Recombinant human complement component C2 produced in a human cell line restores the classical complement pathway activity in-vitro: an alternative treatment for C2 deficiency diseases

Background: Complement C2 deficiency is the most common genetically determined complete complement deficiency and is associated with a number of diseases. Most prominent are the associations with recurrent serious infections in young children and the development of systemic lupus erythematosus (SLE) in adults. The links with these diseases reflect the important role complement C2 plays in both innate immunity and immune tolerance. Infusions with normal fresh frozen plasma for the treatment of associated disease have demonstrated therapeutic effects but so far protein replacement therapy has not been evaluated. Results: Human complement C2 was cloned and expressed in a mammalian cell line. The purity of recombinant human C2 (rhC2) was greater than 95% and it was characterized for stability and activity. It was sensitive to C1s cleavage and restored classical complement pathway activity in C2-deficient serum both in a complement activation ELISA and a hemolytic assay. Furthermore, rhC2 could increase C3 fragment deposition on the human pathogen Streptococcus pneumoniae in C2-deficient serum to levels equal to those with normal serum. Conclusions: Taken together these data suggest that recombinant human C2 can restore classical complement pathway activity and may serve as a potential therapeutic for recurring bacterial infections or SLE in C2-deficient patients

How do COPD patients respond to exacerbations?

<p>Abstract</p> <p>Background</p> <p>Although timely treatment of COPD exacerbations seems clinically important, nearly half of these exacerbations remain unreported and subsequently untreated. Recent studies have investigated incidence and impact of failure to seek medical treatment during exacerbations. Yet, little is known about type and timing of other self-management actions in periods of symptom deterioration. The current prospective study aims at determining the relative incidence, timing and determinants of three types of patient responses.</p> <p>Methods</p> <p>In a multicentre observational study, 121 patients (age 67 ± 11 years, FEV₁pred. 48 ± 19) were followed for 6 weeks by daily diary symptom recording. Three types of action were assessed daily: planning periods of rest, breathing techniques and/or sputum clearing (type-A), increased bronchodilator use (type-B) and contacting a healthcare provider (type-C).</p> <p>Results</p> <p>Type-A action was taken in 70.7%, type-B in 62.7% and type C in 17.3% of exacerbations (n = 75). Smokers were less likely to take type-A and B actions. Type-C actions were associated with more severe airflow limitation and increased number of hospital admissions in the last year.</p> <p>Conclusions</p> <p>Our study shows that most patients are willing to take timely self-management actions during exacerbations. Future research is needed to determine whether the low incidence of contacting a healthcare provider is due to a lack of self-management or healthcare accessibility.</p

Action Plan to enhance self-management and early detection of exacerbations in COPD patients; a multicenter RCT

<p>Abstract</p> <p>Background</p> <p>Early detection of exacerbations by COPD patients initiating prompt interventions has shown to be clinically relevant. Until now, research failed to identify the effectiveness of a written individualized Action Plan (AP) to achieve this.</p> <p>Methods/Design</p> <p>The current multicenter, single-blind RCT with a follow-up period of 6 months, evaluates the hypothesis that individualized AP's reduce exacerbation recovery time. Patients are included from regular respiratory nurse clinics and allocated to either usual care or the AP intervention. The AP provides individualized treatment prescriptions (pharmaceutical and non-pharmaceutical) related to a color coded symptom status (reinforcement at 1 and 4 months). Although usually not possible in self-management trials, we ensured blinding of patients, using a modified informed consent procedure in which patients give consent to postponed information. Exacerbations in both study arms are defined using the Anthonisen symptom diary-card algorithm. The Clinical COPD Questionnaire (CCQ) is assessed every 3-days. CCQ-recovery time of an exacerbation is the primary study outcome. Additionally, healthcare utilization, anxiety, depression, treatment delay, and self-efficacy are assessed at baseline and 6 months. We aim at including 245 COPD patients from 7 hospitals and 5 general practices to capture the a-priori sample size of at least 73 exacerbations per study arm.</p> <p>Discussion</p> <p>This RCT identifies if an AP is an effective component of self-management in patients with COPD and clearly differentiates from existing studies in its design, outcome measures and generalizability of the results considering that the study is carried out in multiple sites including general practices.</p> <p>Trial Registration</p> <p>NCT00879281</p

ICE COLD ERIC – International collaborative effort on chronic obstructive lung disease: exacerbation risk index cohorts – Study protocol for an international COPD cohort study

<p>Abstract</p> <p>Background</p> <p>Chronic Obstructive Pulmonary Disease (COPD) is a systemic disease; morbidity and mortality due to COPD are on the increase, and it has great impact on patients' lives. Most COPD patients are managed by general practitioners (GP). Too often, GPs base their initial assessment of patient's disease severity mainly on lung function. However, lung function correlates poorly with COPD-specific health-related quality of life and exacerbation frequency. A validated COPD disease risk index that better represents the clinical manifestations of COPD and is feasible in primary care seems to be useful. The objective of this study is to develop and validate a practical COPD disease risk index that predicts the clinical course of COPD in primary care patients with GOLD stages 2–4.</p> <p>Methods/Design</p> <p>We will conduct 2 linked prospective cohort studies with COPD patients from GPs in Switzerland and the Netherlands. We will perform a baseline assessment including detailed patient history, questionnaires, lung function, history of exacerbations, measurement of exercise capacity and blood sampling. During the follow-up of at least 2 years, we will update the patients' profile by registering exacerbations, health-related quality of life and any changes in the use of medication. The primary outcome will be health-related quality of life. Secondary outcomes will be exacerbation frequency and mortality. Using multivariable regression analysis, we will identify the best combination of variables predicting these outcomes over one and two years and, depending on funding, even more years.</p> <p>Discussion</p> <p>Despite the diversity of clinical manifestations and available treatments, assessment and management today do not reflect the multifaceted character of the disease. This is in contrast to preventive cardiology where, nowadays, the treatment in primary care is based on patient-specific and fairly refined cardiovascular risk profile corresponding to differences in prognosis. After completion of this study, we will have a practical COPD-disease risk index that predicts the clinical course of COPD in primary care patients with GOLD stages 2–4. In a second step we will incorporate evidence-based treatment effects into this model, such that the instrument may guide physicians in selecting treatment based on the individual patients' prognosis.</p> <p>Trial registration</p> <p>ClinicalTrials.gov Archive NCT00706602</p

CTGF is a central mediator of tissue remodeling and fibrosis and its inhibition can reverse the process of fibrosis

CTGF is a secreted matricellular protein with very complex biology. It has been shown to modulate many signaling pathways leading to cell adhesion and migration, angiogenesis, myofibroblast activation, and extracellular matrix deposition and remodeling, which together lead to tissue remodeling and fibrosis. It has been reported in the literature that inhibition of CTGF expression by siRNA prevents CCl4-induced liver fibrosis and can reverse fibrosis when administered after significant collagen deposition is observed. A monoclonal antibody to CTGF that is currently in clinical development (FG-3019) has demonstrated the ability to reverse vascular stiffening and improve cardiac function in a rat model of diabetic complications. FG-3019 has also exhibited activity in a murine radiation-induced pulmonary fibrosis model. When FG-3019 was administered to mice after a significant radiation-induced increase in lung density could be observed by CT imaging, the density of the lungs was observed to decrease over the period during which the antibody was administered and to remain stable after therapy had ceased. When considered together, these data indicate that inhibition of CTGF can prevent and reverse the process of fibrosis

Osteopenia Due to Enhanced Cathepsin K Release by BK Channel Ablation in Osteoclasts

BACKGROUND: The process of bone resorption by osteoclasts is regulated by Cathepsin K, the lysosomal collagenase responsible for the degradation of the organic bone matrix during bone remodeling. Recently, Cathepsin K was regarded as a potential target for therapeutic intervention of osteoporosis. However, mechanisms leading to osteopenia, which is much more common in young female population and often appears to be the clinical pre-stage of idiopathic osteoporosis, still remain to be elucidated, and molecular targets need to be identified. METHODOLOGY/PRINCIPAL FINDINGS: We found, that in juvenile bone the large conductance, voltage and Ca(2+)-activated (BK) K(+) channel, which links membrane depolarization and local increases in cytosolic calcium to hyperpolarizing K(+) outward currents, is exclusively expressed in osteoclasts. In juvenile BK-deficient (BK(-/-)) female mice, plasma Cathepsin K levels were elevated two-fold when compared to wild-type littermates. This increase was linked to an osteopenic phenotype with reduced bone mineral density in long bones and enhanced porosity of trabecular meshwork in BK(-/-) vertebrae as demonstrated by high-resolution flat-panel volume computed tomography and micro-CT. However, plasma levels of sRANKL, osteoprotegerin, estrogene, Ca(2+) and triiodthyronine as well as osteoclastogenesis were not altered in BK(-/-) females. CONCLUSION/SIGNIFICANCE: Our findings suggest that the BK channel controls resorptive osteoclast activity by regulating Cathepsin K release. Targeted deletion of BK channel in mice resulted in an osteoclast-autonomous osteopenia, becoming apparent in juvenile females. Thus, the BK(-/-) mouse-line represents a new model for juvenile osteopenia, and revealed the BK channel as putative new target for therapeutic controlling of osteoclast activity

Eating patterns in the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil): an exploratory analysis

Abstract: The food consumption of 15,071 public employees was analyzed in six Brazilian cities participating in the baseline for Brazilian Longitudinal Study of Adult Health (ELSA-Brasil, 2008-2010) with the aim of identifying eating patterns and their relationship to socio-demographic variables. Multiple correspondence and cluster analysis were applied. Four patterns were identified, with their respective frequencies: "traditional" (48%); "fruits and vegetables" (25%); "pastry shop" (24%); and "diet/light" (5%) The "traditional" and "pastry shop" patterns were more frequent among men, younger individuals, and those with less schooling. "Fruits and vegetables" and "diet/light" were more frequent in women, older individuals, and those with more schooling. Our findings show the inclusion of new items in the "traditional" pattern and the appearance of the "low sugar/low fat" pattern among the eating habits of Brazilian workers, and signal socio-demographic and regional differences

Domiciliary pulse-oximetry at exacerbation of chronic obstructive pulmonary disease: prospective pilot study

The ability to objectively differentiate exacerbations of chronic obstructive pulmonary disease (COPD) from day-to-day symptom variations would be an important development in clinical practice and research. We assessed the ability of domiciliary pulse oximetry to achieve this