Bradykinin differentiates human lung fibroblasts to a myofibroblast phenotype via the B2 receptor

BACKGROUND: The identification of factors mediating the transition of lung fibroblasts into myofibroblasts is considered fundamental in the comprehension of abnormal reparative processes. Bradykinin, a mediator known for its proinflammatory action, is able to induce cytokine production and contractility in fibroblast cultures. OBJECTIVES: In this study the ability of bradykinin to drive fibroblast into a myofibroblast phenotype at the cellular and molecular level was evaluated. METHODS: alpha-Smooth muscle actin (alpha-SMA) expression and TGF-beta in bradykinin stimulated fibroblasts were tested by means of flow cytometry, Western blot, and RT-PCR. Cell proliferation and collagen production were evaluated by the colorimetric methylthiazol tetrazolium assay and sirius red assay, respectively. Which bradykinin receptor mediates the expression of alpha-SMA was evaluated using selective B1 and B2 blocking agents. Furthermore, the effect of bradykinin on extracellular signal-regulated kinase 1/2 phosphorylation was explored. RESULTS: Bradykinin caused in lung fibroblasts a significant increase in alpha-SMA at the cellular and molecular level. The B2 receptor was held responsible for this effect because a specific receptor antagonist had entirely blocked this effect. Bradykinin was able to induce fibroblast proliferation and collagen production. Bradykinin significantly activated mitogen-activated protein kinase pathway by phosphorylating extracellular signal-regulated kinase 1/2, whereas PD98059, a specific inhibitor, was able to block myofibroblast induction. Although bradykinin induced an increase of TGF-beta on fibroblasts, the blockage of this cytokine did not alter alpha-SMA expression. CONCLUSION: The data support the hypothesis that bradykinin may be involved in bronchial remodeling and lung fibrosis beyond its well recognized proinflammatory activity, also suggesting a new potential therapeutic strategy to control altered reparatory processes.     

An Intriguing Case Report of Functional Mitral Regurgitation Treated With MitraClip

Functional mitral regurgitation (FMR) is frequent in patients with heart failure (HF). It develops as a consequence of left ventricle (LV) geometry alterations, causing imbalance between increased tethering forces and decreased closing forces exerted on the mitral valve apparatus during systole.FMR is known to change at rest and during effort, due to preload–afterload changes, myocardial ischemia, and/or LV dysfunction. Despite optimized medical therapy, an FMR can be responsible of shortness of breath limiting quality of life and decompensation. In this report, we present a case of dynamic FMR treated with MitraClip.MitraClip implantation is a successful and innovative opportunity for HF patients with FMR.     

Exploring Autoimmunity in a Cohort of Children with Genetically Confirmed Aicardi–Goutières Syndrome

Purpose

The purpose of this study was to explore the presence of autoimmune manifestations and characterize the autoantibody production in a cohort of patients with Aicardi–Goutières syndrome (AGS).

Methods

Seventeen patients with a genetically-confirmed diagnosis of AGS were recruited. At the time of enrollment, past medical and family history was reviewed, looking for possible signs or symptoms of autoimmune disorders. Blood samples were taken, for the detection of a panel of autoantibodies: anti-nuclear, anti-double-stranded-DNA, anti-nucleosome, anti-extractable nuclear antigens, anti-cardiolipin IgG/IgM, anti-β2glycoprotein I IgG/IgM, and anti-neutrophil cytoplasmic. We also measured complement levels determined as C3 and C4 quantification and total complement activity, measured as CH50.

Results

Nine of seventeen patients presented with at least one first- or second-degree relative with a history of autoimmune diseases (the childrens’ mother or grand-mother in the majority of cases). A specific autoimmune disease was present in only one AGS patient, namely an autoimmune thyroiditis. Autoantibodies were present in 9/17 patients, with different patterns of positivity. Complement levels were normal in all the patients. There was no correlation between auto-antibody production and personal or family history of autoimmune diseases.

Conclusions

Definite autoimmune diseases are not common in patients with AGS. Autoantibodies are mainly directed towards nucleic acids-containing elements but seem not to be pathogenic and, rather, may represent an epiphenomenon of the enhanced interferon production.

     

Red cell pyruvate kinase deficiency: molecular and clinical aspects

Red cell pyruvate kinase (PK) deficiency is the most frequent enzyme abnormality of the glycolytic pathway causing hereditary non-spherocytic haemolytic anaemia. The degree of haemolysis varies widely, ranging from very mild or fully compensated forms, to life-threatening neonatal anaemia and jaundice necessitating exchange transfusions. Erythrocyte PK is synthesized under the control of the PK-LR gene located on chromosome 1. To date, more than 150 different mutations in the PK-LR gene have been associated with PK deficiency. First attempts to delineate the biochemical and clinical consequences of the molecular defect were mainly based on the observation of the few homozygous patients and on the analysis of the three-dimensional structure of the enzyme. More recently, the comparison of the recombinant mutants of human red cell PK with the wild-type enzyme has enabled the effects of amino acid replacements on the enzyme molecular properties to be determined and help to correlate genotype to clinical phenotype.     

Efficacy of oxycodone/acetaminophen and codeine/acetaminophen vs. conventional therapy in elderly women with persistent, moderate to severe osteoarthritis-related pain

We aimed to evaluate the efficacy and safety of oxycodone/acetaminophen (O/A) and codeine/acetaminophen (C/A) vs. conventional therapy (CT) without opioids in older women suffering from osteoarthritis (OA)-related pain, sub-optimally responsive to prior conventional treatments. We performed a 6 week, randomized, single blind, controlled study in three nursing homes. We enrolled 154 women with painful OA. They were assigned to treatment with O/A (n = 52) and C/A (n = 52) vs. CT (n = 50). We evaluated at baseline and at week 6: average pain in the last week (mean pain, MeP), pain at rest (RP), pain in movement (MP) (numeric rating scale, NRS); depressive symptoms (Beck Depression Inventory-II, BDI-II); functional status (activities of daily living, ADL) and cognitive status (mini mental state evaluation, MMSE). We considered the adverse events (AEs) in the study period. At week 6, MeP, RP and MP were significantly reduced in all three groups (p < 0.001); compared to CT, O/A and C/A were associated with greater reductions in MeP (p < 0.001 and p = 0.004, respectively), in RP (p = 0.028 and p = 0.032, respectively) in MP (p < 0.001 and p = 0.002, respectively) and with significant improvement in BDI-II score (p = 0.05 and p = 0.04, respectively) and ADL value (p = 0.04 and p = 0.05, respectively). AE rates did not differ between groups.     

Screening for risk of violence using service users’ self‐perceptions: A prospective study from an acute mental health unit

Service users’ self‐perception of risk has rarely been emphasized in violence risk assessments. A recent review pointed to the importance of a multidisciplinary approach, because different perspectives may provide a deeper and improved understanding of risk assessment. The aim of this study was to investigate service users’ perceptions of their own risk of committing violence, using a self‐report risk scale, to determine the feasibility and efficacy of this potential violence risk marker during acute mental health hospitalization. All service users admitted to a psychiatric emergency hospital in Norway during one calendar year were included (N = 512). Nearly 80% self‐reported no risk or low risk; only seven (1.4%) reported moderate risk or high risk. Service users who reported moderate risk, high risk, don't know, or won't answer were more likely to be violent (OR = 4.65, 95% CI = 2.79–7.74) compared with those who reported no risk or low risk. There was a significant gender interaction with higher OR for women on both univariate and multivariate analyses. Although the OR was higher for women, women's violence rate (11.0%) was almost half that of men (21.8%). For women, sensitivity and specificity were 0.55 and 0.88, respectively; corresponding values for men were 0.40 and 0.80. Inclusion of self‐perception of violence risk is the first step towards service users’ collaborative involvement in violence prediction; these results indicate that self‐perception can contribute to violence risk assessments in acute mental health settings. Findings also indicate that there are gender differences in these assessments.