OMERACT workshop: repair of structural damage in rheumatoid arthritis

This article describes the process and results of a workshop aimed at reviewing data on repair of structural damage collected by the OMERACT Subcommittee on Healing of Erosions and at defining a priority list for the subsequent research agenda.     

Novel Phage Lysin Capable of Killing the Multidrug-Resistant Gram-Negative Bacterium Acinetobacter baumannii in a Mouse Bacteremia Model

Acinetobacter baumannii, a Gram-negative multidrug-resistant (MDR) bacterium, is now recognized as one of the more common nosocomial pathogens. Because most clinical isolates are found to be multidrug resistant, alternative therapies need to be developed to control this pathogen. We constructed a bacteriophage genomic library based on prophages induced from 13 A. baumannii strains and screened it for genes encoding bacteriolytic activity. Using this approach, we identified 21 distinct lysins with different activities and sequence diversity that were capable of killing A. baumannii. The lysin (PlyF307) displaying the greatest activity was further characterized and was shown to efficiently kill (>5-log-unit decrease) all tested A. baumannii clinical isolates. Treatment with PlyF307 was able to significantly reduce planktonic and biofilm A. baumannii both in vitro and in vivo. Finally, PlyF307 rescued mice from lethal A. baumannii bacteremia and as such represents the first highly active therapeutic lysin specific for Gram-negative organisms in an array of native lysins found in Acinetobacter phage.     

In Vitro Activity and Resistance Profile of Dasabuvir,a Nonnucleoside Hepatitis C Virus Polymerase Inhibitor

Dasabuvir (ABT-333) is a nonnucleoside inhibitor of the RNA-dependent RNA polymerase encoded by the hepatitis C virus (HCV) NS5B gene. Dasabuvir inhibited recombinant NS5B polymerases derived from HCV genotype 1a and 1b clinical isolates, with 50% inhibitory concentration (IC₅₀) values between 2.2 and 10.7 nM, and was at least 7,000-fold selective for the inhibition of HCV genotype 1 polymerases over human/mammalian polymerases. In the HCV subgenomic replicon system, dasabuvir inhibited genotype 1a (strain H77) and 1b (strain Con1) replicons with 50% effective concentration (EC₅₀) values of 7.7 and 1.8 nM, respectively, with a 13-fold decrease in inhibitory activity in the presence of 40% human plasma. This level of activity was retained against a panel of chimeric subgenomic replicons that contained HCV NS5B genes from 22 genotype 1 clinical isolates from treatment-naive patients, with EC₅₀s ranging between 0.15 and 8.57 nM. Maintenance of replicon-containing cells in medium containing dasabuvir at concentrations 10-fold or 100-fold greater than the EC₅₀ resulted in selection of resistant replicon clones. Sequencing of the NS5B coding regions from these clones revealed the presence of variants, including C316Y, M414T, Y448C, Y448H, and S556G, that are consistent with binding to the palm I site of HCV polymerase. Consequently, dasabuvir retained full activity against replicons known to confer resistance to other polymerase inhibitors, including the S282T variant in the nucleoside binding site and the M423T, P495A, P495S, and V499A single variants in the thumb domain. The use of dasabuvir in combination with inhibitors targeting HCV NS3/NS4A protease (ABT-450 with ritonavir) and NS5A (ombitasvir) is in development for the treatment of HCV genotype 1 infections.     

Implantable cardioverter-defibrillators in patients with left ventricular noncompaction

Background: Left ventricular noncompaction (LVNC) is a rare, congenital cardiomyopathy and can be associated with heart failure, embolic events, arrhythmias, and sudden cardiac death. Implantation of implantable cardioverter-defibrillators in these patients is a treatment option, but data on long-term follow-up are limited. The aim of the study was to analyze the clinical outcome of patients with LVNC who were treated with an implantable cardioverter-defibrillator (ICD).
Methods: We conducted a retrospective study on 12 patients (mean age: 45 ± 13 years, range 20–60) with LVNC, who underwent ICD implantation for secondary (n = 8) and primary (n = 4) prevention.
Results: During a median follow-up of 36 months, five patients (42%) presented with appropriate ICD therapy: in four of the eight patients (50%) in whom the ICD was implanted as a secondary prevention and in one of the four patients (25%) for whom the ICD was implanted for primary prevention. In eight patients (66%) supraventricular tachyarrhythmias were documented. Improvement of left ventricular function could be observed in one of two patients with a biventricular ICD.
Conclusions: Potentially life-threatening ventricular tachyarrhythmias may occur in patients with LVNC. ICD therapy may be effective for primary and secondary prevention in these patients. Due to the high prevalence of supraventricular tachyarrhythmias devices with reliable detection enhancements should be considered.     

Bisoprolol vs. carvedilol in elderly patients with heart failure: rationale and design of the CIBIS-ELD trial

Background  Chronic heart failure (CHF) is a widespread disease with severe quality of life impairment and a poor prognosis. Beta-blockers are the mainstay of CHF therapy; yet they are under-prescribed and under-dosed in clinical practice. This is particularly evident in elderly patients, which may be due to a fear of side-effects or intolerance. Beta-blockers have further not been adequately tested in patients with diastolic CHF, which is particularly common in elderly patients. Finally, comparative data on the use of different beta-blockers in patients with CHF is scarce. Aim  To compare the tolerance of bisoprolol and carvedilol in elderly patients with CHF. Methods  CIBIS-ELD is an investigator-initiated, multi-centre, 1:1 randomised, double-blind, phase III trial comparing bisoprolol and carvedilol in patients ≥65 years with systolic or diastolic CHF. Recruitment started in April 2005 and is anticipated to be completed by April 2008 with at least 800 patients enrolled. Perspective  This is the first large scale head to head beta-blockers trial in an elderly population with CHF. Besides determining which of two standard beta-blockers is best tolerated in elderly patients with systolic or diastolic CHF, we expect to gain further insight into the treatment of the particular population of patients with diastolic CHF. This trial was supported by the Competence Network of Heart Failure funded by the Federal Ministry of Education and Research (BMBF, project number 01GI0205) and is registered with number ISRCTN34827306 at .     

Similarities in stress physiology among patients with chronic pain and headache disorders: evidence for a common pathophysiological mechanism?

One common feature of chronic musculoskeletal pain and headaches are that they are both influenced by stress. Among these, tension-type headache (TTH), fibromyalgia (FMS) and chronic shoulder/neck pain (SNP) appear to have several similarities, both with regard to pathophysiology, clinical features and demographics. The main hypothesis of the present study was that patients with chronic pain (TTH, FMS and SNP) had stress-induced features distinguishing them from migraine patients and healthy controls. We measured pain, blood pressure, heart rate (HR) and skin blood flow (BF) during (1 h) and after (30 min) controlled low-grade cognitive stressor in 22 migraine patients, 18 TTH patients, 23 FMS patients, 29 SNP patients and 44 healthy controls. FMS patients had a lower early HR response to stress than migraine patients, but no differences were found among FMS, TTH and SNP patients. Finger skin BF decreased more in FMS patients compared to migraine patients, both during and after the test. When comparing chronic pain patients (chronic TTH, FMS and SNP) with those with episodic pain (episodic TTH and migraine patients) or little or no pain (healthy controls), different adaptation profiles were found during the test for systolic and diastolic blood pressure, HR and skin BF in the chronic group. In conclusion, these results suggest that TTH, FMS and SNP patients may share common pathophysiological mechanisms regarding the physiological responses to and recovery from low-grade cognitive stress, differentiating them from episodic pain conditions such as migraine.     

Liberal vs. conservative vasopressor use to maintain mean arterial blood pressure during resuscitation of septic shock: an observational study

OBJECTIVE: The optimal role of vasopressor therapy in septic shock is not known. We hypothesized that the variability in the use of vasopressors to treat hypotension is associated with subsequent organ failures. DESIGN: Retrospective observational single-center cohort study. SETTING: Tertiary care hospital. PATIENTS AND PARTICIPANTS: Consecutive patients with septic shock. MEASUREMENT AND RESULTS: Ninety-five patients were enrolled. Serial blood pressure recordings and vasopressor use were collected during the first 12h of septic shock. Median duration of hypotension that was not treated with vasopressors was 1.37h (interquartile range [IQR] 0.62-2.66). Based on the observed variability, we evaluated liberal (duration of untreated hypotension < median) vs. conservative (duration of untreated hypotensionn > median) vasopressor therapy. Compared with patients who received conservative vasopressor therapy, patients treated liberally had similar baseline organ impairment [median Sequential Organ Failure Assessment (SOFA) score 8 vs. 8, p = 0.438] were more likely to be younger (median age 70 vs. 77 years, p = 0.049), to require ventilator support (78 vs. 49%, p < 0.001), and to have progression of organ failures after 24h (59 vs. 37%, p = 0.032). When adjusted for age and mechanical ventilation, early therapy aimed at achieving global tissue perfusion [odds ratio (OR) 0.33, 95% confidence interval (CI) 0.11-0.88), and early adequate antibiotic therapy (OR 0.27, 95% CI 0.09-0.76), but not liberal vasopressor use (OR 2.13, 95% CI 0.80-5.84), prevented progression of organ failures. CONCLUSIONS: In our retrospective study, early adequate antibiotics and achieving adequate global perfusion, but not liberal vasopressor therapy, were associated with improved organ failures after septic shock. Clinical trials which compare conservative vs. liberal vasopressor therapy are warranted.