Regeneration of defects in articular cartilage in rat knee joints by CCN2 (connective tissue growth factor).

CTGF/CCN2, a hypertrophic chondrocyte-specific gene product, possessed the ability to repair damaged articular cartilage in two animal models, which were experimental osteoarthritis and full-thickness defects of articular cartilage. These findings suggest that CTGF/CCN2 may be useful in regeneration of articular cartilage. INTRODUCTION: Connective tissue growth factor (CTGF)/CCN2 is a unique growth factor that stimulates the proliferation and differentiation, but not hypertrophy, of articular chondrocytes in vitro. The objective of this study was to investigate the therapeutic use of CTGF/CCN2. MATERIALS AND METHODS: The effects of recombinant CTGF/CCN2 (rCTGF/CCN2) on repair of damaged cartilage were evaluated by using both the monoiodoacetic acid (MIA)-induced experimental rat osteoarthritis (OA) model and full-thickness defects of rat articular cartilage in vivo. RESULTS: In the MIA-induced OA model, quantitative real-time RT-PCR assays showed a significant increase in the level of CTGF/CCN2 mRNA, and immunohistochemical analysis and in situ hybridization revealed that the clustered chondrocytes, in which clustering indicates an attempt to repair the damaged cartilage, produced CTGF/CCN2. Therefore, CTGF/CCN2 was suspected to play critical roles in cartilage repair. In fact, a single injection of rCTGF/CCN2 incorporated in gelatin hydrogel (rCTGF/CCN2-hydrogel) into the joint cavity of MIA-induced OA model rats repaired their articular cartilage to the extent that it became histologically similar to normal articular cartilage. Next, to examine the effect of rCTGF/CCN2 on the repair of articular cartilage, we created defects (2 mm in diameter) on the surface of articular cartilage in situ and implanted rCTGF/CCN2-hydrogel or PBS-hydrogel therein with collagen sponge. In the group implanted with rCTGF/CCN2-hydrogel collagen, new cartilage filled the defect 4 weeks postoperatively. In contrast, only soft tissue repair occurred when the PBS-hydrogel collagen was implanted. Consistent with these in vivo effects, rCTGF/CCN2 enhanced type II collagen and aggrecan mRNA expression in mouse bone marrow-derived stromal cells and induced chondrogenesis in vitro. CONCLUSION: These findings suggest the utility of CTGF/CCN2 in the regeneration of articular cartilage.     

Predictors of survival after liver transplantation for hepatocellular carcinoma associated with Hepatitis C.

The efficacy of orthotopic liver transplantation (OLT) for hepatocellular carcinoma (HCC) associated with hepatitis C virus (HCV) is not well defined. This study examines the variables that may determine the outcome of OLT for HCC in HCV patients. From 1990 to 1999, 463 OLTs were performed for HCV cirrhosis. Of these patients, 67 with concurrent HCC were included in the study. Univariate and multivariate analyses considered the following variables: gender, pTNM stage, tumor size, number of nodules, vascular invasion, incidental tumors, adjuvant chemotherapy, preoperative chemoembolization, alpha-fetoprotein (AFP) tumor marker, lobar distribution, and histological grade. Overall OLT survival of HCV patients diagnosed with concomitant HCC was significantly lower when compared to patients who underwent OLT for HCV alone at 1, 3, and 5 years (75%, 71%, and 55% versus 84%, 76%, and 75%, respectively; P < 0.01). Overall survival of patients with stage I HCC was significantly better than patients with stage II, III, or IV (P < .05). Eleven of 67 patients developed tumor recurrence. Sites of recurrence included transplanted liver (5), lung (5), and bone (1). Twenty-four of 67 patients (36%) died during the follow-up time. Causes of deaths included recurrent HCC in 8 of 24 patients (12%) and recurrent HCV in 3 of 24 patients (4.5%), whereas 13 (19.5%) patients died from causes that were unrelated to HCV or HCC. Both univariate and multivariate analysis demonstrated that pTNM status (I versus II, III, and IV; P < .05) was a reliable prognostic indicator for patient survival. Presence of vascular invasion (P = .0001) and advanced pTNM staging (P = .038) increased risk of recurrence. Multivariate analysis showed that pretransplant chemoembolization and adjuvant chemotherapy reduced risk of death after OLT in HCC recipients. In conclusion, this study demonstrates the effectiveness of OLT for patients with HCC in a large cohort of chronic HCV patients. Advanced tumor stage, and particularly vascular invasion, are poor prognostic indicators for tumor recurrence. Early pTNM stage, adjuvant chemotherapy, and preoperative chemoembolization were associated with positive outcomes for patients who underwent OLT for concomitant HCV and HCC.     

Impact of an inflammation-based prognostic system on patients undergoing surgery for hepatocellular carcinoma: a retrospective study of 398 Japanese patients

BackgroundFew studies have investigated the Glasgow Prognostic Score (GPS) in patients with hepatocellular carcinoma (HCC).MethodsThis study compared the prognostic value of the GPS and Cancer of the Liver Italian Program (CLIP) score in patients undergoing surgery for HCC.ResultsA total of 398 patients were evaluated retrospectively. Kaplan–Meier analyses revealed that GPS (P < .001) and CLIP score (P < .001) were associated with overall survival. GPS could classify patients with low CLIP score (0 or 1) into 3 independent groups (P < .001). Univariate analyses selected GPS (P = .006) and CLIP score (P = .002) as the predictive factors associated with overall survival. Multivariate analysis using these 2 scoring systems disclosed that both GPS (P = .025) and CLIP score (P = .010) were associated with overall survival.ConclusionsGPS is not only an important predictor of overall survival after surgical treatment of HCC as well as CLIP score, but also is able to clearly divide patients with low CLIP score into 3 independent groups.     

Weight gain in childhood and bone mass in female college students

The attainment of maximal peak bone mass early on in life is one of the most important strategies for the prevention of osteoporosis in women. The aim of this study was to clarify the correlation between gains in body size in all growth phases in childhood and adult bone mass in women. The subjects were 86 female first-year university students, aged 18–21 years. We measured the subjects bone mineral content (BMC) and bone mineral density (BMD) at the lumbar spine and the left hip, including the femoral neck, with dual energy X-ray absorptiometry. Each subject was measured for current height and weight. Height and weight at birth, and at 1.5, and 3 years were obtained from each maternity record book, and those between 6 and 18 years were obtained from their school health records. Other information, including physical activity and calcium intake, was obtained through an interview. Bivariate analysis showed that weight gains during the periods from birth to 1.5 years and from 9 to 12 years significantly correlated with both BMC and BMD values at any site. The stepwise method of multiple regression analysis showed that a weight gain during the period from birth to 1.5 years was significantly associated with BMC at the lumbar spine (P = 0.0001) and at the femoral neck (P = 0.0290) and with BMD at the lumbar spine (P = 0.0387). Birth weight was significantly associated with BMC at the lumbar spine (P = 0.0474) and the total hip (P = 0.0352), and weight gain during the period from 9 to 12 years was significantly associated with BMC at the femoral neck (P = 0.0376). In conclusion, birth weight and weight gain in infancy are important determinants of bone mass in young women. Additionally, a girls prepubertal growth spurt is likely to be a key phase for the acquisition of bone mass in relation to body weight. Our findings suggest that osteoporosis prevention programs may need to start very early in the life cycle.     

Right ventricular 18F-FDG uptake is an important indicator for cardiac involvement in patients with suspected cardiac sarcoidosis

Purpose

Cardiac sarcoidosis is most commonly found in the left ventricular (LV) free wall. Presence in the right ventricle (RV) is less common but might be useful for detecting cardiac involvement of sarcoidosis. ¹⁸F-fluorodeoxyglucose (¹⁸F-FDG) PET has been used to detect LV regions with cardiac sarcoidosis. However, the same has not been done for RV involvement. The aims of the current study were to evaluate RV ¹⁸F-FDG uptake and its relationship to the distribution of LV wall ¹⁸F-FDG-positive segments in the LV, and to evaluate whether patients with positive RV ¹⁸F-FDG uptake met the 1993 diagnostic criteria of the Japanese Ministry of Health and Welfare (JMHW) guidelines regarding sarcoidosis with suspected cardiac involvement.

Method

Fifty-nine biopsy-proven extra-cardiac sarcoidosis patients (age 56.1 ± 14.7 years) with suspected cardiac involvement based on abnormal electrocardiography or echocardiography findings underwent fasting ¹⁸F-FDG PET or PET/CT. The LV wall was divided into 17 segments and RV uptake was also evaluated.

Result

Among 59 patients, 35 (59.3 %) showed some abnormal ¹⁸F-FDG uptake in the RV and/or LV wall. With respect to the RV wall, 13 (22.0 %) showed abnormal ¹⁸F-FDG uptake. The number of LV-involved segments was 4.8 ± 2.4 in the patients with RV ¹⁸F-FDG uptake, which was significantly higher than in the patients without RV uptake, 1.8 ± 2.2 (P < 0.0001). Patients with RV uptake more frequently met the diagnostic criteria of the 1993 JMHW guidelines (n = 27), than did those without RV uptake (84.6 vs. 34.8 %, P = 0.0033).

Conclusion

¹⁸F-FDG PET identified RV involvement less frequently than LV involvement in this study population. However, patients who had RV uptake showed a greater number of LV-involved segments and met the JMHW diagnostic criteria more frequently. Although RV uptake is less frequent, ¹⁸F-FDG RV uptake may be useful in diagnosing cardiac involvement in sarcoidosis.

Clinical trial registration

UMIN000006533.     

Collaborative action of M-CSF and CTGF/CCN2 in articular chondrocytes: possible regenerative roles in articular cartilage metabolism

It is known that expression of the macrophage colony-stimulating factor (M-CSF) gene is induced in articular chondrocytes upon inflammation. However, the functional role of M-CSF in cartilage has been unclear. In this study, we describe possible roles of M-CSF in the protection and maintenance of the articular cartilage based on the results of experiments using human chondrocytic cells and rat primary chondrocytes. Connective tissue growth factor (CTGF/CCN2) is known to be a potent molecule to regenerate damaged cartilage by promoting the growth and differentiation of articular chondrocytes. Here, we uncovered the fact that M-CSF induced the mRNA expression of the ctgf/ccn2 gene in those cells. Enhanced production of CTGF/CCN2 protein by M-CSF was also confirmed. Furthermore, M-CSF could autoactivate the m-csf gene, forming a positive feed-back network to amplify and prolong the observed effects. Finally, promotion of proteoglycan synthesis was observed by the addition of M-CSF. These findings taken together indicate novel roles of M-CSF in articular cartilage metabolism in collaboration with CTGF/CCN2, particularly during an inflammatory response. Such roles of M-CSF were further supported by the distribution of M-CSF producing chondrocytes in experimentally induced rat osteoarthritis cartilage in vivo.     

Risk Factors for Early Recurrence of Single Lesion Hepatocellular Carcinoma After Curative Resection

Background and objectives

Hepatic resection is established as the treatment for HCC. However, patients sometimes experience early recurrence of HCC (ER HCC) after curative resection.

Methods

A retrospective analysis was conducted for 193 patients with single HCC who underwent curative liver resection in our medical center between April 2000 and March 2013. We divided the cohort into two groups; early recurrence group (ER G) which experienced recurrence within 6 months after resection, and non-early recurrence group (NER G). Risk factors for ER HCC were analyzed.

Results

Thirty-nine out of 193 (20.2 %) patients had ER HCC. Univariate analysis showed Glasgow prognostic score (GPS, p = 0.036), neutrophil to lymphocyte ratio (NLR, p = 0.001), level of PIVKA-II (p = 0.0001), level of AFP (p = 0.0001), amounts of blood loss (p = 0.001), operating time (p = 0.002), tumor size (p = 0.0001), stage III and IV (p = 0.0001), and microvascular invasions (portal vein: p = 0.0001 and hepatic vein: p = 0.001) to be associated with ER HCC. By multivariate analysis, there were significant differences in high NLR (p = 0.029) and high AFP (p = 0.0001) in patients with ER HCC.

Conclusions

Preoperative high AFP (more than 250 ng/ml) and high NLR (more than 1.829) were independent risk factors for ER HCC.

     

Left thoracotomy approach in reoperative off-pump coronary revascularization

Objective: Reoperative coronary bypass grafting is at high risk. Particularly in redo cases where the patent graft is running near the midline of the sternum, the graft may be exposed to injury by a median sternotomy and subsequent dissection. Whereas, off-pump bypass grafting from the left axillary artery or descending thoracic artery by a left thoracotomy approach is safe for preventing graft damage.Methods: From March 1998 to February 2002, we performed off-pump coronary artery bypass grafting by a left thoracotomy approach in 9 patients. The left axillary artery was used as the inflow vessel in 4 cases, and the descending thoracic, aorta in 5.Results: The radial artery was anastomosed proximally to the axillary artery in 4 cases and the descending thoracic aorta in one case. The saphenous vein graft was anastomosed, proximally to the descending thoracic aorta in 4 cases. Transdiaphragmatic minimally invasive bypass grafting for the right coronary artery was simultaneously performed in 3 cases. Postoperative cardiac events were ventricular arrhythmia in 6 cases and supraventricular arrhythmia in 3 cases. There was no damage to the patent grafts. Postoperative coronary angiography performed, in 8 cases revealed all the grafts to be patent without stenosis. Cardiac symptoms were not found after the operation in any of the cases.Conclusions: These procedures can prevent the injury to patent grafts caused by a median sternotomy, and will be one of the useful strategies for reoperative off-pump coronary artery bypass grafting.     

Glycosaminoglycan and proteoglycan inhibit the depolymerization of beta2-microglobulin amyloid fibrils in vitro

BACKGROUND: Although several kinds of evidence suggest that glycosaminoglycans (GAGs) and proteoglycans (PGs) may contribute to the development of beta2-microglobulin-related (Abeta2m) amyloidosis, the precise roles of these molecules for the development of Abeta2m amyloidosis are poorly understood. METHODS: We investigated the effects of GAGs and PGs on the depolymerization of Abeta2m amyloid fibrils at a neutral pH, as well as on the formation of the fibrils at an acidic pH in vitro, using fluorescence spectroscopy with thioflavin T and electron microscopy. RESULTS: Depolymerization of Abeta2m amyloid fibrils at pH 7.5 at 37 degrees C was inhibited dose-dependently by the presence of some GAGs (heparin, dermatan sulfate, or heparan sulfate) or PGs (biglycan, decorin, or keratan sulfate proteoglycan). Electron microscopy revealed that a significant amount of Abeta2m amyloid fibrils remained in the reaction mixture with some lateral aggregation. Second, when monomeric beta2m was incubated with aggrecan, biglycan, decorin, or heparin at pH 2.5 at 37 degrees C for up to 21 days, the thioflavin T fluorescence increased depending on dose and time. Electron microscopy revealed the formation of rigid and straight fibrils similar to Abeta2m amyloid fibrils in beta2m incubated with biglycan for 21 days. CONCLUSION: These results suggest that some GAGs and PGs could enhance the deposition of Abeta2m amyloid fibrils in vivo, possibly by binding directly to the surface of the fibrils and stabilizing the conformation of beta2m in the fibrils, as well as by acting as a scaffold for the polymerization of beta2m into the fibrils.     

Ball-valve gastric tumor associated with anomalous junction of the pancreatico-biliary ductal system and a right-sided round ligament: Report of a case

We report the case of a ball-valve gastric tumor associated with anomalous junction of the pancreatico-biliary ductal system (AJPBDS) and a right-sided round ligament, misdiagnosed preoperatively as advanced gastric cancer with pancreatic head invasion. A 72-year-old woman presented with chest pain, but laboratory data showed only anemia. Gastroscopy revealed a bleeding polypoid gastric tumor in the anterior wall of the stomach, herniating into the duodenum (ball-valve syndrome), and a Bormann type-2 tumor in the posterior wall. Ultrasonography showed gallbladder stones, dilatation of the intrahepatic bile duct and pancreatic duct, and a left-sided gallbladder (attributed to a right-sided round ligament with anomalous branches of the portal veins). Laparotomy revealed that the gastric tumors were not advanced cancer invading the pancreatic head. Intraoperative cholangiography showed an AJPBDS, causing dilatation of the intrahepatic bile duct and pancreatic duct. We performed distal gastrectomy and cholecystectomy without biliary diversion. Microscopy revealed that the polypoid tumor was a hyperplastic polyp.