Use of biosimilars in inflammatory bowel disease: Statements of the Italian Group for Inflammatory Bowel Disease

The introduction of biological therapies, particularly anti-TNFα agents, has revolutionized the management of inflammatory bowel disease in those cases which are refractory to conventional treatment; however these drugs are not risk-free and their use has substantially increased the cost of treatment. As marketing protection expires for original, first-generation biopharmaceuticals, lower-cost “copies” of these drugs produced by competitor companies—referred to as biosimilars—are already entering the market. In September 2013, the European Medicines Agency approved two infliximab biosimilars for treatment of adult and paediatric inflammatory bowel disease patients, a decision based largely on efficacy and safety data generated in studies of patients with ankylosing spondylitis and rheumatoid arthritis. For many clinicians, extrapolation practices and the general question of interchangeability between biosimilars and reference biologics are cause for concern. In the present paper, the Italian Group for inflammatory bowel disease presents its statements on these issues, with emphasis on the peculiar clinical characteristics of inflammatory bowel disease and the importance of providing physicians and patients with adequate information and guarantees on the safety and efficacy of these new drugs in the specific setting of inflammatory bowel disease.     

The well-being of community residents in remission from major depression disorder

This study hypothesized that the well-being of community residents in remission from major depression disorder (MDD) would not be significantly different from those without MDD. Data from the Midlife in the United States Survey (MIDUS), a prospective general population survey conducted in 1995 and 2004, were analysed. A comparison of the psychological well-being scores, Big Five personality scores and life satisfaction scores of remitted and non-remitted respondents revealed generally small effect size differences. The remitted group were more likely than the non-remitted group to have had past-year panic disorder at follow-up. In general, these results suggest that the well-being of respondents in MDD remission was relatively high.     

Gz- and not Gi-proteins are coupled to pre-junctional μ-opioid receptors in bovine airways

We investigated the signal transmission pathway by which activation of μ-opioid receptors attenuates acetylcholine (ACh) release in bovine trachealis. Electrical stimulation (ES)-induced [³H]-ACh release was determined in bovine tracheal smooth muscle strips pre-incubated with either the Gi-protein inhibitor pertussis toxin (PTX, 500 ng/ml and 1 μg/ml) or the Gz-protein specific inhibitor arachidonic acid (AA, 10⁻⁶ M and 10⁻⁵ M) and then treated with DAMGO (D-Ala²,N-MePhe⁴,Gly-ol⁵-enkephalin) 10⁻⁵ M. Indomethacin 10⁻⁵ M was used to block AA cascade. The inhibitory effect of DAMGO on ES-induced [³H]-ACh release was PTX-insensitive, but, by contrast, ablated by AA in a concentration-dependent manner. AA 10⁻⁵ M alone reduced [³H]-ACh release, an effect that was prevented by iberiotoxin 10⁻⁷ M, suggesting an involvement of Ca²⁺-activated K⁺-channels. Western blot analysis consistently showed immunoreactive bands against a specific antibody anti-Gz-α subunit at ∼40 kDa, consistent with the presence of Gz-protein. The present findings suggest that in isolated bovine trachealis, activation of μ-opioid receptors inhibits ACh-release through a signal transmission pathway involving Gz-protein rather than Gi-protein.     

The microRNA cluster C19MC is deregulated in parathyroid tumours

A subset of over-expressed microRNAs (miRNAs) identified in parathyroid carcinomas (Ca) compared to normal glands belongs to C19MC, a cluster on chromosome 19q13.4 involved in stem cell biology and tumourigenesis. In this study, the expression of C19MC-MIR371-3 clusters and the molecular mechanisms presiding their modulation were investigated in a series of six normal parathyroids, 24 adenomas (Ad), 15 Ca and five matched metastases. The general expression levels of C19MC or MIR371-3 clusters in Ad lesions did not differ from normal glands, while they distinguished Ad from Ca at unsupervised hierarchical cluster analysis (P=0.0008). MIR517C showed the most significant difference in expression between Ca and Ad (P=0.0003) and it positively correlated with serum calcium, parathormone and tumour weight. In regard to the molecular mechanism determining C19MC cluster activation, we could detect C19MC copy number (CN) gain in ten Ca (67%) extending distal to the MIR371-3 cluster in almost all samples. Conversely, only four Ad (16%) showed C19MC amplification, with one case presenting distal genomic aberration to MIR371-3. Globally, CN variations of 19q13.4 loci were significantly associated with MIR517C up-regulation (P=0.006). Opposite to normal glands where C19MC promoter was methylated, hypomethylation occurred in 15 out of 30 analysed tumours. Though the epigenetic status did not correlate with C19MC miRNA expression levels, loss of C19MC promoter methylation was significantly associated with Ca and metastatic disease (P=0.01). In conclusion, C19MC cluster aberrations are a characteristic of Ca with respect to Ad. Altogether, these evidences point towards a role for 19q13.4 miRNA clusters as oncogenes in parathyroid tumourigenesis.     

Differentiation of cardiac and noncardiac dyspnea using bioelectrical impedance vector analysis (BIVA)

BackgroundThere is no gold standard for the differential diagnosis of acute dyspnea despite the usefulness of N-terminal pro–B-type natriuretic peptide (NT-proBNP) and lung ultrasound. No study has evaluated the contribution of bioelectrical impedance vector analysis (BIVA) in discriminating between cardiac and noncardiac dyspnea. We sought to determine whether a relationship exists between ultrasound detection of lung congestion, NT-proBNP, and BIVA in patients with acute dyspnea.Methods and ResultsEligible patients were between 50 and 95 years, with an estimated glomerular filtration rate of ≥30 mL min^?1 1.73 m^?2, who presented to an emergency department with dyspnea. Dyspnea was classified by reviewers blinded to BIVA as cardiac or noncardiac based on physical examination, electrocardiogram, chest X-ray, NT-proBNP, and B-lines of lung congestion on ultrasound. Overall, 315 patients were enrolled (median age 77 years, 48% male). An adjudicated diagnosis of cardiac dyspnea was established in 169 (54%). Using BIVA, vector positions below ?1 SD of the Z-score of reactance were associated with peripheral congestion (χ² = 115; P < .001). BIVA measures were reasonably accurate in discriminating cardiac and noncardiac dyspnea (69% sensitivity, 79% specificity, 80% area under the receiver operating characteristic curve).ConclusionsIn patients presenting with acute dyspnea, the combination of BIVA and lung ultrasound may provide a rapid noninvasive method to determine the cause of dyspnea.     

Can we predict and prevent adverse events related to high-voltage implantable cardioverter defibrillator lead failure?

Background  

In 2007, great concern arose regarding failure of implantable cardioverter defibrillator (ICD) leads from several manufacturers.