The St. George's Respiratory Questionnaire in Pulmonary Sarcoidosis.

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.

A Population Dose-Response Model for Inhaled Technosphere Insulin Administered to Healthy Subjects.

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.

Sarcoidosis extent relates to molecular variability.

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.

Tadalafil therapy for sarcoidosis-associated pulmonary hypertension.

Sarcoidosis-associated pulmonary hypertension (SAPH) is estimated to occur in at least 5% or more of sarcoidosis patients, and it contributes to significant morbidity and mortality. Optimal therapy for SAPH is not well established. We performed a 24-week open-label trial of tadalafil for SAPH at 2 academic medical centers. Subjects were required to have confirmed sarcoidosis plus a right heart catheterization within 12 months of enrollment showing a mean pulmonary artery pressure ≥ 25 mmHg, a pulmonary artery wedge pressure ≤ 15 mmHg, and a calculated pulmonary vascular resistance ≥ 3 Wood units. Subjects received 20 mg/day of tadalafil for the first 4 weeks and then 40 mg/day for the subsequent 20 weeks. Sixteen patients were screened, 12 of whom met criteria for enrollment. At 24 weeks, there was no overall improvement in 6-minute walk distance (6MWD). Five of the 12 subjects dropped out of the study early (2 for social reasons, 3 for medical reasons). There was no significant change in short form 36, St. George's respiratory questionnaire, or maximum Borg dyspnea scores over the 24 weeks. There were no significant adverse events or laboratory abnormalities clearly related to tadalafil in the cohort. The study did not meet the primary end point of change in 6MWD because of the small sample size. Tadalafil was generally safely administered in this cohort of SAPH patients. There was a relatively high dropout rate but no major adverse events and no clinical worsening. Larger studies are needed to explore this question further. (Trial registration: ClinicalTrials.gov identifier: NCT01324999).

STRETCHY ELECTRONICS. Hierarchically buckled sheath-core fibers for superelastic electronics, sensors, and muscles.

Superelastic conducting fibers with improved properties and functionalities are needed for diverse applications. Here we report the fabrication of highly stretchable (up to 1320%) sheath-core conducting fibers created by wrapping carbon nanotube sheets oriented in the fiber direction on stretched rubber fiber cores. The resulting structure exhibited distinct short- and long-period sheath buckling that occurred reversibly out of phase in the axial and belt directions, enabling a resistance change of less than 5% for a 1000% stretch. By including other rubber and carbon nanotube sheath layers, we demonstrated strain sensors generating an 860% capacitance change and electrically powered torsional muscles operating reversibly by a coupled tension-to-torsion actuation mechanism. Using theory, we quantitatively explain the complementary effects of an increase in muscle length and a large positive Poisson's ratio on torsional actuation and electronic properties.

Real-time quantitative reverse transcription-polymerase chain reaction to detect propionibacterial ribosomal RNA in the lymph nodes of Chinese patients with sarcoidosis.

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.

Calcium and vitamin D metabolism in sarcoidosis.

BACKGROUND: Sarcoidosis associated hypercalcemia (SAHC) may be secondary to excessive levels of 1,25-(OH)2 vitamin D3 produced by autonomous 1-alpha-hydroxylase activity within the granulomas.  The frequency, treatment, and consequences of hypercalcemia remain unclear. STUDY DESIGN AND METHODS: Two patient cohorts were studied.  In Cohort 1, the prevalence of hypercalcemia in 1606 sarcoidosis patients seen during a six year period was analyzed along with treatment and outcome. Cohort 2 consisted of  261 sarcoidosis patients with measured 25-(OH) vitamin D3 and 1,25-(OH) vitamin D3 levels. In forty patients, serial levels of 25-(OH) vitamin D3 and 1,25-(OH) vitamin D3 were measured at least three months apart without change in therapy. RESULTS: SAHC was identified in 97 of 1606 (6%) of patients studied and additional nine (0.6%) patients had primary hyperparathyroidism. Post treatment follow up was available in 86 SAHC patients. Hypercalcemia improved in >90% of patients, including eight patients treated solely with vitamin D supplement withdrawal. Renal insufficiency, documented in 41 (42%) of SAHC patients, improved with hypercalcemia treatment.  In 80% of Cohort 2 patients low 25-(OH) vitamin D3 levels were measured with only one patient having a low 1,25(OH)2 vitamin D3 level. Elevated 1,25(OH)2 vitamin D3 levels, which were measured in 11% of patients, were higher for those with a history of hypercalcemia. CONCLUSION: Sarcoidosis associated hypercalcemia, which is often accompanied by renal insufficiency, responds to treatment of sarcoidosis and withdrawal of vitamin D supplementation. Measurement of serum vitamin 1,25(OH)2 vitamin D3 appears to best evaluate vitamin D status in sarcoidosis patients.

Treatment of sarcoidosis.

The treatment of pulmonary sarcoidosis is based on several factors. These include changes in pulmonary physiology, presence of extra-pulmonary disease, and symptoms. Several immunosuppressive agents have been studied and recommendations regarding the utility of these different agents have evolved. While glucocorticoids remain the most commonly used agent, other drugs have been used as steroid sparing and for those patients who progress despite routine treatment. Non immunosuppressive agents also play a role in the therapy of pulmonary sarcoidosis patients. These include treatments for pulmonary hypertension, infection, and fatigue.

Effect of obesity on patient-reported outcomes in sarcoidosis.

OBJECTIVES: To assess the impact of high body mass index (BMI) on patient-reported outcomes in sarcoidosis patients and healthy persons. METHODS: In this case-control study, we investigated symptoms of fatigue and dyspnoea, health status, BMI and spirometric tests in 184 sarcoidosis patients and the same number of sex- and age-matched healthy subjects. Fatigue was assessed using the fatigue scale (FS), dyspnoea was determined by the baseline dyspnoea index (BDI) and health status was measured using the respiratory-specific St George's Respiratory Questionnaire (SGRQ). RESULTS: There were significantly more subjects with increased BMI (≥25 kg/m(2)) among the sarcoidosis patients than among the healthy volunteers ((2) 37.675, P < 0.01). Sarcoidosis patients also had a greater probability of having a higher BMI (P < 0.01, OR 1.18, 95%CI 1.071.3). We found significantly lower BDI scores and forced expiratory volume in 1 s/forced vital capacity, as well as higher total SGRQ and total FS scores in sarcoidosis patients than in healthy individuals (P < 0.01 for all differences). CONCLUSION: Sarcoidosis significantly reduces patients' health status, both independently and also due to increased BMI. Reduction in BMI may contribute to improved spirometry results and health status of patients with sarcoidosis.

Receptor-mediated inhibition of small bowel migrating complex by GLP-1 analog ROSE-010 delivered via pulmonary and systemic routes in the conscious rat.

BACKGROUND: ROSE-010, a Glucagon-Like Peptide-1 (GLP-1) analog, reduces gastrointestinal motility and relieves acute pain in patients with irritable bowel syndrome (IBS). The rat small bowel migrating myoelectric complex (MMC) is a reliable model of pharmacological effects on gastrointestinal motility. Accordingly, we investigated whether ROSE-010 works through GLP-1 receptors in gut musculature and its effectiveness when administered by pulmonary inhalation. MATERIALS AND METHODS: Rats were implanted with bipolar electrodes at 5, 15 and 25 cm distal to pylorus and myoelectric activity was recorded. First, intravenous or subcutaneous injections of ROSE-010 or GLP-1 (1, 10, 100 µg/kg) with or without the GLP-1 receptor blocker exendin(9-39)amide (300 µg/kg·h), were studied. Second, ROSE-010 (100, 200 µg/kg) Technosphere® powder was studied by inhalation. RESULTS: The baseline MMC cycle length was 17.5±0.8 min. GLP-1 and ROSE-010, administered intravenously or subcutaneously, significantly inhibited myoelectric activity and prolonged MMC cycling; 100 µg/kg completely inhibited spiking activity for 49.1±4.2 and 73.3±7.7 min, while the MMC cycle length increased to 131.1±11.4 and 149.3±15.5 min, respectively. Effects of both drugs were inhibited by exendin(9-39)amide. Insufflation of ROSE-010 (100, 200 µg/kg) powder formulation totally inhibited myoelectric spiking for 52.6±5.8 and 70.1±5.4 min, and increased MMC cycle length to 102.6±18.3 and 105.9±9.5 min, respectively. CONCLUSIONS: Pulmonary delivery of ROSE-010 inhibits gut motility through the GLP-1R similar to natural GLP-1. ROSE-010 causes receptor-mediated inhibition of MMC comparable to that of intravenous or subcutaneous administration. This suggests that ROSE-010 administered as a Technosphere® inhalation powder has potential in IBS pain management and treatment.

A novel multi-parameter scoring system for distinguishing sarcoidosis from sputum negative tuberculosis.

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.

Management of ocular sarcoidosis.

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.

Endpoints for clinical trials of sarcoidosis.

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.

Defining the clinical outcome status (COS) in sarcoidosis: results of WASOG Task Force.

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.

Manufacturing polymer/carbon nanotube composite using a novel direct process.

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.

C-reactive protein predicts response to infliximab in patients with chronic sarcoidosis.

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.