Overexpression of BCLXL in Osteoblasts Inhibits Osteoblast Apoptosis and Increases Bone Volume and Strength

The Bcl2 family proteins, Bcl2 and BclXL, suppress apoptosis by preventing the release of caspase activators from mitochondria through the inhibition of Bax subfamily proteins. We reported that BCL2 overexpression in osteoblasts using the 2.3 kb Col1a1 promoter increased osteoblast proliferation, failed to reduce osteoblast apoptosis, inhibited osteoblast maturation, and reduced the number of osteocyte processes, leading to massive osteocyte death. We generated BCLXL (BCL2L1) transgenic mice using the same promoter to investigate BCLXL functions in bone development and maintenance. Bone mineral density in the trabecular bone of femurs was increased, whereas that in the cortical bone was similar to that in wild‐type mice. Osteocyte process formation was unaffected and bone structures were similar to those in wild‐type mice. A micro‐CT analysis showed that trabecular bone volume in femurs and vertebrae and the cortical thickness of femurs were increased. A dynamic bone histomorphometric analysis revealed that the mineralizing surface was larger in trabecular bone, and the bone‐formation rate was increased in cortical bone. Serum osteocalcin but not TRAP5b was increased, BrdU‐positive osteoblastic cell numbers were increased, TUNEL‐positive osteoblastic cell numbers were reduced, and osteoblast marker gene expression was enhanced in BCLXL transgenic mice. The three‐point bending test indicated that femurs were stronger in BCLXL transgenic mice than in wild‐type mice. The frequency of TUNEL‐positive primary osteoblasts was lower in BCLXL transgenic mice than in wild‐type mice during cultivation, and osteoblast differentiation was enhanced but depended on cell density, indicating that enhanced differentiation was mainly owing to reduced apoptosis. Increased trabecular and cortical bone volumes were maintained during aging in male and female mice. These results indicate that BCLXL overexpression in osteoblasts increased the trabecular and cortical bone volumes with normal structures and maintained them majorly by preventing osteoblast apoptosis, implicating BCLXL as a therapeutic target of osteoporosis. © 2016 American Society for Bone and Mineral Research.     

Intracardiac echocardiography to diagnose pannus formation after aortic valve replacement

A 66-year-old female, under regular follow-up for 20 years after aortic valve replacement (19-mm Carbomedics), presented dyspnea on effort and hypotension during hemodialysis. A transthoracic echocardiogram showed elevation of transvalvular velocity up to 4 m/s, but the structure around the aortic prosthesis was difficult to observe due to artifacts. Fluoroscopy revealed normal motion of the leaflets of the mechanical valve. Intracardiac echocardiography (ICE) revealed a pannus-like structure in the left ventricular outflow tract. Transesophageal echocardiogram also revealed this structure. ICE can visualize structural abnormalities around a prosthetic valve after cardiac surgery even in patients in whom conventional imaging modalities failed.     

Rationale and Design of the Multicenter Trial on Japan Working Group on the Effects of Angiotensin Receptor Blockers Selection (Azilsartan vs. Candesartan) on Diastolic Function in the Patients Suffering from Heart Failure with Preserved Ejection Fraction: J-TASTE Trial

Background

Previous studies suggest that the pathophysiology of heart failure with preserved ejection fraction (HFpEF) is characterized not only by high ventricular stiffness, but also by vascular stiffness. Azilsartan has higher vascular affinity compared with other angiotensin II receptor blockers (ARBs), which were proven to have no beneficial effects on clinical outcomes in patients with HFpEF in earlier clinical trials. We aimed to test the hypothesis that azilsartan may improve left ventricular diastolic function in HFpEF patients with hypertension in this trial.

Methods

The Effects of Angiotensin Receptor Blockers on Diastolic Function in Patients Suffering from Heart Failure with Preserved Ejection Fraction: J-TASTE trial is a multicenter, randomized, open-labeled, and assessor(s)-blinded, active controlled using candesartan, parallel-group clinical trial, to compare changes in left ventricular (LV) diastolic dysfunction between HFpEF patients with hypertension who have received candesartan or azilsartan for 48 weeks. The primary endpoint is the change in early diastolic wave height/early diastolic mitral annulus velocity (E/e’) assessed by echocardiography from the baseline to the end of the study (48 weeks). A total of 190 patients will be recruited into the study.

Conclusions

The design of the J-TASTE trial will provide data on whether differences between the effects of the two tested drugs on LV diastolic function exist in HFpEF patients with hypertension and will improve understanding of the pathophysiological role of vascular stiffness on diastolic function.

     

Gastric cancer with metastasis to the gingiva

The present case report describes a gastric cancer which showed unusual metastasis in the oral region. A 56-year-old male patient underwent total gastrectomy and splenectomy due to advanced gastric cancer in the upper third of the stomach. Fifteen months later, he presented with anorexia and gingival swelling of durations of approximately 3 and 1 month, respectively. The gastric tumor was histologically a signet ring cell and a poorly differentiated cancer with a moderate degree of vascular invasion. Biopsy specimens from the gingival tumor revealed a signet ring cell cancer. Other metastatic sites were the brain, limb bones and abdominal lymph nodes. A bone scintigram revealed an abnormal uptake in the limb bones, while it did not exhibit any abnormality in the oral region. Correlation between the histology of the gingival tumor with that of the gastric cancer, as well as the absence of a gingival tumor at the time of prior gastrectomy, led to a diagnosis that the gingival tumor was a metastasis from gastric cancer. Gastric cancer metastasizing to the oral region, either the osseus or the oral soft tissue, is very rare. Although it cannot be proved without an autopsy, negative findings in the mandible by bone scanning in the present case suggest that direct gingival metastasis can be considered, rather than mandibular metastasis involving the gingiva. Hematogenous spread could be a mechanism of metastasis for this unusual tumor.     

Periarticular osteophyte formation protects against total knee arthroplasty in rheumatoid arthritis patients with advanced joint damage

Clinical Rheumatology - Periarticular osteophyte formation is observed during the repair of damaged joints in rheumatoid arthritis (RA); however, little is known about its clinical and functional...     

Risk factors and prediction of bleeding after gastric endoscopic submucosal dissection in patients on antithrombotic therapy: newly developed bleeding prediction application software,SAMURAI model

Bleeding after gastric endoscopic submucosal dissection (ESD) remains problematic, especially in patients receiving antithrombotic therapy. Therefore, this study aimed to identify the risk factors. In this retrospective study, patients (n = 1,207) who underwent gastric ESD while receiving antithrombotic therapy were enrolled at Osaka Medical and Pharmaceutical University Hospital and 18 other referral hospitals in Japan. Risks of post-ESD bleeding were calculated using multivariable logistic regression. The dataset was divided into a derivation cohort and a validation cohort. We created a prediction model using the derivation cohort. The accuracy of the model was evaluated using the validation cohort. Post-ESD bleeding occurred in 142 (11.8%) participants. Multivariable analysis yielded an odds ratio of 2.33 for aspirin, 4.90 for P2Y12 receptor antagonist, 1.79 for cilostazol, 0.95 for other antithrombotic agents, 6.53 for warfarin, 5.65 for dabigatran, 7.84 for apixaban, 10.45 for edoxaban, 6.02 for rivaroxaban, and 1.46 for heparin bridging. The created prediction model was called safe ESD management using the risk analysis of post-bleeding in patients with antithrombotic therapy (SAMURAI). This model had good predictability, with a C-statistic of 0.77. In conclusion, use of the SAMURAI model will allow proactive management of post-ESD bleeding risk in patients receiving antithrombotic therapy.     

Retro-labyrinthine Lesion Site Detected by Galvanic Vestibular Stimulation Elicited Vestibular-evoked Myogenic Potentials in Patients with Auditory Neuropathy

Objective:Auditory neuropathy(AN)is a unique pattern of hearing loss with preservation of hair cell function.The condition is characterized by the presence of o...