Reg3α and Reg3ß Expressions Followed by JAK2/STAT3 Activation Play a Pivotal Role in the Acceleration of Liver Hypertrophy in a Rat ALPPS Model.

To explore the underlying mechanism of rapid liver hypertrophy by liver partition in associating liver partition and portal vein ligation for staged hepatectomy (ALPPS), liver partition at different sites was investigated. Increased inflammatory cytokines owing to the liver partition have been reportedly responsible. If this were true, rapid liver hypertrophy should be achieved regardless of where the liver was split. A male Sprague-Dawley rat model was created, in which a liver split was placed inside the portal vein ligated lobe (PiLL), in addition to the ALPPS and portal vein ligation (PVL) models. Liver regeneration rate, inflammatory cytokine levels, activation status of the Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) pathway and expressions of regenerating islet-derived (Reg)3α and Reg3ß were investigated. The liver regeneration rate was significantly higher in the ALPPS group than in the PiLL group, whereas inflammatory cytokine levels were nearly equal. Additional volume increase in ALPPS group over PVL and PiLL groups was JAK2/STAT3-dependent. Reg3α and Reg3ß expressions were observed only in the ALPPS group. An increase in inflammatory cytokines was not enough to describe the mechanism of rapid liver hypertrophy in ALPPS. Expressions of Reg3α and Reg3ß could play an important role in conjunction with an activation of the JAK2/STAT3 pathway.

Hepatic Stellate Cells Play a Functional Role in Exacerbating Ischemia-Reperfusion Injury in Rat Liver.

PURPOSE: The involvement of hepatic stellate cells (HSCs) with ischemia-reperfusion (I/R) injury in rat liver was examined using gliotoxin, which is known to induce HSC apoptosis. METHODS: Male Sprague-Dawley rats were used. HSC was represented by a glial fibrillary acidic protein (GFAP)-positive cell. Liver ischemia was produced by cross-clamping the hepatoduodenal ligament. The degree of I/R injury was evaluated by a release of aminotransferases. Sinusoidal diameter and sinusoidal perfusion rates were examined using intravital fluorescence microscopy. RESULTS: Gliotoxin significantly decreased the number of GFAP-positive cells 48 h after dosing (2.50 ± 0.19% [mean ± SD] in the nontreated group vs. 1.91 ± 0.46% in the gliotoxin-treated group). Liver damage was significantly suppressed by the pretreatment with gliotoxin. Sinusoidal diameters in zone 3 were wider in the gliotoxin group (10.25 ± 0.35 µm) than in the nontreated group (8.21 ± 0.50 µm). The sinusoidal perfusion rate was maintained as well in the gliotoxin group as in normal livers, even after I/R. CONCLUSIONS: Pretreatment with gliotoxin significantly reduced the number of HSCs in the liver and further suppressed liver injury following I/R. It is strongly suggested that HSCs play a functional role in exacerbating the degree of I/R injury of the liver.

High serum C1q-binding adiponectin levels in male patients with acute coronary syndrome.

BACKGROUND: The complement system is part of the immune system in acute coronary syndrome (ACS). Adiponectin has anti-atherogenic and anti-inflammatory properties. Adiponectin and C1q form a protein complex in blood, and serum C1q binding adiponectin (C1q-APN) can be measured. We investigated the comparative evaluation of serum C1q-APN levels in males with ACS, stable angina pectoris (SAP) versus controls. METHODS: The study subjects were 138 Japanese patients who underwent diagnostic coronary angiography. Blood total adiponectin (Total-APN), C1q-APN and C1q were measured by enzyme-linked immunosorbent assays. Patients were divided into three groups according to the clinical condition: ACS (n = 78), SAP (n = 41) or normal coronary (NC, n = 19) groups. RESULTS: Serum C1q levels were significantly higher in the ACS group (54.9±1.2 µg/mL) than in the NC group (48.0±2.5 µg/mL). Although serum Total-APN levels were significantly lower in the SAP and ACS groups, compared with the NC group (7.0±0.5, 7.2±0.3, 10.6±2.0 µg/mL, respectively), serum C1q-APN levels were significantly higher in the ACS group than in the NC and SAP groups (112.1±4.1, 66.3±4.4, 65.7±2.9 units/mL, respectively). CONCLUSIONS: Patients with ACS had higher serum C1q-APN levels. TRIAL REGISTRATION: UMIN000002997.

A pilot three-month sitagliptin treatment increases serum adiponectin level in Japanese patients with type 2 diabetes mellitus--a randomized controlled trial START-J study.

BACKGROUND: The dipeptidyl-peptidase-IV (DPP-4) inhibitors, including sitagliptin, are used for the treatment of type 2 diabetes mellitus (T2DM). Adiponectin, an adipocyte-derived circulating protein, has anti-atherosclerotic and anti-diabetic properties and is effectively elevated in bloodstream by thiazolidinediones, an insulin sensitizer. However, the effect of sitagliptin treatment on serum adiponectin level in T2DM has not fully elucidated in Japanese T2DM patients. The aim of the present study was to examine the effect of sitagliptin treatment on serum adiponectin levels in T2DM subjects. METHODS: Twenty-six consecutive Japanese T2DM outpatients were recruited between April 2011 and March 2013, and randomized into the control (conventional treatment, n = 10) group and sitagliptin treatment group (n = 16). Serum adiponectin was measured by enzyme-linked immunosorbent assay. RESULTS: Indices of glycemic control, such as hemoglobin A1c, glycated albumin, and 1.5-anhydro-D-glucitol, were significantly improved after the three-month treatment in both the control and sitagliptin groups. Serum adiponectin level was significantly increased in sitagliptin group from 6.7 ± 0.8 to 7.4 ± 1.0 µg/mL without change of body mass index (p = 0.034), while serum adiponectin level was not altered in the control group (p = 0.601). CONCLUSION: In Japanese T2DM patients, serum adiponectin level was elevated by three-month treatment with sitagliptin without change of body weight. TRIAL REGISTRATION: UMIN000004721.

High-dose corticosteroid therapy for erlotinib-induced interstitial lung disease in Japanese patient with advanced pancreatic cancer.

CONTEXT: Erlotinib is a selective epidermal growth factor receptor tyrosine kinase inhibitor used as a target therapy against non-small lung cancer and advanced pancreatic cancer. A regimen of erlotinib plus gemcitabine has been proven to prolong overall survival in the patient with advanced pancreatic cancer. In addition to common adverse effects, such as diarrhea, mucositis and skin rash (acne form eruptions), acute interstitial lung disease (ILD) has been reported as an infrequent but potentially fatal complication. We here report a case of a Japanese patient with erlotinib-induced ILD in whom high-dose corticosteroid therapy was successful. CASE REPORT: A fifty-five-year-old male with cancer of the head of the pancreas with multiple liver metastases started treatment with gemcitabine plus erlotinib. On the 13th day of erlotinib treatment, he had high fever. Chest computed tomography (CT) scan showed a diffuse ground-glass like infiltration of both lungs. He was diagnosed with ILD, and high-dose corticosteroid therapy was started. Two weeks after the introduction of steroid therapy, the reticular shadow faded away on CT. He was successfully treated with corticosteroid for erlotinib-induced acute ILD although he died 6 months after the initiation of chemotherapy owing to disease progression. CONCLUSION: we showed a case of a successfully treated Japanese patient of erlotinib-induced ILD. Because erlotinib-induced ILD would frequently occur in Japanese patients, closer attention to ILD should be paid for Japanese patients than in Western populations. If erlotinib-induced ILD occurs, a high-dose corticosteroid therapy would be a useful option of treatment.

Gene expression levels of S100 protein family in blood cells are associated with insulin resistance and inflammation (Peripheral blood S100 mRNAs and metabolic syndrome).

OBJECTIVE: Visceral fat obesity is located upstream of metabolic syndrome and atherosclerotic diseases. Accumulating evidences indicate that several immunocytes including macrophages infiltrate into adipose tissue and induce chronic low-grade inflammation. We recently analyzed the association between visceral fat adiposity and the gene expression profile in peripheral blood cells in human subjects and demonstrated the close relationship of visceral fat adiposity and disturbance of circadian rhythm in peripheral blood cells. In a series of studies, we herein investigated the association of visceral fat adiposity and mRNA levels relating to inflammatory genes in peripheral blood cells. APPROACH AND RESULTS: Microarray analysis was performed in peripheral blood cells from 28 obese subjects. Reverse transcription-polymerase chain reaction (RT-PCR) was conducted by using blood cells from 57 obese subjects. Obesity was defined as body mass index (BMI) greater than 25 kg/m2 according to the Japanese criteria. Gene expression profile analysis was carried out with Agilent whole human genome 4×44K oligo-DNA microarray. Gene ontology (GO) analysis showed that 14 genes were significantly associated with visceral fat adiposity among 239 genes relating to inflammation. Among 14 genes, RT-PCR demonstrated that S100A8, S100A9, and S100A12 positively correlated with visceral fat adiposity in 57 subjects. Stepwise multiple regression analysis showed that S100A8 and S100A12 mRNA levels were closely associated with HOMA-IR and S100A9 mRNA was significantly related to adiponectin and CRP. CONCLUSIONS: Peripheral blood mRNA levels of S100 family were closely associated with insulin resistance and inflammation.

Gastric cancer simultaneously complicated with extrahepatic bile duct metastasis and portal vein tumor thrombus: a case report.

BACKGROUND: Gastric cancer metastatic to the extrahepatic bile duct or accompanied by portal vein tumor thrombus (PVTT) is rare. To our knowledge, there have been no cases complicated with both of these factors. CASE PRESENTATION: A 72-year-old man presented with icterus and melena. A biochemical blood test showed abnormal values for hepatobiliary enzymes and a tumor marker, and abdominal computed tomography scan revealed wall thickening of the lower bile duct with intra- and extra-hepatic bile duct dilatation and PVTT. A biopsy of the lower bile duct during endoscopic retrograde cholangiopancreatography demonstrated a moderately differentiated tubular adenocarcinoma. Moreover, gastroduodenoscopy showed a type 3 tumor at the lesser curvature of the gastric antrum, and an endoscopic biopsy demonstrated a moderately differentiated tubular adenocarcinoma. We diagnosed concomitant gastric cancer and distal bile duct accompanied by PVTT, and pancreatoduodenectomy with combined resection of the portal vein was performed. The resected specimen revealed a tumor in the lesser curvature of the gastric antrum and circumferential wall thickening in the lower bile duct. In pathological findings, infiltration of a moderately differentiated tubular adenocarcinoma from the mucosal layer to the subserosal layer of the stomach was observed. In contrast, a moderately differentiated tubular adenocarcinoma demonstrating the same histological type as the gastric cancer had spread not to the mucosal layer but mainly to the fibromuscular layer of the lower bile duct. Immunohistochemical staining showed identical patterns between gastric cancer and the bile duct tumor: negativity for cytokeratin 7 (CK7), and positivity for CK19 and 20. Therefore, the final diagnosis was extrahepatic bile duct metastasis from gastric cancer with PVTT. Unfortunately, multiple liver metastases occurred in the early postoperative period and chemotherapy was conducted, but the patient died 12 months after the surgery. CONCLUSIONS: In the diagnosis of extrahepatic bile duct metastasis, immunohistochemical staining of gastric cancer and the bile duct tumor was essential and helpful as decisive evidence.

Usefulness of Liver Uptake Rate Constant in 99mTc-GSA Scintigraphy for the Risk Stratification of Patients Undergoing Hepatectomy: A New Method for Calculation.

Introduction: The use of technetium 99m diethylenetriaminepentaacetic acid-galactosyl human serum albumin (99mTc-GSA) scintigraphy parameters, HH15 and LHL15, in assessing the future liver remnant function is not expedient because of their nonlinear behaviour against liver volume. Uptake rate constant for the binding of 99mTc-GSA to asialoglycoprotein receptors is probably more favourable, but the reported calculation methods are complex. We devised a simple method to calculate the uptake rate constant, KrGSA. Methods: Radioactivity counts for the entire liver and heart regions were extracted at 10, 20, and 30 min. Using whole liver and heart volumes measured from single-photon emission computed tomography images, free radioactivity corresponding to the liver blood pool was subtracted. The time activity curve was fitted to the equation L(t) = L(∞) × [1 - Exp (-kt)] using Microsoft Office Excel (add-in free programme Solver)®, where L(∞) is the count at plateau level and k denotes KrGSA. Results: KrGSA values accurately identified liver cirrhosis and were similar to the KICG. The areas under the curve for KrGSA and KICG in the receiver operating characteristic analysis were 0.808 and 0.795, respectively, and a good correlation was seen between KrGSA and KICG. Discussion/Conclusion: KrGSA can be utilized as an alternative to KICG in assessing the future liver remnant function.

Adiponectin ameliorates hypoxia-induced pulmonary arterial remodeling.

We have demonstrated that adiponectin has anti-atherosclerotic properties. We also reported hypoadiponectinemia and nocturnal reduction in circulating adiponectin concentrations in patients of severe obstructive sleep apnea-hypopnea syndrome (OSAS). OSAS is often complicated with pulmonary hypertension. In this study, we investigated the effect of adiponectin on chronic hypoxia-induced pulmonary arterial remodeling in mice. Exposure of mice to 3-weeks sustained hypoxia (10% O(2)) resulted in significant accumulation of adiponectin in pulmonary arteries. The percentage media wall thickness (%MT), representing pulmonary arterial remodeling, under hypoxic condition, was greater in adiponectin-knockout mice than wild-type mice. Overexpression of adiponectin significantly decreased hypoxia-induced pulmonary arterial wall thickening and right ventricular hypertrophy. These findings demonstrate for the first time that overexpression of adiponectin suppresses the development of hypoxic-induced pulmonary remodeling, and that adiponectin may combat a new strategy for pulmonary vascular changes that underlie pulmonary hypertension in OSAS.

Effect of Lansoprazole on the Control of the Intragastric pH in a Patient with Short Bowel Syndrome.

A 40-year-old man suffered from short bowel syndrome. Since a large amount of intestinal output and watery diarrhea hampered his quality of life, we tried to control the intestinal output by reducing the secretion of gastric acid with lansoprazole. Because the small intestine was only 10 cm in length and effective absorption of oral lansoprazole was doubtful, we monitored his intragastric pH for 24 hours and confirmed that the holding time above pH 3.0 was 14.5 hours (60.4%). He spent his home life eating porridge during the day, and receiving total parenteral nutrition of 1,100 mL/day at night while taking lansoprazole as an oral tablet (30 mg) once a day.

Exacerbation of albuminuria and renal fibrosis in subtotal renal ablation model of adiponectin-knockout mice.

OBJECTIVE: Obesity is recognized increasingly as a major risk factor for kidney disease. We reported previously that plasma adiponectin levels were decreased in obesity, and that adiponectin had defensive properties against type 2 diabetes and hypertension. In this study, we investigated the role of adiponectin for kidney disease in a subtotal nephrectomized mouse model. METHODS AND RESULTS: Subtotal (5/6) nephrectomy was performed in adiponectin-knockout (APN-KO) and wild-type (WT) mice. The procedure resulted in significant accumulation of adiponectin in glomeruli and interstitium in the remnant kidney. Urinary albumin excretion, glomerular hypertrophy, and tubulointerstitial fibrosis were significantly worse in APN-KO mice compared with WT mice. Intraglomerular macrophage infiltration and mRNA levels of vascular cell adhesion molecule (VCAM)-1, MCP-1, tumor necrosis factor (TNF)-alpha, transforming growth factor (TGF)-beta1, collagen type I/III, and NADPH oxidase components were significantly increased in KO mice compared with WT mice. Treatment of APN-KO mice with adenovirus-mediated adiponectin resulted in amelioration of albuminuria, glomerular hypertrophy, and tubulointerstitial fibrosis and reduced the elevated levels of VCAM-1, MCP-1, TNF-alpha, TGF-beta1, collagen type I/III, and NADPH oxidase components mRNAs to the same levels as those in WT mice. CONCLUSIONS: Adiponectin accumulates to the injured kidney, and prevents glomerular and tubulointerstitial injury through modulating inflammation and oxidative stress.

Domino Reconstruction of the Portal Vein Using the External Iliac Vein and an ePTFE Graft in Pancreatic Surgery.

BACKGROUND: In the portal vein resection of long distance, an interposition by autologous vein is mandatory. External iliac vein (EIV) has been used, but harvesting the EIV is associated with severe venous congestion of the affected lower extremity. We have reconstructed the EIV using a ringed expanded polytetrafluoroethylene (ePTFE) graft. METHODS: Thirteen patients underwent this surgery. The right EIV was used for reconstructing the portal vein, and the retrieved portion of EIV was interposed by the ePTFE graft. We evaluated size and length of the graft, graft patency, girth of thigh, time for reconstruction of EIV, and graft infection. RESULTS: ePTFE grafts of 8 or 10 mm in diameter were used. The length of ePTFE graft used was 4.4 ± 0.5 cm. Graft patency was kept in 76.9% patients. Graft obstruction was encountered in three patients, and the girth of right thigh increased by about 10 cm. Time for reconstruction of EIV was 29.5 ± 6.8 min. Graft infection did not occur in any patients. CONCLUSIONS: Reconstruction of the EIV using a ringed ePTFE graft seems to be a feasible option for preventing the swelling of the affected lower extremity after procurement of EIV for repairing the portal vein.

Increased serum C1q-binding adiponectin complex to total-adiponectin ratio in men with multi-vessel coronary disease.

BACKGROUND: Adiponectin plays a role as a positive contributor to the stabilization of atherosclerotic plaques. Circulating total adiponectin (Total-APN) levels associates with the number of coronary vessels in men with coronary artery disease (CAD). We recently reported that adiponectin binds to C1q in human blood, and serum C1q-binding adiponectin (C1q-APN) /Total-APN levels are associated with CAD in type 2 diabetic subjects. The present study investigated the relationship between circulating C1q-APN levels and the number of angiographic coronary artery vessel in male subjects. METHODS: The study subjects were 53 male Japanese patients who underwent diagnostic coronary angiography. Blood total adiponectin (Total-APN), high-molecular weight adiponectin (HMW-APN), C1q-APN and C1q were measured by enzyme-linked immunosorbent assays. RESULTS: Serum C1q-APN/Total-APN ratio significantly increased in subjects with single and multi-vessel coronary diseases (p = 0.029 for trend, the Kruskal-Wallis test). However, serum Total-APN, HMW-APN, C1q-APN and C1q levels did not correlate with number of diseased coronary vessels. CONCLUSION: Serum C1q-APN/Total-APN ratio progressively increases in men with single and multi-vessel coronary disease. TRIAL REGISTRATION: UMIN000002997.

Coexistence of visceral fat accumulation and sleep-disordered breathing correlates with coronary artery disease.

AIM: Visceral adiposity is linked with sleep-disordered breathing (SDB) (called Syndrome Z), and both correlate with coronary artery disease (CAD). The aim of the present study was to determine the significance of excess visceral fat, SDB and circulating levels of biomarkers in CAD in Japanese men. METHODS: SDB, visceral fat area (VFA), and circulating levels of biomarkers were assessed in 60 Japanese male patients who underwent coronary angiography and overnight cardiorespiratory monitoring. RESULTS: Age-adjusted logistic analysis showed a significant relationship between CAD and diabetes, hypertension, dyslipidemia, SDB (AHI ≥5 events/hour), visceral fat accumulation (VFA ≥100 cm(2)), the combination of visceral fat accumulation and hypertension or dyslipidemia, as well as the combination of visceral fat accumulation and SDB. Patients with VFA ≥100 cm(2) and SDB had significantly lower serum adiponectin levels and higher serum soluble CD40 ligand levels than those with VFA<100 cm(2) and SDB. The prevalence of CAD was significantly higher in patients with VFA ≥100 cm(2) and SDB than in patients with VFA <100 cm(2) and AHI <5 events/hour, patients with VFA<100 cm(2) and AHI ≥5 events/hour or patients with VFA ≥100 cm(2) and AHI <5 events/hour (93% versus 14%, p <0.001, 53%, p <0.01 or 63%, p <0.01, respectively). CONCLUSIONS: The present study indicates that patients with both visceral fat accumulation and SDB develop CAD in association with hypoadiponectinemia and inflammatory activity.

Enhancement of liver regeneration by adenosine triphosphate-sensitive K⁺ channel opener (diazoxide) after partial hepatectomy.

BACKGROUND: Enhancement of liver regeneration is a matter of importance after partial liver transplantation including small-for-size grafting. Mitochondrial adenosine triphosphate (ATP)-sensitive K⁺ (mitoKATP) channel plays an important role in mitochondrial bioenergetics, which is a prerequisite for liver regeneration. However, the ATP-sensitive K⁺ (KATP) channel in hepatocytes is incompletely understood. We investigated the KATP channel in hepatocytes and examined the effects of diazoxide, a potent KATP channel opener, on liver regeneration using a rat model. METHODS: Using rat primary hepatocytes, expression and localization of KATP channel subunits, Kir6.x and sulfonylurea receptor (SUR)x, were studied by polymerase chain reaction, Western blotting, and immunostaining. To investigate the role of KATP channel openers in liver regeneration, we allocated rats into four groups: control (vehicle) (n=24), diazoxide (n=24), vehicle plus channel blocker (n=6), and diazoxide plus channel blocker (n=6) groups. After 70% partial hepatectomy, hepatic tissue ATP levels, liver-to-body weight ratio, and proliferation rate of hepatocytes were examined. RESULTS: KATP channel subunits, Kir6.1 and SUR1, were detected on hepatic mitochondria. During liver regeneration, liver-to-body weight ratio, proliferation rate of hepatocytes, and the hepatic ATP level were significantly higher in the diazoxide group than the control group at 2 days after partial hepatectomy. These effects of diazoxide were neutralized by a KATP channel blocker. CONCLUSIONS: We demonstrated the existence of a mitoKATP channel in hepatocytes composed of Kir6.1 and SUR1. Diazoxide could enhance liver regeneration by keeping a higher ATP content of the liver tissue. These results suggest that diazoxide will sustain the mitochondrial energetics through the mitoKATP channel opening.

Metabolic syndrome correlates intracoronary stenosis detected by multislice computed tomography in male subjects with sleep-disordered breathing.

BACKGROUND: Sleep-disordered breathing (SDB), especially obstructive sleep apnea (OSA), has frequent complications include hypertension, dyslipidemia and insulin resistance based on abdominal obesity or excess visceral fat (called Syndrome Z). OSA is a potential risk factor for cardiovascular diseases. The clinical characteristics of Japanese OSA subjects with OSA remain unclear. The present study investigated prevalence and predictive factors of intracoronary stenosis detected by multislice computed tomography (MSCT) in Japanese male subjects with SDB/OSA. FINDINGS: The study (O-VFStudy) subjects were 39 Japanese men with SDB/OSA who underwent all-night cardiorespiratory monitoring with fully attended polysomnography, and moreover both fat computed tomography (CT) scan and 64-row MSCT coronary angiography. The prevalence of coronary stenosis in this selected population with SDB/OSA was 15%. Logistic regression analysis showed a significant relationship between age-adjusted CAD and metabolic syndrome (p < 0.05), but not serum adiponectin levels and nocturnal fall in adiponectin. Subjects with the metabolic syndrome had significantly higher prevalence of CAD (31.3 versus 4.3%, p = 0.033), and lower levels of serum adiponectin (4.5 ± 0.6 versus 6.4 ± 0.6 µg/mL, p = 0.014), compared with groups without the metabolic syndrome. CONCLUSIONS: The present study describes that the prevalence of greater than 50% intracoronary stenotic lesions detected by MSCT was 15% and the metabolic syndrome was correlated with intracoronary stenosis detected by MSCT in Japanese SDB/OSA subjects. TRIAL REGISTRATION: UMIN 000002997https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr.cgi?function=brows&action=brows&type=summary&recptno=R000003633&language=E.

Liver epithelial cells proliferate under hypoxia and protect the liver from ischemic injury via expression of HIF-1 alpha target genes.

BACKGROUND: The remnant liver after extended liver resection is susceptible to ischemic injury, resulting in the failure of liver regeneration and liver dysfunction. The present study is aimed to investigate the protective role of the liver epithelial cells (LEC), a liver progenitor cell, on hepatocytes with ischemia in vitro and in vivo. METHODS: LECs were isolated from rats and cultured under hypoxic conditions (2% O(2)). The cell viability and intracellular ATP levels were measured. The activation of hypoxia-inducible factor-1α (HIF-1α) was assessed by immunofluorescence. The expression of pyruvate dehydrogenase kinase-1 (PDK-1), stromal cell-derived factor-1 (SDF-1), and chemokine receptor 4 (CXCR4) were measured. Hepatocytes were treated with SDF-1 or LEC-conditioned medium under hypoxia, and cell viability was assessed. Finally, hemorrhagic shock was induced in rats with in vivo induction of endogenous LECs, and liver damage was assessed. RESULTS: In LECs, but not in hepatocytes, cellular viability and intracellular ATP levels were maintained, and nuclear translocation of HIF-1α and expression of pyruvate dehydrogenase kinase-1 mRNA were increased under hypoxic culture conditions. LECs express SDF-1, and CXCR4 expression was increased in hepatocytes under hypoxia. The survival of hepatocytes under hypoxic condition was significantly increased after treatment with SDF-1 or LEC-conditioned medium. The protective effect of conditioned medium was impaired by CXCR4 antagonists. In vivo induction of endogenous LECs suppressed elevation of serum AST and ALT levels after hemorrhage shock and ischemia-reperfusion. CONCLUSION: LECs are resistant to hypoxia and have a protective role for hepatocytes against hypoxia. Our results suggest that induction of endogenous LECs protected the liver from lethal insults by paracrine signaling of SDF-1 and differentiation into parenchymal cells.

Effective use of gemcitabine in the treatment of undifferentiated carcinoma with osteoclast-like giant cells of the pancreas with portal vein tumor thrombus.

A 74-year-old woman had an undifferentiated carcinoma with osteoclast-like giant cells (UCWOGC) in the body of the pancreas with massive portal vein tumor thrombus (PVTT). Because the PVTT progressed so rapidly into the right portal branch, the patient first underwent distal pancreatectomy and tumor thrombectomy to prevent life-threatening portal venous obstruction. Although a recurrent PVTT had developed early postoperatively, systemic gemcitabine treatment was so effective that it induced complete remission 5 months after the initiation of chemotherapy. The patient continued to be in complete response for 12 months, and has survived for 19 months since surgery.

A pilot investigation of visceral fat adiposity and gene expression profile in peripheral blood cells.

Evidence suggests that visceral fat accumulation plays a central role in the development of metabolic syndrome. Excess visceral fat causes local chronic low-grade inflammation and dysregulation of adipocytokines, which contribute in the pathogenesis of the metabolic syndrome. These changes may affect the gene expression in peripheral blood cells. This study for the first time examined the association between visceral fat adiposity and gene expression profile in peripheral blood cells. The gene expression profile was analyzed in peripheral blood cells from 28 obese subjects by microarray analysis. Reverse transcription-polymerase chain reaction (RT-PCR) was performed using peripheral blood cells from 57 obese subjects. Obesity was defined as body mass index (BMI) greater than 25 kg/m(2) according to the Japanese criteria, and the estimated visceral fat area (eVFA) was measured by abdominal bioelectrical impedance. Analysis of gene expression profile was carried out with Agilent whole human genome 4 × 44 K oligo-DNA microarray. The expression of several genes related to circadian rhythm, inflammation, and oxidative stress correlated significantly with visceral fat accumulation. Period homolog 1 (PER1) mRNA level in blood cells correlated negatively with visceral fat adiposity. Stepwise multiple regression analysis identified eVFA as a significant determinant of PER1 expression. In conclusion, visceral fat adiposity correlated with the expression of genes related to circadian rhythm and inflammation in peripheral blood cells.