Assessing mechanical integrity of spinal fusion by in situ endochondral osteoinduction in the murine model

<p>Abstract</p> <p>Background</p> <p>Historically, radiographs, micro-computed tomography (micro-CT) exams, palpation and histology have been used to assess fusions in a mouse spine. The objective of this study was to develop a faster, cheaper, reproducible test to directly quantify the mechanical integrity of spinal fusions in mice.</p> <p>Methods</p> <p>Fusions were induced in ten mice spine using a previously described technique of in situ endochondral ossification, harvested with soft tissue, and cast in radiolucent alginate material for handling. Using a validated software package and a customized mechanical apparatus that flexed and extended the spinal column, the amount of intervertebral motion between adjacent vertebral discs was determined with static flexed and extended lateral spine radiographs. Micro-CT images of the same were also blindly reviewed for fusion.</p> <p>Results</p> <p>Mean intervertebral motion between control, non-fused, spinal vertebral discs was 6.1 ± 0.2° during spine flexion/extension. In fusion samples, adjacent vertebrae with less than 3.5° intervertebral motion had fusions documented by micro-CT inspection.</p> <p>Conclusions</p> <p>Measuring the amount of intervertebral rotation between vertebrae during spine flexion/extension is a relatively simple, cheap (<$100), clinically relevant, and fast test for assessing the mechanical success of spinal fusion in mice that compared favorably to the standard, micro-CT.</p

Identifying susceptibility genes for primary ovarian insufficiency on the high-risk genetic background of a fragile X premutation

This is the final version. Available on open access from Elsevier via the DOI in this recordObjective: To identify modifying genes that explains the risk of fragile X-associated primary ovarian insufficiency (FXPOI). Design: Gene-based, case/control association study, followed by a functional screen of highly ranked genes using a Drosophila model. Setting: Participants were recruited from academic and clinical settings. Patient(s): Women with a premutation (PM) who experienced FXPOI at the age of 35 years or younger (n = 63) and women with a PM who experienced menopause at the age of 50 years or older (n = 51) provided clinical information and a deoxyribonucleic acid sample for whole genome sequencing. The functional screen was on the basis of Drosophila TRiP lines. Intervention(s): Clinical information and a DNA sample were collected for whole genome sequencing. Main Outcome Measures: A polygenic risk score derived from common variants associated with natural age at menopause was calculated and associated with the risk of FXPOI. Genes associated with the risk of FXPOI were identified on the basis of the P-value from gene-based association test and an altered level of fecundity when knocked down in the Drosophila PM model. Results: The polygenic risk score on the basis of common variants associated with natural age at menopause explained approximately 8% of the variance in the risk of FXPOI. Further, SUMO1 and KRR1 were identified as possible modifying genes associated with the risk of FXPOI on the basis of an untargeted gene analysis of rare variants. Conclusions: In addition to the large genetic effect of a PM on ovarian function, the additive effects of common variants associated with natural age at menopause and the effect of rare modifying variants appear to play a role in FXPOI risk.Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)Fundacion Merck Salu

Lymphangiogenesis Is Required for Pancreatic Islet Inflammation and Diabetes

Lymphangiogenesis is a common phenomenon observed during inflammation and engraftment of transplants, but its precise role in the immune response and underlying mechanisms of regulation remain poorly defined. Here we showed that in response to injury and autoimmunity, lymphangiogenesis occurred around islets and played a key role in the islet inflammation in mice. Vascular endothelial growth factors receptor 3 (VEGFR3) is specifically involved in lymphangiogenesis, and blockade of VEGFR3 potently inhibited lymphangiogenesis in both islets and the draining LN during multiple low-dose streptozotocin (MLDS) induced autoimmune insulitis, which resulted in less T cell infiltration, preservation of islets and prevention of the onset of diabetes. In addition to their well-known conduit function, lymphatic endothelial cells (LEC) also produced chemokines in response to inflammation. These LEC attracted two distinct CX3CR1hi and LYVE-1+ macrophage subsets to the inflamed islets and CX3CR1hi cells were influenced by LEC to differentiate into LYVE-1+ cells closely associated with lymphatic vessels. These observations indicate a linkage among lymphangiogenesis and myeloid cell inflammation during insulitis. Thus, inhibition of lymphangiogenesis holds potential for treating insulitis and autoimmune diabetes

Land Use Change Dynamics in Southern California: Does Geographic Elasticity Matter?

This article examines how municipal planning contexts can shape urban land use dynamics by investigating the parcel-level land use changes in a five-county Southern California metropolitan area between 1990 and 2005. An analysis, based on a multinomial logit model, shows that land use change patterns significantly vary by municipalities that were situated in heterogeneous planning contexts. More specifically, cities with limited ability to expand their jurisdictional boundaries are found to provide more recreational areas and urban open spaces, while restricting nonconventional land uses. However, no evidence of a shift from single-family to multifamily residential development is detected for such cities