Search

Summary Objective Abnormal remodeling of subchondral bone (SB) induced by estrogen deficiency has been shown to be involved in osteoarthritis (OA). Raloxifene (RAL) is commonly used to treat postmenopausal osteoporosis (OP). However, little is known about its effects on OA combined with estrogen deficiency. This study was performed to evaluate the efficacy of RAL on patella baja-induced patellofemoral joint OA (PFJOA) in an ovariectomized rat model. Design Patellar ligament shortening (PLS) and ovariectomy (OVX) were performed simultaneously in 3-month-old female Sprague–Dawley rats, which were treated with RAL (10 mg/kg/day) or vehicle at 72 h postoperatively for 10 weeks. PFJOA was assessed by immunohistochemistry (IHC), real-time polymerase chain reaction (PCR), tartrate-resistant acid phosphatase (TRAP) staining, enzyme-linked immunosorbent assay (ELISA), micro-computed tomography (μCT), histomorphology and behavioral analyses. Results X-ray examinations showed that patella baja was successfully established by PLS. Histomorphological analysis revealed that PFJOA was significantly exacerbated by OVX and markedly alleviated by RAL. Moreover, RAL improved cartilage metabolism by decreasing MMP-13, ADAMTS-4, and caspase-3 and increasing Col-II and aggrecan at both the protein and mRNA levels. Furthermore, RAL markedly improved bone mass and SB microarchitecture and reduced osteoclast numbers and the serum osteocalcin and CTX-I levels. Although RAL showed a trend toward reducing pain sensitivity based on mechanical allodynia testing, this result was not statistically significant. Conclusion These findings demonstrate that RAL treatment retards PFJOA progression in an ovariectomized rat model, suggesting that it may be a potential candidate for amelioration of the progression of PFJOA accompanied by postmenopausal OP.

In this study, the neuro-modulation effect of topical mesenchymal stem cells (MSCs) was tested in a rodent middle carotid artery occlusion (MCAO) model. Twenty-four hours after MCAO, craniotomy was made and 0.8 × 106 GFP-MSCs were topically applied to the exposed parietal cortex. The MSCs were fixed in position by a thin layer of fibrin glue (N = 30). In the control group, saline were topically applied to the ipsilateral parietal cortex (N = 30). Three days after topical application, few GFP-positive cells were found in the ischemic penumbra. They expressed GFAP and NeuN. Topical MSCs triggered microglial activation, astrocytosis and cellular proliferation at day 3. The recovery of neurological functions were significantly enhanced as determined in Rotarod test and Morris Water Maze test with smaller infarct volume. PCR array showed that expressions of ten genes of neurogenesis were altered in the penumbra region (fold change > 1.25, p

BACKGROUND Patella baja, or patella infera, consists of a low-lying patella that results in a limited range of motion, joint pain, and crepitations. Patellofemoral joint osteoarthritis (PFJOA) is a subtype OA of the knee. This study aimed to develop a reproducible and reliable rat model of PFJOA. MATERIAL AND METHODS Three-month-old female Sprague-Dawley rats (n=24) included a baseline group (n=8) that were euthanized at the beginning of the study. The sham group (n=8), and the patella ligament shortening (PLS) group (n=8) were euthanized and evaluated at ten weeks. The PLS model group (n=8) underwent insertion of a Kirschner wire under the patella tendon to induce patella baja. At ten weeks, the sham group and the PLS group were compared using X-ray imaging, macroscopic appearance, histology, immunohistochemistry, TUNEL staining for apoptosis, and micro-computed tomography (micro-CT). The patella height was determined using the modified Insall-Salvati (MIS) ratio. RESULTS The establishment of the rat model of patella baja in the PLS group at ten weeks was confirmed by X-ray. In the PLS group, patella volume, sagittal length, and cross-sectional area were significantly increased compared with the sham group. The PFJ showed typical lesions of OA, confirmed macroscopically and histologically. Compared with the sham group, in the rat model of PFJOA, there was increased cell apoptosis, and immunohistochemistry showed increased expression of biomarkers of osteoarthritis, compared with the sham group. CONCLUSIONS A rat model of PFJOA was developed that was confirmed by changes in cartilage and subchondral bone.

Gait analysis has been widely used to examine the behavioral presentation of numerous neurological disorders. Thorough murine model evaluation of the subarachnoid hemorrhage (SAH)-associated gait deficits is missing. This study measures gait deficits using a clinically relevant murine model of SAH to examine associations between gait variability and SAH-associated gene expressions. A total of 159 dynamic and static gait parameters from the endovascular perforation murine model for simulating clinical human SAH were determined using the CatWalk system. Eighty gait parameters and the mRNA expression levels of 35 of the 88 SAH-associated genes were differentially regulated in the diseased models. Totals of 42 and 38 gait parameters correlated with the 35 SAH-associated genes positively and negatively with Pearson's correlation coefficients of >0.7 and

BACKGROUND Type 2 diabetes mellitus (T2DM) and estrogen deficiency both predispose fracture patients to increased risk of delayed union or nonunion. The present study investigated the effects of strontium ranelate (SR) on fracture healing in ovariectomized (OVX) diabetic rats. MATERIAL AND METHODS A mid-shaft fracture was established in female normal control (CF), diabetic (DF), and OVX diabetic (DOF) rats. Treated DOF rats received either insulin alone (DOFI) or combined with SR (DOFIS). All rats were euthanized at 2 or 3 weeks after fracture. Fracture healing was evaluated using radiological, histological, immunohistochemical, and micro-computed tomography analyses. RESULTS At 3 weeks after fracture, radiological and histological evaluations demonstrated delayed fracture healing in the DF group compared with the CF group, which was exacerbated by OVX, as indicated by the significantly lower X-ray score, BMD, BV/TV, and Md.Ar/Ps.Cl.Ar, and the markedly decreased OCN and Col I expression in the DOF group. All these changes were prevented by insulin alone or combined with SR treatment. In comparison with the DOFI group, DOFIS rats displayed markedly higher OCN expression at 2 weeks after fracture and Col I expression at 2 and 3 weeks after fracture. CONCLUSIONS These results demonstrated delayed fracture healing with preexisting estrogen deficiency and T2DM. While insulin alone and combined with SR were both effective in promoting bone fracture healing in this model, their combined treatment showed significant improvement in promoting osteogenic marker expression, but not of the radiological appearance, compared with insulin alone.

Vascular mimicry (VM) is a critical complement for microcirculation and is implicated in tumor progression. We showed that IL-6 derived from tumor cells and stroma cells promoted tumor cells to form a VM structure, whereas blocking the IL-6 signaling by RNA interference, IL-6-neutralizing antibody, or STAT3 inhibitor suppressed the VM formation of tumor cells. Mechanism investigations revealed that IL-6 stimulated VM formation by activating STAT3, in turn upregulating VE-cadherin expression and MMP2 activity. Further analyses identified a positive association between the activation of IL-6-STAT3 signaling and the formation of the VM structure in human HCC tissues. However, miR-29b repressed the expression of STAT3 and MMP2 by directly binding to the 3′ UTRs of their mRNAs. Consistently, both gain- and loss-of-function analyses showed that miR-29b suppressed tumor cells to form tube structures in vitro. The in vivo studies further disclosed that intratumoral injection of the miR-29b-expressing viruses significantly inhibited the IL-6-promoted VM formation in mouse xenografts, and downregulation of miR-29b was correlated with the presence of VM in human HCC tissues. This study elucidates a miR-29b-IL-6 signaling cascade and its role in VM formation, which provide potential targets for cancer therapy. Keywords: interleukin 6, STAT3, microRNA-29b, vascular mimicry

Ovariectomized (OVX) rats with type 2 diabetes mellitus (T2DM) with femur fracture received vehicle, insulin, or insulin plus parathyroid hormone (PTH) treatment for 2 and 3 weeks. Radiography, histomorphometry, histology, and immunohistochemistry in callus were evaluated. Reports about effects of PTH plus insulin on callus formation of osteoporotic fracture with T2DM were limited. This study was designed to investigate the effects of the combination of PTH and insulin on fracture healing in OVX rats with T2DM. Two-month-old female rats were randomly divided into five groups: normal fracture (F), OVX fracture (OF), T2DM + OVX fracture (DOF), insulin-treated (2–4 u/daylight, 4–6 u/night, DOFI), and treated with insulin and PTH (50 μg/kg/day, 5 days/week, DOFIP). A closed mid-shaft fracture was established in the right femurs of all rats after 6 weeks of OVX. Rats were euthanized at 2 and 3 weeks post-fracture according to the time schedule, respectively. The administration of insulin alone or insulin combined with PTH significantly increased mineralized bone volume fraction (BV/TV) and connectivity density (Conn.D) compared with those of the DOF group at 3 weeks post-fracture and also increased cartilaginous callus area ratio in the DOFI and DOFIP groups at 2 weeks and bony callus area ratio in the DOFIP groups at both the 2 and 3 weeks post-fracture. OVX rats with T2DM exhibited a marked delay in the fracture healing process; insulin treatment ameliorated these effects, and the healing process was enhanced following treatment with a combination of insulin and PTH.

Vascular mimicry (VM) describes the phenomenon that tumor cells but not endothelial cells form vascular-like channels, which provide blood perfusion for tumor tissues. VM is associated with tumor growth, metastasis and worse survival of different cancers. The mechanisms of VM formation remain largely unknown. We showed that the conditioned medium of cancer-associated fibroblast (CM-CAF) promoted tumor cells to form capillary-like structure in vitro . Consistently, co-implantation of CAFs with tumor cells significantly enhanced VM formation in mouse xenografts, and higher amount of CAFs was found in VM + human HCC tissues compared to VM − ones. However, the CM-CAF-promoted VM formation was attenuated when TGF-β or SDF1 signaling was abrogated. Similar to CM-CAF, recombinant TGF-β1 and SDF1 induced VM formation. We further disclosed that the CAF-secreted TGF-β and SDF1 enhanced the expression of VE-cadherin, MMP2 and laminin5γ2 via TGF-βR1 and CXCR4 in tumor cells, thereby promoted VM formation. Moreover, tumor cells with high activity of self-sustaining TGF-β signaling displayed strong capability of VM formation. Subsequent investigations showed that miR-101, which was down-regulated in both tumor cells and CAFs, suppressed the CAF-promoted VM formation in vitro and in vivo . Gain- and loss-of-function analyses revealed that miR-101 attenuated TGF-β signaling transduction by targeting TGF-βR1 and Smad2 in tumor cells, and simultaneously abrogated SDF1 signaling by suppressing SDF1 expression in CAFs and inhibiting VE-cadherin expression in tumor cells. Our findings suggest that the miR-101-TGF-β/SDF1-VE-cadherin/MMP2/LAMC2 networks regulate VM formation and represent the potential targets for cancer therapy.

At present, the number of App users in China is soaring, but it still faces the problem of low user stickiness. The interactive design approach of fitness App is proposed to improve the App and motive users to form the habit of permanent use of fitness App, and ultimately achieve the goal of increasing the fitness App’s stickiness. The ideal fitness App lifecycle can be divided into three stages: the initial trial stage, the habit-forming stage, and the habit-keeping stage. It is proposed that fitness App should improve user experience in three stages of the ideal lifecycle by improving interaction design at the three levels of “instinct level, behavior level and reflective level”. The specific interaction design approach at the instinct level, behavior level and reflective level are also put forward.

Objectives: We aimed to investigate the prevalence and pattern of cognitive dysfunction in patients with traumatic bifrontal contusions and their association with functional outcome.

Cognitive impairment is a major factor contributing to poor functional outcome after subarachnoid hemorrhage caused by a ruptured cerebral aneurysm (aSAH). Montreal Cognitive Assessment (MoCA) has been shown to be superior to the Mini-Mental State Examination in screening for cognitive domain deficit and correlating to functional outcome in aSAH patients. The aim of the current study was to determine the Montreal Cognitive Assessment (MoCA) score change that was associated with change of health in general in an aSAH patient cohort. We recruited aSAH patients from a regional neurosurgical center over a 3-year period. Patient assessments including MoCA and global rating of change (GRoC) were carried out at at 3 and 12months after aSAH. Anchor-based and distribution-based approaches were adopted to calculate the Minimum Clinically Important Difference (MID). One hundred and seventy-five aSAH patients completed both 3-month and 1-year assessments and consented for participation. Employing the distribution-based approach for the 3-month and 1-year MoCA scores, the MID estimates equated to a change of 2.0 and 1.1 respectively. Employing the anchor-based approach (with GRoC), the MID estimate of MoCA (median, IQR) was 2, 1-4. In conclusion, we found that the MID of MoCA score associated with change of health in general in aSAH patients was 2. The MID provides guidance for future clinical trial design targeting on cognitive dysfunction after aSAH.

Background Delayed cerebral infarction ( DCI ) is a major cause of morbidities after aneurysmal subarachnoid hemorrhage ( SAH ) and typically starts at day 4 to 7 after initial hemorrhage. Micro RNA s (mi RNAs ) play an important role in posttranscriptional gene expression control, and distinctive patterns of circulating mi RNA changes have been identified for some diseases. We aimed to investigate mi RNA s that characterize SAH patients with DCI compared with those without DCI . Methods and Results Circulating mi RNA s were collected on day 7 after SAH in healthy, SAH ‐free controls (n=20), SAH patients with DCI (n=20), and SAH patients without DCI (n=20). We used the LASSO (least absolute shrinkage and selection operator) method of regression analysis to characterize mi RNA s associated with SAH patients with DCI compared with those without DCI . In the 28 dysregulated mi RNA s associated with DCI and SAH , we found that a combination of 4 mi RNA s (miR‐4532, miR‐4463, miR‐1290, and miR‐4793) could differentiate SAH patients with DCI from those without DCI with an area under the curve of 100% (95% CI 1.000–1.000, P RNA combination could also distinguish SAH patients with or without DCI from healthy controls with areas under the curve of 99.3% (95% CI 0.977–1.000, P CI 0.685–0.955, P Conclusions We found a 4‐mi RNA combination that characterized SAH patients with DCI . The findings could guide future mechanistic study to develop therapeutic targets.

Subarachnoid hemorrhage (SAH) is an important cause of stroke mortality and morbidity, especially in the young stroke population. Recent evidences indicate that neuroinflammation plays a critical role in both early brain injury and the delayed brain deterioration after SAH, including cellular and molecular components. Cerebral vasospasm (CV) can lead to death after SAH and independently correlated with poor outcome. Neuroinflammation is evidenced to contribute to the etiology of vasospasm. Besides, systemic inflammatory response syndrome (SIRS) commonly occurs in the SAH patients, with the presence of non-infectious fever and systematic complications. In this review, we summarize the evidences that indicate the prominent role of inflammation in the pathophysiology of SAH. That may provide the potential implications on diagnostic and therapeutic strategies.

Subarachnoid hemorrhage (SAH) is a subtype of stroke with disastrous outcomes of high disability and mortality. A variety of endeavors have been developed to explore a SAH animal model for investigation of the disease. Among these models, the endovascular perforation SAH model was considered to be the most simulative to the clinical human SAH because it reproduces several pathophysiology procedures and presents some of the most important post-hemorrhage features. An applicable SAH animal model should have the characteristics of low mortality rate, limited surgical manipulation, and adaptation to many species, which permits reproducibility and standardization. An intensive discussion of how to improve the techniques and refine the procedure has taken place in the last decade. This report describes our experiences with a murine model of SAH. We aim to standardize and optimize the procedures to establish a relatively stable animal model for SAH research.