Effects of sclerostin antibody on bone healing

Promoting bone healing after a fracture has been a frequent subject of research. Recently, sclerostin antibody(Scl-Ab) has been introduced as a new anabolic agent for the treatment of osteoporosis. Scl-Ab activates the canonical Wnt(cWnt)-β-catenin pathway, leading to an increase in bone formation and decrease in bone resorption. Because of its rich osteogenic effects, preclinically, Scl-Ab has shown positive effects on bone healing in rodent models; researchers have reported an increase in bone mass, mechanical strength, histological bone formation, total mineralized callus volume, bone mineral density, neovascularization, proliferating cell nuclear antigen score, and bone morphogenic protein expression at the fracture site after Scl-Ab administration. In addition, in a rat critical-size femoral-defect model, the Scl-Ab-treated group demonstrated a higher bone healing rate. On the other hand, two clinical reports have researched Scl-Ab in bone healing and failed to show positive effects in the femur and tibia. This review discusses why Scl-Ab appears to be effective in animal models of fracture healing and not in clinical cases.     

STK11/LKB1 Peutz-Jeghers Gene Inactivation in Intraductal Papillary-Mucinous Neoplasms of the Pancreas

Despite the growing awareness of intraductal papillary-mucinous neoplasms (IPMNs) of the pancreas among clinicians, the molecular features of IPMNs have not been well characterized. Previous reports suggest that inactivation of the STK11/LKB1, a tumor-suppressor gene responsible for Peutz-Jeghers syndrome (PJS), plays a role in the pathogenesis of gastrointestinal hamartomas as well as several cancers, including pancreatic adenocarcinoma. Using polymerase chain reaction amplification of five microsatellite markers from the 19p13.3 region harboring the STK11/LKB1 gene, we analyzed DNA from 22 IPMNs for loss of heterozygosity (LOH). LOH at 19p13.3 was identified in 2 of 2 (100%) IPMNs from patients with PJS and 5 of 20 (25%) from patients lacking features of PJS (7 of 22, 32% overall). Sequencing analysis of the STK11/LKB1 gene in these IPMNs with LOH revealed a germline mutation in one IPMN that arose in a patient with PJS and a somatic mutation in 1 of the 20 sporadic IPMNs. None of the 22 IPMNs showed hypermethylation of the STK11/LKB1 gene. These results suggest that the STK11/LKB1 gene is involved in the pathogenesis of some IPMNs.     

Abnormal right atrial electrograms predict the transition to chronic atrial fibrillation in paced patients with sick sinus syndrome

Although pacing therapy for sick sinus syndrome (SSS) is established, the risk of developing chronic atrial fibrillation (CAF) makes pacing therapy infeasible in some patients. We evaluated whether electrophysiological characteristics of atrial muscle can serve as predictors of the transition to CAF after pacemaker implantation in patients with SSS. Eighty-nine patients with SSS underwent electrophysiological study before pacing therapy. Catheter mapping of 12 right atrial sites was performed during sinus rhythm during electrophysiological. An abnormal atrial electrogram was defined as having a duration of 100 ms or longer, or eight or more fragmented deflections, or both. Right atrial extrastimulation was also performed for atrial vulnerability. After electrophysiological study, all patients underwent pacemaker implantation and were followed up. During the follow-up period of 85 +/- 50 months, development of CAF was observed in 12 patients (group A). The remaining 77 patients remained in sinus rhythm (group B). There were significantly more abnormal atrial electrograms in group A than group B (2.7 +/- 2.3 vs 0.8 +/- 1.2; P < 0.001). The distribution of abnormal atrial electrograms was also greater in group A; patients in group A had more abnormal atrial electrograms than patients in group B in both the high and middle right atrium (P < 0.005 and P < 0.01, respectively). Kaplan-Meier analysis showed that almost 50% of the paced patients with abnormal atrial electrograms (n = 42) developed CAF (P < 0.005). Our data suggest that the existence of abnormal atrial electrograms is predictive of the transition to CAF in paced patients with SSS.     

Accommodation in a refugee shelter as a risk factor for peptic ulcer bleeding after the Great East Japan Earthquake: a case–control study of 329 patients

Background

We have reported that the total number of peptic ulcers (PUs) had increased 1.5-fold after the Great East Japan Earthquake compared with those of the previous year, and that hemorrhagic ulcers were more prominently increased by 2.2-fold. The aim of this study is to determine the risk factors for bleeding ulcers after the Great East Japan Earthquake.

Methods

Clinical data of all peptic ulcer subjects endoscopically detected at the 7 major hospitals in the middle of the stricken area during the 3 months after the earthquake were retrospectively collected. Based on endoscopic and laboratory findings, peptic ulcer cases were divided into 227 bleeding ulcer cases and 102 non-bleeding controls. Other than ordinary risk factors for bleeding ulcers, the refugee shelter was included in the analysis as a unique confounder after the earthquake. Multiple logistic regression analyses were used to adjust for potential confounders.

Results

Eighty-seven (27 %) of 329 PUs emerged from refuge shelters, and the majority (76 of 87) of PUs occurring in such shelters was the bleeding type. Multivariate regression showed that residence in a shelter was a strong risk factor for ulcer bleeding with OR (95 % CI): 4.4 (2.1–9.6, p < 0.0001), independent of the progressiveness of ulcer diseases.

Conclusions

Accommodation in a refugee shelter can be a strong risk factor for ulcer bleeding after a large-scale disaster. Since acid-suppressive drugs are supposed to decrease the risk for stress-induced ulcer bleeding, our results will encourage effective use of a limited medical resource in such catastrophic events.

     

Chronic Cigarette Smoke Causes Oxidative Damage and Apoptosis to Retinal Pigmented Epithelial Cells in Mice

The purpose of this study was to determine whether mice exposed to chronic cigarette smoke develop features of early age-related macular degeneration (AMD). Two month old C57Bl6 mice were exposed to either filtered air or cigarette smoke in a smoking chamber for 5 h/day, 5 days/week for 6 months. Eyes were fixed in 2.5% glutaraldehyde/2% paraformaldehyde and examined for ultrastructural changes by transmission electron microscopy. The contralateral eye was fixed in 2% paraformaldehyde and examined for oxidative injury to the retinal pigmented epithelium (RPE) by 8-oxo-7,8-dihydro-2′-deoxyguanosine (8-OHdG) immunolabeling and apoptosis by TUNEL labeling. Mice exposed to cigarette smoke had immunolabeling for 8-OHdG in 85±3.7% of RPE cells counted compared to 9.5±3.9% in controls (p<0.00001). Bruch membrane was thicker in mice exposed to smoke (1086±332 nm) than those raised in air (543±132 nm; p=0.0069). The two most pronounced ultrastructural changes (severity grading scale from 0–3) seen were a loss of basal infoldings (mean difference in grade=1.98; p<0.0001), and an increase in intracellular vacuoles (mean difference in grade=1.7; p<0.0001). Ultrastructural changes to Bruch membrane in cigarette-smoke exposed mice were smaller in magnitude but consistently demonstrated significantly higher grade injury in cigarette-exposed mice, including basal laminar deposits (mean difference in grade=0.54; p<0.0001), increased outer collagenous layer deposits (mean difference in grade=0.59; p=0.002), and increased basal laminar deposit continuity (mean difference in grade=0.4; p<0.0001). TUNEL assay showed a higher percentage of apoptotic RPE from mice exposed to cigarette smoke (average 8.0±1.1%) than room air (average 0±0%; p=0.043). Mice exposed to chronic cigarette smoke develop evidence of oxidative damage with ultrastructural degeneration to the RPE and Bruch membrane, and RPE cell apoptosis. This model could be useful for studying the mechanism of smoke induced changes during early AMD.     

Risk factors of post-operative recurrence and adequate surgical approach to improve long-term outcomes of hepatocellular carcinoma

Introduction

A high recurrence rate of hepatocellular carcinoma (HCC) remains a significant concern. The risk factors for recurrence were analysed and the optimal surgical approaches were investigated.

Methods

The subjects comprised 280 consecutive patients with primary solitary HCC measuring ≤5 cm in diameter, who underwent curative resections. Multivariate analysis was conducted to identify the risk factors for post-operative recurrence, and the clinical significance of an anatomic resection was evaluated.

Results

Multivariate analysis identified HCV infection, a des-gamma-carboxyprothrombin level >100 mAU/ml, underlying cirrhosis, the presence of microvascular invasion, the presence of micrometastases and non-anatomic resection as being significant risk factors for post-operative recurrence. The 5-year recurrence rate was 56.7% in the anatomic resection (AR) group and 74.7% in the non-AR group. The 5-year survival rate was 82.2% in the AR group and 71.9% in the non-AR group. Local recurrence within the same segment was observed in 25% of the patients of the non-AR group. The prognostic superiority of AR was confirmed only in patients with histopathological evidence of microvascular invasion and/or micrometastases, and in patients having a solitary HCC measuring 2 to 5 cm in diameter.

Conclusions

Anatomic resection may decrease local recurrence and improve the surgical outcomes in solitary HCC measuring 2 to 5 cm in diameter.     

A case of primary splenic angiosarcoma with intraperitoneal hemorrhage treated by transcatheter arterial embolization

Splenic tumors are very rare. In Japan only 42 cases of splenic angiosarcoma have been reported. We encountered a case of spontaneous rupture of a splenic angiosarcoma and liver metastasis. A 60-year-old woman who suddenly went into hemorrhagic shock presented at our hospital. Then acute spontaneously ruptured spleen and hepatic tumors were diagnosed by abdominal CT. After emergency TAE, the patient was hemodynamically stable, but died of liver failure 13 days after admission. The pathological diagnosis was primary splenic angiosarcoma with multiple organ metastasis on autopsy. Splenic angiosarcoma should be kept in mind in the differential diagnosis of splenomegaly or splenic tumor. TAE can be effective in primary hemostasis for angiosarcoma with intraperitoneal hemorrhage from multiple tumors.     

Prevalence and risk factors for non-alcoholic fatty liver disease among adults in an urban Sri Lankan population

Background and Aims:  Non-alcoholic fatty liver disease (NAFLD) is an emerging problem in the Asia–Pacific region. However, its prevalence and risk factors in Asian (especially South Asian) communities is poorly studied. In this study, the aim was to determine the community prevalence and risk factors for NAFLD among adults in an urban Sri Lankan population.
Methods:  The study population consisted of 35–64-year-old adults, selected by stratified random sampling. NAFLD was diagnosed on established ultrasound criteria for fatty liver, safe alcohol consumption (< 14 units/week for men, < 7 units/week for females) and absence of hepatitis B and C markers. Blood pressure (BP) and anthropometric measurements were made, and fasting glucose, glycosylated hemoglobin, serum lipids, fasting serum insulin and serum alanine aminotransferase (ALT) were determined.
Results:  Of the 2985 study participants, 974 (32.6%) had NAFLD (605 [62.1%] women, mean age 52.8 years [standard deviation, 7.3]). On multivariate analysis, obesity, acanthosis nigricans, insulin resistance, elevated diastolic BP, fasting plasma glucose, plasma triglycerides, and ALT twice the upper limit of the reference range or more were independently associated with NAFLD.
Conclusion:  The prevalence of NAFLD among adults in this urban Sri Lankan community is high and is strongly associated with constituent features of the metabolic syndrome.     

Intense PET signal in the degenerative necrosis superimposed on chronic pancreatitis

Although fluorine-18 deoxyglucose-positron emission tomography (FDG-PET) is a sensitive diagnostic modality in detecting malignant tumors, differential diagnosis of malignant tumors from inflammatory lesion is challenging. We experienced a case of acute degenerative necrosis superimposed on chronic pancreatitis, which was difficult to distinguish from pancreatic cancer. The patient was a 66-year-old man with a complaint of upper abdominal pain. Abdominal computed tomography revealed low-density masses in the head and body of the pancreas. FDG-PET revealed intense accumulations at the head and body of the pancreas (mean standard uptake value for the head and body pancreatic tumors was 4.1 and 6.7, respectively) corresponding to the 2 tumors detected by computed tomography. Because of a possible malignant pancreatic tumor, the patient underwent pylorus-preserving pancreatoduodenectomy. Histologic examination of the resected specimen revealed a characteristic of chronic pancreatitis in a nontumorous area. Two tumors detected by FDG-PET consisted of degenerative necrosis surrounded by granulation tissue. The amount of granulation tissue was correlated to the levels of standard uptake value. No malignant tumors were observed. This case suggests a limitation of FDG-PET in distinguishing malignant neoplastic lesions in the pancreas, especially from acute degenerative changes in chronic pancreatitis. Repetitive PET examination is recommended for the accurate diagnosis.