RESUMO
RATIONALE: The Saint George's Respiratory Questionnaire (SGRQ) is a frequently used tool to assess health status in pulmonary disease patients. However, its performance characteristics in sarcoidosis patients are not well characterized. METHODS: Data from a clinical trial of 138 symptomatic adults with sarcoidosis were used to examine the performance characteristics of SGRQ. Data were available at both baseline and week 24. Other assessments included FVC, FEV1, ATS dyspnea score, Borg's CR 10 dyspnea score, 6-min walk distance (6MWD), and Short Form-36 Physical Component Summary (SF-36 PCS) score. RESULTS: Baseline SGRQ was 46.8, indicating impaired health status. At baseline, SGRQ total score correlated significantly with % predicted FVC, FEV1, ATS dyspnea score, Borg's CR 10 dyspnea score, 6MWD, and SF-36 PCS (r = - 0.37, - 0.32, 0.57, 0.40, - 0.55, and - 0.80, respectively, p < 0.001). Change from baseline in SGRQ score also statistically significantly correlated with change from baseline in these parameters at week 24: r = - 0.25, - 0.20, 0.30, 0.22, - 0.20, - 0.45, respectively (p < 0.05). CONCLUSIONS: The SGRQ correlated with other outcome measures in sarcoidosis initially and with treatment. Improvement in FVC % predicted correlated with improvement in SGRQ. These data suggest the SGRQ may function as a reliable endpoint in clinical sarcoidosis trials.
Assuntos
Nível de Saúde , Qualidade de Vida , Sarcoidose Pulmonar/complicações , Inquéritos e Questionários , Adulto , Antirreumáticos/uso terapêutico , Método Duplo-Cego , Feminino , Humanos , Infliximab/uso terapêutico , Masculino , Pessoa de Meia-Idade , Avaliação de Resultados em Cuidados de Saúde , Valor Preditivo dos Testes , Estudos Prospectivos , Reprodutibilidade dos Testes , Testes de Função Respiratória , Sarcoidose Pulmonar/tratamento farmacológico , Sarcoidose Pulmonar/psicologia , Avaliação de SintomasRESUMO
The molecular basis of sarcoidosis phenotype heterogeneity and its relationship to effective treatment of sarcoidosis have not been elucidated. Peripheral samples from sarcoidosis subjects who participated in a Phase II study of golimumab [anti-tumour necrosis factor (TNF)-α] and ustekinumab [anti-interleukin (IL)-12p40] were used to measure the whole blood transcriptome and levels of serum proteins. Differential gene and protein expression analyses were used to explore the molecular differences between sarcoidosis phenotypes as defined by extent of organ involvement. The same data were also used in conjunction with an enrichment algorithm to identify gene expression changes associated with treatment with study drugs compared to placebo. Our analyses revealed marked heterogeneity among the three sarcoidosis phenotypes included in the study cohort, including striking differences in enrichment of the interferon pathway. Conversely, enrichments of multiple pathways, including T cell receptor signalling, were similar among phenotypes. We also identify differences between treatment with golimumab and ustekinumab that may explain the differences in trends for clinical efficacy observed in the trial. We find that molecular heterogeneity is associated with sarcoidosis in a manner that may be related to the extent of organ involvement. These findings may help to explain the difficulty in identifying clinically efficacious sarcoidosis treatments and suggest hypotheses for improved therapeutic strategies.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Sarcoidose/terapia , Transdução de Sinais/efeitos dos fármacos , Transcriptoma , Ustekinumab/uso terapêutico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Método Duplo-Cego , Feminino , Humanos , Pulmão/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Fenótipo , Sarcoidose/sangue , Pele/efeitos dos fármacos , Linfócitos T Citotóxicos/efeitos dos fármacos , Estados Unidos , Adulto JovemRESUMO
The aim of this study was to investigate the diagnostic value of using the copy number of propionibacterial rRNA as a biomarker for sarcoidosis. Ribosomal RNA of Propionibacterium acnes and P. granulosum was measured by real-time quantitative reverse transcription-polymerase chain reaction (RT-PCR) using formalin-fixed and paraffin-embedded tissue of lymph node biopsy from 65 Chinese patients with sarcoidosis, 45 with tuberculosis and 50 controls with other diseases (23 with non-specific lymphadenitis and 27 with mediastinal lymph node metastasis from lung cancer). The receiver operating characteristic (ROC) curve was analysed to determine an optimal cut-off value for diagnosis, and the diagnostic accuracy of the cut-off value was evaluated in additional tissue samples [24 patients with sarcoidosis and 22 with tuberculosis (TB)]. P. acnes or P. granulosum rRNA was detected in 48 of the 65 sarcoidosis samples but only in four of the 45 TB samples and three of the 50 control samples. Analysis of the ROC curve revealed that an optimal cut-off value of the copy number of propionibacterial rRNA for diagnosis of sarcoidosis was 50·5 copies/ml with a sensitivity and specificity of 73·8 and 92·6%, respectively. Based on the cut-off value, 19 of the 24 additional sarcoidosis samples exhibited positive P. acnes or P. granulosum, whereas only one of the 22 additional TB samples was positive, resulting in a sensitivity and specificity of 79·2 and 95·5%, respectively. These findings suggest that propionibacteria might be associated with sarcoidosis granulomatous inflammation. Detection of propionibacterial rRNA by RT-PCR might possibly distinguish sarcoidosis from TB.
Assuntos
Infecções por Bactérias Gram-Positivas/diagnóstico , Linfonodos/patologia , Propionibacterium/genética , RNA Ribossômico/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa/métodos , Sarcoidose/diagnóstico , Adulto , Idoso , Povo Asiático , China , Feminino , Dosagem de Genes , Infecções por Bactérias Gram-Positivas/etnologia , Infecções por Bactérias Gram-Positivas/microbiologia , Interações Hospedeiro-Patógeno , Humanos , Linfonodos/microbiologia , Masculino , Pessoa de Meia-Idade , Propionibacterium/classificação , Propionibacterium/fisiologia , Propionibacterium acnes/genética , Propionibacterium acnes/fisiologia , RNA Bacteriano/genética , Curva ROC , Reprodutibilidade dos Testes , Sarcoidose/etnologia , Sarcoidose/microbiologia , Tuberculose/diagnóstico , Tuberculose/etnologia , Tuberculose/microbiologia , Adulto JovemRESUMO
BACKGROUND: A step wise approach to the use of cytotoxic and anti-tumor necrosis factor (TNF) antibodies has been developed for managing chronic sarcoidosis. OBJECTIVES: To provide a summary of our experience with immunosuppressive agents especially methotrexate and the anti-tumor necrosis factor antibodies in treating chronic ocular sarcoidosis. STUDY DESIGN AND METHODS: This was a retrospective review of 1587 sarcoidosis patients seen at one center over a six year period. All patients with definite or probable ocular sarcoidosis were identified. RESULTS: A total of 465 (29%) of the sarcoidosis patients experienced ocular disease. Of these, 365 patients were treated with methotrexate (MTX) for their eye disease with 281 (77% of those started on MTX) still receiving MTX at the end of the study. Methotrexate was the only systemic therapy prescribed in 115 patients while 101 patients also received concurrent prednisone. Other combinations administered include MTX plus azathioprine and/or leflunomide. A total of 25 patients were treated with the monoclonal anti-TNF antibodies infliximab (19 patients) or adalimumab (6 patients). While all patients initially responded to anti-TNF therapy, only ten patients experienced a sustained response with ongoing therapy or complete remission of ocular disease. Recurrent infections, adverse drug events, or financial constraints were responsible for most drug discontinuations. CONCLUSION: Most cases of chronic ocular sarcoidosis respond well to immunosuppressive therapy. However, patients may require combination therapy to achieve and maintain disease control. The use of anti-TNF agents for refractory disease is encouraging but can be accompanied by significant toxicity.
Assuntos
Oftalmopatias/terapia , Imunossupressores/uso terapêutico , Sarcoidose/terapia , Adulto , Anticorpos Monoclonais/uso terapêutico , Doença Crônica , Quimioterapia Combinada , Oftalmopatias/diagnóstico , Oftalmopatias/imunologia , Feminino , Humanos , Imunossupressores/efeitos adversos , Masculino , Metotrexato/uso terapêutico , Pessoa de Meia-Idade , Ohio , Estudos Retrospectivos , Sarcoidose/diagnóstico , Sarcoidose/imunologia , Resultado do Tratamento , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/imunologiaRESUMO
BACKGROUND: Sarcoidosis is a granulomatous disorder of unknown cause, affecting multiple organs. Tuberculosis is the world's second most common cause of death from infectious diseases. Due to the similar clinical, radiological and histopathological pictures in sarcoidosis and tuberculosis, Mycobacterium tuberculosis has been considered as potential infectious factor. However, it remains difficult to distinguish sarcoidosis from tuberculosis, especially when sputum examinations for mycobacterium are negative. METHODS: 1. to establish a scoring system for differentiating sarcoidosis and tuberculosis: We collected the risk factors, laboratory data and the data of clinical, radiographic, pathological manifestations from the 117 of sarcoidosis patients and 181 of sputum negative tuberculosis patient. And we put them into the designed form. Based on the results of univariate analysis, clinical experience and the literature, we further selected 13 variables that were more supportive to distinguish the two diseases. Finally 9 variables were selected based on logistic regression to establish the scoring systems with significant differences between the two diseases. The beta-coefficient form the logistic regression were used to calculate the weight of each variable. Four types of comprehensive scoring models were established in the end (clinical-- radiographic; clinical--radiographic--radionuclide; clinical--radiographic--pathological and clinico-radiographic--radionuclide--pathological group). Receiver operating characteristics (ROC) analysis was used to determine an optimal cutoff point for each scoring system. 2. to validate the accuracy of the established scoring system: 73 of new sarcoidosis patients and 57 of new tuberculosis patients were chosen to assess the diagnosis accuracy of the four scoring systems. RESULTS: 1. we established four types of comprehensive scoring models, included clinical--radiographic; clinical--radiographic--radionuclide; clinical--radiographic--pathological and clinico--radiographic--radionuclide--pathological scoring models, the optimal cutoff values respectively were 9, 17, 18 and 22, the sensitivity and specificity of the four scoring system to distinguish the two diseases respectively were: 93.16% (109/117) and 97.79% (177/181), 92.31% (108/117) and 98.90% (179/181); 93.16% (109/117) and 98.90% (179/181); 94.87% (111/117) and 98.90% (179/181). 2. Validation of the scoring systems with 130 new patients (73 of sarcoidosis and 57 of tuberculosis):, the sensitivity and specificity of CR, CRE, CRP, CREP were 91.78% (67/73) and 87.72% (50/57), 97.26% (69/73) and 98.25% (56/57), 94.52% (71/73) and 96.49% (55/57), 98.63% (72/73) and 98.25% (56/57) respectively. CONCLUSIONS: The four scoring systems established by this study can be utilized to differentiate sarcoidosis and sputum negative tuberculosis effectively. Based on the availability of clinical-radiographical/histopathological data, any of the four diagnostic scoring systems were reliable tools for differential diagnosis, with increased information leading to better discrimination.
Assuntos
Biópsia , Diagnóstico por Imagem , Pulmão , Sarcoidose Pulmonar/diagnóstico , Tuberculose Pulmonar/diagnóstico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Distribuição de Qui-Quadrado , Diagnóstico Diferencial , Diagnóstico por Imagem/métodos , Feminino , Humanos , Modelos Logísticos , Pulmão/diagnóstico por imagem , Pulmão/patologia , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Mycobacterium tuberculosis/isolamento & purificação , Valor Preditivo dos Testes , Curva ROC , Radiografia , Cintilografia , Reprodutibilidade dos Testes , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Sarcoidose Pulmonar/complicações , Sensibilidade e Especificidade , Escarro/microbiologia , Tuberculose Pulmonar/complicações , Tuberculose Pulmonar/microbiologia , Adulto JovemRESUMO
Over the past few years an increasing number of prospective controlled sarcoidosis treatment trials have been completed. Unfortunately, these studies utilize different endpoints making comparisons between studies difficult. At the recent World Association of Sarcoidosis and other Granulomatous disease (WASOG) meeting, a session was dedicated to the evaluation of clinical endpoints for various disease manifestations. These included pulmonary, pulmonary hypertension, fatigue, cutaneous, and a classification of clinical disease phenotypes. Based on the available literature and our current understanding of the disease, recommendations for clinical evaluation were proposed for each disease category. For example, it was recommended that pulmonary studies should include changes in the forced vital capacity. Additionally, it was recommended that all trials should incorporate measurement of quality of life.
Assuntos
Ensaios Clínicos como Assunto/métodos , Gerenciamento Clínico , Sarcoidose Pulmonar/diagnóstico , Sarcoidose Pulmonar/terapia , Humanos , Qualidade de Vida , Testes de Função Respiratória , Índice de Gravidade de DoençaRESUMO
The clinical outcome of sarcoidosis is quite variable. Several scoring systems have been used to assess the level of disease and clinical outcome. The definition of clinical phenotypes has become an important goal as genetic studies have identified distinct genotypes associated with different clinical phenotypes. In addition, treatment strategies have been developed for patients with resolving versus non resolving disease. A task force was established by the World Association of Sarcoidosis and Other Granulomatous diseases (WASOG) to define clinical phenotypes of the disease based on the clinical outcome status (COS). The committee chose to examine patients five years after diagnosis to determine the COS. Several features of the disease were incorporated into the final nine categories of the disease. These included the current or past need for systemic therapy, the resolution of the disease, and current status of the condition. Sarcoidosis patients who were African American or older were likely to have a higher COS, indicating more chronic disease. The COS may be useful in future studies of sarcoidosis.
Assuntos
Comitês Consultivos , Predisposição Genética para Doença , Pneumologia , Sarcoidose Pulmonar , Adolescente , Adulto , Idoso , Criança , Congressos como Assunto , Diagnóstico Diferencial , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Morbidade , Fenótipo , Estudos Retrospectivos , Sarcoidose Pulmonar/diagnóstico , Sarcoidose Pulmonar/epidemiologia , Sarcoidose Pulmonar/genética , Adulto JovemRESUMO
A direct process for manufacturing polymer carbon nanotube (CNT)-based composite yarns is reported. The new approach is based on a modified dry spinning method of CNT yarn and gives a high alignment of the CNT bundle structure in yarns. The aligned CNT structure was combined with a polymer resin and, after being stressed through the spinning process, the resin was cured and polymerized, with the CNT structure acting as reinforcement in the composite. Thus the present method obviates the need for special and complex treatments to align and disperse CNTs in a polymer matrix. The new process allows us to produce a polymer/CNT composite with properties that may satisfy various engineering specifications. The structure of the yarn was investigated using scanning electron microscopy coupled with a focused-ion-beam system. The tensile behavior was characterized using a dynamic mechanical analyzer. Fourier transform infrared spectrometry was also used to chemically analyze the presence of polymer on the composites. The process allows development of polymer/CNT-based composites with different mechanical properties suitable for a range of applications by using various resins.
Assuntos
Nanocompostos/química , Nanotecnologia/instrumentação , Nanotecnologia/métodos , Nanotubos de Carbono/química , Polímeros/química , Módulo de Elasticidade , Elastômeros/química , Microscopia Eletrônica de Varredura , Nanocompostos/ultraestrutura , Nanotubos de Carbono/ultraestrutura , Polímeros/síntese química , Poliuretanos/química , Espectroscopia de Infravermelho com Transformada de Fourier , Estresse Mecânico , Propriedades de Superfície , Temperatura , Resistência à TraçãoRESUMO
BACKGROUND: This study assessed the value of C-reactive protein as a predictor of disease severity and response to infliximab therapy in patients with chronic pulmonary sarcoidosis. DESIGN: Sera were collected through week 52 from 138 patients with chronic pulmonary sarcoidosis who received placebo or infliximab in a randomized, double-blind, placebo-controlled study. We evaluated the response to therapy by baseline CRP using a dichotomous cutpoint (0.8 mg/dL) for the change from baseline in percent-predicted forced vital capacity (FVC), Saint George's Respiratory Questionnaire (SGRQ), 6-minute walk distance (6MWD), Borg's CR10 dyspnea score, and Physician Organ Assessment (POA). RESULTS: CRP was elevated in 36% of patients at baseline, and was significantly reduced by infliximab by week 2. Among patients with elevated baseline CRP, infliximab-treated patients improved significantly compared with placebo-treated patients in percent-predicted FVC (+2.5 versus -2.6%), 6MWD (+8.0 versus -34.1), Borg's CR10 dyspnea score (pre-6MWD -0.8 versus +0.9, post-6MWD -1.1 versus +0.8), and POA (-3.1 versus -0.3). Patients with lower CRP levels at baseline did not show significant differences between the placebo and infliximab groups in most endpoints evaluated. CONCLUSIONS: In chronic sarcoidosis patients, elevated CRP appears to identify a subset with more severe disease who may respond better to treatment with infliximab.
Assuntos
Anti-Inflamatórios/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Proteína C-Reativa/metabolismo , Sarcoidose Pulmonar/tratamento farmacológico , Adulto , Biomarcadores/sangue , Doença Crônica , Ensaios Clínicos Fase II como Assunto , Método Duplo-Cego , Dispneia/tratamento farmacológico , Dispneia/imunologia , Teste de Esforço , Tolerância ao Exercício , Feminino , Humanos , Infliximab , Masculino , Pessoa de Meia-Idade , Estudos Multicêntricos como Assunto , Ensaios Clínicos Controlados Aleatórios como Assunto , Estudos Retrospectivos , Sarcoidose Pulmonar/imunologia , Sarcoidose Pulmonar/fisiopatologia , Índice de Gravidade de Doença , Inquéritos e Questionários , Fatores de Tempo , Resultado do Tratamento , Estados Unidos , Capacidade Vital , CaminhadaRESUMO
The clinical assessment of new formulations of human insulin is problematic due to the inability to distinguish between endogenous insulin and exogenously administered insulin. The usual methods to surmount the problem of distinguishing between endogenous and exogenous human insulin include evaluation in subjects with no or little endogenous insulin, hyper-insulinemic clamp studies or the administration of somatostatin to suppress endogenous insulin secretion. All of these methods have significant drawbacks. This paper describes a method for C-Peptide correction based upon a mixed effects linear regression of multiple time point sampling of C-Peptide and insulin. This model was able to describe each individual's insulin to C-Peptide relationship using the data from four different phase I clinical trials involving both subjects with and without type 2 diabetes in which insulin and C-Peptide were measured. These studies used hyper-insulinemic euglycemic clamps or meal challenges and subjects received insulin or Glucagon-like peptide 1 (GLP-1). It was possible to determine the exogenously administered insulin concentration from the measured total insulin concentration. A simple statistical technique can be used to determine each individual's insulin to C-Peptide relationship to estimate exogenous and endogenous insulin following the administration of regular human insulin. This technique will simplify the assessment of new formulations of human insulin.
Assuntos
Peptídeo C/sangue , Hipoglicemiantes/farmacocinética , Insulina/sangue , Insulina/farmacocinética , Disponibilidade Biológica , Glicemia , Diabetes Mellitus Tipo 2/sangue , Peptídeo 1 Semelhante ao Glucagon/sangue , Peptídeos Semelhantes ao Glucagon/administração & dosagem , Técnica Clamp de Glucose , Teste de Tolerância a Glucose , Humanos , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/sangue , Insulina/administração & dosagem , Doença Pulmonar Obstrutiva Crônica/sangueRESUMO
Nanotube fibers are expected to have a wide range of applications from energy storage to high-strength mechanical devices. But as Baughman explains in his Perspective, methods for making such fibers have been of limited success. In contrast, the process reported by Vigolo et al. shows great promise. Together with a recently reported, more economically viable nanotube production process, this method may open the door to large-scale devices and materials based on carbon nanotubes.
RESUMO
The appearance of superconductivity at relatively high temperatures in alkali metal-doped C(60) fullerene provides the challenge to both understand the nature and origin of the superconductivity and to determine the upper limit of the superconducting transition temperature (T(c)). Towards the latter goal, it is shown that doping with potassium-thallium and rubidium-thallium alloys in the 400 to 430 degrees C temperature range increases the T(c) of C(60)/C(70) mixtures to 25.6 K and above 45 K, respectively. Similar increases in T(c) were also observed upon analogous doping of pure C(60). Partial substitution of potassium with thallium in interstitial sites between C(60) molecules is suggested by larger observed unit cell parameters than for the K(3)C(60) and K(4)C(60) phases. Contrary to previous results for C(60) doped with different alkali metals, such expansion does not alone account for the changes in critical temperature.
RESUMO
RATIONALE: Patients with sarcoidosis associated pulmonary hypertension (SAPH) have responded to systemic prostacyclin therapy. OBJECTIVES: To determine the rate of response to inhaled prostacyclin, iloprost, in SAPH. METHODS: Sarcoidosis patients with pulmonary hypertension and no evidence for left ventricular dysfunction were enrolled in an open label, prospective study. Patients underwent right heart catheterization and six minute walk (6MW) test. Quality of life was evaluated using several instruments, including the Saint George Respiratory Questionnaire (SGRQ). Patients received 5 mcg of inhaled iloprost every 2-3 hours while awake. After four months of therapy, patients underwent repeat cardiac catheterization, 6 MW test, and completed quality of life questionnaires. MEASUREMENTS AND MAIN RESULTS: Of the 22 patients enrolled, 15 completed all 16 weeks of therapy. The most common reasons for study discontinuation included drug associated cough (3 patients) and compliance with the prescribed number of treatments per day (2 patients). Six patients experienced a 20% or greater decrease in pulmonary vascular resistance (PVR) from baseline with five of these six patients also showing > or = 5 mm Hg reduction in PA mean. Although three patients improved the 6MW distance by at least 30 meters, only one had a decrease in PVR. At 16 weeks a significant decrease was reported in the SGRQ activity score (p = 0.0273), with seven patients having a 4 point or greater decrease. CONCLUSION: Inhaled iloprost as monotherapy was associated with an improvement in pulmonary hemodynamics and quality of life as assessed by the SGRQ activity score in some sarcoidosis patients with SAPH.
Assuntos
Hipertensão Pulmonar/induzido quimicamente , Iloprosta/efeitos adversos , Pressão Propulsora Pulmonar/efeitos dos fármacos , Sarcoidose Pulmonar/tratamento farmacológico , Vasodilatadores/efeitos adversos , Administração por Inalação , Adulto , Idoso , Feminino , Seguimentos , Humanos , Hipertensão Pulmonar/fisiopatologia , Iloprosta/administração & dosagem , Masculino , Pessoa de Meia-Idade , Prognóstico , Qualidade de Vida , Sarcoidose Pulmonar/fisiopatologia , Inquéritos e Questionários , Vasodilatadores/administração & dosagemRESUMO
BACKGROUND: Fatigue is a major problem in sarcoidosis. Fatigue has mainly been examined in patients from The Netherlands. OBJECTIVE: The aims of the study were to establish the prevalence of fatigue in US and Dutch patients and to determine whether fatigue was related to the common demographic and clinical parameters. DESIGN: Two patients groups were studied: Dutch outpatients at Maastricht University Medical Center in The Netherlands (n = 121) and US patients at the University of Cincinnati Medical Center in the USA (n = 126). Both groups completed the Fatigue Assessment Scale. Clinical data were gathered from the patients' medical files. RESULTS: The prevalence of fatigue was similar in the US and Dutch patients, but more severe in the latter group. Fatigue was unrelated to demographic and clinical parameters in the total group. However, when examining the US and Dutch patients separately, fatigue was associated with age, extrapulmonary involvement and drug use in the US group. CONCLUSIONS: Dutch patients report more severe fatigue compared with US patients. Interestingly, fatigue was related to clinical and demographical parameters in the US patients, although no such relationships was found in the Dutch patients.
Assuntos
Fadiga/epidemiologia , Sarcoidose/complicações , Adulto , Idoso , Idoso de 80 Anos ou mais , Fadiga/etiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Países Baixos/epidemiologia , Prevalência , Sarcoidose/epidemiologia , Estados Unidos/epidemiologiaRESUMO
N-methyl-D-aspartate (NMDA) and non-NMDA receptors play a key role in synaptic transmission and plasticity in the vertebrate central nervous system. Previous studies have suggested that although both receptor types are present at synapses, the NMDA receptors may be relatively uniformly distributed. We have combined iontophoretic mapping of NMDA and non-NMDA receptors with immunohistochemical localization of synaptic vesicles along dendrites of single neocortical neurons to determine the relationship between NMDA and non-NMDA receptor distribution and the location of synapses. We find that when corrections for glutamate diffusion are made, NMDA responses are concentrated at focal "hot spots" that coincide with non-NMDA hot spots and that there is an excellent correlation between these hot spots and synapses.
Assuntos
Córtex Cerebral/metabolismo , Neurônios/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Receptores de Neurotransmissores/metabolismo , Sinapses/metabolismo , Animais , Células Cultivadas , Córtex Cerebral/citologia , Glutamatos/metabolismo , Imuno-Histoquímica , Concentração Osmolar , Receptores de Glutamato , Coloração e RotulagemRESUMO
The aim of the present study was to investigate the efficacy of infliximab for the treatment of extrapulmonary sarcoidosis. A prospective, randomised, double-blind, placebo-controlled trial was conducted, with infliximab at 3 and 5 mg x kg(-1) body weight administered over 24 weeks. Extrapulmonary organ severity was determined by a novel severity tool (extrapulmonary physician organ severity tool; ePOST) with an adjustment for the number of organs involved (ePOSTadj). In total, 138 patients enrolled in the trial of infliximab versus placebo for the treatment of chronic corticosteroid-dependent pulmonary sarcoidosis. The baseline severity of extrapulmonary organ involvement, as measured by ePOST, was similar across treatment groups. After 24 weeks of drug-therapy study, the change from baseline to week 24 in ePOST was greater for the combined infliximab group compared with the placebo group. After adjustment for the number of extrapulmonary organs involved, the improvement in ePOSTadj observed in the combined infliximab group was also greater than that observed in placebo-treated patients, after 24 weeks of therapy. The improvements in ePOST and ePOSTadj were not maintained during a subsequent 24-week washout period. Infliximab may be beneficial compared with placebo in the treatment of extrapulmonary sarcoidosis in patients already receiving corticosteroids, as assessed by the severity tool described in the present study.
Assuntos
Anti-Inflamatórios/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Sarcoidose/tratamento farmacológico , Corticosteroides/uso terapêutico , Anti-Inflamatórios/efeitos adversos , Anticorpos Monoclonais/efeitos adversos , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Humanos , Infliximab , Masculino , Pessoa de Meia-Idade , Índice de Gravidade de Doença , Resultado do TratamentoRESUMO
Sarcoidosis patients with chronic disease often require prolonged treatment. Although alternatives to corticosteroids have been frequently administered in this disease, corticosteroids remain the mainstay of treatment. However disabling side effects which accompany prolonged treatment can necessitate the use of alternative, steroid-sparing agents. The tumor necrosis factor (TNF) inhibitors can be useful in treating chronic sarcoidosis. Among the biologic agents which inhibit TNF, infliximab has been studied most extensively in sarcoidosis with fewer reports available for adalimumab and etanercept. This review will summarize the available evidence to identify the best candidate to receive an anti-TNF regimen as well as the relative benefits and side effects of the three anti-TNF biological agents for treating sarcoidosis. A stepwise approach is proposed to increase the likelihood of disease improvement for patients who experience an inadequate response to an anti-TNF agent.
Assuntos
Anti-Inflamatórios/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Sarcoidose/tratamento farmacológico , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Adalimumab , Anticorpos Monoclonais Humanizados , Humanos , Infliximab , Sarcoidose/sangue , Resultado do Tratamento , Fator de Necrose Tumoral alfa/sangueRESUMO
BACKGROUND: The clinical and pathological features of sarcoidosis and tuberculosis may mimic each other, and when the caseous necrosis is not seen in tuberculosis tissue, differentiation is not easy. OBJECTIVE: This study evaluates the ability of real-time PCR quantification and sets the quantitive value to differentiate sarcoidosis from TB. METHODS: Formalin-fixed and paraffin-embedded sections of biopsy samples, from 104 patients with sarcoidosis, 31 patients with tuberculosis, and 55 controls with other respiratory diseases (26 with nonspecific lymphadenitis and 29 with emphysema bullae), were collected to amplify insertion sequence IS986 of Mycobacterium tuberculosis (MTB) genome by real-time quantitative PCR. The diagnostic performance of qualitative and quantitative analysis of real-time quantitative PCR was assessed by receiver-operating characteristic (ROC) curves. RESULTS: MTB DNA was detected in 20 of the 104 sarcoidosis samples and 7 of the 55 control samples, but was detected in all of the 31 tuberculosis samples. The numbers of MTB genomes were 0-4.71x10(3) copies per ml in sarcoidosis samples, 1.58x10(2)-5.43x10(7) copies per ml in tuberculosis samples and 0-1.02x10(3) copies per ml in controls with quantitative analysis. Receiver-operating characteristic (ROC) curves showed that MTB genome quantification had greater diagnostic performance than MTB genome qualitation in discriminating patients with sarcoidosis from those with tuberculosis (area under the ROC curves: 0.994 vs 0.904, P<0.001). The sensitivity and specificity of qualitative analysis were 100% and 80.8% respectively. At cutoff value of 1.14x10(3) copies per ml for MTB genome quantification, the sensitivity was 96.8% and specificity was 98.1%. CONCLUSIONS: The real time PCR quantification is a valuable test for differentiation between sarcoidosis and tuberculosis, and the MTB genome copies number of 1.14x10(3) copies per ml should be preferred as quantitative cutoff value for the differentiation.
Assuntos
DNA Bacteriano/análise , Mycobacterium tuberculosis/genética , Reação em Cadeia da Polimerase/métodos , Sarcoidose/diagnóstico , Tuberculose/diagnóstico , Biópsia , Diagnóstico Diferencial , Humanos , Mycobacterium tuberculosis/isolamento & purificação , Prognóstico , Estudos Retrospectivos , Sensibilidade e Especificidade , Tuberculose/microbiologiaRESUMO
Technosphere insulin (TI), an inhaled insulin with a fast onset of action, provides a novel option for the control of prandial glucose. A euglycemic glucose clamp study was performed to compare the effects of TI and regular human insulin (RHI) on the induced glucose infusion rate (GIR) in healthy volunteers. Generation of a dose-response relationship between insulin dose and effect (expressed as AUC of GIR) was not possible from the clinical data directly. The GIR recording time was too short to capture the full effect and higher doses were not tested. Thus, a pharmacokinetic-GIR model was developed to simulate GIR for a sufficient time window of 20 h and for higher doses. A dose-response model was then generated from the simulated GIR profiles. The resulting model provides an ED50 for TI that is 5-fold higher than for RHI, a ratio that can be used as conversion factor for equivalent doses of RHI and TI.
Assuntos
Hipoglicemiantes/farmacocinética , Insulina/farmacocinética , Modelos Biológicos , Administração por Inalação , Adulto , Glicemia , Estudos Cross-Over , Relação Dose-Resposta a Droga , Feminino , Técnica Clamp de Glucose , Voluntários Saudáveis , Humanos , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/farmacologia , Insulina/administração & dosagem , Insulina/farmacologia , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
BACKGROUND: Some sarcoidosis patients never need therapy, but many still require therapy more than 2 years after initial diagnosis. AIM: To determine what features at initial presentation are associated with treatment 2 years later. METHODS: Patients with biopsy-confirmed sarcoidosis enrolled in the ACCESS (A Case Control Etiologic Study of Sarcoidosis) study were initially evaluated within 6 months of diagnosis. Pulmonary function, chest X-ray and dyspnoea score were measured, and systemic therapy for the sarcoidosis recorded. Organ involvement was assessed using a standardized instrument. A subset (n = 215) were seen 18-24 months later for follow-up, and these patients constitute our study group. RESULTS: Ten patients had only received therapy before the first visit, with no further therapy, and were excluded from analysis. Of the remaining 205, 95 were not on therapy at the initial visit and 75 (79%) of these were never treated during follow-up. Of the 110 initially on therapy, 52 (47%) remained on therapy at follow-up. Other initial features associated with continued therapy were the level of dyspnoea and predicted vital capacity. On logistic regression, only dyspnoea and therapy at initial visit remained significant. Patients on systemic therapy at initial evaluation were more likely to be on therapy at follow-up (OR 3.6, p = 0.003). Neither ethnicity nor gender independently predicted therapy at follow-up. DISCUSSION: This study group represents a sample of newly diagnosed sarcoidosis patients. However, this is a referral population, and there was no set protocol for treatment. Use of systemic therapy within the first 6 months after diagnosis appears to be strongly associated with continued use of therapy 2 years later.