Congenital scoliosis is a common type of vertebral malformation. Genetic susceptibility has been implicated in congenital scoliosis. We evaluated 161 Han Chinese persons with sporadic congenital scoliosis, 166 Han Chinese controls, and 2 pedigrees, family members of which had a 16p11.2 deletion, using comparative genomic hybridization, quantitative polymerase-chain-reaction analysis, and DNA sequencing. We carried out tests of replication using an additional series of 76 Han Chinese persons with congenital scoliosis and a multicenter series of 42 persons with 16p11.2 deletions. We identified a total of 17 heterozygous TBX6 null mutations in the 161 persons with sporadic congenital scoliosis (11%); we did not observe any null mutations in TBX6 in 166 controls (P<3.8×10⁻⁶). These null alleles include copy-number variants (12 instances of a 16p11.2 deletion affecting TBX6) and single-nucleotide variants (1 nonsense and 4 frame-shift mutations). However, the discordant intrafamilial phenotypes of 16p11.2 deletion carriers suggest that heterozygous TBX6 null mutation is insufficient to cause congenital scoliosis. We went on to identify a common TBX6 haplotype as the second risk allele in all 17 carriers of TBX6 null mutations (P<1.1×10⁻⁶). Replication studies involving additional persons with congenital scoliosis who carried a deletion affecting TBX6 confirmed this compound inheritance model. In vitro functional assays suggested that the risk haplotype is a hypomorphic allele. Hemivertebrae are characteristic of TBX6-associated congenital scoliosis. Compound inheritance of a rare null mutation and a hypomorphic allele of TBX6 accounted for up to 11% of congenital scoliosis cases in the series that we analyzed. (Funded by the National Basic Research Program of China and others.)

Background: The therapeutic potential of exosomes derived from stem cells has attracted increasing interest recently, because they can exert similar paracrine functions of stem cells and overcome the limitations of stem cells transplantation. Exosomes derived from bone mesenchymal stem cells (BMSC-Exos) have been confirmed to promote osteogenesis and angiogenesis. The magnetic nanoparticles (eg. Fe₃O₄, γ-Fe₂O₃) combined with a static magnetic field (SMF) has been commonly used to increase wound healing and bone regeneration. Hence, this study aims to evaluate whether exosomes derived from BMSCs preconditioned with a low dose of Fe₃O₄ nanoparticles with or without the SMF, exert superior pro-osteogenic and pro-angiogenic activities in bone regeneration and the underlying mechanisms involved. Methods: Two novel types of exosomes derived from preconditioned BMSCs that fabricated by regulating the contents with the stimulation of magnetic nanoparticles and/or a SMF. Then, the new exosomes were isolated by ultracentrifugation and characterized. Afterwards, we conducted in vitro experiments in which we measured osteogenic differentiation, cell proliferation, cell migration, and tube formation, then established an in vivo critical-sized calvarial defect rat model. The miRNA expression profiles were compared among the exosomes to detect the potential mechanism of improving osteogenesis and angiogenesis. At last, the function of exosomal miRNA during bone regeneration was confirmed by utilizing a series of gain- and loss-of-function experiments in vitro. Results: 50 µg/mL Fe₃O₄ nanoparticles and a 100 mT SMF were chosen as the optimum magnetic conditions to fabricate two new exosomes, named BMSC-Fe₃O₄-Exos and BMSC-Fe₃O₄-SMF-Exos. They were both confirmed to enhance osteogenesis and angiogenesis in vitro and in vivo compared with BMSC-Exos, and BMSC-Fe₃O₄-SMF-Exos had the most marked effect. The promotion effect was found to be related to the highly riched miR-1260a in BMSC-Fe₃O₄-SMF-Exos. Furthermore, miR-1260a was verified to enhance osteogenesis and angiogenesis through inhibition of HDAC7 and COL4A2, respectively. Conclusion: These results suggest that low doses of Fe₃O₄ nanoparticles combined with a SMF trigger exosomes to exert enhanced osteogenesis and angiogenesis and that targeting of HDAC7 and COL4A2 by exosomal miR-1260a plays a crucial role in this process. This work could provide a new protocol to promote bone regeneration for tissue engineering in the future. Graphical

Aberrant proliferation of nucleus pulposus cell is implicated in the pathogenesis of intervertebral disc degeneration. Recent findings revealed that microRNAs, a class of small noncoding RNAs, could regulate cell proliferation in many pathological conditions. Here, we showed that miR-10b was dramatically upregulated in degenerative nucleus pulposus tissues when compared with nucleus pulposus tissues isolated from patients with idiopathic scoliosis. Moreover, miR-10b levels were associated with disc degeneration grade and downregulation of HOXD10. In cultured nucleus pulposus cells, miR-10b overexpression stimulated cell proliferation with concomitant translational inhibition of HOXD10 whereas restored expression of HOXD10 reversed the mitogenic effect of miR-10b. MiR-10b-mediated downregulation of HOXD10 led to increased RhoC expression and Akt phosphorylation. Either knockdown of RhoC or inhibition of Akt abolished the effect of miR-10b on nucleus pulposus cell proliferation. Taken together, aberrant miR-10b upregulation in intervertebral disc degeneration could contribute to abnormal nucleus pulposus cell proliferation through derepressing the RhoC-Akt pathway by targeting HOXD10. Our study also underscores the potential of miR-10b and the RhoC-Akt pathway as novel therapeutic targets in intervertebral disc degeneration.

Using an improved method, the multilayer fermentation method, bacterial cellulose (BC) was produced by Gluconacetobacter xylinus. The structure and morphology were analysed by an electronic microscope. The surface area and tensile strength were characterised. In vitro, the cytotoxicity of BC was determined by the proliferation, adhesion property, morphology, and viability of human adipose-derived stem cells (hASCs). Full-thickness skin wounds were made on the backs of 35 mice. The wounds were subsequently treated with two types of gauzes, two types of BC films, and three types of skin grafts using 5 mice per group, respectively. The improved method was reproducible and more efficient to control the thickness and homogeneity of BC. Low cytotoxicity of the BC film and good proliferation of hASCs on the BC film were observed. Histological examinations demonstrated significant fresh tissue regeneration and capillary formation in the wound area in the BC groups on day 7 compared with those in other groups. Pathological studies also showed a faster and better healing effect and less inflammatory response in the BC groups than those in other groups. These results indicate high clinical potential of the BC biosynthesized by our improved method.

Background Type 2 diabetes is associated with acute and chronic complications and poses a large economic, social, and medical burden on patients and their families as well as society. Objective This study aims to evaluate the direct economic burden of type 2 diabetes in China. Data source: systematic review on cost of illness, health care costs, direct service costs, drug costs, and health expenditures in relation to type 2 diabetes was conducted up to 2014 using databases such as Pubmed; EBSCO; Elsevier ScienceDirect, Web of Science; and a series of Chinese databases, including Wanfang Data, China National Knowledge Infrastructure (CNKI), and the China Science and Technology Journal Database. Factors influencing hospitalization and drug fees were also identified. Study eligibility criteria: (1) estimation of the direct economic burden including hospitalization and outpatient cost of type 2 diabetes patients in China; (2) evaluation of the factors influencing the direct economic burden. Articles only focusing on the cost-effectiveness analysis of diabetes drugs were excluded. Results The direct economic burden of type 2 diabetes has increased over time in China, and in 2008, the direct medical cost reached $9.1 billion, Both outpatient and inpatient costs have increased. Income level, type of medical insurance, the level of hospital care, and type and number of complications are primary factors influencing diabetes related hospitalization costs. Compared to urban areas, the direct non-medical cost of type 2 diabetes in rural areas is significantly greater. Conclusions The direct economic burden of type 2 diabetes poses a significant challenge to China. To address the economic burden associated with type 2 diabetes, measures need to be taken to reduce prevalence rate and severity of diabetes and hospitalization cost.