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1.
Neurobiol Dis ; 190: 106363, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37996040

RESUMO

Sporadic Creutzfeldt-Jakob disease (sCJD), the most common human prion disease, is thought to occur when the cellular prion protein (PrPC) spontaneously misfolds and assembles into prion fibrils, culminating in fatal neurodegeneration. In a genome-wide association study of sCJD, we recently identified risk variants in and around the gene STX6, with evidence to suggest a causal increase of STX6 expression in disease-relevant brain regions. STX6 encodes syntaxin-6, a SNARE protein primarily involved in early endosome to trans-Golgi network retrograde transport. Here we developed and characterised a mouse model with genetic depletion of Stx6 and investigated a causal role of Stx6 expression in mouse prion disease through a classical prion transmission study, assessing the impact of homozygous and heterozygous syntaxin-6 knockout on disease incubation periods and prion-related neuropathology. Following inoculation with RML prions, incubation periods in Stx6-/- and Stx6+/- mice differed by 12 days relative to wildtype. Similarly, in Stx6-/- mice, disease incubation periods following inoculation with ME7 prions also differed by 12 days. Histopathological analysis revealed a modest increase in astrogliosis in ME7-inoculated Stx6-/- animals and a variable effect of Stx6 expression on microglia activation, however no differences in neuronal loss, spongiform change or PrP deposition were observed at endpoint. Importantly, Stx6-/- mice are viable and fertile with no gross impairments on a range of neurological, biochemical, histological and skeletal structure tests. Our results provide some support for a pathological role of Stx6 expression in prion disease, which warrants further investigation in the context of prion disease but also other neurodegenerative diseases considering syntaxin-6 appears to have pleiotropic risk effects in progressive supranuclear palsy and Alzheimer's disease.


Assuntos
Síndrome de Creutzfeldt-Jakob , Doenças Priônicas , Príons , Camundongos , Humanos , Animais , Síndrome de Creutzfeldt-Jakob/genética , Síndrome de Creutzfeldt-Jakob/patologia , Príons/genética , Príons/metabolismo , Estudo de Associação Genômica Ampla , Camundongos Transgênicos , Encéfalo/metabolismo , Doenças Priônicas/genética , Doenças Priônicas/patologia , Proteínas Qa-SNARE/genética , Proteínas Qa-SNARE/metabolismo
2.
Ann Surg ; 274(6): e507-e514, 2021 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-31663972

RESUMO

BACKGROUNDS: To determine the potential survival benefit associated with robotic-assisted laparoscopic prostatectomy (RALP) compared to open radical prostatectomy (ORP) for prostate cancer. SUMMARY OF BACKGROUND DATA: RALP has become the dominant surgical approach for localized disease in the absence of randomized clinical evidence and despite of the factor that RALP is more expensive than ORP. METHODS: We performed a cohort study involving patients who underwent RALP and ORP for localized prostate cancer at the Commission on Cancer- accredited hospitals in the United States. Overall survival was analyzed using the Kaplan-Meier method, log-rank test, Cox proportional hazards models, and propensity score-matched analyses. An interrupted time-series analysis using the surveillance, epidemiology, and end results program database was also performed. RESULTS: From 2010 to 2011, 37,645 patients received RALP and 12,655 patients received ORP. At a median follow-up of 60.7 months, RALP was associated with improved overall survival by both univariate [hazard ratio (HR), 0.69; P < 0.001] and multivariate analysis (HR, 0.76; P < 0.001) compared with ORP. Propensity score-matched analysis demonstrated improved 5-year all-cause mortality (3.9% vs 5.5%, HR, 0.73; P < 0.001) for RALP. The interrupted time-series analysis demonstrated the adoption of robotic surgery coincided with a systematic improvement in the 5-year cancer-specific survival rate of 0.17% (95% confidence interval, 0.06-0.25) per year after 2003 (P = 0.004 for change of trend), as compared to the time before adoption of RALP (1998-2003, annual percentage change, 0.01%; 95% confidence interval, -0.06 to 0.08). Sensitivity analysis suggested that the results from the interrupted time-series analysis were consistent with the improvement in the all-cause mortality demonstrated in the survival analysis (P = 0.87). CONCLUSIONS: In this epidemiologic analysis, RALP was associated with a small but statistically significant improvement in 5-year all-cause mortality compared to ORP for localized prostate cancer. This is the first time in the literature to report a survival benefit with RALP. Our findings have significant quality and cost implications, and provide assurance regarding a dominant adoption of more expensive technology in the absence of randomized controlled trials.


Assuntos
Laparoscopia/métodos , Prostatectomia/métodos , Neoplasias da Próstata/mortalidade , Neoplasias da Próstata/cirurgia , Procedimentos Cirúrgicos Robóticos , Idoso , Humanos , Análise de Séries Temporais Interrompida , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Pontuação de Propensão , Modelos de Riscos Proporcionais
3.
Clin Infect Dis ; 68(11): 1823-1830, 2019 05 17.
Artigo em Inglês | MEDLINE | ID: mdl-30239599

RESUMO

BACKGROUND: Overcoming ß-lactam resistance in pathogens such as Pseudomonas aeruginosa is a major clinical challenge. Rapid molecular diagnostics (RMDs) have the potential to inform selection of empiric therapy in patients infected by P. aeruginosa. METHODS: In this study, we used a heterogeneous collection of 197 P. aeruginosa that included multidrug-resistant isolates to determine whether 2 representative RMDs (Acuitas Resistome test and VERIGENE gram-negative blood culture test) could identify susceptibility to 2 newer ß-lactam/ß-lactamase inhibitor (BL-BLI) combinations, ceftazidime/avibactam (CZA) and ceftolozane/tazobactam (TOL/TAZO). RESULTS: We found that the studied RMD platforms were able to correctly identify BL-BLI susceptibility (susceptibility sensitivity, 100%; 95% confidence interval [CI], 97%, 100%) for both BLs-BLIs. However, their ability to detect resistance to these BLs-BLIs was lower (resistance sensitivity, 66%; 95% CI, 52%, 78% for TOL/TAZO and 33%; 95% CI, 20%, 49% for CZA). CONCLUSIONS: The diagnostic platforms studied showed the most potential in scenarios where a resistance gene was detected or in scenarios where a resistance gene was not detected and the prevalence of resistance to TOL/TAZO or CZA is known to be low. Clinicians need to be mindful of the benefits and risks that result from empiric treatment decisions that are based on resistance gene detection in P. aeruginosa, acknowledging that such decisions are impacted by the prevalence of resistance, which varies temporally and geographically.


Assuntos
Antibacterianos/uso terapêutico , Compostos Azabicíclicos/uso terapêutico , Ceftazidima/uso terapêutico , Cefalosporinas/uso terapêutico , Farmacorresistência Bacteriana Múltipla , Técnicas de Diagnóstico Molecular/normas , Infecções por Pseudomonas/tratamento farmacológico , Tazobactam/uso terapêutico , Antibacterianos/farmacologia , Combinação de Medicamentos , Genótipo , Humanos , Testes de Sensibilidade Microbiana , Técnicas de Diagnóstico Molecular/métodos , Infecções por Pseudomonas/microbiologia , Pseudomonas aeruginosa/efeitos dos fármacos , Sensibilidade e Especificidade , Resistência beta-Lactâmica , Inibidores de beta-Lactamases/farmacologia , Inibidores de beta-Lactamases/uso terapêutico
4.
J Natl Compr Canc Netw ; 17(1): 29-37, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30659127

RESUMO

Background: Chemotherapy with or without pelvic radiotherapy (RT) is included in the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for metastatic anal cancer (MAC), despite limited clinical evidence for RT in this setting. In addition, increasing evidence shows that local therapies, including RT, may increase patient survival for some types of metastatic cancers. The purpose of this study was to evaluate the patterns of care and association between definitive pelvic RT and overall survival (OS) for patients with MAC. Methods: The National Cancer Database was analyzed to evaluate OS of patients with newly diagnosed MAC treated with chemotherapy with or without pelvic RT. Those who did not undergo treatment, treated with surgery, or without baseline variables were excluded. OS was analyzed using the Kaplan-Meier method, log-rank test, Cox proportional hazards models, and propensity score-matched analyses. Results: From 2004 through 2015, 437 patients received chemotherapy alone and 1,020 received pelvic chemoradiotherapy (CRT). At a median follow-up of 17.3 months, CRT was associated with improved OS on univariate (P<.001) and multivariate analysis (hazard ratio [HR], 0.70; 95% CI, 0.61-0.81; P<.001). Propensity score-matched analysis demonstrated superior median survival (21.3 vs 15.9 months) and 2-year OS rates (46% vs 34%) with CRT compared with chemotherapy alone (P<.001). Landmark analyses limited to long-term survivors of ≥1, ≥2, and ≥4 years showed improved OS with CRT in all subsets (all P<.05). CRT with therapeutic doses (≥45 Gy) was associated with longer median survival than palliative doses (<45 Gy) and chemotherapy alone (24.9 vs 10.9 vs 15.6 months, respectively; P<.001). The benefit of CRT was present among not only those with distant lymph node metastasis (HR, 0.63; P=.04) but also those with distant organ disease (HR, 0.74; P<.001). Conclusions: In this large hypothesis-generating analysis, patients with newly diagnosed MAC who received definitive pelvic RT with chemotherapy lived significantly longer than those who received chemotherapy alone. Prospective trials evaluating definitive local RT for MAC are warranted.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias do Ânus/terapia , Carcinoma de Células Escamosas/terapia , Quimiorradioterapia/estatística & dados numéricos , Metástase Linfática/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias do Ânus/mortalidade , Neoplasias do Ânus/patologia , Carcinoma de Células Escamosas/mortalidade , Carcinoma de Células Escamosas/secundário , Quimiorradioterapia/métodos , Quimiorradioterapia/normas , Feminino , Seguimentos , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Guias de Prática Clínica como Assunto , Padrões de Prática Médica/estatística & dados numéricos , Estudos Prospectivos , Dosagem Radioterapêutica , Sistema de Registros/estatística & dados numéricos , Taxa de Sobrevida , Fatores de Tempo , Resultado do Tratamento , Estados Unidos/epidemiologia
5.
Eur Respir J ; 50(5)2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-29097432

RESUMO

Endobronchial ultrasound transbronchial needle aspiration (EBUS TBNA) is an established, minimally invasive way to sample intrathoracic abnormalities. The EBUS scope can be passed into the oesophagus to perform endoscopic ultrasound with bronchoscope-guided fine-needle aspiration (EUS-B-FNA). In cases of suspected lung cancer, a combination of the two techniques is now recommended by consensus guidelines. EBUS TBNA is usually performed by pulmonologists; however, the learning curve for EUS-B-FNA, which may be performed during the same procedure, has not been described.A multicentre, observational Australian study, using prospectively collected data from three experienced pulmonologists was conducted. Cumulative sum (cusum) analysis was used to generate visual learning curves.A total of 152 target lesions were sampled in 137 patients, with an overall sensitivity for malignancy of 94.8%. The sensitivity for malignant lesions outside of the 2009 International Association for the Study of Lung Cancer lymph node map (largely intraparenchymal lesions) was 92.9%. All three operators were competent by conventional cusum criteria. There was one case of pneumothorax, and no episodes of mediastinitis or oesophageal perforation were observed.Our data suggest that experienced pulmonologists can safely and accurately perform EUS-B-FNA, with a high diagnostic sensitivity for both lymph node and non-nodal lesions.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Competência Clínica/estatística & dados numéricos , Interpretação Estatística de Dados , Aspiração por Agulha Fina Guiada por Ultrassom Endoscópico/métodos , Neoplasias Pulmonares/diagnóstico , Austrália , Aspiração por Agulha Fina Guiada por Ultrassom Endoscópico/efeitos adversos , Humanos , Linfonodos/patologia , Mediastino/patologia , Estadiamento de Neoplasias , Pneumotórax/etiologia , Estudos Prospectivos , Pneumologistas , Sensibilidade e Especificidade
6.
Intern Med J ; 47(2): 205-210, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-27860078

RESUMO

BACKGROUND: Transoesophageal endobronchial ultrasound (EBUS) video-bronchoscope insertion provides pulmonologists access to conduct endoscopic fine-needle aspiration (EUS-B-FNA) of mediastinal lymph node (LN) lesions and also assist in lung cancer staging by sampling left adrenal gland (LAG) lesions. Limited literature has described additional diagnostic value whilst maintaining patient safety. To elicit whether combining endoscopic transoesophageal fine-needle aspiration using convex probe bronchoscope (EUS-B-FNA) and EBUS bronchoscopy enhances the diagnostic yield of mediastinal nodal staging in lung cancer, whilst maintaining safety. METHODS: All eligible patients with paraoesophageal lesions on thoracic computed tomography (CT) underwent pulmonologist-performed EUS-B-FNA at two tertiary centres and were included in this prospective observational cohort study. RESULTS: EUS-B-FNA sampling was performed at 69 mediastinal LN lesion sites, including 17 sites inaccessible to bronchoscopic sampling. Four LAG lesions were sampled via EUS-B-FNA. There were no complications. EBUS-TBNA was augmented by EUS-B-FNA because of accessibility of sampling lesions otherwise unamenable bronchoscopically, thereby increasing diagnostic utility. Diagnostic sensitivity of EUS-B-FNA for malignancy in mediastinal LN lesions was 88% (51 of 58). For mediastinal LN lesions not amenable to EBUS-TBNA, the sensitivity for diagnosis of malignancy via EUS-B-FNA was 88% (15 of 17). Diagnostic sensitivity of EUS-B-FNA for malignancy in LAG lesions was 50% (2 of 4). CONCLUSION: EUS-B-FNA is a precise and safe approach in the evaluation and staging of lung cancer when performed by a pulmonologist. It complements and increases the diagnostic utility of EBUS-TBNA by further coverage of mediastinal LN stations and access to LAG lesions.


Assuntos
Broncoscopia , Aspiração por Agulha Fina Guiada por Ultrassom Endoscópico , Endossonografia , Neoplasias Pulmonares/diagnóstico por imagem , Austrália , Humanos , Neoplasias Pulmonares/patologia , Linfonodos/patologia , Estadiamento de Neoplasias , Estudos Prospectivos , Pneumologistas , Sensibilidade e Especificidade , Tomografia Computadorizada por Raios X
7.
J Neurosci ; 34(18): 6140-5, 2014 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-24790184

RESUMO

Alzheimer's disease (AD) is associated with pathological assembly states of amyloid-ß protein (Aß). Aß-related synaptotoxicity can be blocked by anti-prion protein (PrP) antibodies, potentially allowing therapeutic targeting of this aspect of AD neuropathogenesis. Here, we show that intravascular administration of a high-affinity humanized anti-PrP antibody to rats can prevent the plasticity-disrupting effects induced by exposure to soluble AD brain extract. These results provide an in vivo proof of principle for such a therapeutic strategy.


Assuntos
Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/farmacologia , Anticorpos Monoclonais/administração & dosagem , Região CA1 Hipocampal/efeitos dos fármacos , Potenciação de Longa Duração/efeitos dos fármacos , Fragmentos de Peptídeos/farmacologia , Príons/imunologia , Idoso de 80 Anos ou mais , Análise de Variância , Animais , Biofísica , Vias de Administração de Medicamentos , Estimulação Elétrica , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Masculino , Príons/metabolismo , Ratos , Ratos Wistar , Lobo Temporal/química , Lobo Temporal/metabolismo
8.
Brain ; 135(Pt 3): 819-32, 2012 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-22366797

RESUMO

Mutations in the charged multivesicular body protein 2B (CHMP2B) gene cause frontotemporal lobar degeneration. The mutations lead to C-terminal truncation of the CHMP2B protein. We generated Chmp2b knockout mice and transgenic mice expressing either wild-type or C-terminally truncated mutant CHMP2B. The transgenic CHMP2B mutant mice have decreased survival and show progressive neurodegenerative changes including gliosis and increasing accumulation of p62- and ubiquitin-positive inclusions. The inclusions are negative for the TAR DNA binding protein 43 and fused in sarcoma proteins, mimicking the inclusions observed in patients with CHMP2B mutation. Mice transgenic for mutant CHMP2B also develop an early and progressive axonopathy characterized by numerous amyloid precursor protein-positive axonal swellings, implicating altered axonal function in disease pathogenesis. These findings were not observed in Chmp2b knockout mice or in transgenic mice expressing wild-type CHMP2B, indicating that CHMP2B mutations induce degenerative changes through a gain of function mechanism. These data describe the first mouse model of dementia caused by CHMP2B mutation and provide new insights into the mechanisms of CHMP2B-induced neurodegeneration.


Assuntos
Axônios/patologia , Complexos Endossomais de Distribuição Requeridos para Transporte/genética , Corpos de Inclusão/patologia , Degeneração Neural/patologia , Neurônios/patologia , Envelhecimento/fisiologia , Animais , Western Blotting , Demência Frontotemporal/patologia , Gliose/patologia , Humanos , Imuno-Histoquímica , Íntrons/genética , Estimativa de Kaplan-Meier , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Microscopia Eletrônica , RNA/biossíntese , RNA/genética , Reação em Cadeia da Polimerase em Tempo Real , Análise de Sobrevida
9.
PLoS One ; 18(11): e0294465, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37976283

RESUMO

Oligomers formed from monomers of the amyloid ß-protein (Aß) are thought to be central to the pathogenesis of Alzheimer's disease (AD). Unsurprisingly for a complex disease, current mouse models of AD fail to fully mimic the clinical disease in humans. Moreover, results obtained in a given mouse model are not always reproduced in a different model. Cellular prion protein (PrPC) is now an established receptor for Aß oligomers. However, studies of the Aß-PrPC interaction in different mouse models have yielded contradictory results. Here we performed a longitudinal study assessing a range of biochemical and histological features in the commonly used J20 and APP-PS1 mouse models. Our analysis demonstrated that PrPC ablation had no effect on amyloid accumulation or oligomer production. However, we found that APP-PS1 mice had higher levels of oligomers, that these could bind to recombinant PrPC, and were recognised by the OC antibody which distinguishes parallel, in register fibrils. On the other hand, J20 mice had a lower level of Aß oligomers, which did not interact with PrPC when tested in vitro and were OC-negative. These results suggest the two mouse models produce diverse Aß assemblies that could interact with different targets, highlighting the necessity to characterise the conformation of the Aß oligomers concomitantly with the toxic cascade elicited by them. Our results provide an explanation for the apparent contradictory results found in APP-PS1 mice and the J20 mouse line in regards to Aß toxicity mediated by PrPC.


Assuntos
Doença de Alzheimer , Proteínas PrPC , Príons , Humanos , Camundongos , Animais , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/metabolismo , Proteínas Priônicas/genética , Estudos Longitudinais , Proteínas PrPC/genética , Proteínas PrPC/metabolismo , Camundongos Transgênicos
10.
Lancet ; 377(9764): 487-93, 2011 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-21295339

RESUMO

BACKGROUND: Variant Creutzfeldt-Jakob disease (vCJD) is a fatal neurodegenerative disorder originating from exposure to bovine-spongiform-encephalopathy-like prions. Prion infections are associated with long and clinically silent incubations. The number of asymptomatic individuals with vCJD prion infection is unknown, posing risk to others via blood transfusion, blood products, organ or tissue grafts, and contaminated medical instruments. We aimed to establish the sensitivity and specificity of a blood-based assay for detection of vCJD prion infection. METHODS: We developed a solid-state binding matrix to capture and concentrate disease-associated prion proteins and coupled this method to direct immunodetection of surface-bound material. Quantitative assay sensitivity was assessed with a serial dilution series of 10⁻7 to 10⁻¹° of vCJD prion-infected brain homogenate into whole human blood, with a baseline control of normal human brain homogenate in whole blood (10⁻6). To establish the sensitivity and specificity of the assay for detection of endogenous vCJD, we analysed a masked panel of 190 whole blood samples from 21 patients with vCJD, 27 with sporadic CJD, 42 with other neurological diseases, and 100 normal controls. Samples were masked and numbered by individuals independent of the assay and analysis. Each sample was tested twice in independent assay runs; only samples that were reactive in both runs were scored as positive overall. FINDINGS: We were able to distinguish a 10⁻¹° dilution of exogenous vCJD prion-infected brain from a 10⁻6 dilution of normal brain (mean chemiluminescent signal, 1·3×105 [SD 1·1×104] for vCJD vs 9·9×104 [4·5×10³] for normal brain; p<0·0001)­an assay sensitivity that was orders of magnitude higher than any previously reported. 15 samples in the masked panel were scored as positive. All 15 samples were from patients with vCJD, showing an assay sensitivity for vCJD of 71·4% (95% CI 47·8­88·7) and a specificity of 100% (95% CIs between 97·8% and 100%). INTERPRETATION: These initial studies provide a prototype blood test for diagnosis of vCJD in symptomatic individuals, which could allow development of large-scale screening tests for asymptomatic vCJD prion infection. FUNDING: UK Medical Research Council.


Assuntos
Encéfalo/metabolismo , Síndrome de Creutzfeldt-Jakob/diagnóstico , Medições Luminescentes , Príons/sangue , Anticorpos/sangue , Estudos de Casos e Controles , Síndrome de Creutzfeldt-Jakob/sangue , Ensaio de Imunoadsorção Enzimática , Humanos , Príons/imunologia , Ligação Proteica , Sensibilidade e Especificidade , Aço Inoxidável
11.
Neuron ; 53(3): 325-35, 2007 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-17270731

RESUMO

Currently, no treatment can prevent the cognitive and motor decline associated with widespread neurodegeneration in prion disease. However, we previously showed that targeting endogenous neuronal prion protein (PrP(C)) (the precursor of its disease-associated isoform, PrP(Sc)) in mice with early prion infection reversed spongiform change and prevented clinical symptoms and neuronal loss. We now show that cognitive and behavioral deficits and impaired neurophysiological function accompany early hippocampal spongiform pathology. Remarkably, these behavioral and synaptic impairments recover when neuronal PrP(C) is depleted, in parallel with reversal of spongiosis. Thus, early functional impairments precede neuronal loss in prion disease and can be rescued. Further, they occur before extensive PrP(Sc) deposits accumulate and recover rapidly after PrP(C) depletion, supporting the concept that they are caused by a transient neurotoxic species, distinct from aggregated PrP(Sc). These data suggest that early intervention in human prion disease may lead to recovery of cognitive and behavioral symptoms.


Assuntos
Transtornos Cognitivos/prevenção & controle , Transtornos Cognitivos/psicologia , Proteínas PrPC/genética , Doenças Priônicas/genética , Doenças Priônicas/psicologia , Desempenho Psicomotor/fisiologia , Animais , Axônios/fisiologia , Comportamento Animal/fisiologia , Encéfalo/patologia , Discriminação Psicológica/fisiologia , Eletrofisiologia , Hipocampo/patologia , Imuno-Histoquímica , Potenciação de Longa Duração/fisiologia , Transtornos da Memória/etiologia , Transtornos da Memória/psicologia , Camundongos , Camundongos Transgênicos , Atividade Motora/fisiologia , Músculo Esquelético/fisiologia , Comportamento de Nidação/fisiologia , Doenças Priônicas/patologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Sinapses/patologia , Sinapses/fisiologia , Percepção Visual/fisiologia
14.
Proc Natl Acad Sci U S A ; 105(29): 10238-43, 2008 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-18632556

RESUMO

Prion diseases are fatal neurodegenerative conditions for which there is no effective treatment. Prion propagation involves the conversion of cellular prion protein, PrP(C), to its conformational isomer, PrP(Sc), which accumulates in disease. Here, we show effective therapeutic knockdown of PrP(C) expression using RNAi in mice with established prion disease. A single administration of lentivirus expressing a shRNA targeting PrP into each hippocampus of mice with established prion disease significantly prolonged survival time. Treated animals lived 19% and 24% longer than mice given an "empty" lentivirus, or not treated, respectively. Lentivirally mediated RNAi of PrP also prevented the onset of behavioral deficits associated with early prion disease, reduced spongiform degeneration, and protected against neuronal loss. In contrast, mice receiving empty virus or no treatment developed early cognitive impairment and showed severe spongiosis and neuronal loss. The focal use of RNAi therapeutically in prion disease further supports strategies depleting PrP(C), which we previously established to be a valid target for prion-based treatments. This approach can now be used to define the temporal, quantitative, and regional requirements for PrP knockdown for effective treatment of prion disease and to explore mechanisms involved in predegenerative neuronal dysfunction and its rescue.


Assuntos
Terapia Genética/métodos , Doenças Priônicas/terapia , Príons/antagonistas & inibidores , Príons/genética , Interferência de RNA , Animais , Sequência de Bases , Comportamento Animal , Genes Reporter , Proteínas de Fluorescência Verde/genética , Hipocampo/patologia , Hipocampo/fisiopatologia , Lentivirus/genética , Camundongos , Camundongos Transgênicos , Dados de Sequência Molecular , Proteínas PrPC/antagonistas & inibidores , Proteínas PrPC/genética , Proteínas PrPC/metabolismo , Proteínas PrPSc/metabolismo , Doenças Priônicas/genética , Doenças Priônicas/fisiopatologia , Doenças Priônicas/psicologia , Proteínas Priônicas , Príons/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , RNA Interferente Pequeno/administração & dosagem , RNA Interferente Pequeno/genética
15.
J Geriatr Oncol ; 12(2): 227-234, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-32978102

RESUMO

BACKGROUND: Fatigue is a common side effect of radiation therapy and can dramatically affect the quality of life in older cancer patients. We compared a home-based graduated walking intervention with a fixed walking recommendation.recommendation to exercise to determine the effects of these interventions during adjuvant radiotherapy (RT) on older women with breast cancer. METHODS: A randomized phase 2 trial in women ≥65 years, with stage 0-3 breast cancer. Prior to initiating breast RT, women were randomized to a Home-Based Graduated Walking Program (HBGWP) or a fixed walking recommendation. The primary outcome of fatigue was measured by the Total Disruption Index (TDI) of the Fatigue Symptom Inventory (FSI). Secondary outcomes including a short physical performance battery (SPPB) and questionnaires on exercise, physical function, fatigue (PROMIS Fatigue), and fatigue-related symptoms were collected at 3 time points. The primary goal was to compare the change in TDI between arms at the end of RT. Random coefficients models were used to determine the association between arm, fatigue, and exercise over time. Linear regression models were used to describe the change in outcome variables between visits. RESULTS: Median age of the 54 participants (27 per arm) was 69 years (range 65-84). The baseline characteristics were similar between study arms. The number of minutes walking per week increased in both arms (mean 21 min/wk. baseline to 83 min/wk. end of RT, p < 0.01) and physical function improved over time in both arms (median 10.5 at baseline to 12 at end of RT, p < 0.01).There was no significant difference in change in TDI between arms (2.7 ± 9.9 vs. 1.8 ± 14.0, p = 0.61)between baseline and end of RT. However, in our linear regression model increasing walking over time was associated with statistically significant lower levels of fatigue (-2.44+/- 1.04, p = 0.04), but not in posthoc subgroup analyses. CONCLUSION: The HBGWP did not decrease fatigue more than the fixed recommendation to exercise. Both the graduated intervention and fixed recommendation lead to increased walking which was associated with lower fatigue in this study of older adult breast cancer patients.


Assuntos
Neoplasias da Mama , Caminhada , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/complicações , Neoplasias da Mama/radioterapia , Exercício Físico , Terapia por Exercício , Fadiga/etiologia , Feminino , Humanos , Qualidade de Vida
16.
Respir Care ; 55(12): 1686-92, 2010 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-21122177

RESUMO

BACKGROUND: Recent studies described a progressive decline in lung volumes in adult bronchiectasis. Interstitial lung disease is also a feature of bronchiectasis, but whether this is associated with a decline in lung diffusing capacity (measured as the diffusing capacity of the lung for carbon monoxide [D(LCO)]) is not well known. OBJECTIVE: To assess longitudinal decline in diffusing capacity of the lung for carbon monoxide (D(LCO)) in adult bronchiectasis. METHODS: Sixty-one subjects had a detailed baseline clinical and laboratory assessment, then were followed regularly with clinical and lung-function assessment for a median 7 years. RESULTS: Baseline spirometry demonstrated mild obstructive lung disease, with a mean FEV(1) of 72% of predicted, mean forced vital capacity 87% of predicted, and normal D(LCO) (mean D(LCO) 88% of predicted, and mean D(LCO) adjusted for alveolar volume [D(LCO)/V(A)] 100% of predicted). There was an accelerated decline in D(LCO) and D(LCO)/V(A) over the 7-year period. The median D(LCO) decline was 2.9% of predicted per year (95% CI 2.3-4.1% of predicted per year). The median D(LCO)/V(A) decline was 2.4% of predicted per year (95% CI 2.1-4.0% of predicted per year). There was a significant relationship between D(LCO) decline and age and decline in FEV(1). CONCLUSIONS: In our cohort of patients with bronchiectasis there was a progressive D(LCO) decline.


Assuntos
Bronquiectasia/complicações , Bronquiectasia/fisiopatologia , Capacidade de Difusão Pulmonar/fisiologia , Adulto , Fatores Etários , Idoso , Bronquiectasia/metabolismo , Feminino , Volume Expiratório Forçado/fisiologia , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Espirometria , Fatores de Tempo , Capacidade Vital/fisiologia
17.
COPD ; 6(2): 130-6, 2009 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-19378226

RESUMO

Bronchiectasis is a heterogeneous disorder with a large number of etiologic factors. The main symptom is a chronic productive cough. The aim of this study was to describe the phenotypes of patients with bronchiectasis who had developed a chronic productive cough in childhood (before 16 years of age) compared with those who had developed a productive cough as adults. One hundred and eighty-two subjects with bronchiectasis diagnosed by computed tomography scanning were studied. Subjects all had a detailed clinical review and assessment of potential etiologic factors performed by the investigators. There were 107 (59%) subjects who developed a chronic productive cough in childhood and 75 (41%) subjects who developed a chronic productive cough in adulthood. There were significant differences in a number of parameters between the two groups including duration of cough, frequency of exacerbations, presence of rhinosinusitis, crackles on examination and lung function. The adult group could be further divided into those who had developed a cough whilst smoking and those who had no obvious relationship with smoking. In conclusion there were a number of significant differences between the child onset and adult onset group that may reflect different phenotypes of bronchiectasis.


Assuntos
Bronquiectasia/complicações , Tosse/epidemiologia , Adolescente , Adulto , Idade de Início , Bronquiectasia/diagnóstico por imagem , Bronquiectasia/fisiopatologia , Criança , Pré-Escolar , Doença Crônica , Estudos de Coortes , Feminino , Volume Expiratório Forçado , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Fatores de Tempo , Tomografia Computadorizada por Raios X , Adulto Jovem
18.
Am J Emerg Med ; 26(4): 516.e1-2, 2008 May.
Artigo em Inglês | MEDLINE | ID: mdl-18410831

RESUMO

Portal vein thrombosis secondary to protein C deficiency is a rare finding. Diagnosing a portal vein thrombosis itself is difficult due to nonspecific symptoms such as nausea, vomiting, anorexia, and weight loss. Proving that a protein C deficiency is the cause of a portal vein thrombosis is even more difficult as an extensive and thorough workup is required to rule out malignancies, myeloproliferative disorders, and hypercoaguable states which can all lead to thromboses. Patients require anticoagulation to prevent two dangerous complications of portal vein thrombosis; portal hypertension leading to esophageal varices with massive hemetemesis and extension of thrombus from the portal vein into the mesenteric veins leading to intestinal ischemia and death. In this case report, we present a patient with the complaint of painless jaundice who was found to have an incidental finding of portal vein thrombosis secondary to protein C deficiency. The different etiologies of portal vein thrombosis, along with diagnosis and treatment options will be discussed and highlighted.


Assuntos
Coledocolitíase/complicações , Icterícia/etiologia , Veia Porta , Deficiência de Proteína C/complicações , Trombose Venosa/etiologia , Humanos , Achados Incidentais , Masculino , Pessoa de Meia-Idade
19.
Pract Radiat Oncol ; 8(4): 275-278, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29452874

RESUMO

PURPOSE: The purpose of this study was to survey the accessibility and quality of prostate-specific antigen (PSA) screening information from National Cancer Institute (NCI) cancer center and public health organization Web sites. METHODS AND MATERIALS: We surveyed the December 1, 2016, version of all 63 NCI-designated cancer center public Web sites and 5 major online clearinghouses from allied public/private organizations (cancer.gov, cancer.org, PCF.org, USPSTF.org, and CDC.gov). Web sites were analyzed according to a 50-item list of validated health care information quality measures. Web sites were graded by 2 blinded reviewers. Interrater agreement was confirmed by Cohen kappa coefficient. RESULTS: Ninety percent of Web sites addressed PSA screening. Cancer center sites covered 45% of topics surveyed, whereas organization Web sites addressed 70%. All organizational Web pages addressed the possibility of false-positive screening results; 41% of cancer center Web pages did not. Forty percent of cancer center Web pages also did not discuss next steps if a PSA test was positive. Only 6% of cancer center Web pages were rated by our reviewers as "superior" (eg, addressing >75% of the surveyed topics) versus 20% of organizational Web pages. Interrater agreement between our reviewers was high (kappa coefficient = 0.602). CONCLUSION: NCI-designated cancer center Web sites publish lower quality public information about PSA screening than sites run by major allied organizations. Nonetheless, information and communication deficiencies were observed across all surveyed sites. In an age of increasing patient consumerism, prospective prostate cancer patients would benefit from improved online PSA screening information from provider and advocacy organizations. Validated cancer patient Web educational standards remain an important, understudied priority.


Assuntos
Comunicação em Saúde/métodos , Internet , Programas de Rastreamento/métodos , Neoplasias da Próstata/prevenção & controle , Humanos , Masculino , National Cancer Institute (U.S.) , Antígeno Prostático Específico/análise , Qualidade da Assistência à Saúde , Inquéritos e Questionários , Estados Unidos
20.
J Bronchology Interv Pulmonol ; 24(2): 117-124, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28005836

RESUMO

BACKGROUND: Transesophageal introduction of the endobronchial ultrasound (EBUS) videobronchoscope allows pulmonologists to perform endoscopic ultrasound fine-needle aspiration (EUS-B-FNA) of mediastinal lesions. Safety, diagnostic accuracy, and feasibility of EUS-B-FNA in evaluation of pulmonary parenchymal lesions are not established. METHODS: All patients undergoing pulmonologist-performed EUS-B-FNA of parenchymal lung lesions at 2 tertiary centers were included in this prospective observational cohort study. RESULTS: EUS-B-FNA sampling of parenchymal lesions was performed in 27 patients. Mean (±SD) lesion size was 36±16 mm. Seven lesions were ≤18 mm. Pneumothorax occurred in 1 patient (3.7%, 95% confidence interval, 0.001%-19%). Ten target lesions (36%) were in locations inaccessible to bronchoscopic sampling via the airways, and 9 lesions were inaccessible to EBUS-guided transbronchial needle aspiration and in locations associated with low diagnostic yield from radial EBUS. EUS-B-FNA was diagnostic in 26 patients (96%), and sensitivity of EUS-B-FNA was 100% (95% confidence interval, 87%-100%) for both lung cancer (n=21) and for pulmonary metastatic lesions (n=5). CONCLUSIONS: Pulmonologist-performed EUS-B-FNA is safe and accurate in the evaluation parenchymal lung lesions. Diagnostic accuracy is high. EUS-B-FNA may achieve access to sites not amenable to other forms of bronchoscopic sampling, or increase diagnostic accuracy in patients where anatomic position predicts a low diagnostic yield.


Assuntos
Adenocarcinoma/patologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma de Células Escamosas/patologia , Aspiração por Agulha Fina Guiada por Ultrassom Endoscópico/métodos , Esofagoscopia/métodos , Neoplasias Pulmonares/patologia , Complicações Pós-Operatórias/epidemiologia , Carcinoma de Pequenas Células do Pulmão/patologia , Adenocarcinoma/diagnóstico por imagem , Broncoscópios , Carcinoma Pulmonar de Células não Pequenas/diagnóstico por imagem , Carcinoma de Células Escamosas/diagnóstico por imagem , Estudos de Coortes , Aspiração por Agulha Fina Guiada por Ultrassom Endoscópico/efeitos adversos , Esofagoscopia/efeitos adversos , Humanos , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/secundário , Pneumotórax/etiologia , Complicações Pós-Operatórias/etiologia , Estudos Prospectivos , Pneumologistas , Sensibilidade e Especificidade , Carcinoma de Pequenas Células do Pulmão/diagnóstico por imagem , Tomografia Computadorizada por Raios X
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