PTC Therapeutics.

In vitro hypoxic preconditioning (HP) of mesenchymal stem cells (MSCs) could ameliorate their viability and tissue repair capabilities after transplantation into the injured tissue through yet undefined mechanisms. There is also experimental evidence that HP enhances the expression of both stromal-derived factor-1 (SDF-1) receptors, CXCR4 and CXCR7, which are involved in migration and survival of MSCs in vitro, but little is known about their role in the in vivo therapeutic effectiveness of MSCs in renal ischemia/reperfusion (I/R) injury. Here, we evaluated the role of SDF-1-CXCR4/CXCR7 pathway in regulating chemotaxis, viability and paracrine actions of HP-MSCs in vitro and in vivo. Compared with normoxic preconditioning (NP), HP not only improved MSC chemotaxis and viability but also stimulated secretion of proangiogenic and mitogenic factors. Importantly, both CXCR4 and CXCR7 were required for the production of paracrine factors by HP-MSCs though the former was only responsible for chemotaxis while the latter was for viability. SDF-1α expression was upregulated in postischemic kidneys. After 24 h systemical administration following I/R, HP-MSCs but not NP-MSCs were selectively recruited to ischemic kidneys and this improved recruitment was abolished by neutralization of CXCR4, but not CXCR7. Furthermore, the increased recruitment of HP-MSCs was associated with enhanced functional recovery, accelerated mitogenic response, and reduced apoptotic cell death. In addition, neutralization of either CXCR4 or CXCR7 impaired the improved therapeutic potential of HP-MSCs. These results advance our knowledge about SDF-1-CXCR4/CXCR7 axis as an attractive target pathway for improving the beneficial effects of MSC-based therapies for renal I/R.

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Among different species of mites, Demodex folliculorum and Demodex brevis are the only two that affect the human eye. Because demodicosis is highly age-dependent and can be found in asymptomatic adults, the pathogenicity of these mites has long been debated. Herein, we summarize our research experience including our most recent study regarding Demodex infestation as a potential cause of ocular inflammatory diseases. Specifically, we describe the pathogenesis of demodicosis and then discuss the results of work investigating the associations and relationships between ocular demodicosis and blepharitis, meibomian gland diseases, and keratitis, in turn. This is followed by some discussion of the diagnosis of demodicosis, and concludes with a brief discussion of the evidence for different treatments for ocular demodicosis. Collectively, our studies suggest a strong correlation between ocular demodicosis and ocular surface inflammatory conditions, such as blepharitis, chalazia, MGD, and keratitis. Further investigation of the underlying pathogenic mechanism is warranted.

In designing longitudinal studies, researchers must determine the number of subjects to randomize based on the power to detect a clinically meaningful treatment difference and a proposed analysis plan. In this paper, we present formulas for sample size estimation and an assessment of statistical power for a two-treatment repeated measures design allowing for subject attrition. These formulas can be used for comparing two treatment groups across time in terms of linear contrasts. Subjects are assumed to drop out of the study at random so that the missing data do not alter the parameters of interest.

BackgroundThe identification of cell-free fetal DNA (cffDNA) facilitated non-invasive prenatal screening (NIPS) through analysis of cffDNA in maternal plasma. However, challenges regarding its clinical implementation become apparent. Factors affecting fetal fraction should be clarified to guide its clinical application.ResultsA total of 13,661 pregnant subjects with singleton pregnancies who undertook NIPS were included in the study. Relationship of gestational age, maternal BMI, and maternal age with the cffDNA fetal fraction in maternal plasmas for NIPS was investigated. Compared with 13 weeks (12.74%) and 14–18 weeks group (12.73%), the fetal fraction in gestational ages of 19–23 weeks, 24–28 weeks, and more than 29 weeks groups significantly increased to 13.11%, 16.14%, and 21.17%, respectively (P < 0.01). Compared with fetal fraction of 14.54% in the maternal BMI group of < 18.5 kg/m2, the percentage of fetal fraction in the group of 18.5–24.9 kg/m2 (13.37%), 25–29.9 kg/m2 (12.20%), 30–34.9 kg/m2 (11.32%), and 35–39.9 kg/m2 (11.57%) decreased significantly (P < 0.01). Compared with the fetal fraction of 14.38% in the group of 18–24 years old, the fetal fraction in the maternal age group of 25–29 years old group (13.98%) (P < 0.05), 30–34 years old group (13.18%) (P < 0.01), 35–39 years old group (12.34%) (P < 0.01), and ≥ 40 years old (11.90%) group (P < 0.01) decreased significantly.ConclusionsThe percentage of fetal fraction significantly increased with increase of gestational age. Decreased fetal fraction with increasing maternal BMI was found. Maternal age was also negatively related to the fetal fraction.

The parallel gatekeeping strategy proposed by Dmitrienko et al. (Statist. Med. 2003; 22:2387-2400) provides a flexible framework for the pursuit of strong control on study wise type I error rate. This paper further explores the application of the weighted Simes parallel gatekeeping procedure recommended by Dmitrienko et al. and proposes some modifications to it to better incorporate the interrelationships of different hypotheses in actual clinical trials and to achieve better power performance. We first propose a simple method to quantitatively control the impact of secondary tests on the testing of primary hypotheses. We then introduce a matched gatekeeping procedure to exemplify how to address special relationships between individual primary and secondary tests following the parallel gatekeeping framework. Our simulation study demonstrates that the enhanced gatekeeping procedures generally result in more powerful tests than the parallel gatekeeping procedure in Dmitrienko et al. whenever applicable.

It is unknown whether a scaffold containing both small intestinal submucosa (SIS) and mesenchymal stem cells (MSCs) for transplantation may improve pancreatic islet function and survival. In this study, we examined the effects of a SIS-MSC scaffold on islet function and survival in vitro and in vivo. MSCs and pancreatic islets were isolated from Sprague-Dawley rats, and SIS was isolated from Bamei pigs. The islets were apportioned among 3 experimental groups as follows: SIS-islets, SIS-MSC-islets and control-islets. In vitro, islet function was measured by a glucose-stimulated insulin secretion test; cytokines in cultured supernatants were assessed by enzyme-linked immunosorbent assay; and gene expression was analyzed by reverse transcription-quantitative PCR. In vivo, islet transplantation was performed in rats, and graft function and survival were monitored by measuring the blood glucose levels. In vitro, the SIS-MSC scaffold was associated with improved islet viability and enhanced insulin secretion compared with the controls, as well as with the increased the expression of insulin 1 (Ins1), pancreatic and duodenal homeobox 1 (Pdx1), platelet endothelial cell adhesion molecule 1 [Pecam1; also known as cluster of differentiation 31 (CD31)] and vascular endothelial growth factor A (Vegfa) in the islets, increased growth factor secretion, and decreased tumor necrosis factor (TNF) secretion. In vivo, the SIS-MSC scaffold was associated with improved islet function and graft survival compared with the SIS and control groups. On the whole, our findings demonstrate that the SIS-MSC scaffold significantly improved pancreatic islet function and survival in vitro and in vivo. This improvement may be associated with the upregulation of insulin expression, the improvement of islet microcirculation and the secretion of cytokines.