Additional benefit of combined therapy with melatonin and apoptotic adipose‐derived mesenchymal stem cell against sepsis‐induced kidney injury

This study tested whether combined therapy with melatonin and apoptotic adipose‐derived mesenchymal stem cells (A‐ADMSCs) offered additional benefit in ameliorating sepsis‐induced acute kidney injury. Adult male Sprague–Dawley rats (n = 65) were randomized equally into five groups: Sham controls (SC), sepsis induced by cecal‐ligation and puncture (CLP), CLP‐melatonin, CLP‐A‐ADMSC, and CLP‐melatonin‐A‐ADMSC. Circulating TNF‐α level at post‐CLP 6 hr was highest in CLP and lowest in SC groups, higher in CLP‐melatonin than in CLP‐A‐ADMSC and CLP‐melatonin‐A‐ADMSC groups (all P < 0.001). Immune reactivity as reflected in the number of splenic helper‐, cytoxic‐, and regulatory‐T cells at post‐CLP 72 hr exhibited the same pattern as that of circulating TNF‐α among all groups (P < 0.001). The histological scoring of kidney injury and the number of F4/80+ and CD14+ cells in kidney were highest in CLP and lowest in SC groups, higher in CLP‐melatonin than in CLP‐A‐ADMSC and CLP‐melatonin‐A‐ADMSC groups, and higher in CLP‐A‐ADMSC than in CLP‐melatonin‐A‐ADMSC groups (all P < 0.001). Changes in protein expressions of inflammatory (RANTES, TNF‐1α, NF‐κB, MMP‐9, MIP‐1, IL‐1β), apoptotic (cleaved caspase 3 and PARP, mitochondrial Bax), fibrotic (Smad3, TGF‐β) markers, reactive‐oxygen‐species (NOX‐1, NOX‐2), and oxidative stress displayed a pattern identical to that of kidney injury score among the five groups (all P < 0.001). Expressions of antioxidants (GR+, GPx+, HO‐1, NQO‐1+) were lowest in SC group and highest in CLP‐melatonin‐A‐ADMSC group, lower in CLP than in CLP‐melatonin and CLP‐A‐ADMSC groups, and lower in CLP‐melatonin‐ than in CLP‐A‐ADMSC‐tretaed animals (all P < 0.001). In conclusion, combined treatment with melatonin and A‐ADMSC was superior to A‐ADMSC alone in protecting the kidneys from sepsis‐induced injury.     

A simple Bayesian decision‐theoretic design for dose‐finding trials

A flexible and simple Bayesian decision‐theoretic design for dose‐finding trials is proposed in this paper. In order to reduce the computational burden, we adopt a working model with conjugate priors, which is flexible to fit all monotonic dose‐toxicity curves and produces analytic posterior distributions. We also discuss how to use a proper utility function to reflect the interest of the trial. Patients are allocated based on not only the utility function but also the chosen dose selection rule. The most popular dose selection rule is the one‐step‐look‐ahead (OSLA), which selects the best‐so‐far dose. A more complicated rule, such as the two‐step‐look‐ahead, is theoretically more efficient than the OSLA only when the required distributional assumptions are met, which is, however, often not the case in practice. We carried out extensive simulation studies to evaluate these two dose selection rules and found that OSLA was often more efficient than two‐step‐look‐ahead under the proposed Bayesian structure. Moreover, our simulation results show that the proposed Bayesian method's performance is superior to several popular Bayesian methods and that the negative impact of prior misspecification can be managed in the design stage. Copyright © 2012 John Wiley & Sons, Ltd.     

Pulmonary Atresia with Ventricular Septal Defect and Multifocal Pulmonary Blood Supply: Does an Intensive Interventional Approach Improve the Outcome?

Introduction. Pulmonary atresia with ventricular septal defect (VSD) continues to be associated with significant morbidity and mortality, with significant institutional variation in therapeutic strategies. This study reports a single center experience utilizing an intensive transcatheter approach to promote pulmonary vascular growth. Methods. A retrospective analysis of 20 patients undergoing surgical and transcatheter treatment for pulmonary atresia with VSD between 2002 and 2010. Results. The median age at initial surgical palliation was 6.3 months (8 days to 2.5 years). Eleven patients (group 1) underwent initial surgical palliation without VSD closure and nine patients (group 2) underwent an initial complete repair with fenestrated or complete VSD closure. Group 1 had a smaller Nakata index (54 mm²/m² vs. 134 mm²/m², P= .04) and a smaller absolute native pulmonary artery diameter (2.7 mm vs. 4.5 mm, P= .01) than group 2. Intraoperative angiography was performed in 10 cases to evaluate if early transcatheter intervention was warranted. The median follow‐up during the study period was 2.3 years (1.6 months to 8.3 years). Of the 16 patients who survived the initial early postoperative period, 15 patients (94%) went on to receive surgical (n = 11) and/or interventional (n = 25) catheterization procedures. There was improvement in the mean Nakata index from the initial presurgical evaluation to the most recent catheterization data (38.4 mm²/m² vs. 169.7 mm²/m², P≤ .05). To date, two of 11 (18%) patients in group 1 ultimately underwent surgical VSD closure. Overall mortality was six of 20 (30%) with four deaths in group 1 and two deaths in group 2. There were no procedural deaths. Conclusions. Combining surgical unifocalization procedures with subsequent early and intensive catheter‐based pulmonary artery rehabilitation may improve vascular growth, ultimately rendering many patients suitable for fenestrated VSD closure. Risk stratification, including intraoperative exit angiography, is essential to determine the need for early transcatheter interventions.     

Prevalence and factors associated with uveitis in spondylarthritis patients in France: Results from an observational survey

Objective

To accurately estimate the prevalence of and the factors associated with uveitis in spondylarthritis (SpA) patients in France.

Methods

In an observational survey of SpA patients (diagnosis confirmed by the European Spondylarthropathy Study Group and/or Amor's criteria) consulting their rheumatologist for routine followup, we collected information regarding present/past history of uveitis, as well as detailed characteristics of the disease. Factors independently associated with uveitis were determined.

Results

From September 2008 to January 2009, 202 rheumatologists participated in the survey and recruited 902 patients (61% men) with a mean ± SD age of 45.3 ± 13.4 years and a mean ± SD disease duration of 10.4 ± 9.6 years. The SpA diagnoses were ankylosing spondylitis (71%), psoriatic arthritis (18%), or other SpA (11%). The HLA–B27 positivity rate was 76%. Uveitis prevalence was 32.2% (95% confidence interval [95% CI] 29.1–35.3%) since psoriasis and inflammatory bowel disease were 22.3% (95% CI 19.5–25.0%) and 8.6% (95% CI 6.7–10.5%), respectively. Recurrence of uveitis occurred in 52.3% and complications occurred in 11.7% of patients. Factors independently associated with uveitis were HLA–B27 positivity (adjusted odds ratio [OR_adj] 2.97 [95% CI 1.83–4.81], P < 0.0001) and disease duration (OR_adj 1.28 [95% CI 1.16–1.41], P < 0.0001 for ≥10 years).

Conclusion

Results indicate that uveitis is the most common extraarticular feature of SpA, occurring preferentially in HLA–B27–positive patients over the entire course of the disease.