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Spinal muscular atrophy is treated with onasemnogene abeparvovec, which replaces the missing survival motor neuron 1 gene via an adeno-associated virus vector. As of July 1, 2020, we had identified 3 infants who developed thrombotic microangiopathy following onasemnogene abeparvovec. Early recognition and treatment of drug-induced thrombotic microangiopathy may lessen mortality and morbidity.
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Produtos Biológicos/efeitos adversos , Atrofia Muscular Espinal/tratamento farmacológico , Proteínas Recombinantes de Fusão/efeitos adversos , Microangiopatias Trombóticas/induzido quimicamente , Produtos Biológicos/uso terapêutico , Feminino , Humanos , Lactente , Proteínas Recombinantes de Fusão/uso terapêuticoRESUMO
BACKGROUND: Data on combining molecular therapies that increase survival motor neuron protein for spinal muscular atrophy type 1 (SMA1) is lacking. METHODS: This was a retrospective study describing our centers' experiences in treating SMA1 patients with combination therapy. RESULTS: Five children received nusinersen and onasemnogene abeparvovec-xioi (onasemnogene). Four were receiving nusinersen prior to onasemnogene. Nusinersen was continued in three. Marked liver enzyme elevations resulted in prolonged corticosteroid treatment in two patients with hospitalization and liver biopsy in one; milder liver enzyme elevations were noted in the other two. One patient received onasemnogene first, and then nusinersen. No adverse effects were noted. All patients improved. CONCLUSIONS: Combination molecular therapy is tolerated in SMA1 patients. Further studies are needed to determine whether there are circumstances in which combination therapy would be more efficacious than either monotherapy. Prolonged corticosteroid use and liver toxicity monitoring may be necessary with onasemnogene therapy.
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Produtos Biológicos/uso terapêutico , Oligonucleotídeos/uso terapêutico , Proteínas Recombinantes de Fusão/uso terapêutico , Atrofias Musculares Espinais da Infância/tratamento farmacológico , Pré-Escolar , Quimioterapia Combinada , Feminino , Humanos , Lactente , Masculino , Estudos Retrospectivos , Resultado do TratamentoRESUMO
The coronavirus disease 2019 (COVID-19) pandemic has resulted in reorganization of healthcare settings affecting the delivery of clinical care to patients with spinal muscular atrophy (SMA). There is a concern that patients with SMA may be at increased risk of manifesting severe symptoms of COVID-19. Currently approved therapies for SMA improve survival and motor function; however, their delivery requires an increased exposure to the health system and a dedicated healthcare team. In this study, we discuss consensus recommendations pertaining to care of SMA patients during the pandemic. We highlight that SMA treatments should not be perceived as elective. Decisions regarding the delay of treatments should be made with consideration of the potential risks of COVID-19 exposure and the risk of that delay. We emphasize the importance of collaborative treatment decisions between the patient, family, and healthcare provider, considering any geographic- or institution-specific policies and precautions for COVID-19.
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Betacoronavirus , Consenso , Infecções por Coronavirus/complicações , Atenção à Saúde/métodos , Gerenciamento Clínico , Atrofia Muscular Espinal/terapia , Pandemias , Pneumonia Viral/complicações , COVID-19 , Infecções por Coronavirus/epidemiologia , Humanos , Atrofia Muscular Espinal/complicações , Pneumonia Viral/epidemiologia , SARS-CoV-2RESUMO
Sneddon syndrome (SS) is an episodic or chronic, slowly progressive disorder and characterized by generalized livedo racemosa (patchy, violaceous, skin discoloration) and recurrent cerebrovascular events. The histopathology of skin and brain is remarkable for a noninflammatory thrombotic vasculopathy involving medium- and small-sized dermal and cerebral arteries, respectively. Approximately 80% of the SS patients are women with a median age of diagnosis at 40 years. However, the onset of the disease during childhood have been reported. Etiopathogenesis of SS is unknown with 2 primary mechanisms proposed - autoimmune/inflammatory versus thrombophilia. SS is primarily classified as antiphospholipid positive or negative type. Neurological manifestations usually occur in 3 phases: (1) prodromal symptoms such as headaches, dizziness, and vertigo, (2) recurrent strokes, and (3) early onset dementia. Livedo racemosa precedes the onset of recurrent strokes by more than 10 years, but in many instances, the significance of the skin lesion is recognized only after the appearance of the stroke. The involvement of the heart valves, systolic labile hypertension, and retinal changes are also commonly associated with this syndrome. Treatment of SS is primarily based on anecdotal reports. Antiplatelet and antithrombotic agents are used for secondary stroke prophylaxis, and a recent study showed a relatively lower stroke recurrence rate with the universal use of antiplatelet/antithrombotic agents. Routine use of anti-inflammatory or immunosuppressive therapies is controversial. Neuropsychiatric prognosis of SS is relatively poor with predominant deficits in the concentration, attention, visual perception, and visuospatial skills.
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Artérias Cerebrais/patologia , Livedo Reticular/etiologia , Pele/irrigação sanguínea , Síndrome de Sneddon/complicações , Acidente Vascular Cerebral/etiologia , Anti-Inflamatórios/uso terapêutico , Artérias Cerebrais/efeitos dos fármacos , Fibrinolíticos/uso terapêutico , Humanos , Imunossupressores/uso terapêutico , Livedo Reticular/patologia , Livedo Reticular/fisiopatologia , Livedo Reticular/prevenção & controle , Inibidores da Agregação Plaquetária/uso terapêutico , Recidiva , Fatores de Risco , Síndrome de Sneddon/tratamento farmacológico , Síndrome de Sneddon/patologia , Síndrome de Sneddon/fisiopatologia , Acidente Vascular Cerebral/patologia , Acidente Vascular Cerebral/fisiopatologia , Acidente Vascular Cerebral/prevenção & controle , Resultado do TratamentoRESUMO
We sought to determine the prevalence of interictal epileptiform discharges (IEDs) in healthy 11- and 12-year-old children. Sixth grade students with no history of seizure, or neurologic or psychiatric disease, were enrolled in a longitudinal physical activity intervention study. Per study protocol, each student had two EEG recordings approximately 6months apart. Epileptiform discharges were present in 4 (2.9%) of 140 students: centrotemporal in three and generalized in one. In three children, the discharges were still present six months later. None of the children had developed seizures a minimum of one year after the second EEG. These results are consistent with those of two landmark European studies performed nearly a half century ago, before the modern era of digital EEG. Healthy 11- and 12-year-old children with no history of seizure may have centrotemporal or generalized epileptiform discharges on EEG, which can persist for at least 6months. Based on both our results and those of the two prior European studies, such discharges, if found incidentally in otherwise healthy children in this age group, should not prompt further evaluation or treatment.
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Encéfalo/fisiopatologia , Eletroencefalografia , Epilepsia/fisiopatologia , Criança , Feminino , Humanos , MasculinoAssuntos
Edema/diagnóstico por imagem , Hidrocefalia/diagnóstico por imagem , Doenças da Medula Espinal/diagnóstico por imagem , Anormalidades Múltiplas/genética , Doença Aguda , Pré-Escolar , Deleção Cromossômica , Cromossomos Humanos Par 7/genética , Anormalidades Craniofaciais/complicações , Anormalidades Craniofaciais/genética , Transtornos de Deglutição/complicações , Transtornos de Deglutição/genética , Deficiências do Desenvolvimento/complicações , Deficiências do Desenvolvimento/genética , Edema/etiologia , Feminino , Refluxo Gastroesofágico/complicações , Refluxo Gastroesofágico/genética , Comunicação Interatrial/complicações , Comunicação Interatrial/genética , Humanos , Hidrocefalia/complicações , Hidrocefalia/cirurgia , Leucomalácia Periventricular/complicações , Leucomalácia Periventricular/genética , Imageamento por Ressonância Magnética , Microcefalia/complicações , Microcefalia/genética , Hipotonia Muscular/complicações , Hipotonia Muscular/genética , Doenças da Medula Espinal/etiologia , Derivação VentriculoperitonealRESUMO
Spinal Muscular Atrophy is a neurodegenerative disease which can lead to muscle weakness, paralysis, and in some cases death. There are many factors that contribute to the severity of symptoms and those factors can be used to determine the best course of treatment for the patients. We looked through published literature to create a set of considerations for treatment in patients with Spinal Muscular Atrophy including age, type, SMN2 copies, and any familial considerations. This can serve as a guide for what to consider in the treatment of SMA patients clinically.
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Background and Objectives: Spinal muscular atrophy (SMA) is an autosomal recessive progressive neurodegenerative primary motor neuron disorder caused by biallelic variants of the survival motor neuron 1 (SMN1) gene. The most recent SMA best practice recommendations were published in 2018 shortly after the approval of the first SMN-enhancing treatment. The availability of disease-modifying therapies for 5q SMA and implementation of SMA newborn screening (NBS) has led to urgency to update the SMA best practice recommendations for diagnosis and to reevaluate the current classification of SMA. In addition, the availability of disease-modifying therapies has opened the door to explore improved diagnosis of adult-onset SMA. Methods: A systematic literature review was conducted on SMA NBS. An SMA working group of American and European health care providers developed recommendations through a modified Delphi technique with serial surveys and virtual meeting feedback on SMA diagnosis to fill information gaps for topics with limited evidence. A community working group of an individual with SMA and caregivers provided insight and perspective on SMA diagnosis and support through a virtual meeting to guide recommendations. Results: The health care provider working group achieved consensus that SMA NBS is essential to include in the updated best practice for SMA diagnosis (100%). Recommendations for the following are described: characterizing NBS-identified infants before treatment; minimum recommendations for starting or offering SMA NBS in a state or country; recommendations for activities and services to be provided by an SMA specialty care center accepting SMA NBS referrals; and recommendations for partnership with individuals with SMA and caregivers to support NBS-identified infants and their caregivers. Limited data are available to advance efficient diagnosis of adult-onset SMA. Discussion: Updating best practice recommendations for SMA diagnosis to include SMA NBS implementation is essential to advancing care for individuals with SMA. In addition to testing, processes for the efficient management of positive newborn screen with access to knowledgeable and skilled health care providers and access to treatment options is critical to successful early diagnosis. Additional evidence is required to improve adult-onset SMA diagnosis.
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Introduction: Suicide is a global phenomenon. Psychiatric disorders are estimated to contribute to a large proportion of suicides; however, impulsive suicide is also common. Among the ages of 15-29 years, suicide was the second leading cause of death worldwide and has been hypothesized to have reduced response inhibition and decision-making abilities as contributing factors, which directly relate to impaired executive functioning and suicidal behavior. Aim: This study aimed to study sociodemography, method, and pattern of suicide, and response inhibition in suicide survivors. Material and Methods: A case-control study was designed in a tertiary medical center in Madhya Pradesh using convenient sampling of suicide survivors and controls from the general population over 3 months. Data collection was semi-structured pro forma, and response inhibition was assessed using the Stroop test. Statistical analysis was performed using IBM Statistical Package for the Social Sciences (SPSS) Windows version 25.0. Independent-samples Student's t-test, Chi-square test, and Mann-Whitney U-test were used for analyzing means of continuous data, nominal data, and ordinal data, respectively. The level of significance was at P < 0.05. Result: A total of 126 suicide survivors and 99 controls were assessed after the end of the study period. Age (mean age for cases 25.4 ± 9.16; controls 23 ± 7.9), gender (F ~ M), and socioeconomic status were used to match cases and controls. 85.7% of suicide survivors had no history of suicide, but the majority had precipitating factors. Anomic suicide was the most common type, and poisoning was the most common method of suicide. Response inhibition between cases and control was significantly different. Conclusion: The majority of suicide attempts were impulsive in youth, with no gender discrimination. Response inhibition seemed to play a role in a suicide attempt.
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To determine the frequency, predictors, and outcomes of seizures in patients with myelomeningocele, we retrospectively analyzed the data from patients with myelomeningocele followed longitudinally at a single center from 1975 to 2013. We identified a total of 122 patients (61% female). The mean follow-up duration was 11.1 years (minimum-maximum = 0-34.5 years, SD = 8.8, median = 9.1 years). A total of 108 (88.5%) patients had hydrocephalus, and 98 (90.7%) of those patients required a ventriculoperitoneal shunt procedure. Twenty-four (19.7%) patients manifested with seizures, 23 of whom had hydrocephalus. The average age of seizure onset was 4.8 years (median 2 years of age). Falx dysgenesis (P = .004), lumbar myelomeningocele (P = .007), and cortical atrophy (P = .028) were significantly associated with epileptic seizure development. The average seizure-free period at the last follow-up in patients with a history of myelomeningocele and seizures was 8.1 years. We conclude that myelomeningocele patients with seizures have an overall good prognosis with considerable long-term seizure freedom.
Assuntos
Meningomielocele/epidemiologia , Convulsões/epidemiologia , Derivação Arteriovenosa Cirúrgica , Causalidade , Pré-Escolar , Estudos de Coortes , Feminino , Seguimentos , Humanos , Incidência , Estudos Longitudinais , Masculino , Meningomielocele/terapia , Estudos RetrospectivosRESUMO
OBJECTIVE: The US risdiplam expanded access program (EAP; NCT04256265) was opened to provide individuals with Type 1 or 2 spinal muscular atrophy (SMA) who had no satisfactory treatment options access to risdiplam prior to commercial availability. The program was designed to collect safety data during risdiplam treatment. METHODS: Patients were enrolled from 23 non-preselected sites across 17 states and treated with risdiplam orally once daily. Eligible patients had a 5q autosomal recessive Type 1 or 2 SMA diagnosis, were aged ≥2 months at enrollment, and were ineligible for available and approved SMA treatments or could not continue treatment due to a medical condition, lack/loss of efficacy, or the COVID-19 pandemic. RESULTS: Overall, 155 patients with Type 1 (n = 73; 47.1%) or 2 SMA (n = 82; 52.9%) were enrolled and 149 patients (96.1%) completed the EAP (defined as obtaining access to commercial risdiplam, if desired). The median treatment duration was 4.8 months (range, 0.3-9.2 months). The median patient age was 11 years (range, 0-50 years), and most patients (n = 121; 78%) were previously treated with a disease-modifying therapy. The most frequently reported adverse events were diarrhea (n = 10; 6.5%), pyrexia (n = 7; 4.5%), and upper respiratory tract infection (n = 5; 3.2%). The most frequently reported serious adverse event was pneumonia (n = 3; 1.9%). No deaths were reported. INTERPRETATION: In the EAP, the safety profile of risdiplam was similar to what was reported in pivotal risdiplam clinical trials. These safety data provide further support for the use of risdiplam in the treatment of adult and pediatric patients with SMA.
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Tratamento Farmacológico da COVID-19 , Atrofia Muscular Espinal , Adulto , Compostos Azo/uso terapêutico , Criança , Humanos , Atrofia Muscular Espinal/tratamento farmacológico , Pandemias , PirimidinasRESUMO
INTRODUCTION: Early-onset epileptic encephalopathies are among the most severe early-onset epilepsies, leading to progressive neurodegeneration. An increasing number of novel genetic causes continue to be uncovered as the primary etiology. RESULTS: We report a girl infant of Semitic (Saudi Arabian) descent who presented with multifocal seizures and later developed intractable infantile spasms and myoclonic seizures. Her clinical features and electroencephalography were consistent with early-onset epileptic encephalopathy. Whole exome sequence analysis showed homozygous novel pathogenic variant (variant p.Q287PfsX27; coding DNA c.858_862delACAAA) in the SYNJ1 gene. CONCLUSION: This is a newly described early-onset epileptic encephalopathy secondary to a critical reduction of the dual phosphatase activity of SYNJ. Clinical features include early-onset intractable focal, myoclonic seizures, infantile spasms, and hypotonia progressing to spastic quadriparesis, opisthotonus, dystonia, profound developmental delay, and a progressive neurodegenerative course. Brain magnetic resonance imaging is usually normal. Electroencephalography shows diffuse slowing with multifocal epileptiform discharges or modified hypsarrhythmia. These findings further expand the clinical spectrum of synaptic dysregulation in patients with severe epilepsy and emphasize the importance of this biological pathway in seizure pathophysiology.
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Bcl-2-associated athanogene 3 (BAG3) myopathy is a rare myofibrillar myopathy characterized by toe walking and clumsiness in the first decade with rapid progression to cardiomyopathy and restrictive lung disease in the second decade. Most patients (18 patients) have the c.626C >T (p.Pro209Leu) mutation. We describe BAG3 myopathy due to p.Pro209Leu in a 13-year-old girl with initial prominent neuropathic phenotype and no cardiac or respiratory involvement. Parents reported toe walking and clumsiness since 3 years old. Examination at the age of 13 years showed findings suggestive of Charcot-Marie-Tooth disease. Nerve conduction studies revealed demyelinating polyneuropathy. Next-generation sequencing panel for inherited neuropathies was unrevealing. Whole exome sequencing identified a de novo mutation in BAG3. Muscle biopsy confirmed myofibrillar myopathy. No cardiac involvement or symptoms of respiratory involvement at the age of 14 years. This case emphasizes the phenotypic variability of BAG3 myopathy and the importance of thorough electrophysiological examination and muscle pathology for establishing a precise diagnosis.
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Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Reguladoras de Apoptose/genética , Miopatias Congênitas Estruturais/diagnóstico , Fenótipo , Adolescente , Feminino , Humanos , Mutação , Miopatias Congênitas Estruturais/genéticaRESUMO
The expedient synthesis of 1,5-benzothiazepines using LaY zeolite under stirring condition is reported and synthesized compound screened for cytotoxic activity. The reaction produces the product in relatively low yields and requires a long time when they were performed in various solvents under conventional and microwave irradiation. Thus, the procedure provides a simple and green synthetic methodology under environmentally friendly conditions.
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Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Tiazepinas/síntese química , Tiazepinas/farmacologia , Catálise , Ensaios de Seleção de Medicamentos Antitumorais , Células HL-60 , Humanos , Zeolitas/químicaRESUMO
Asymmetry in frontal alpha activation (FAA) has been associated with specific behavior patterns. Greater activation in the left frontal cortex is related to "approach" motivation, while greater activation in the right cortex is associated with "withdrawal" motivation. Moreover, resting FAA is stable over time among adults. This stability has not been demonstrated among adolescents, and the correspondence between resting FAA and personality has been inconsistently observed. The present study examined stability of FAA and the association between resting FAA and behavioral activation among adolescents. At baseline and 4 months, 99 adolescents completed a resting electroencephalogram (EEG) and a pencil-and-paper measure of personality (BIS/BAS). FAA showed good stability over time (Intra-class correlation coefficient=0.65, p<0.001), but there was no correlation between FAA and personality. Results are interpreted in light of a capability model of FAA; namely, that asymmetry may emerge under conditions of stimulation and recede during resting.
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Lobo Frontal/fisiologia , Motivação/fisiologia , Personalidade/fisiologia , Adolescente , Criança , Eletroencefalografia , Feminino , Humanos , Estudos Longitudinais , Masculino , Testes de PersonalidadeRESUMO
1,3,5-Triazine derivatives were screened for phototoxicity as well as the cytotoxic activities against leukemia and adenocarcinoma derived cell lines in comparison to the normal human keratinocytes. A simple and environmentally friendly procedure has been developed for the synthesis of 1,3,5-triazine derivatives under microwave irradiation in the presence of a HY zeolite. The catalyst can be recovered and reused. Thus, the procedure provides a simple and green synthetic methodology under environmentally friendly conditions. Structure-activity relationships between the chemical structures and antimycobacterial and photosynthesis-inhibiting activity of the evaluated compounds are also discussed.
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Adenocarcinoma/tratamento farmacológico , Antineoplásicos/farmacologia , Queratinócitos/efeitos dos fármacos , Leucemia/tratamento farmacológico , Fotossíntese/efeitos dos fármacos , Triazinas/farmacologia , Adenocarcinoma/patologia , Antineoplásicos/síntese química , Linhagem Celular Tumoral/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Concentração Inibidora 50 , Queratinócitos/citologia , Queratinócitos/patologia , Leucemia/patologia , Testes de Sensibilidade Microbiana , Modelos Químicos , Relação Estrutura-Atividade , Triazinas/síntese químicaRESUMO
3-Unsubstituted 4-hydroxyquinolin-2(1H)-one containing F and CF(3) substituent in ring is important pharmacological and synthetic target and basic synthones for a number of antibacterial fluoroquinolones and is promising potent and selective glycine site NMDA receptors. A simple facile one-step microwave enhanced multigram synthesis of such fluorinated quinolones in reasonable purity has been developed in excellent yield (85-94%) in 3-5 min, whereas conventional synthesis required the harsh conditions, long reaction period with use of environmentally unacceptable regents giving the required product in lower yield. The phototoxicity as well as the cytotoxic activities of the title compounds are evaluated against leukemia- and adenocarcinoma-derived cell lines in comparison to the normal human keratinocytes. Structure-activity relationships between the chemical structures and the antimycobacterial, antifungal activity of the evaluated compounds are also discussed.
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Antineoplásicos/química , Hidroxiquinolinas/química , Micro-Ondas , Fármacos Fotossensibilizantes/química , Antibacterianos/síntese química , Antibacterianos/química , Antibacterianos/farmacologia , Antifúngicos/síntese química , Antifúngicos/química , Antifúngicos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Proliferação de Células , Ensaios de Seleção de Medicamentos Antitumorais , Flúor/química , Humanos , Hidroxiquinolinas/síntese química , Hidroxiquinolinas/farmacologia , Testes de Sensibilidade Microbiana , Estrutura Molecular , Fármacos Fotossensibilizantes/síntese química , Fármacos Fotossensibilizantes/farmacologia , Relação Estrutura-Atividade , Células Tumorais CultivadasRESUMO
Microwave activation coupled with dry media technique as a green chemistry procedure has been applied to synthesis of a series of some new title compounds. They have been obtained by the reaction of in situ synthesized 1,3-dihydro-3-[2-(phenyl/4-fluorophenyl)-2-oxoethylidene)-indol-2(1H)-one (4a, b) with substituted aminobenzenethiols (5a-d). The key intermediates 4a, b were also prepared in one step by this improved technique by reacting isatin and substituted acetophenones (2a, b). The results obtained under microwave irradiation when compared with that following conventional method demonstrate the versatility of the process. The title compounds 7a-e have also been screened for their antifungal and antitubercular activity, 7a and 7e showing maximum inhibition of growth of Alternaria alternata and Fusarium oxysporium and 7b, c, e revealing significant antitubercular activity.