PGD13 Does the Duration of Pulmonary Rehabilitation Affect the Magnitude of Patient Response?

OBJECTIVE: To determine if there is a dosage effect associated with the length of pulmonary rehabilitation (PR).
METHODS: We used a battery of outcome measures to quantify the amount of change that was achieved from baseline to discharge in 286 patients completing a PR program in 1 of 12 institutions participating in PROAS. The programs were of varying durations. Paired t-tests indicated overall that while the pulmonary rehabilitation programs did not yield improvements in physiologic (FEV1, FVC, % predicted FEV1) outcomes, the patients did achieve significant improvements in symptomatic (Borg score), functional (6-minute walk), general healthrelated quality of life [SF-36 Health Survey (SF-36)], and disease-specific HRQL [Chronic Respiratory Disease Questionnaire (CRQ) variables.
RESULTS: Based on a series of stepwise multiple regressions using the amount of change in each outcome variable as the dependent variable and adjusting for the corresponding baseline value and 11 clinical and sociodemographic characteristics, the number of hours of education (HREDU, 13.5 hr ± 6.7), activities of daily living (HRADL, 2.2 hr ± 6.6), and psychosocial support (6.5 hr ± 5.6) both individually and collectively (42.4 hr ± 11.8) generally did not contribute to explaining the magnitude of change achieved by the patients. However, the number of hours of supervised exercise (HREX, 25.4 hr ± 9.2) did contribute to explaining increases in 5 of the 8 SF-36 domains: physical function (p = 0.027), physical role (p = 0.0002), health perceptions (p = 0.0167), vitality (p = 0.034), and social function (p = 0.0035).
CONCLUSION: These data suggest that outcomes specifically related to pulmonary diseases are not affected by a longer duration for this type of intervention, but that broader, population-based assessments may need an additional period of intervention, or elapsed time, to detect improvement.     

Tendons: high-field-strength, surface coil MR imaging

High-resolution magnetic resonance (MR) images of the tendons of the hands, wrists, feet, and ankles of six healthy volunteers and six cadavers were obtained using receive-only surface coils and reduced-field-of-view imaging. Normal anatomy was identified and compared with gross anatomic sections of the six cadavers. Experimentally produced tears of the calcaneal (Achilles) tendon in domestic swine were identified on MR images. The hands and feet of 11 patients were examined, and a variety of pathologic lesions were identified, including acute posttraumatic rupture, acute tenosynovitis, chronic tendonitis, and postsurgical complications. MR imaging provides inherently greater soft-tissue contrast than any other currently available imaging modality. With the use of surface coils and reduced-field-of-view imaging to enhance spatial resolution, MR imaging has become a valuable tool for imaging tendons. Advantages over other available modalities include excellent depiction of anatomic detail, superior contrast resolution, and the potential for multiplanar imaging.     

Clinical islet isolation outcomes with a highly purified neutral protease for pancreas dissociation

Background: Pancreas dissociation is a critical initial component of the islet isolation procedure and introduces high variability based on factors including the enzyme type, specificity and potency. Product refinement and alterations to the application strategies have improved isolation outcomes over time; however, islet utilization from donor organs remains low. In this study we evaluate a low endotoxin-high activity grade neutral protease in clinical islet isolation.

Materials and Methods: The use of a non-collagenolytic enzyme, either thermolysin or high active neutral protease, was randomized in clinical islet isolations to evaluate efficacy. Additionally a retrospective comparison to neutral protease NB was conducted.

Results:The thermolysin group had lower trapped islet population and increased purity and post-culture islet mass in comparison to high active grade neutral protease. Comparison of neutral protease NB GMP grade to high active neutral protease displayed no measurable difference in islet mass or viability and transplantation outcomes at 1 mo post-transplant were favorable for both groups.

Conclusions: High activity neutral protease can generate clinical grade islets and may prove beneficial to islet function and viability based on a reduced endotoxin load but dosing of neutral protease requires ongoing optimization.     

Glycogen synthase kinase-3 (GSK-3) regulates TGF-β1-induced differentiation of pulmonary fibroblasts

Background

Chronic lung diseases such as asthma, COPD and pulmonary fibrosis are characterized by abnormal extracellular matrix (ECM) turnover. TGF-β is a key mediator stimulating ECM production by recruiting and activating lung fibroblasts and initiating their differentiation process into more active myofibroblasts. Glycogen synthase kinase-3 (GSK-3) regulates various intracellular signalling pathways; its role in TGF-β₁-induced myofibroblast differentiation is currently largely unknown.

Purpose

To determine the contribution of GSK-3 signalling in TGF-β₁-induced myofibroblast differentiation.

Experimental Approach

We used MRC5 human lung fibroblasts and primary pulmonary fibroblasts of individuals with and without COPD. Protein and mRNA expression were determined by immunoblotting and RT-PCR analysis respectively.

Results

Stimulation of MRC5 and primary human lung fibroblasts with TGF-β₁ resulted in time- and dose-dependent increases of α-sm-actin and fibronectin expression, indicative of myofibroblast differentiation. Pharmacological inhibition of GSK-3 by SB216763 dose-dependently attenuated TGF-β₁-induced expression of these myofibroblasts markers. Moreover, silencing of GSK-3 by siRNA or pharmacological inhibition by CT/CHIR99021 fully inhibited the TGF-β₁-induced expression of α-sm-actin and fibronectin. The effect of GSK-3 inhibition on α-sm-actin expression was similar in fibroblasts from individuals with and without COPD. Neither smad, NF-κB nor ERK1/2 were involved in the inhibitory actions of GSK-3 inhibition by SB126763 on myofibroblast differentiation. Rather, SB216763 increased the phosphorylation of CREB, which in its phosphorylated form acts as a functional antagonist of TGF-β/smad signalling.

Conclusion and Implication

We demonstrate that GSK-3 signalling regulates TGF-β₁-induced myofibroblast differentiation by regulating CREB phosphorylation. GSK-3 may constitute a useful target for treatment of chronic lung diseases.     

Soluble CD40L in children and adolescents with type 1 diabetes: relation to microvascular complications and glycemic control

CD40‐soluble CD40 ligand (sCD40L) interactions might constitute an important mediator for vascular inflammation that initiates diabetic microangiopathy. Little is known about the relation between sCD40L and glycemic control. Therefore, this study aimed to evaluate sCD40L levels in patients with type 1 diabetes and its relation to microvascular complications and metabolic control. Sixty patients with type 1 diabetes were compared with 30 healthy control subjects. Detailed medical history, thorough clinical examination, and laboratory assessment of high‐sensitivity C‐reactive protein, glycemic control, and the presence of microvascular complications were performed. Measurement of serum sCD40L levels was done using enzyme‐linked immunosorbent assay. Patients were divided into two groups according to the presence of microvascular complications. Serum sCD40L levels were significantly elevated in patients with type 1 diabetes in both groups compared with healthy controls (p < 0.001). Patients with microvascular complications had higher serum sCD40L concentrations than non‐complicated cases (median, 13 000 vs. 450 pg/mL; p < 0.001). Serum sCD40L cutoff value of 530 pg/mL was able to differentiate complicated from non‐complicated cases (p < 0.001). Patients with microalbuminuria or peripheral neuropathy showed higher levels of sCD40L when compared with patients without these complications (p < 0.05). Serum sCD40L levels were positively correlated with hemoglobin A1c and urinary albumin excretion (p < 0.001). We suggest that serum sCD40L levels are elevated in type 1 diabetes, particularly in patients with microvascular complications and a significant correlation with glycemic control exists. Therefore, measurement of serum sCD40L levels in poorly controlled patients would help to identify those at high risk of developing microvascular complications.     

Prevalence of calcium pyrophosphate and monosodium urate crystals in synovial fluid of patients with previously diagnosed joint diseases

ObjectiveThe main aim of this study was to investigate the frequency of monosodium urate (MSU) and calcium pyrophosphate (CPP) crystals in synovial fluid (SF) obtained from patients with previously diagnosed joint diseases.MethodsWe reviewed the results of SF analysis of 5020 samples identifying those collected from patients with a previously definite diagnosis (2370 samples). SF analysis results, age, sex, diagnosis and disease duration were recorded from computerized records of patients’ archives.ResultsThe prevalence of CPP crystals in SF was 22.28% in osteoarthritis (OA), 8.28% in rheumatoid arthritis (RA), 3.82% in psoriatic arthritis (PsA), 2.79% in other spondyloarthropathies (SpA), 10% in septic arthritis (SeA), 0.66% in gout and 9.18% in the miscellanea of joint diseases, respectively. The prevalence of MSU crystals in SF was 0.30% in RA, 3.34% in PsA, 0.70% in other SpA, 0.80% in acute CPP crystal arthritis (CPP-CA), 0% in OA, reactive arthritis (ReA), SeA, juvenile idiopathic arthritis (JIA) and miscellanea.In OA group, we observed that age and SF inflammatory indices were higher in SF positive to CPP crystals with respect to those without crystals (P < 0.0001). In RA, we found that the group of patients with CPP crystals was significantly older (P = 0.001) and had a SF less inflammatory (P = 0.022) with respect to that without crystals but with a higher disease duration than those without crystals.ConclusionCrystals can be detected more frequently than expected in SF from joint diseases with a previous established diagnosis. This highlights the importance of SF analysis for the diagnosis of possible comorbidities linked to the presence of crystals.