Contralateral Cruciate Survival in Dogs with Unilateral Non-Contact Cranial Cruciate Ligament Rupture

BACKGROUND: Non-contact cranial cruciate ligament rupture (CrCLR) is an important cause of lameness in client-owned dogs and typically occurs without obvious injury. There is a high incidence of bilateral rupture at presentation or subsequent contralateral rupture in affected dogs. Although stifle synovitis increases risk of contralateral CrCLR, relatively little is known about risk factors for subsequent contralateral rupture, or whether therapeutic intervention may modify this risk. METHODOLOGY/PRINCIPAL FINDINGS: We conducted a longitudinal study examining survival of the contralateral CrCL in client-owned dogs with unilateral CrCLR in a large baseline control population (n = 380), and a group of dogs that received disease-modifying therapy with arthroscopic lavage, intra-articular hyaluronic acid and oral doxycycline (n = 16), and were followed for one year. Follow-up in treated dogs included analysis of mobility, radiographic evaluation of stifle effusion and arthritis, and quantification of biomarkers of synovial inflammation. We found that median survival of the contralateral CrCL was 947 days. Increasing tibial plateau angle decreased contralateral ligament survival, whereas increasing age at diagnosis increased survival. Contralateral ligament survival was reduced in neutered dogs. Our disease-modifying therapy did not significantly influence contralateral ligament survival. Correlative analysis of clinical and biomarker variables with development of subsequent contralateral rupture revealed few significant results. However, increased expression of T lymphocyte-associated genes in the index unstable stifle at diagnosis was significantly related to development of subsequent non-contact contralateral CrCLR. CONCLUSION: Subsequent contralateral CrCLR is common in client-owned dogs, with a median ligament survival time of 947 days. In this naturally occurring model of non-contact cruciate ligament rupture, cranial tibial translation is preceded by development of synovial inflammation. However, treatment with arthroscopic lavage, intra-articular hyaluronic acid and oral doxycycline does not significantly influence contralateral CrCL survival

Role of Calcitonin Gene-Related Peptide in Bone Repair after Cyclic Fatigue Loading

Calcitonin gene related peptide (CGRP) is a neuropeptide that is abundant in the sensory neurons which innervate bone. The effects of CGRP on isolated bone cells have been widely studied, and CGRP is currently considered to be an osteoanabolic peptide that has effects on both osteoclasts and osteoblasts. However, relatively little is known about the physiological role of CGRP in-vivo in the skeletal responses to bone loading, particularly fatigue loading.We used the rat ulna end-loading model to induce fatigue damage in the ulna unilaterally during cyclic loading. We postulated that CGRP would influence skeletal responses to cyclic fatigue loading. Rats were fatigue loaded and groups of rats were infused systemically with 0.9% saline, CGRP, or the receptor antagonist, CGRP(8-37), for a 10 day study period. Ten days after fatigue loading, bone and serum CGRP concentrations, serum tartrate-resistant acid phosphatase 5b (TRAP5b) concentrations, and fatigue-induced skeletal responses were quantified. We found that cyclic fatigue loading led to increased CGRP concentrations in both loaded and contralateral ulnae. Administration of CGRP(8-37) was associated with increased targeted remodeling in the fatigue-loaded ulna. Administration of CGRP or CGRP(8-37) both increased reparative bone formation over the study period. Plasma concentration of TRAP5b was not significantly influenced by either CGRP or CGRP(8-37) administration.CGRP signaling modulates targeted remodeling of microdamage and reparative new bone formation after bone fatigue, and may be part of a neuronal signaling pathway which has regulatory effects on load-induced repair responses within the skeleton

Effects of ADIPOQ polymorphisms on PCOS risk: a meta-analysis

Abstract Background Whether adiponectin (ADIPOQ) polymorphisms are associated with the risk of polycystic ovary syndrome (PCOS) remain controversial. Therefore, we performed this study to better explore correlations between ADIPOQ polymorphisms and PCOS risk. Methods Literature retrieve was conducted in PubMed, Medline and Embase. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated. Results Eighteen studies were enrolled for analyses. Pooled overall analyses showed that rs1501299 polymorphism was significantly associated with PCOS risk (recessive model: p = 0.02, OR = 0.77, 95%CI 0.62–0.95; allele model: p = 0.001, OR = 1.15, 95%CI 1.06–1.26). Further subgroup analyses according to ethnicity of participants revealed that rs1501299 and rs2241766 polymorphisms were both significantly correlated with PCOS risk in Caucasians. In addition, rs1501299 polymorphism was also significantly correlated with PCOS risk in East Asians. Conclusions Our findings indicated that rs1501299 and rs2241766 polymorphisms might serve as genetic biomarkers of PCOS in certain ethnicities

Bone CGRP is increased by mechanical loading.

<p>Cyclic fatigue loading of the right ulna resulted in increased CGRP concentrations in both the fatigue-loaded (right) ulna and the contralateral (left) ulna, when compared to the Baseline group. No differences in CGRP concentrations were seen between the Sham group and the Baseline group. The Fatigue group also had increased CGRP concentrations compared to the Sham group. * −<i>p</i><0.05 versus the relevant baseline control bone. Error bars represent standard error of the mean. Baseline group n = 12; Sham group n = 12; Fatigue group n = 12.</p

Functional adaptation in female rats: the role of estrogen signaling.

Sex steroids have direct effects on the skeleton. Estrogen acts on the skeleton via the classical genomic estrogen receptors alpha and beta (ERα and ERβ), a membrane ER, and the non-genomic G-protein coupled estrogen receptor (GPER). GPER is distributed throughout the nervous system, but little is known about its effects on bone. In male rats, adaptation to loading is neuronally regulated, but this has not been studied in females.We used the rat ulna end-loading model to induce an adaptive modeling response in ovariectomized (OVX) female Sprague-Dawley rats. Rats were treated with a placebo, estrogen (17β-estradiol), or G-1, a GPER-specific agonist. Fourteen days after OVX, rats underwent unilateral cyclic loading of the right ulna; half of the rats in each group had brachial plexus anesthesia (BPA) of the loaded limb before loading. Ten days after loading, serum estrogen concentrations, dorsal root ganglion (DRG) gene expression of ERα, ERβ, GPER, CGRPα, TRPV1, TRPV4 and TRPA1, and load-induced skeletal responses were quantified. We hypothesized that estrogen and G-1 treatment would influence skeletal responses to cyclic loading through a neuronal mechanism. We found that estrogen suppresses periosteal bone formation in female rats. This physiological effect is not GPER-mediated. We also found that absolute mechanosensitivity in female rats was decreased, when compared with male rats. Blocking of adaptive bone formation by BPA in Placebo OVX females was reduced.Estrogen acts to decrease periosteal bone formation in female rats in vivo. This effect is not GPER-mediated. Gender differences in absolute bone mechanosensitivity exist in young Sprague-Dawley rats with reduced mechanosensitivity in females, although underlying bone formation rate associated with growth likely influences this observation. In contrast to female and male rats, central neuronal signals had a diminished effect on adaptive bone formation in estrogen-deficient female rats

Targeted remodeling of bone microdamage.

<p>Photomicrographs of calcified transverse sections of ulna at 60% of bone length, from proximal to distal <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0020386#pone.0020386-Kotha1" target="_blank">[37]</a>. Fatigue loading induced microcrack formation and targeted remodeling. (<b>A</b>) Branching microcracks can be appreciated histologically in fatigue-loaded bones. (<b>B</b>) Targeted remodeling resulted in resorption space formation around the areas of microcracking. Bones were bulk-stained with Villanueva bone stain. Black arrows indicate fatigue damage; white asterisks are labeling resorption spaces. Bar = 0.5 mm.</p

CGRP or CGRP_8–37 administration did not influence plasma TRAP5b in vivo.

<p>Plasma concentrations of CGRP and TRAP5b, normalized to plasma total protein, 10 days after fatigue loading. (<b>A</b>) Rats in the CGRP group had higher plasma CGRP concentrations when compared to rats in the Saline and CGRP_8–37 groups. No differences were seen between the Saline group and the CGRP_8–37 group. (<b>B</b>) Administration of CGRP or CGRP_8–37 did not have an effect on plasma TRAP5b levels. Error bars represent standard error of the mean. Saline group, n = 8; CGRP group n = 12; CGRP_8–37 group, n = 12.</p

Reparative bone formation induced by fatigue loading was increased after treatment with CGRP or CGRP_8–37.

<p>Confocal photomicrographs of calcified transverse sections of ulna at 60% of bone length, from proximal to distal <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0020386#pone.0020386-Kotha1" target="_blank">[37]</a>. Administration of either CGRP or CGRP_8–37 for 10 days after cyclic fatigue loading of the right ulna increased reparative bone formation in the loaded ulna compared with saline-treated rats. Endosteal bone formation was particularly evident after CGRP_8–37 treatment. Rats treated with CGRP_8–37 also had greater bone formation in the contralateral (left) ulna, which was not loaded, when compared to the left ulna of the saline-treated rats. New bone formation was double labeled with calcein. White arrows indicate periosteal new woven bone formation; pink arrows indicate endosteal new bone. Bar = 250 µm. Cr, cranial; Cd, caudal; Med, medial; Lat, lateral. Saline group, n = 8; CGRP group n = 12; CGRP_8–37 group, n = 12.</p

Schematic diagram of the rat ulna loading model.

<p>The antebrachium was placed horizontally in loading cups attached to a materials testing machine. The medio-lateral diaphyseal curvature of the rat ulna is accentuated through axial compression, most of which is translated into a bending moment, which is greatest at ∼60% the total bone length measured from the proximal end of the ulna <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0020386#pone.0020386-Kotha1" target="_blank">[37]</a>. Ulnae underwent cyclic fatigue loading, initiated at −3,000 µε, with incremental increases in load until fatigue was initiated. Loading was then terminated when 40% loss of stiffness was attained. Reproduced from <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0020386#pone.0020386-Sample2" target="_blank">[43]</a> with permission from John Wiley & Sons.</p