Biomechanical gait analysis for a hip disarticulation prosthesis: power source for the swing phase of a hip disarticulation prosthetic limb.

[Purpose] This study aimed to clarify the power source for the swing phase of a hip disarticulation prosthetic limb using biomechanical gait analysis. [Participants and Methods] In this cross-sectional study, six participants who underwent hip disarticulation and seven healthy adults were recruited. Their gaits were assessed using the three-dimensional motion analysis and four force plates. [Results] From pre-swing to initial swing, the angle of the lumbar spine's angle changed by 9° from the flexion to extension positions. However, the power of the lumbar spine was <0.003 W/kg for the entire gait cycle. The peak value of joint moment and hip joint power on the unaffected side were 1 nm/kg and 0.7 W/kg, respectively. From pre-swing to initial swing, the prosthetic limb is pushed forward by extension of the hip joint on the intact side, while the spine returns to the flexion direction. [Conclusion] The hip extension force on the unaffected side was the main force responsible for swinging out the prosthesis, not the lumbar vertebrae's force.

Synthetic lethal interaction of combined CD26 and Bcl-xL inhibition is a powerful anticancer therapy against hepatocellular carcinoma.

AIM: CD26 is a membrane glycoprotein that has multiple functions, including dipeptidyl peptidase IV activity. CD26 expression varies in different tumor types, and its role in tumor growth in hepatocellular carcinoma (HCC) remains unclear. METHODS: CD26 expression levels were examined in resected HCC and surrounding non-cancerous lesions. The effect of CD26 knockdown on the cellular proliferation of HepG2 or Huh7 cells, both of which highly express CD26, was studied in vitro. RESULTS: CD26 mRNA expression levels were significantly increased in HCC compared with their surrounding non-cancerous lesions. We confirmed that various HCC cell lines, especially HepG2 and Huh7 cells, showed high expression levels of CD26. siRNA-mediated knockdown of CD26 suppressed hepatoma cell growth in vitro. CD26 knockdown induced cell cycle arrest through the upregulation of Cip/Kip family proteins, p21 in HepG2 cells and p27 in Huh7 cells. CD26 knockdown did not affect apoptosis, but it increased expressions of the pro-apoptotic proteins Bim and Bak and the anti-apoptotic protein Bcl-xL, suggesting an addiction of CD26 knockdown cells to Bcl-xL for survival. We thus treated CD26 knockdown cells with ABT-737, a Bcl-xL/-2/-w inhibitor, and observed that the synthetic lethal interaction of combined Bcl-xL and CD26 inhibition induced significant apoptosis and impaired cellular viability. CONCLUSION: CD26 mRNA was overexpressed in HCC, and its inhibition suppressed cellular proliferation through cell cycle arrest. The combined use of CD26 knockdown with a Bcl-xL inhibitor further elicited substantial apoptosis and therefore may serve as a powerful anticancer combination therapy against HCC.

The Bcl-2 homology domain 3 (BH3)-only proteins Bim and bid are functionally active and restrained by anti-apoptotic Bcl-2 family proteins in healthy liver.

An intrinsic pathway of apoptosis is regulated by the B-cell lymphoma-2 (Bcl-2) family proteins. We previously reported that a fine rheostatic balance between the anti- and pro-apoptotic multidomain Bcl-2 family proteins controls hepatocyte apoptosis in the healthy liver. The Bcl-2 homology domain 3 (BH3)-only proteins set this rheostatic balance toward apoptosis upon activation in the diseased liver. However, their involvement in healthy Bcl-2 rheostasis remains unknown. In the present study, we focused on two BH3-only proteins, Bim and Bid, and we clarified the Bcl-2 network that governs hepatocyte life and death in the healthy liver. We generated hepatocyte-specific Bcl-xL- or Mcl-1-knock-out mice, with or without disrupting Bim and/or Bid, and we examined hepatocyte apoptosis under physiological conditions. We also examined the effect of both Bid and Bim disruption on the hepatocyte apoptosis caused by the inhibition of Bcl-xL and Mcl-1. Spontaneous hepatocyte apoptosis in Bcl-xL- or Mcl-1-knock-out mice was significantly ameliorated by Bim deletion. The disruption of both Bim and Bid completely prevented hepatocyte apoptosis in Bcl-xL-knock-out mice and weakened massive hepatocyte apoptosis via the additional in vivo knockdown of mcl-1 in these mice. Finally, the hepatocyte apoptosis caused by ABT-737, which is a Bcl-xL/Bcl-2/Bcl-w inhibitor, was completely prevented in Bim/Bid double knock-out mice. The BH3-only proteins Bim and Bid are functionally active but are restrained by the anti-apoptotic Bcl-2 family proteins under physiological conditions. Hepatocyte integrity is maintained by the dynamic and well orchestrated Bcl-2 network in the healthy liver.

Carbamazepine promotes liver regeneration and survival in mice.

BACKGROUND & AIMS: Carbamazepine (CBZ), a widely used anticonvulsant and mood stabilizer, activates multiple proliferative and pro-survival pathways. Here, we hypothesize that CBZ may promote hepatocellular proliferation and ameliorate liver regeneration. METHODS: C57BL6/J mice were orally administered CBZ or vehicle and underwent a 70% partial hepatectomy (PHx), 85% PHx or treatment with carbon tetrachloride (CCl4). Liver regeneration was determined by liver to body weight ratio, hepatocyte proliferation markers, and activation of intracellular signalling pathways. RESULTS: Two to 5days after the 70% PHx, the liver to body weight ratio was significantly higher in the CBZ-treated mice than in the vehicle-treated mice. CBZ treatment upregulated the number of proliferative hepatocytes following PHx or CCl4 treatment, as assessed by intrahepatic Ki-67 staining, BrdU uptake, and PCNA protein expression. PHx surgery induced the expression of several cyclins and activated Akt/mTOR signalling pathways, all of which were enhanced by CBZ treatment. The administration of the mTOR inhibitor temsirolimus abrogated the hepato-proliferative effect of CBZ. CBZ treatment significantly improved the survival rate of the mice that underwent lethal 85% massive hepatectomy. CONCLUSIONS: CBZ demonstrated a novel hepato-proliferative effect through the activation of the mTOR signalling pathway in hepatectomised mice. CBZ has the potential to be a therapeutic option for facilitating efficient liver regeneration in patients subjected to liver surgery.

Lipiodol accumulation and transarterial chemoembolization efficacy for HCC patients.

BACKGROUND/AIMS: To elucidate the prognostic factors for hepatocellular carcinoma (HCC) patients treated with transarterial chemoembolization (TACE). METHODOLOGY: We studied 85 TACE-treated HCC patients, including 117 lesions, who fulfilled the Milan criteria. The area of iodized poppy-seed oil (lipiodol) accumulation on CT immediately after TACE was classified into three groups, by comparing with the area of HCC detected by CT during hepatic arteriography; accumulation surrounding the HCC lesion (group I), accumulation involving the entire area of the HCC lesion (group II), and accumulation that covered a portion of the HCC lesion (group III). RESULTS: Among 85 patients, the 1- and 2-year disease free survival (DFS) rates were 67% and 50% in group I, 49% and 29% in group II and 29% and 15% in group III. DFS rate was higher in group I than in groups II and III (p=0.016 and p<0.001). Difference in DFS by lipiodol accumulation pattern was evident in patients aged 75 or younger. CONCLUSIONS: Lipiodol accumulation pattern as evaluated by CT immediately after TACE may be a powerful indicator of the therapeutic efficacy of TACE in HCC patients.

Inflammatory pseudotumor of the liver and spleen diagnosed by percutaneous needle biopsy.

An inflammatory pseudotumor (IPT) is a relatively rare lesion characterized by chronic infiltration of inflammatory cells and areas of fibrosis. IPTs are difficult to diagnose because of the absence of specific symptoms or of characteristic hematological or radiological findings. In this study, a case of a woman aged over 70 years was reported, who presented with a general malaise lasting more than two months. A computed tomography scan demonstrated a diffusely spread lesion of the liver with a portal vein occlusion and a splenic lesion surrounded by a soft density layer. Since the percutaneous liver biopsy showed findings that suggested an IPT, although the radiological findings did not exclude the possibility of a malignancy, we performed a percutaneous spleen biopsy to enable a more definitive diagnosis. The microscopic findings from the spleen specimen lead us to a diagnosis of IPT involving the liver and spleen. Subsequent steroid pulse therapy was effective, and rapid resolution of the disease was observed.

Prior splenic irradiation reduces hematologic adverse events during chemotherapy in pancreatic tail cancer: a report of a patient with liver cirrhosis.

Thrombocytopenia is a major complication of liver cirrhosis that often limits the use of anticancer drugs. In this report, we describe a thrombocytopenic patient with liver cirrhosis who developed pancreatic tail cancer and underwent splenic irradiation. Particular emphasis was placed on the impact of irradiation on thrombocytopenia. A 73-year-old male with liver cirrhosis was diagnosed with pancreatic tail cancer infiltrating the splenic hilum by computed tomography (CT) and pancreatic juice cytology. His baseline platelet count was 84 × 10(3)/mm(3). A total of 50 Gy of irradiation to the pancreatic tail and splenic hilum was carried out as local therapy for pancreatic cancer. Splenic irradiation was also expected to reverse liver cirrhosis-related thrombocytopenia, which was making systemic chemotherapy difficult to administer in this patient. One month later, systemic gemcitabine chemotherapy was commenced. At the start of chemotherapy, his platelet count remained at 93 × 10(3)/mm(3), but rose to 246 × 10(3)/mm(3) 2.5 months later, which allowed the administration of chemotherapy without any remarkable hematologic toxicities. Post-irradiation CT revealed a low density area indicating irradiation-induced necrotic tissue that had expanded into the surrounding non-tumorous spleen parenchyma, and which may have impacted positively on the thrombocytopenia. Our case report suggests that splenic irradiation may be a potential therapeutic option for liver cirrhosis-related thrombocytopenia, especially in patients who require systemic chemotherapy for cancer.

Autofluorescence imaging videoendoscopy in the diagnosis of chronic atrophic fundal gastritis.

PURPOSE: Diagnosis of chronic atrophic fundal gastritis (CAFG) is important to understand the pathogenesis of gastric diseases and assess the risk of gastric cancer. Autofluorescence imaging videoendoscopy (AFI) may enable the detection of mucosal features not apparent by conventional white-light endoscopy. The purpose of this study was to estimate the diagnostic ability of AFI in CAFG. METHODS: A total of 77 patients were enrolled. Images of the gastric body in AFI and white-light mode were taken to assess the extent of gastritis, and biopsies were taken from green (n = 119) and purple (n = 146) mucosa in AFI images. The diagnostic accuracy of green mucosa for CAFG was investigated according to the Sydney system. RESULTS: In per-patient analysis, the accuracy of green mucosa in patients with activity, inflammation, atrophy and intestinal metaplasia was 64, 93, 88 and 81%, respectively. In per-biopsy analysis, the accuracy for activity, inflammation, atrophy and intestinal metaplasia was 55, 62, 76 and 76%, respectively. Green areas in the gastric body exhibited more inflammation (p < 0.001), atrophy (p < 0.001) and intestinal metaplasia (p < 0.001), whereas purple areas rarely contained atrophy or intestinal metaplasia. The kappa statistics for inter- and intra-observer agreement of AFI on assessing the extent of CAFG were 0.66 and 0.47, while those for white-light endoscopy were 0.56 and 0.39. CONCLUSIONS: AFI could diagnose the extent of CAFG as a green area in the gastric body, with higher reproducibility compared with white-light endoscopy. Therefore, AFI may be a useful adjunct to endoscopy to identify patients at high risk of developing gastric cancer.

Improved diagnosis of well-differentiated hepatocellular carcinoma with gadolinium ethoxybenzyl diethylene triamine pentaacetic acid-enhanced magnetic resonance imaging and Sonazoid contrast-enhanced ultrasonography.

AIM: Two new imaging modalities have been developed recently that are directed at the focal liver lesions: gadolinium ethoxybenzyl diethylene triamine pentaacetic acid (Gd-EOB-DTPA)-enhanced magnetic resonance imaging (MRI) and Sonazoid contrast-enhanced ultrasonography (CEUS). We investigated the usefulness of these modalities for the diagnosis of small (<2 cm), well-differentiated hepatocellular carcinoma (HCC). METHODS: A total of 15 nodules from 13 patients, which were histologically diagnosed as well-differentiated HCC, were subjected to this study. Lesions that showed hypervascularity in the arterial phase and washout in the portal or late non-hemodynamic phase were regarded as HCC in the dynamic studies of all imaging modalities. RESULTS: By multidetector computed tomography (MDCT), six of 15 (40%) nodules were diagnosed as HCC. Gd-EOB-DTPA-enhanced MRI diagnosed HCC in nine of the 15 (60%) nodules. Of the nine nodules that were not diagnosed by MDCT, four could be diagnosed by Gd-EOB-DTPA-enhanced MRI. In Sonazoid CEUS, 10 of 15 nodules (67%) were diagnosed as HCC. Four of nine nodules that could not be diagnosed as HCC by MDCT, were diagnosed by Sonazoid CEUS. A total of 11 of the 15 (73%) nodules were diagnosed as HCC by Gd-EOB-DTPA-enhanced MRI and Sonazoid CEUS in addition to MDCT. CONCLUSION: Gd-EOB-DTPA-enhanced MRI and Sonazoid CEUS had greater diagnostic value for small, well-differentiated HCC than did conventional MDCT.

Hepatocellular carcinoma arising from non-cirrhotic nonalcoholic steatohepatitis.

PURPOSE: Characteristics of hepatocellular carcinoma (HCC) complicating nonalcoholic steatohepatitis (NASH) are still controversial. Most NASH related HCCs are believed to develop from cirrhotic liver, but case reports about HCC arising from non-cirrhotic NASH have been accumulating recently. This study is designed to elucidate characteristics of NASH related HCC diagnosed with high accuracy by using surgically resected specimens that contain larger areas to validate than biopsy specimens. METHODS: For this study, 1168 patients who underwent hepatic resection at Osaka Medical Center for Cancer and Cardiovascular Diseases were enrolled. Patients who had clinically obvious causes of chronic liver dysfunction, such as viral and alcoholic hepatitis, were excluded. Histological diagnosis of NASH was confirmed according to Brunt's criterion. RESULTS: Eight (1%) patients were diagnosed with NASH. Six (75%) of them showed non-cirrhosis in non-cancerous areas. Stages of fibrosis in the non-cirrhotic patients were mild fibrosis (F2) in five and moderate fibrosis (F3) in one. All patients complicated with metabolic diseases. Although all these patients without cirrhosis were evaluated pathologically at tumor-node-metastasis stages I or II, three (50%) had multiple recurrences of tumor within a short time after surgery. CONCLUSION: This study indicates HCC might arise frequently from non-cirrhotic NASH. While further studies are needed to confirm this observation, both cirrhotic and non-cirrhotic NASH warrant regular screening for HCC.