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.     

Measurement of relative fat content by proton magnetic resonance spectroscopy using a clinical imager

The aim of this study was to determine the applicability of a proton magnetic resonance (MR) spectroscopy-based technique using a clinical 1.5-T MR imager for assessment of relative fat content. Proton MR spectra were obtained from a trunk phantom and 23 volunteers using a single free induction decay measurement. The ratios of fat methyl and methylene proton resonance to the water proton resonance were compared with the ratio of oil weight to water weight for the phantom, and with the ratio of body fat to lean body mass estimated by bioelectrical impedance analysis for the human subjects. Good linear relationships were found between the MR metabolite ratio and the ratio of oil weight to water weight (r = 0.9989), and the ratio of body fat to lean body mass (r = 0.9169). This MR spectroscopy-based technique is sufficiently accurate and may be applicable to assessment of human body composition.     

Effect of Inflammation on Costimulation Blockade-Resistant Allograft Rejection

Previously, we reported that allogeneic skin grafts were rapidly rejected by CD28 and CD40 ligand double deficient mice mediated by CD8⁺ T cells. These results indicated that some elements in addition to CD28- and CD40-mediated costimulation provide stimulatory signals for the activation of donor-specific CD8⁺ T cells. In this report, we investigated the role of inflammation associated with transplantation on costimulation-independent priming of CD8⁺ T cell during graft rejection. B6 RAG1 KO mice were transplanted with BALB/c-skin and adoptively transferred with syngeneic CD8⁺ T cells the same day or 50 days after transplantation. When blockade of CD28- and CD40-mediated costimulation failed to prevent acute rejection of freshly transplanted skin grafts, it efficiently delayed rejection of well-healed skin grafts. These results showed that factors associated with transplantation have essential roles in inducing costimulation blockade-resistant allograft rejection. Costimulation blockade failed to prevent acute graft-infiltration of NK cells and increasing expression of intragraft IL-12 and IL-15. These factors may trigger the graft-infiltration and priming of CD8⁺ T cells to induce costimulation blockade-resistant allograft rejection.     

Bilateral multiple sclerosing hemangiomas of the lung

This report presents a case of bilateral multiple sclerosing hemangiomas of the lung in a 73-year-old woman. A computed tomography (CT) scan of the chest showed a total of three well-defined small nodules in the right and left lower lobes of the lung. Because malignant metastatic lung tumors were highly suspected, a wedge resection of the left lower lobe was performed to obtain a definitive diagnosis. Histopathologically, two tumors of the left lower lobe were composed of epithelial-like cuboidal cells covering the surface of papillary protrusions and sheets of round to polygonal cells underneath the epithelial-like cells. The final diagnosis was that both tumors were sclerosing hemangiomas. After surgery the residual lesion of the right lower lobe was carefully followed by chest CT. The size of the right lung nodule did not change over the course of 9 years, and no new lesion has emerged.     

Influence of activity level on the outcome of treatment of lateral ankle ligament rupture

Background  Few studies of treatment of lateral ankle ligament rupture have given careful consideration to the activity levels of patients. In the present study, we investigated whether a patient’s activity level influences the outcome of the treatment of lateral ankle ligament rupture and whether treatment should be determined according to activity level. Methods  A total of 115 consecutive patients with lateral ankle ligament rupture were treated with short-term cast immobilization followed by functional bracing. We divided preinjury activity levels and activity levels at follow-up into four classes according to the International Knee Documentation Committee standards. Follow-up examination 1 year after injury included clinical assessment (anterior drawer test, range of motion, maximum circumference of the calf, tenderness, swelling), reinjury assessment, and functional evaluation by means of the Karlsson scoring system. Results  We found significant differences in ankle stability and reinjuries between the four groups classified by their preinjury activity level. The number of patients with ankle instability and reinjury was significantly higher in the high-activity group than in the low-activity groups. We also found significant difference between groups classified by activity level at follow-up with regard to the Karlsson score. Conclusions  The outcome of treatment of lateral ankle ligament rupture is significantly influenced by the patient activity level, and treatment may need to be determined according to this activity level.     

Biphasic pulmonary blastoma with rapid progression

We report a rare case of biphasic pulmonary blastoma (BPB) with rapid progression in a 75-year-old man. Computed tomography (CT) of the chest revealed a well-defined tumor shadow measuring 8 × 6 cm in the right upper lobe. CT-guided lung biopsy revealed malignant cells with sarcomatous elements. Right upper lobectomy and systemic lymph node dissection with chest wall resection were performed. Histopathologically, the tumor was composed of immature embryoniclike mesenchymal and epithelial components that resembled embryonic lung tissue. The final diagnosis was BPB classified as pathological stage IIB (T3N0M0). Two months later, the tumor recurred in the right supraclavicular lymph nodes. The patient died of respiratory failure due to tumor progression 7 months after surgery.     

Preoperative histological grading of meningiomas using apparent diffusion coefficient at 3T MRI

Purpose

We assessed whether a high b-value DWI at b = 4000 s/mm² would discriminate the histopathological differentiation of the tumor grade of meningiomas, and also focused on the relationship between radiologic features and the tumor grade.

Materials and methods

We acquired DWI at 3T with b = 1000 and b = 4000 s/mm² in 77 patients (42, 31 and 4 patients were WHO grades I (G1), II (G2), and III (G3), respectively). The apparent diffusion coefficient (ADC) was measured by placing multiple regions of interest (ROIs) on ADC maps. The ADC values of each tumor were determined preoperatively from several ROIs, and expressed as the minimum (ADC_MIN), mean (ADC_MEAN), and maximum absolute values (ADC_MAX). We evaluated the relationship between ADCs and histological findings, and assessed the radiologic features such as tumor location, tumor size, presence/absence of peritumoral edema, shape of the tumor, presence/absence of bone destruction or hyperplasia, status of contrast enhancement, presence/absence of calcification and cyst.

Results

ADCs of the meningiomas were inversely correlated with the histological grade of meningiomas. According to results of the discriminant analysis, the apparent log likelihood value was greatest for ADC_MIN at b = 4000. Furthermore, only the ADC_MIN value at b = 4000 was significantly correlated with the histological grade of meningiomas when we performed a multiple logistic regression analysis to identify the significant independent factors such as shape of tumor, presence/absence of bone destruction, status of contrast enhancement, presence/absence of cyst and ADC_MIN at b = 4000.

Conclusion

A meningioma with a low ADC_MIN at a high b-value might imply a high-grade meningioma.     

GABAergic Interneurons at Supraspinal and Spinal Levels Differentially Modulate the Antinociceptive Effect of Nitrous Oxide in Fischer Rats

Background: The study hypothesizes that nitrous oxide (N2O) releases opioid peptide in the brain stem, which results in inhibition of [gamma]-aminobutyric acid-mediated (GABAergic) neurons that tonically inhibit the descending noradrenergic inhibitory neurons (DNIN), resulting in activation of DNIN. In the spinal cord, activation of DNIN leads to the release of norepinephrine, which inhibits nociceptive processing through direct activation of [alpha]2 adrenoceptor and indirect activation of GABAergic neurons through [alpha]1 adrenoceptor. Arising from this hypothesis, it follows that GABAergic neurons will modulate the antinociceptive effect of N2O in diametrically opposite directions at supraspinal and spinal levels. The authors have tested this tenet and further examined the effect of midazolam, a GABA-mimetic agent, on N2O-induced antinociceptive effect.

Methods: Adult male Fischer rats were administered muscimol (GABAA receptor agonist) intracerebroventricularly (icv), gabazine (GABAA receptor antagonist) intrathecally (intrathecal), or midazolam intraperitoneally (intraperitoneal). Fifteen minutes later, they were exposed to air or 75% N2O and were subjected to the plantar test after 30 min of gas exposure. In some animals administered with midazolam, gas exposure was continued for 90 min, and the brain and spinal cord were examined immunohistochemically.

Results: The N2O-induced antinociceptive effect, which was attenuated by icv muscimol, intrathecal gabazine, and intraperitoneal midazolam. Midazolam inhibited N2O-induced c-Fos expression (a marker of neuronal activation) in the pontine A7 and spinal cord.     

Intercellular adhesion molecule-1-deficient mice are resistant against renal injury after induction of diabetes

Diabetic nephropathy is a leading cause of end-stage renal failure. Several mechanisms, including activation of protein kinase C, advanced glycation end products, and overexpression of transforming growth factor (TGF)-beta, are believed to be involved in the pathogenesis of diabetic nephropathy. However, the significance of inflammatory processes in the pathogenesis of diabetic microvascular complications is poorly understood. Accumulation of macrophages and overexpression of leukocyte adhesion molecules and chemokines are prominent in diabetic human kidney tissues. We previously demonstrated that intercellular adhesion molecule (ICAM)-1 mediates macrophage infiltration into the diabetic kidney. In the present study, to investigate the role of ICAM-1 in diabetic nephropathy, we induced diabetes in ICAM-1-deficient (ICAM-1(-/-)) mice and ICAM-1(+/+) mice with streptozotocin and examined the renal pathology over a period of 6 months. The infiltration of macrophages was markedly suppressed in diabetic ICAM-1(-/-) mice compared with that of ICAM-1(+/+) mice. Urinary albumin excretion, glomerular hypertrophy, and mesangial matrix expansion were significantly lower in diabetic ICAM-1(-/-) mice than in diabetic ICAM-1(+/+) mice. Moreover, expressions of TGF-beta and type IV collagen in glomeruli were also suppressed in diabetic ICAM-1(-/-) mice. These results suggest that ICAM-1 is critically involved in the pathogenesis of diabetic nephropathy.     

Anatomy and pathomechanics of ring and small finger carpometacarpal joint injuries

PURPOSE: The purpose of this study was to detail the pathomechanics and pathoanatomy of fracture dislocations of the ring finger and small finger carpometacarpal (CMC) joint by duplicating the pathomechanics of the fist blow. METHODS: A custom-made jig was used to position 20 fresh-frozen cadaver upper extremities in forearm neutral rotation, 90 degrees of elbow flexion, 20 degrees of wrist extension, and 20 degrees and 30 degrees of flexion at the ring and small finger CMC joint, respectively. First 7.7 kg of weight were dropped from a height of 0.76 m to 1.1 m to axially load the ring and small metacarpal (MC) heads through a custom-made apparatus. Fluoroscopic examination before and after loading, and detailed dissection after loading, were used to identify any osseous and/or ligamentous injuries. RESULTS: The most common fractures were a dorsal capitate fracture and a middle MC dorsal base fracture. The most common combinations of fractures were the dorsal capitate and dorsal hamate fractures. Multiple fractures often were identified in a number of locations including dorsally: the capitate, hamate, and index through small metacarpal bases, and volarly: the hook of the hamate and the middle through the small MC bases. CONCLUSIONS: The patterns of injuries encountered at the ring and small CMC joints can be explained by the direction and force of the applied load, position of the CMC joint at the time of loading, and the constraints imposed by specific CMC ligaments. A detailed analysis of the fracture patterns and associated ligament anatomy suggests that the typical ring and small carpometacarpal fracture dislocations are a more complex combination of fractures than identified by plain radiographs alone. The complexity of these injuries is greater than previously recognized and is most likely the result of a combination of axial load and shear stresses resulting in carpal fractures and ligament avulsions as well as fracture dislocations. This study suggests that computed tomography may be the preferred diagnostic imaging method for complete assessment of these injuries.