RESUMO
Bronchoscopic lung volume reduction (BLVR) using intrabullous autologous blood instillation has been reported in single cases where other techniques are not possible. We present the use of three-dimensional navigation to instill autologous blood into emphysematous bullae for BLVR. A 62-year-old man presented with increasing dyspnea, due to emphysema with a conglomerate of giant bullae with two particularly large bullae. Surgical treatment was refused, so bronchoscopic autologous blood instillation into the bronchial segment leading to the large bullae was attempted, but was unsuccessful; blood failed to penetrate into the bullous cavity. Dyspnea worsened over the following year. We therefore performed another bronchoscopy and punctured a large bulla with a needle and created a tunnel from the central airways. Puncture position and direction were determined using a prototype of an electromagnetic navigation system. Under fluoroscopic guidance, a catheter was placed via the tunnel into the bulla and blood was instilled. This resulted in an almost complete shrinkage of the bullae, reduction of residual volume, and marked improvement in dyspnea within 4 months. To our knowledge, this is the first reported case of successful BLVR by navigated bronchoscopy with transbronchial puncture, dilatation, and autologous blood instillation into a giant bulla.
Assuntos
Transfusão de Sangue Autóloga/métodos , Imageamento Tridimensional/métodos , Pneumonectomia , Enfisema Pulmonar , Cirurgia Assistida por Computador/métodos , Sistemas de Navegação Cirúrgica , Bronquíolos/diagnóstico por imagem , Humanos , Masculino , Pessoa de Meia-Idade , Gravidade do Paciente , Pneumonectomia/instrumentação , Pneumonectomia/métodos , Enfisema Pulmonar/diagnóstico , Enfisema Pulmonar/fisiopatologia , Enfisema Pulmonar/cirurgia , Testes de Função Respiratória/métodos , Tomografia Computadorizada por Raios X/métodos , Resultado do TratamentoRESUMO
The proteasome processes proteins to facilitate immune recognition and host defense. When inherently defective, it can lead to aberrant immunity resulting in a dysregulated response that can cause autoimmunity and/or autoinflammation. Biallelic or digenic loss-of-function variants in some of the proteasome subunits have been described as causing a primary immunodeficiency disease that manifests as a severe dysregulatory syndrome: chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE). Proteasome maturation protein (POMP) is a chaperone for proteasome assembly and is critical for the incorporation of catalytic subunits into the proteasome. Here, we characterize and describe POMP-related autoinflammation and immune dysregulation disease (PRAID) discovered in two unrelated individuals with a unique constellation of early-onset combined immunodeficiency, inflammatory neutrophilic dermatosis, and autoimmunity. We also begin to delineate a complex genetic mechanism whereby de novo heterozygous frameshift variants in the penultimate exon of POMP escape nonsense-mediated mRNA decay (NMD) and result in a truncated protein that perturbs proteasome assembly by a dominant-negative mechanism. To our knowledge, this mechanism has not been reported in any primary immunodeficiencies, autoinflammatory syndromes, or autoimmune diseases. Here, we define a unique hypo- and hyper-immune phenotype and report an immune dysregulation syndrome caused by frameshift mutations that escape NMD.
Assuntos
Predisposição Genética para Doença , Chaperonas Moleculares/genética , Mutação/genética , Degradação do RNAm Mediada por Códon sem Sentido/genética , Sequência de Bases , Linhagem Celular , Estresse do Retículo Endoplasmático , Éxons/genética , Família , Mutação da Fase de Leitura/genética , Heterozigoto , Humanos , Síndromes de Imunodeficiência/genética , Imunofenotipagem , Recém-Nascido , Inflamação/patologia , Interferon Tipo I/metabolismo , Masculino , Proteínas Mutantes/metabolismo , Fenótipo , Complexo de Endopeptidases do Proteassoma/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Síndrome , Resposta a Proteínas não DobradasRESUMO
This study was designed to identify bioactive compounds that alter the cellular shape of the fission yeast Schizosaccharomyces pombe by affecting functions involved in the cell cycle or cell morphogenesis. We used a multidrug-sensitive fission yeast strain, SAK950 to screen a library of 657 actinomycete bacteria and identified 242 strains that induced eight different major shape phenotypes in S. pombe These include the typical cell cycle-related phenotype of elongated cells, and the cell morphology-related phenotype of rounded cells. As a proof of principle, we purified four of these activities, one of which is a novel compound and three that are previously known compounds, leptomycin B, streptonigrin and cycloheximide. In this study, we have also shown novel effects for two of these compounds, leptomycin B and cycloheximide. The identification of these four compounds and the explanation of the S. pombe phenotypes in terms of their known, or predicted bioactivities, confirm the effectiveness of this approach.
Assuntos
Actinomyces/química , Produtos Biológicos/isolamento & purificação , Produtos Biológicos/farmacologia , Forma Celular , Avaliação Pré-Clínica de Medicamentos , Schizosaccharomyces/citologia , Produtos Biológicos/análise , Forma Celular/efeitos dos fármacos , Quinase 1 do Ponto de Checagem/metabolismo , Cicloeximida/farmacologia , Dano ao DNA , Ácidos Graxos Insaturados/farmacologia , Fenótipo , Schizosaccharomyces/efeitos dos fármacos , Espectrometria de Massas por Ionização por ElectrosprayRESUMO
IMPORTANCE: No current medications improve neuropathy in subjects with Charcot-Marie-Tooth disease type 1A (CMT1A). Ascorbic acid (AA) treatment improved the neuropathy of a transgenic mouse model of CMT1A and is a potential therapy. A lower dosage (1.5 g/d) did not cause improvement in humans. It is unknown whether a higher dosage would prove more effective. OBJECTIVE: To determine whether 4-g/d AA improves the neuropathy of subjects with CMT1A. DESIGN: A futility design to determine whether AA was unable to reduce worsening on the CMT Neuropathy Score (CMTNS) by at least 50% over a 2-year period relative to a natural history control group. SETTING: Three referral centers with peripheral nerve clinics (Wayne State University, Johns Hopkins University, and University of Rochester). PARTICIPANTS: One hundred seventy-four subjects with CMT1A were assessed for eligibility; 48 did not meet eligibility criteria and 16 declined to participate. The remaining 110 subjects, aged 13 to 70 years, were randomly assigned in a double-masked fashion with 4:1 allocation to oral AA (87 subjects) or matching placebo (23 subjects). Sixty-nine subjects from the treatment group and 16 from the placebo group completed the study. Two subjects from the treatment group and 1 from the placebo group withdrew because of adverse effects. INTERVENTIONS: Oral AA (4 g/d) or matching placebo. MAIN OUTCOMES AND MEASURES: Change from baseline to year 2 in the CMTNS, a validated composite impairment score for CMT. RESULTS: The mean 2-year change in the CMTNS was -0.21 for the AA group and -0.92 for the placebo group, both better than natural history (+1.33). This was well below 50% reduction of CMTNS worsening from natural history, so futility could not be declared (P > .99). CONCLUSIONS AND RELEVANCE: Both treated patients and those receiving placebo performed better than natural history. It seems unlikely that our results support undertaking a larger trial of 4-g/d AA treatment in subjects with CMT1A. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00484510.