemic, with higher case fatality and mortality rates observed in Paraná, while Santa Catarina had a higher incidence rate over the three years of the COVID-19 pandemic.

Update of the Brazilian consensus recommendations on Duchenne muscular dystrophy / Atualização das recomendações do consenso brasileiro para distrofia muscular de Duchenne

Abstract In the last few decades, there have been considerable improvements in the diagnosis and care of Duchenne muscular dystrophy (DMD), the most common childhood muscular dystrophy. International guidelines have been published and recently reviewed. A group of Brazilian experts has developed a standard of care based on a literature review with evidence-based graded recommendations in a two-part publication. Implementing best practice management has helped change the natural history of this chronic progressive disorder, in which the life expectancy for children of the male sex in the past used to be very limited. Since the previous publication, diagnosis, steroid treatment, rehabilitation, and systemic care have gained more significant insights with new original work in certain fields. Furthermore, the development of new drugs is ongoing, and some interventions have been approved for use in certain countries. Therefore, we have identified the need to review the previous care recommendations for Brazilian patients with DMD. Our objective was to create an evidence-based document that is an update on our previous consensus on those topics.

Resumo Nas últimas décadas, houve progressos significativos no diagnóstico e no tratamento da distrofia muscular de Duchenne (DMD), considerada a distrofia muscular mais comum na infância. Diretrizes internacionais foram publicadas e revisadas recentemente. Um grupo de especialistas brasileiros desenvolveu um padrão de atendimento baseado em revisão de literatura, com recomendações graduadas pautadas em evidências compiladas em uma publicação dividida em duas partes. A implementação de melhores práticas de manejo ajudou a modificar a história natural desta doença crônica, progressiva, que, no passado, oferecia uma expectativa de vida muito limitada para crianças do sexo masculino. Desde a publicação desse consenso anterior, o diagnóstico, o tratamento com esteroides, a reabilitação e os cuidados sistêmicos ganharam novas possibilidades a partir da divulgação dos resultados de trabalhos originais em algumas dessas áreas. Além disso, as pesquisas e o desenvolvimento de novos fármacos estão em andamento, e algumas intervenções já foram aprovadas para uso em determinados países. Nesse contexto, identificamos a necessidade de rever as recomendações anteriores sobre o manejo dos pacientes brasileiros com DMD. Nosso objetivo principal foi elaborar uma atualização baseada em evidências sobre esses tópicos do consenso.

New insights about myofibrillar myopathies: the role of metalloproteinases 2 and 9 in the pathogenesis

Backgroung: There are few reports suggesting that gene expression and activation of various matrix metalloproteinases (MMPs) are deregulated. MMP-2 and MMP-9 represent the two MMPs, which degrade type IV collagen, the component of basement membrane. Methods: We analysed the involvement of gelatinases, MMP-2 and MMP-9, in the pathogenesis of myofibrillar myopathy (MFM). Muscle specimens from 23 patients well diagnosed with MFM, were immunostained by MMP-2 and MMP-9. We analysed qualitatively the immunoexpression in three compartments: subsarcolemmal (SSC), intracytoplasmic (ICC) and perinuclear (PNC).Results: 95,7% and 100% samples showed MMP-2 and MMP-9 upregulation ICC, respectively. PNC showed MMP-2 (82,6%) and MMP-9 (8,7%) regulation (p<0.001). SSC and ICC did not present statistical significance. There was no correlation between mutated gene and immunohistochemical pattern distribution.Conclusion: Our results suggest that MMP-2 and/or MMP-9 could participate in the pathomechanism of MFM, causing damage of sarcomere and deposition of protein aggregates.

Introdução: Existem poucos relatos sugerindo que a expressão gênica e a ativação de várias metaloproteinases de matriz (MMPs) estão desreguladas. MMP-2 e MMP-9 representam as duas MMPs, que degradam o colágeno tipo IV, o componente da membrana basal.Método: Analisamos o envolvimento das gelatinases, MMP-2 e MMP-9, na patogênese da miopatia miofibrilar (MFM). Amostras de músculos de 23 pacientes bem diagnosticados com MFM foram imunocoradas por MMP-2 e MMP-9. Analisamos qualitativamente a imunoexpressão em três compartimentos: subsarcolemal (SSC), intracitoplasmático (ICC) e perinuclear (PNC).Resultados: 95,7% e 100% das amostras apresentaram ICC de regulação positiva de MMP-2 e MMP-9, respectivamente. PNC mostrou regulação MMP-2 (82,6%) e MMP-9 (8,7%) (p <0,001). SSC e ICC não apresentaram significância estatística. Não houve correlação entre o gene mutado e a distribuição do padrão imunohistoquímico.Conclusão: Nossos resultados sugerem que MMP-2 e / ou MMP-9 podem participar do patomecanismo da MFM, causando dano ao sarcômero e deposição de agregados proteicos.

Guillain-Barre syndrome related to COVID-19: muscle and nerve biopsy findings

BACKGROUND: the involvement of the peripheral nervous system (PNS) in COVID-19 is rare and, to date, morphological aspects from muscle and nerve biopsies have not been reported. Here, we describe a case of Guillain-Barré Syndrome (GBS) related to COVID-19 and demonstrate findings from peripheral nerve and skeletal muscle biopsies. A 79-year-old man presented with progressive weakness in both legs over one-week, evolving to both arms and urinary retention within 6 days. Four days earlier, he had a cough, febrile sensation and mild respiratory discomfort. On admission, his was afebrile, and without respiratory distress. A neurological examination disclosed asymmetric proximal weakness, diminished reflexes and no sensitive abnormalities. Three days later, the patient presented with bilateral facial weakness and proximal muscle strength worsened. Deep tendon reflexes and plantar responses were absent. Both superficial and profound sensitivity were decreased. From this point, oxygen saturation worsened, and the patient was placed on mechanical ventilation. CSF testing revealed one cell and protein 185 mg/dl. A chest CT showed the presence of ground-glass opacities and RT-PCR for SARS-CoV-2 was positive. The muscle biopsy revealed moderate neuromyopathic findings with positive expression for MHC-class I, C5b9, CD8 and CD68. The nerve biopsy showed inflammatory infiltrates predominantly with endoneurial compound formed by CD45 and CD68. The patient was treated with Oseltamivir for 9 days followed by IVIG for 5 days and died three days later of septic shock. DISCUSSION: this is the first documented case of GBS associated with COVID-19 with a muscle and nerve anatomopathological study. A systematic review about neurological complications caused by COVID-19 described 11 patients with GBS. The morphological features reported in our patient showed signs of involvement of the immune system, suggesting that direct viral invasion could have played a role in the pathogenesis of peripheral nerve injury. Hereafter, further research will be necessary to understand the triggers for these cells migrating into the peripheral nerve.

INTRODUÇÃO: O envolvimento do sistema nervoso periférico (SNP) na COVID-19 é raro e, até o momento, os aspectos morfológicos de biópsias de músculo e nervo não foram relatados. Descrevemos um caso de Síndrome de Guillain-Barré (SGB) na vigência de COVID-19 destacando os achados na biopsia de músculo e nervo. Um homem de 79 anos apresentou fraqueza progressiva em ambas as pernas ao longo de uma semana, evoluindo para ambos os braços e retenção urinária em 6 dias. Quatro dias antes, apresentou tosse, sensação febril e leve desconforto respiratório. Na admissão, apresentava-se afebril e sem alteração respiratória. O exame neurológico mostrou fraqueza proximal assimétrica, reflexos diminuídos e sensibilidade preservada. Três dias após, o paciente evoluiu com fraqueza facial bilateral e piora da força muscular proximal. Reflexos tendinosos profundos e cutâneo plantar ausentes bilateralmente. A sensibilidade superficial e profunda estavam diminuídas. Evoluiu com piora na saturação de oxigênio sendo colocado sob ventilação mecânica. O exame de liquor revelou uma célula e aumento de proteína (185 mg / dl). A TC de tórax revelou a presença de opacidades em vidro fosco e o RT-PCR para SARS-CoV-2 foi positivo. A biópsia muscular mostrou achados neuromiopáticos moderados com imunoexpressão positiva para MHC classe I, C5b9, CD8 e CD68. A biópsia de nervo revelou infiltrado inflamatório inflamatórios predominantemente endoneural composto por CD45 e CD68. O paciente foi tratado com Oseltamivir por 9 dias seguido de IVIG por 5 dias indo a óbito após três dias por choque séptico. DISCUSSÃO: Este é o primeiro caso documentado de SGB associada a COVID-19 com estudo anatomopatológico de músculo e nervo. Uma revisão sistemática de complicações neurológicas associadas à COVID-19 descreveu 11 pacientes com SGB. As características morfológicas em nosso paciente mostrando sinais de envolvimento do sistema imunológico sugere que a invasão viral direta pode ter colaborado no processo patogênico da lesão neuromuscular. A partir daí, mais pesquisas serão necessárias para entender os gatilhos para essas células migrarem para o nervo periférico.

Registry of transthyretin amyloidosis in the state of São Paulo (REACT-SP) / Registro em amiloidose transtirretina do estado de São Paulo (REACT-SP)

BACKGROUND: Amyloidosis is a systemic disease that involves multiple organs, characterized by the deposition of amyloid fibrils. Knowledge regarding the epidemiological, clinical, and genetic profile of the population affected by amyloidosis throughout the country is of fundamental importance for establishing diagnostic and therapeutic strategies. OBJECTIVE: To evaluate the epidemiological, clinical, laboratory, imaging, and treatment variables of patients with TTR cardiac amyloidosis. MATERIALS AND METHODS: A multicenter, retrospective, prospective, and observational study based on collection of data on the natural history of patients with TTR amyloidosis, followed in the state of São Paulo. RESULTS: To make it possible to map the regional distribution of the disease, increasing knowledge about the disease among clinicians and specialists in different areas. To evaluate patients with hereditary and wild-type TTR amyloidosis, in addition to following individuals with positive genotype and negative phenotype.

FUNDAMENTO: A amiloidose é uma doença sistêmica com envolvimento de diversos órgãos caracterizada pela deposição de fibrilas amiloides. O conhecimento do perfil epidemiológico, clínico e genético da população acometida por amiloidose no país é de fundamental importância em estratégias para estabelecer o diagnóstico bem como as estratégias terapêuticas. OBJETIVO: Avaliar as variáveis epidemiológicas, clínicas, laboratoriais, de imagem e tratamento dos pacientes com amiloidose cardíaca por transtirretina (TTR). MATERIAL E MÉTODOS: Estudo multicêntrico, retrospectivo, prospectivo e observacional baseado na coleta de dados da história natural dos pacientes com amiloidose TTR seguidos no estado de São Paulo. RESULTADOS: Permitir um mapa da distribuição regional da doença, aumentando o conhecimento da doença entre clínicos e especialistas nas diversas especialidades. Avaliar pacientes com amiloidose por TTR formas familiar e selvagem além de acompanhar indivíduos com genótipo positivo e fenótipo negativo. CONCLUSÃO: As informações coletadas poderão evidenciar uma maior conscientização da doença, criação de novos fluxogramas diagnósticos e de tratamento com impacto direto no conhecimento da história natural da doença e prognóstico dos pacientes.

Reducing body myopathy - A new pathogenic FHL1 variant and literature review.

Reducing body myopathy (RBM) is a rare disease marked by progressive muscle weakness caused by a mutation in FHL1 gene. We describe a new pathogenic variant and contrasted it with 44 other cases identified in the literature. A male child presented at age 3 suffering frequent falls and progressive muscular weakness. At age 8, he was wheelchair-bound and required ventilatory support. His mother and sister died due to the same problem. Creatine kinase was 428 IU/L (<190). Muscle biopsy showed typical reducing bodies, and genetic analysis identified a novel pathogenic hemizygous variant, c.370_375del. We identified 44 previous reported cases separated in two groups: 28 cases with mean age onset 7.6 ±â€¯5 years and 16 with 26.7 ±â€¯4.2 years. The time for the diagnosis was shorter to younger group. The initial symptoms, rigid spine, contractures, scoliosis and axial and neck weaknesses, dysphagia, cardiac involvement, were predominant in younger group. The variant c.369C > G predominated in younger group and c.448T > C in older one. Pathogenic variants positions seemed related to severe phenotype. Most wheelchair patients belonged to younger group. The data from this compilation and our case provided a general characterization spectrum and prognosis between two groups of age onset with RBM.

Cannabinoids in Neurology - Position paper from Scientific Departments from Brazilian Academy of Neurology.

Cannabinoids comprehend endocannabinoids, phytocannabinoids, and synthetic cannabinoids, with actions both in the central and peripherical nervous systems. A considerable amount of publications have been made in recent years, although cannabis has been known for over a thousand years. Scientific Departments from the Brazilian Academy of Neurology described evidence for medical use in their areas. Literature is constantly changing, and possible new evidence can emerge in the next days or months. Prescription of these substances must be discussed with patients and their families, with knowledge about adverse events and their efficacy.

Cognitive dysfunction and psychosis: expanding the phenotype of SPG7.

Spastic paraplegia type 7 (SPG7) is one of the most common forms of autosomal recessive hereditary spastic paraplegia, which can lead to a hybrid spastic-ataxic phenotype. Recently, novel complicated forms of SPG7, including cognitive and social impairment phenotypes, have been reported. We present a SPG7 case with two pathogenic variants in compound heterozygosity in the SPG7 gene, featuring a cerebellar cognitive affective syndrome with psychosis not yet described in the literature.

MR imaging of inherited myopathies: a review and proposal of imaging algorithms.

PURPOSE OF REVIEW: The aims of this review are to discuss the imaging modalities used to assess muscle changes in myopathies, to provide an overview of the inherited myopathies focusing on their patterns of muscle involvement in magnetic resonance imaging (MR), and to propose up-to-date imaging-based diagnostic algorithms that can help in the diagnostic workup. CONCLUSION: Familiarization with the most common and specific patterns of muscular involvement in inherited myopathies is very important for radiologists and neurologists, as imaging plays a significant role in diagnosis and follow-up of these patients. KEY POINTS: • Imaging is an increasingly important tool for diagnosis and follow-up in the setting of inherited myopathies. • Knowledge of the most common imaging patterns of muscle involvement in inherited myopathies is valuable for both radiologists and neurologists. • In this review, we present imaging-based algorithms that can help in the diagnostic workup of myopathies.

Cannabinoids in Neurology - Position paper from Scientific Departments from Brazilian Academy of Neurology / Canabinoides em Neurologia - Artigo de posicionamento dos Departamentos Científicos da Academia Brasileira de Neurologia

ABSTRACT Cannabinoids comprehend endocannabinoids, phytocannabinoids, and synthetic cannabinoids, with actions both in the central and peripherical nervous systems. A considerable amount of publications have been made in recent years, although cannabis has been known for over a thousand years. Scientific Departments from the Brazilian Academy of Neurology described evidence for medical use in their areas. Literature is constantly changing, and possible new evidence can emerge in the next days or months. Prescription of these substances must be discussed with patients and their families, with knowledge about adverse events and their efficacy.

RESUMO Os canabinoides compreendem os endocanabinoides, fitocanabinoides e os canabinoides sintéticos e desempenham ações no sistema nervoso central e periférico. Uma quantidade enorme de publicações tem sido lançada nos últimos anos, embora a cannabis seja conhecida por milênios. Os Departamentos Científicos da Academia Brasileira de Neurologia descreveram as evidências do uso médico em suas áreas. A literatura está em constantes mudanças e possíveis novas evidências podem surgir nos próximos dias ou meses. A prescrição dessas substâncias deve ser discutida com os pacientes e suas famílias, com conhecimento sobre eventos adversos e sua eficácia.

Ixazomib, an oral proteasome inhibitor, exhibits potential effect in dystrophin-deficient mdx mice.

Dystrophin deficiency makes the sarcolemma fragile and susceptible to degeneration in Duchenne muscular dystrophy. The proteasome is a multimeric protease complex and is central to the regulation of cellular proteins. Previous studies have shown that proteasome inhibition improved pathological changes in mdx mice. Ixazomib is the first oral proteasome inhibitor used as a therapy in multiple myeloma. This study investigated the effects of ixazomib on the dystrophic muscle of mdx mice. MDX mice were treated with ixazomib (7.5 mg/kg/wk by gavage) or 0.2 mL of saline for 12 weeks. The Kondziela test was performed to measure muscle strength. The tibialis anterior (TA) and diaphragm (DIA) muscles were used for morphological analysis, and blood samples were collected for biochemical measurement. We observed maintenance of the muscle strength in the animals treated with ixazomib. Treatment with ixazomib had no toxic effect on the mdx mouse. The morphological analysis showed a reduction in the inflammatory area and fibres with central nuclei in the TA and DIA muscles and an increase in the number of fibres with a diameter of 20 µm2 in the DIA muscle after treatment with ixazomib. There was an increase in the expression of dystrophin and utrophin in the TA and DIA muscles and a reduction in the expression of osteopontin and TGF-ß in the DIA muscle of mdx mice treated with ixazomib. Ixazomib was thus shown to increase the expression of dystrophin and utrophin associated with improved pathological and functional changes in the dystrophic muscles of mdx mice.

Side Effects of Chloroquine and Hydroxychloroquine on Skeletal Muscle: a Narrative Review.

PURPOSE OF REVIEW: Concerning adverse neuromuscular effects, there are quite a few reports about the incidence and prevalence of chloroquine (CQ) and hydroxychloroquine (HCQ) myopathy. Given the above, I decided to explore the relationships of these drugs with skeletal muscle in an attempt to clarify how they affect the muscle now and in the future, as millions of people are using CQ and HCQ. RECENT FINDINGS: The literature review identified 28 publications about CQ/HCQ myopathy, totaling 56 patients, from 1963 to 2020. A compilation of all patients was carried out by computing demographic features, clinical aspects, laboratory exams, and clinical evolution. All articles but two represented a large series about incidence and prevalence of the myopathy. Fifty-nine percent used QC, mean daily dose was 393 mg per day, and mean duration of treatment was 37 months. The predominant underlying diseases were rheumatoid arthritis (42.8%) and lupus erythematosus (26.8%). Respiratory distress was present in 12.5% in patients with proximal muscle weakness (87.2%). Dysphagia and cervical and axial weakness were observed in a smaller percentage. Creatine kinase was elevated in 60.7%, and EMG showed a myopathic pattern in 54%. Muscle biopsy showed a vacuolar pattern in 53.7%, and curvilinear bodies (CB) were the predominant ultrastructural finding (86.8%). After drug withdrawal, 85.4% of patients improved, and 12.7% died from other causes than myopathy. SUMMARY: CQ and HCQ myopathy has been known for a long time, but the incidence is low, being described only with long-term use. The use of these drugs for a short period has not been reported, although a prolonged elimination half-life of these drugs actually exists.

Novel variants in POLH and TREM2 genes associated with a complex phenotype of xeroderma pigmentosum variant type and early-onset dementia.

BACKGROUND: Xeroderma pigmentosum (XP) is a rare, genetically heterogeneous, autosomal recessive disorder caused by defects in the genes involved in repairing DNA damaged by ultraviolet radiation. These defects lead to a propensity to develop skin cancer at early ages as a hallmark, and progressive neurological degeneration can be observed in around 25% of patients. Eight clinically heterogeneous groups have been identified so far (XPA to XPG and XPV). Xeroderma pigmentosum variant type (XPV) is associated with pathogenic variants in POLH on chromosome 6, and no neurological dysfunction has been seen in these cases. However, on the same chromosome, it has been shown that TREM2 is associated with some types of dementia, particularly in patients with a behavioral variant frontotemporal phenotype. METHODS: Gene mutational analysis was performed by whole-exome sequencing. RESULTS: We report a case of a Caucasian woman with XP that developed behavioral and cognitive impairment at age 37. Whole-exome sequencing identified novel homozygous variants in POLH c.638C>G (p.Ser213*) and TREM2 c.154C>T (p.Arg52Cys), classifying the patient as XPV and suggesting that her frontotemporal dementia phenotype could be related to the variant in TREM2. CONCLUSION: This paper describes a rare case of a patient with two novel variants in the same chromosome associated with XPV and early-onset dementia.

Evaluation of the gastrointestinal tract in mdx mice: an experimental model of Duchenne muscular dystrophy.

This study describes the functional and morphological alterations in the intestines of mdx mice (n = 4) compared with the intestinal features of C57BL/10 mice (n = 7) at 2 months of age. The whole gut transit time (carmine red) and the upper gut transit time (activated charcoal) were measured, and light microscopy was utilized to view stained sections (H&E and picrosirius red) for histological analysis. No significant difference in mean evacuation time for the whole gut was observed between the two groups, but a significant delay in activated charcoal passage was observed in the mdx mice. Visually, a higher concentration of collagen fibers in the submucosal region was apparent in the mdx mice. The concentration of collagen fibers in the stomach and small intestine suggests a direct relationship with the decrease in motility of the upper gastrointestinal tract in the mdx mice. Further experimental studies should be conducted to develop therapeutic alternatives to collagen inhibition to control these manifestations.