Publications by authors named "Gen Yamamoto"

27 Publications

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Immunotherapy-based targeting of MSLN activated portal fibroblasts is a strategy for treatment of cholestatic liver fibrosis.

Proc Natl Acad Sci U S A 2021 Jul;118(29)

Department of Surgery, University of California San Diego Medical Center, La Jolla, CA 92161;

We investigated the role of mesothelin (Msln) and thymocyte differentiation antigen 1 (Thy1) in the activation of fibroblasts across multiple organs and demonstrated that Msln mice are protected from cholestatic fibrosis caused by Mdr2 (multidrug resistance gene 2) deficiency, bleomycin-induced lung fibrosis, and UUO (unilateral urinary obstruction)-induced kidney fibrosis. On the contrary, Thy1 mice are more susceptible to fibrosis, suggesting that a Msln-Thy1 signaling complex is critical for tissue fibroblast activation. A similar mechanism was observed in human activated portal fibroblasts (aPFs). Targeting of human MSLN aPFs with two anti-MSLN immunotoxins killed fibroblasts engineered to express human mesothelin and reduced collagen deposition in livers of bile duct ligation (BDL)-injured mice. We provide evidence that antimesothelin-based therapy may be a strategy for treatment of parenchymal organ fibrosis.
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http://dx.doi.org/10.1073/pnas.2101270118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8307749PMC
July 2021

Interleukin-17 in Liver Disease Pathogenesis.

Semin Liver Dis 2021 Jun 15. Epub 2021 Jun 15.

Department of Surgery, University of California, San Diego, La Jolla, CA.

Interleukin 17A (IL-17A)-producing T helper 17 (Th17) cells were identified as a subset of T helper cells that play a critical role in host defense against bacterial and fungal pathogens. Th17 cells differentiate from Th0 naïve T-cells in response to transforming growth factor β1 (TGF-β1) and IL-6, the cytokines which also drive development of liver fibrosis, require activation of transcription factor retinoic acid receptor-related orphan nuclear receptor gamma (RORγ). IL-17A signals through the ubiquitously expressed receptor IL-17RA. Expression of IL-17RA is upregulated in patients with hepatitis B virus/hepatitis C virus (HBV/HCV) infections, nonalcoholic steatohepatitis (NASH), alcohol-associated liver disease (AALD), hepatocellular carcinoma (HCC), and experimental models of chronic toxic liver injury. The role of IL-17 signaling in the pathogenesis of NASH- and AALD-induced metabolic liver injury and HCC will be the focus of this review. The role of IL-17A-IL-17RA axis in mediation of the cross-talk between metabolically injured hepatic macrophages, hepatocytes, and fibrogenic myofibroblasts will be discussed.
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http://dx.doi.org/10.1055/s-0041-1730926DOI Listing
June 2021

Novel mouse model for cholestasis-induced liver fibrosis resolution by cholecystojejunostomy.

J Gastroenterol Hepatol 2021 Jan 15. Epub 2021 Jan 15.

Division of Hepato-Biliary-Pancreatic Surgery and Transplantation, Department of Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan.

Background And Aim: Studies on the resolution of liver fibrosis are becoming more important in this era of etiologic eradication. In contrast to the extensive research on the recovery of liver fibrosis induced by hepatotoxic injuries, regression of cholestatic liver fibrosis has been insufficiently examined owing to the limited availability of animal models.

Methods: We examined our novel recanalization mice model of biliary obstruction, involving anastomosis between the gallbladder and jejunum (G-J anastomosis) by invagination. Transgenic mice expressing green fluorescent protein (GFP) under the collagen 1(α)1 promoter underwent G-J anastomosis 14 days after bile duct ligation (BDL) and were sacrificed 14 days later.

Results: Transaminase and total bilirubin levels decreased to almost normal values on day 14 after G-J anastomosis. G-J anastomosis resulted in dramatic reversal of liver fibrosis induced by BDL. Activated portal fibroblasts (PFs) double-positive for GFP and Thy-1 on immunofluorescence in the liver of BDL-injured mice became less noticeable following G-J anastomosis. Messenger RNA expression of markers for activated PFs in the liver was downregulated after anastomosis. Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) were induced by BDL. After anastomosis, expressions of MMP-3, 8 as well as hepatocyte growth factor were further upregulated, whereas those of TIMP-1 and TIMP-3 were markedly downregulated.

Conclusions: Our established G-J anastomosis model is associated with fibrosis resolution and reduced PF activation through reopening of bile duct obstruction and will be valuable for studying the recovery process of cholestatic liver fibrosis.
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http://dx.doi.org/10.1111/jgh.15406DOI Listing
January 2021

Response to: Is ALPlat criterion justified for predicting posthepatectomy liver failure?

Surgery 2020 12 24;168(6):1180-1181. Epub 2020 Sep 24.

Department of Surgery, Kyoto University Graduate School of Medicine, Japan. Electronic address:

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http://dx.doi.org/10.1016/j.surg.2020.08.028DOI Listing
December 2020

Utility of Mac-2 Binding Protein Glycosylation Isomer to Evaluate Graft Status After Liver Transplantation.

Liver Transpl 2021 02 1;27(3):403-415. Epub 2020 Oct 1.

Division of Hepato-Biliary-Pancreatic Surgery and Transplantation, Department of Surgery, Kyoto University, Kyoto, Japan.

Mac-2 binding protein glycosylation isomer (M2BPGi) is a novel liver fibrosis biomarker, but there are few studies on M2BPGi in liver transplantation (LT) recipients. This study aimed to evaluate the utility of M2BPGi measurement in LT recipients. We collected the clinicopathological data of 233 patients who underwent a liver biopsy at Kyoto University Hospital after LT between August 2015 and June 2019. The median values of M2BPGi in patients with METAVIR fibrosis stages F0, F1, F2, and ≥F3 were 0.61, 0.76, 1.16, and 1.47, respectively, whereas those in patients with METAVIR necroinflammatory indexes A0, A1, and ≥A2 were 0.53, 1.145, and 2.24, respectively. Spearman rank correlation test suggested that the necroinflammatory index had a stronger correlation to the M2BPGi value than the fibrosis stage. The area under the receiver operating characteristic curve of M2BPGi to predict ≥A1 was 0.75, which was significantly higher than that of any other liver fibrosis and inflammation marker. Patients with a rejection activity index (RAI) of ≥3 had a higher M2BPGi value than those with RAI ≤ 2 (P = 0.001). Patients with hepatitis C virus viremia had a higher M2BPGi value than sustained virological responders or those with other etiologies. In conclusion, the present study demonstrated that M2BPGi values are more strongly influenced by necroinflammatory activity and revealed M2BPGi, which has been thought to be a so-called fibrosis marker, as a disease activity marker in transplant recipients. M2BPGi measurement may be useful to detect early stage liver inflammation that cannot be detected by routine blood examination of LT recipients.
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http://dx.doi.org/10.1002/lt.25870DOI Listing
February 2021

IL-17 signaling in steatotic hepatocytes and macrophages promotes hepatocellular carcinoma in alcohol-related liver disease.

J Hepatol 2020 05 31;72(5):946-959. Epub 2019 Dec 31.

Department of Surgery, University of California San Diego, La Jolla, CA, USA. Electronic address:

Background & Aims: Chronic alcohol consumption is a leading risk factor for the development of hepatocellular carcinoma (HCC), which is associated with a marked increase in hepatic expression of pro-inflammatory IL-17A and its receptor IL-17RA.

Methods: Genetic deletion and pharmacological blocking were used to characterize the role of IL-17A/IL-17RA signaling in the pathogenesis of HCC in mouse models and human specimens.

Results: We demonstrate that the global deletion of the Il-17ra gene suppressed HCC in alcohol-fed diethylnitrosamine-challenged Il-17ra and major urinary protein-urokinase-type plasminogen activator/Il-17ra mice compared with wild-type mice. When the cell-specific role of IL-17RA signaling was examined, the development of HCC was decreased in both alcohol-fed Il-17ra and Il-17ra mice devoid of IL-17RA in myeloid cells and hepatocytes, but not in Il-17ra mice (deficient in IL-17RA in hepatic stellate cells). Deletion of Il-17ra in myeloid cells ameliorated tumorigenesis via suppression of pro-tumorigenic/inflammatory and pro-fibrogenic responses in alcohol-fed Il-17ra mice. Remarkably, despite a normal inflammatory response, alcohol-fed Il-17ra mice developed the fewest tumors (compared with Il-17ra mice), with reduced steatosis and fibrosis. Steatotic IL-17RA-deficient hepatocytes downregulated the expression of Cxcl1 and other chemokines, exhibited a striking defect in tumor necrosis factor (TNF)/TNF receptor 1-dependent caspase-2-SREBP1/2-DHCR7-mediated cholesterol synthesis, and upregulated the production of antioxidant vitamin D. The pharmacological blocking of IL-17A/Th-17 cells using anti-IL-12/IL-23 antibodies suppressed the progression of HCC (by 70%) in alcohol-fed mice, indicating that targeting IL-17 signaling might provide novel strategies for the treatment of alcohol-induced HCC.

Conclusions: Overall, IL-17A is a tumor-promoting cytokine, which critically regulates alcohol-induced hepatic steatosis, inflammation, fibrosis, and HCC.

Lay Summary: IL-17A is a tumor-promoting cytokine, which critically regulates inflammatory responses in macrophages (Kupffer cells and bone-marrow-derived monocytes) and cholesterol synthesis in steatotic hepatocytes in an experimental model of alcohol-induced HCC. Therefore, IL-17A may be a potential therapeutic target for patients with alcohol-induced HCC.
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http://dx.doi.org/10.1016/j.jhep.2019.12.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7167339PMC
May 2020

ALPlat criterion for the resection of hepatocellular carcinoma based on a predictive model of posthepatectomy liver failure.

Surgery 2020 02 11;167(2):410-416. Epub 2019 Nov 11.

Department of Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan.

Background: The indocyanine green test is used widely to evaluate the risk of posthepatectomy liver failure for hepatocellular carcinoma. A more convenient and reliable scoring system is desired owing to limited accuracy and availability of the indocyanine green test. This study aimed to establish a new selection criterion for liver resection in HCC.

Methods: We reviewed retrospectively 876 patients undergoing a partial hepatectomy for hepatocellular carcinoma between 2007 and 2015 in 8 affiliated hospitals. Posthepatectomy liver failure grades B and C were regarded as posthepatectomy liver failure. We identified the risk factors for posthepatectomy liver failure and established a predictive model based on a formula for the probability of posthepatectomy liver failure. External validation was performed in an additional cohort of 250 patients.

Results: Posthepatectomy liver failure occurred in 92 patients (11%). The area under the receiver operating characteristic curve for the prediction of posthepatectomy liver failure was 0.646 for the platelet count, 0.641 for albumin, 0.623 for the percentage of liver remnant, and 0.607 for the plasma disappearance rate of indocyanine green. Logistic regression analysis provided a formula for the probability of posthepatectomy liver failure consisting of platelet count, albumin, and liver remnant. We defined platelet count + 90 × albumin as the ALPlat index and established an ALPlat-based criterion for operative resection that secured the same risk assumed by the indocyanine green-based criterion (Makuuchi's criterion). This criterion exhibited a greater sensitivity and specificity than the indocyanine green-based criterion in the validation cohort.

Conclusion: The ALPlat criterion is a simple and useful method to assess liver function and to make therapeutic decisions in patients with hepatocellular carcinoma.
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http://dx.doi.org/10.1016/j.surg.2019.09.021DOI Listing
February 2020

Long-term impact and clinical significance of living donor liver transplantation with respect to donor liver restoration and spleen size: A prospective study.

Am J Transplant 2020 03 23;20(3):808-816. Epub 2019 Oct 23.

Division of Hepato-Biliary-Pancreatic Surgery and Transplantation, Department of Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan.

This study aimed to evaluate postoperative long-term liver restoration and splenic enlargement and their clinical significance in living donor liver transplantation. One hundred and sixteen donors who had donated livers more than 5 years previously accepted the invitation to participate in this study. The liver restoration rate and the splenic enlargement rate were calculated as the rate with respect to the original volume. The mean liver restoration rate was 0.99 ± 0.12 and older age was associated with a higher incidence for liver restoration rate <0.95 (P = .005), whereas type of donor operation was not. The donors with liver restoration rate <0.95 showed lower serum albumin levels than those with liver restoration rate ≥0.95. The mean splenic enlargement rate was 1.10 ± 0.16. Right lobe donors demonstrated higher splenic enlargement rate (1.14 ± 0.18) than left lobe/lateral segment donors (1.06 ± 0.13). In the donors with splenic enlargement rate ≥1.10, platelet count was not fully restored to the preoperative level. In conclusion, older age increases the risk for incomplete postoperative liver restoration, which may be associated with a decrease in albumin more than 5 years after donation. Right lobe donation poses a risk of splenic enlargement, which is associated with incomplete restoration of platelet count.
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http://dx.doi.org/10.1111/ajt.15627DOI Listing
March 2020

Impact of Graft Quality and Fluid Overload on Postoperative Massive Ascites After Living Donor Liver Transplantation.

Transplant Proc 2019 Jul - Aug;51(6):1779-1784. Epub 2019 Jul 10.

Department of Hepatobiliary, Pancreas and Transplant Surgery, Kyoto University, Kyoto, Japan.

After living donor liver transplantation, we encounter cases with massive ascites, which is difficult to manage. We analyzed the risk factors for massive ascites after living donor liver transplantation. The subjects were 100 adult recipients who underwent living donor liver transplantation at Kyoto University Hospital from 2013 to 2017. We retrospectively assessed patient, graft, operative factors, and percent fluid overload, which were defined as [(weight on the day - preoperative weight)/preoperative weight] × 100%. We defined the massive ascites group as having a14-day average ascites ≥ 2500 mL and the mild ascites group as having a 14-day average ascites < 2500 mL. Forty-seven patients were included in the massive group, and 53 patients were included in the mild group. There was no difference in short- and long-term survival. In multivariate analysis, the presence of preoperative ascites (P = .0008), 14-day average percent fluid overload ≥ 14.5% (P = .0095), graft-to-recipient weight ratio < 0.86 (P = .0253), and donors' age ≥ 47 years (P = .0466) were identified as independent risk factors for massive ascites after living donor liver transplantation. A liver graft with a small graft-to-recipient weight ratio or from an elderly donor, which may indicate poor graft quality, presence of preoperative ascites, and postoperative fluid overload were associated with massive ascites after living donor liver transplantation.
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http://dx.doi.org/10.1016/j.transproceed.2019.03.038DOI Listing
November 2019

Activated hepatic stellate cells and portal fibroblasts contribute to cholestatic liver fibrosis in MDR2 knockout mice.

J Hepatol 2019 09 7;71(3):573-585. Epub 2019 May 7.

Department of Surgery, University of California San Diego, La Jolla, CA, USA. Electronic address:

Background & Aims: Chronic liver injury often results in the activation of hepatic myofibroblasts and the development of liver fibrosis. Hepatic myofibroblasts may originate from 3 major sources: hepatic stellate cells (HSCs), portal fibroblasts (PFs), and fibrocytes, with varying contributions depending on the etiology of liver injury. Here, we assessed the composition of hepatic myofibroblasts in multidrug resistance gene 2 knockout (Mdr2) mice, a genetic model that resembles primary sclerosing cholangitis in patients.

Methods: Mdr2 mice expressing a collagen-GFP reporter were analyzed at different ages. Hepatic non-parenchymal cells isolated from collagen-GFP Mdr2 mice were sorted based on collagen-GFP and vitamin A. An NADPH oxidase (NOX) 1/4 inhibitor was administrated to Mdr2 mice aged 12-16 weeks old to assess the therapeutic approach of targeting oxidative stress in cholestatic injury.

Results: Thy1 activated PFs accounted for 26%, 51%, and 54% of collagen-GFP myofibroblasts in Mdr2 mice at 4, 8, and 16 weeks of age, respectively. The remaining collagen-GFP myofibroblasts were composed of activated HSCs, suggesting that PFs and HSCs are both activated in Mdr2 mice. Bone-marrow-derived fibrocytes minimally contributed to liver fibrosis in Mdr2 mice. The development of cholestatic liver fibrosis in Mdr2 mice was associated with early recruitment of Gr1 myeloid cells and upregulation of pro-inflammatory cytokines (4 weeks). Administration of a NOX inhibitor to 12-week-old Mdr2 mice suppressed the activation of myofibroblasts and attenuated the development of cholestatic fibrosis.

Conclusions: Activated PFs and activated HSCs contribute to cholestatic fibrosis in Mdr2 mice, and serve as targets for antifibrotic therapy.

Lay Summary: Activated portal fibroblasts and hepatic stellate cells, but not fibrocytes, contributed to the production of the fibrous scar in livers of Mdr2 mice, and these cells can serve as targets for antifibrotic therapy in cholestatic injury. Therapeutic inhibition of the enzyme NADPH oxidase (NOX) in Mdr2 mice reversed cholestatic fibrosis, suggesting that targeting NOXs may be an effective strategy for the treatment of cholestatic fibrosis.
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http://dx.doi.org/10.1016/j.jhep.2019.04.012DOI Listing
September 2019

Efficiency of acoustic radiation force impulse imaging for the staging of graft fibrosis after liver transplantation.

Hepatol Res 2019 Apr 2;49(4):394-403. Epub 2019 Jan 2.

Department of Surgery, Graduate School of Medicine Kyoto University, Kyoto, Japan.

Aim: Liver biopsy is the gold standard for assessing liver fibrosis (LF) after liver transplantation (LT), but its invasiveness limits its utility. This study aimed to evaluate the usefulness of liver stiffness measurement (LSM) using acoustic radiation force impulse (ARFI) imaging to assess LF after LT.

Methods: Between September 2013 and January 2017, 278 patients who underwent liver biopsy after LT in Kyoto University Hospital (Kyoto, Japan) were prospectively enrolled. Liver stiffness measurement was carried out using ARFI imaging; its value was expressed as shear wave velocity (Vs) [m/s]. The LF was evaluated according to METAVIR score (F0-F4). The diagnostic performance of Vs for F2≤ and F3≤ was assessed and compared with that of laboratory tests using receiver operating characteristic (ROC) analysis.

Results: The median Vs values increased according to the progression of LF (F0, 1.18 (0.78-1.92); F1, 1.35 (0.72-3.54); F2, 1.55 (1.05-3.37); F3, 1.84 (1.41-2.97)). The Vs had the highest area under the ROC curve (AUROC) for the prediction of both F2 ≤ and F3 ≤ fibrosis (F2, 0.77; and F3, 0.85). With the cut-off value of Vs >1.31, sensitivity, specificity, positive predictive value, and negative predictive value were 89.4%, 53.3%, 37.3%, and 94.2% in predicting F2≤, respectively. Shear wave velocity diagnosed LF better than any laboratory tests regardless of the type of primary disease.

Conclusions: Acoustic radiation force impulse helps to assess graft LF after LT. The high sensitivity suggested that ARFI might reduce the frequency of liver biopsies by detecting patients who are unlikely to have significant fibrosis after LT. (Unique trial no. UMIN R000028296.).
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http://dx.doi.org/10.1111/hepr.13289DOI Listing
April 2019

Sclerosing encapsulating peritonitis after living-donor liver transplantation: A case series, Kyoto experience.

Ann Hepatobiliary Pancreat Surg 2018 May 30;22(2):144-149. Epub 2018 May 30.

Division of Hepato-Biliary-Pancreatic and Transplant Surgery, Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

Sclerosing encapsulating peritonitis (SEP), or abdominal cocoon is a rare cause of intestinal obstruction, and still etiology remains unknown. We report a series of 4 patients with abdominal cocoon, and all the 4 patients had previously undergone living-donor liver transplantation (LDLT). There was no evidence of SEP before and during LDLT. At the time of diagnosis of SEP, 3 out of 4 patients had ascites. First and fourth patients had multiple episodes or attacks of cholangitis, which were managed by percutaneous transhepatic biliary drainage and hepaticojejunostomy, respectively. All 4 patients presented with intestinal obstruction and 3 of them underwent a successful operation. The fourth patient died due to liver failure and complications of the SEP. The first 3 patients are doing well without SEP recurrence. Our experience suggest that the prognosis of SEP is poor in patients with poor graft liver functions after LDLT.
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http://dx.doi.org/10.14701/ahbps.2018.22.2.144DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5981144PMC
May 2018

Usefulness of Preoperative F-FDG-PET in Detecting Invasive Intraductal Papillary Neoplasm of the Bile Duct.

Anticancer Res 2018 Jun;38(6):3677-3682

Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

Background/aim: Preoperative identification of the invasive component remains challenging in intraductal papillary neoplasm of the bile duct (IPNB). We evaluated the ability of preoperative F-fluorodeoxyglucose positron emission tomography (F-FDG-PET) to differentiate between non-invasive IPNB, invasive IPNB, and papillary cholangiocarcinoma (CCA).

Patients And Methods: The maximum standardized uptake values (SUV) of 11 patients with IPNB (6 non-invasive and 5 invasive) and 20 with papillary CCA who underwent pre-surgical F-FDG-PET were assessed. The SUV cut-off that predicts an invasive component was determined using receiver operating characteristic (ROC) curve analysis.

Results: The SUV in patients with invasive IPNB and papillary CCA were significantly higher than in patients with non-invasive IPNB (p=0.035 and 0.0025, respectively). ROC curve analysis revealed an optimal SUV cut-off of 4.5, which had 94.5% accuracy, 76.0% sensitivity, and 100% specificity.

Conclusion: Our data suggest that the preoperative F-FDG-PET SUV can differentiate non-invasive IPNB from invasive IPNB and papillary CCA.
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http://dx.doi.org/10.21873/anticanres.12645DOI Listing
June 2018

Low Preoperative Platelet Count Predicts Risk of Subclinical Posthepatectomy Liver Failure in Right Lobe Donors for Liver Transplantation.

Liver Transpl 2018 09;24(9):1178-1185

Department of Hepatobiliary, Pancreas and Transplant Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

Living donor right hepatectomy (LDRH) is a common procedure in adult-to-adult living donor liver transplantation, but it is associated with a higher risk of posthepatectomy liver failure (PHLF) compared with left hepatectomy because of a smaller remnant. We identified risk factors for PHLF and other complications in LDRH, verified the appropriateness of the criteria, and explored the possibility of adjusting the minimum remnant liver volume (RLV) based on individual risk. Between October 2005 and November 2017, 254 donors undergoing LDRH at Kyoto University Hospital were enrolled. Clinical data were collected retrospectively. All complications were graded according to the Clavien-Dindo classification. No donors had grade 4 or 5 complications or clinically significant grade B or C PHLF. Grade A PHLF occurred in 30 donors (11.8%). Male sex (P = 0.01), lower preoperative platelet count (PLT; P = 0.01), higher prothrombin time-international normalized ratio (P = 0.03), higher total bilirubin (P = 0.01), smaller RLV (P = 0.03), and greater blood loss (P = 0.04) were associated with increased risk of PHLF in the univariate analysis, whereas PLT, RLV, and blood loss remained significant in the multivariate analysis. Grade 2 or 3 complications were observed in 32 (12.6%) donors. Higher body mass index (BMI; P = 0.002) and larger blood loss (P = 0.02) were identified as risk factors for complications (Clavien-Dindo grade ≥ 2) in univariate analysis. Only BMI remained significant in the multivariate analysis. In conclusion, LDRH is performed safely with acceptable morbidity under the current criteria. Minimum RLV may be marginally adjusted by PLT and reducing intraoperative blood loss minimizes PHLF risk. Liver Transplantation 00 000-000 2018 AASLD.
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http://dx.doi.org/10.1002/lt.25181DOI Listing
September 2018

Mass-forming intrahepatic cholangiocarcinoma with portal vein tumor thrombus and bile duct tumor thrombus: A case report.

Int J Surg Case Rep 2017 8;40:13-16. Epub 2017 Sep 8.

Division of Hepato-Biliary-Pancreatic and Transplant Surgery, Department of Surgery, Graduate School of Medicine, Kyoto University, 54 Kawaharacho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan. Electronic address:

Introduction: We report the first case of mass-forming intrahepatic cholangiocarcinoma (ICC) with portal vein tumor thrombus (PVTT) and bile duct tumor thrombus (BDTT), where the extrahepatic bile duct was preserved with thrombectomy.

Presentation Of Case: A 70-year-old male. Magnetic resonance imaging (MRI) showed the tumor extending from the hepatic hilum to the left hepatic duct with complete obstruction of the left hepatic duct and a defect at the left portal vein. We planned to perform extended left lobectomy, lymph node dissection, extra hepatic bile duct resection and reconstruction based on the diagnosis of mass-forming ICC with left portal vein and left hepatic duct infiltration (cT3N0M0 Stage III). Intraoperative cholangiography revealed a crab claw-like filling defect at the left hepatic duct, which suggested tumor thrombus. Accordingly, we performed thrombectomy. The margin of the left hepatic duct was tumor negative, so we performed extended left lobectomy, lymph node dissection and thrombectomy. Pathologically, the tumor was diagnosed as ICC (pT4N0M0 Stage IVA, vp3, b3). Tumors in the left hepatic duct and left portal vein proved to be tumor thrombus. The postoperative course was uneventful. He is doing well without recurrence.

Discussion: Thrombectomy is performed for hepatocellular carcinoma (HCC) with tumor thrombus. Furthermore, extrahepatic bile duct resection and reconstruction are recommended for ICC. In this case, intraoperative cholangiography was effective for precisely diagnosing. Thrombectomy could reduce surgical stress and prevent complications.

Conclusions: Thrombectomy can be a valid option for ICC with tumor thrombus, as well as for HCC.
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http://dx.doi.org/10.1016/j.ijscr.2017.08.059DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5602881PMC
September 2017

Pancreatic Stellate Cells Have Distinct Characteristics From Hepatic Stellate Cells and Are Not the Unique Origin of Collagen-Producing Cells in the Pancreas.

Pancreas 2017 10;46(9):1141-1151

From the *Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan; †Innovation Center for Immunoregulation and Therapeutics, Graduate School of Medicine, Kyoto University, Kyoto, Japan; and ‡Medical Research Support Center, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

Objectives: The origin of collagen-producing myofibroblasts in pancreatic fibrosis is still controversial. Pancreatic stellate cells (PSCs), which have been recognized as the pancreatic counterparts of hepatic stellate cells (HSCs), are thought to play an important role in the development of pancreatic fibrosis. However, sources of myofibroblasts other than PSCs may exist because extensive studies of liver fibrosis have uncovered myofibroblasts that did not originate from HSCs. This study aimed to characterize myofibroblasts in an experimental pancreatic fibrosis model in mice.

Methods: We used transgenic mice expressing green fluorescent protein via the collagen type I α1 promoter and induced pancreatic fibrosis with repetitive injections of cerulein.

Results: Collagen-producing cells that are negative for glial fibrillary acidic protein (ie, not derived from PSCs) exist in the pancreas. Pancreatic stellate cells had different characteristics from those of HSCs in a very small possession of vitamin A using mass spectrometry and a low expression of lecithin retinol acyltransferase. The microstructure of PSCs was entirely different from that of HSCs using flow cytometry and electron microscopy.

Conclusions: Our study showed that characteristics of PSCs are different from those of HSCs, and myofibroblasts in the pancreas might be derived not only from PSCs but also from other fibrogenic cells.
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http://dx.doi.org/10.1097/MPA.0000000000000901DOI Listing
October 2017

Chronological Profiling of Plasma Native Peptides after Hepatectomy in Pigs: Toward the Discovery of Human Biomarkers for Liver Regeneration.

PLoS One 2017 6;12(1):e0167647. Epub 2017 Jan 6.

Department of Genomic Medical Sciences, Kyoto Prefectural University of Medicine, Graduate School of Medical Science, Kyoto, Japan.

Liver regeneration after partial hepatectomy (PHx) is a time-dependent process, which is tightly regulated by multiple signaling cascades. Failure of this complex process leads to posthepatectomy liver failure (PHLF), which is associated with a high rate of mortality. Thus, it is extremely important to establish a useful biomarker of liver regeneration to help prevent PHLF. Here, we hypothesized that alterations in the plasma peptide profile may predict liver regeneration following PHx and hence we set up a diagnostic platform for monitoring posthepatectomy outcome. We chronologically analyzed plasma peptidomic profiles of 5 partially hepatectomized microminipigs using the ClinProtTM system, which consists of magnetic beads and MALDI-TOF/TOF MS. We identified endogenous circulating peptides specific to each phase of the postoperative course after PHx in pigs. Notably, peptide fragments of histones were detected immediately after PHx; the presence of these fragments may trigger liver regeneration in the very acute phase after PHx. An N-terminal fragment of hemoglobin subunit α (3627 m/z) was detected as an acute-phase-specific peptide. In the recovery phase, the short N-terminal fragments of albumin (3028, 3042 m/z) were decreased, whereas the long N-terminal fragment of the protein (8926 m/z) was increased. To further validate and extract phase-specific biomarkers using plasma peptidome after PHx, plasma specimens of 4 patients who underwent PHx were analyzed using the same method as we applied to pigs. It revealed that there was also phase-specificity in peptide profiles, one of which was represented by a fragment of complement C4b (2378 m/z). The strategy described herein is highly efficient for the identification and characterization of peptide biomarkers of liver regeneration in a swine PHx model. This strategy is feasible for application to human biomarker studies and will yield clues for understanding liver regeneration in human clinical trials.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0167647PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5218562PMC
August 2017

Hepatic vagus nerve regulates Kupffer cell activation via α7 nicotinic acetylcholine receptor in nonalcoholic steatohepatitis.

J Gastroenterol 2017 Aug 2;52(8):965-976. Epub 2017 Jan 2.

Department of Surgery, Graduate School of Medicine, Kyoto University, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, Japan.

Background: Nonalcoholic fatty liver disease ranges from simple steatosis to nonalcoholic steatohepatitis (NASH). Kupffer cells play a central role in promoting hepatic inflammation, which leads to the development of NASH. We investigated the anti-inflammatory effect of hepatic vagus-mediated stimulation of the α7 nicotinic acetylcholine receptor (α7nAChR) on Kupffer cells in NASH pathogenesis.

Methods: Wild-type (WT) mice undergoing hepatic vagotomy (HV) were fed a methionine- and choline-deficient (MCD) diet for 1 week. α7nAChR knockout (α7KO) chimeric mice were generated by transplanting α7KO bone marrow cells into irradiated and Kupffer cell-deleted WT recipients. Kupffer cells were isolated from WT mice and treated with α7nAChR agonist under stimulation by lipopolysaccharide and/or palmitic acid.

Results: HV aggravated MCD diet-induced NASH in both steatosis and inflammation. The hepatic inflammatory response, including the upregulation of tumor necrosis factor alpha (TNFα), interleukin (IL)-12, and monocyte chemoattractant protein 1 (MCP-1), was accelerated in HV mice, accompanied by the downregulation of PPARα pathway genes. Kupffer cells were highly activated via the phosphorylation and nuclear translocation of nuclear factor-kappa B (NF-κB) in MCD diet-fed HV mice. The α7nAchR agonist suppressed the inflammatory response of primary Kupffer cells induced by lipopolysaccharide and palmitic acid by attenuating the NF-κB cascade. α7KO chimeric mice fed an MCD diet for 1 week developed advanced NASH with highly activated Kupffer cells. The hepatic expression of TNFα, IL-12, and MCP-1 was upregulated in α7KO chimeric mice, accompanied by abnormal lipid metabolism.

Conclusions: Hepatic vagus activity regulates the inflammatory response of Kupffer cells via α7nAChR in NASH development.
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http://dx.doi.org/10.1007/s00535-016-1304-zDOI Listing
August 2017

Usefulness of Mac-2 Binding Protein Glycosylation Isomer for Prediction of Posthepatectomy Liver Failure in Patients With Hepatocellular Carcinoma.

Ann Surg 2017 06;265(6):1201-1208

*Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan †Department of Pharmacoepidemiology, Graduate School of Medicine and Public Health, Kyoto University, Kyoto, Japan.

Objective: The aim of this study was to evaluate the usefulness of the Mac-2 binding protein glycosylation isomer (M2BPGi) for the prediction of posthepatectomy liver failure (PHLF) in hepatocellular carcinoma (HCC) patients.

Summary Background Data: M2BPGi is a novel serum marker of liver fibrosis. The usefulness of M2BPGi for the prediction of PHLF has not been evaluated.

Methods: Clinicopathological data were analyzed in 138 HCC patients who underwent liver resection between August 2011 and November 2014. PHLF was evaluated according to the definition of the International Study Group of Liver Surgery. Performance of preoperative parameters in predicting PHLF was determined using receiver operating characteristic (ROC) analysis.

Results: Serum M2BPGi level correlated with the METAVIR fibrosis score. M2BPGi levels of hepatitis C virus (HCV)-positive patients were significantly higher than those of HCV-negative patients, even in the same fibrosis stage. PHLF ≥ Grade B developed in 19 patients (13.8%). The area under the ROC curve (AUROC) of M2BPGi for the prediction of PHLF ≥ Grade B was 0.71. In multivariate analysis, M2BPGi [odds ratio (OR): 2.08, 95% confidence interval (CI) 1.28-3.55], platelet count (OR: 0.39, 95% CI 0.18-0.80), and resection rate (OR: 2.71, 95% CI 1.46-5.40) were the significant factors associated with PHLF ≥ Grade B. The AUROC of the PHLF index defined by these factors was 0.81. Notably, in patients with HCV infection, the predictive ability of M2BPGi for PHLF (AUROC 0.85) was the best among the preoperative parameters.

Conclusions: M2BPGi is a useful predictor of PHLF, especially in patients with HCV infection.
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http://dx.doi.org/10.1097/SLA.0000000000001836DOI Listing
June 2017

Prediction of posthepatectomy liver failure based on liver stiffness measurement in patients with hepatocellular carcinoma.

Surgery 2016 Feb 21;159(2):399-408. Epub 2015 Jul 21.

Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

Background: Posthepatectomy liver failure (PHLF) is a potentially fatal complication, and the accurate prediction of PHLF is essential. Liver stiffness measurement (LSM) has been accepted widely as a noninvasive assessment for liver fibrosis. We aimed to evaluate the usefulness of LSM in predicting PHLF.

Methods: One hundred seventy-seven patients with hepatocellular carcinoma who underwent liver resection between August 2011 and October 2014 were analyzed prospectively. LSM was performed by Virtual Touch Tissue Quantification based on acoustic radiation force impulse imaging, and its value was expressed as the shear wave velocity (Vs) [m/s]. The remnant liver volume rate (Rem) was calculated by computed tomography volumetry. PHLF was diagnosed on the basis of the definition from the International Study Group of Liver Surgery.

Results: PHLF occurred in 38 patients (21.5%): grade A, 17 patients (9.6%); grade B, 15 patients (8.5%); and grade C, 6 patients (3.4%). The area under the receiver operating characteristic curve of the Vs for predicting PHLF was 0.67 for grade ≥A, 0.78 for grade ≥B, and 0.74 for grade C, which was greater than any other preoperative factor for each grade. Multivariate stepwise selection identified 2 significant factors associated with PHLF grade ≥B: Vs (odds ratio, 2.66; 95% confidence interval, 1.69-4.41, P < .01) and Rem (odds ratio, 0.47; 95% confidence interval, 0.27-0.79, P < .01). The logistic model that included the Vs and Rem resulted in an area under the receiver operating characteristic curve of 0.80 for predicting PHLF grade ≥B.

Conclusion: LSM was useful for the prediction of PHLF and the estimation of the safe Rem range.
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http://dx.doi.org/10.1016/j.surg.2015.06.024DOI Listing
February 2016

Migration of splenic lymphocytes promotes liver fibrosis through modification of T helper cytokine balance in mice.

J Gastroenterol 2015 Oct 28;50(10):1054-68. Epub 2015 Feb 28.

Department of Surgery, Graduate School of Medicine, Kyoto University, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, 6068507, Japan.

Background: Sustained liver injury causes liver fibrosis and eventually cirrhosis. Understanding the pathophysiological mechanisms of liver fibrosis and interventions in the fibrotic process is crucial for improving the prognosis of patients with chronic liver diseases. Although studies have shown that splenectomy suppresses liver fibrosis, the mechanism by which this occurs is poorly understood. The present study focuses on the immunological functions of the spleen to investigate its role in liver fibrosis.

Methods: BALB/c and severe combined immunodeficiency (SCID) mice underwent splenectomies or sham operations prior to induction of liver fibrosis with carbon tetrachloride or thioacetamide.

Results: Sirius red staining and hydroxyproline assays showed that splenectomy suppressed liver fibrogenesis in BALB/c mice. Reverse transcription PCR analysis of T helper type 1 (Th1) and T helper type 2 (Th2) cytokines demonstrated that splenectomy shifted the Th1/Th2 balance in the liver towards Th1 dominance. In SCID mice, the inhibitory effect on liver fibrosis was abrogated. The number of CD4(+) T helper lymphocytes in the spleen decreased after liver injury. Green fluorescent protein positive (GFP(+)) splenocytes were transplanted into the spleens of syngeneic wild-type mice to trace their destination after fibrosis induction. GFP(+)CD4(+) lymphocytes appeared in the liver after induction of fibrosis, and flow cytometry revealed the vast majority of them were Th2 lymphocytes. Transfer of splenocytes via the portal vein into syngeneic splenectomized mice cancelled the suppressive effect of splenectomy on liver fibrosis.

Conclusions: The present study demonstrated that Th2-dominant splenic lymphocytes migrate into the liver and promote liver fibrosis by shifting the cytokine balance towards Th2 dominance. Splenectomy suppresses the progression of fibrosis at least partly by restoring the Th1/Th2 balance.
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http://dx.doi.org/10.1007/s00535-015-1054-3DOI Listing
October 2015

Hepatoprotective effect by pretreatment with olprinone in a swine partial hepatectomy model.

Liver Transpl 2014 Jul 26;20(7):838-49. Epub 2014 May 26.

Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

Excessive portal flow to a small remnant liver or small-for-size graft is a primary factor of small-for-size syndrome. We demonstrated that olprinone (OLP), a phosphodiesterase III inhibitor, had a hepatoprotective effect in a rat extended hepatectomy model and a small-for-size liver transplantation model through a modification of the portal venous pressure (PVP). To identify the appropriate dose and duration of treatment for clinical applications, we conducted experiments with a swine partial hepatectomy model. Twenty microminipigs were divided into 4 groups that received the following treatments: (A) saline (control group), (B) OLP at 0.3 μg/kg/minute (preoperative and postoperative administration), (C) OLP at 0.1 μg/kg/minute (preoperative administration), and (D) OLP at 0.3 μg/kg/minute (preoperative administration). The pigs underwent 70% partial hepatectomy. Hemodynamic changes, including changes in PVP, were examined. Liver biopsy was performed 1 and 3 hours after hepatectomy. Blood samples were collected until postoperative day 7 (POD7). In comparison with group A, PVP elevations, periportal edema, and sinusoidal hemorrhaging were attenuated after left Glisson's ligation in groups C and D. Pretreatment with OLP in groups C and D preserved the microstructure of sinusoids and improved the prothrombin activity 1 and 3 hours after hepatectomy. These animals showed better recovery of the remnant liver volume and the plasma disappearance rate of indocyanine green on POD7. In contrast, group B showed exacerbation of liver damage. Measurements of the serum OLP concentration showed that 10 ng/mL OLP was appropriate for a hepatoprotective effect. In conclusion, pretreatment with OLP shows hepatoprotective effects in a swine partial hepatectomy model. OLP may have the potential to ameliorate patients' outcomes after hepatectomy or liver transplantation.
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http://dx.doi.org/10.1002/lt.23884DOI Listing
July 2014

Effects of oral intake of hydrogen water on liver fibrogenesis in mice.

Hepatol Res 2014 Jun 18;44(6):663-677. Epub 2013 Jun 18.

Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

Aim: Liver fibrosis is the universal consequence of chronic liver diseases. Sustained hepatocyte injury initiates an inflammatory response, thereby activating hepatic stellate cells, the principal fibrogenic cells in the liver. Reactive oxygen species are involved in liver injury and are a promising target for treating liver fibrosis. Hydrogen water is reported to have potential as a therapeutic tool for reactive oxygen species-associated disorders. This study aimed to investigate the effects of hydrogen water on liver fibrogenesis and the mechanisms underlying these effects.

Methods: C57BL/6 mice were fed with hydrogen water or control water, and subjected to carbon tetrachloride, thioacetamide and bile duct ligation treatments to induce liver fibrosis. Hepatocytes and hepatic stellate cells were isolated from mice and cultured with or without hydrogen to test the effects of hydrogen on reactive oxygen species-induced hepatocyte injuries or hepatic stellate cell activation.

Results: Oral intake of hydrogen water significantly suppressed liver fibrogenesis in the carbon tetrachloride and thioacetamide models, but these effects were not seen in the bile duct ligation model. Treatment of isolated hepatocyte with 1 μg/mL antimycin A generated hydroxyl radicals. Culturing in the hydrogen-rich medium selectively suppressed the generation of hydroxyl radicals in hepatocytes and significantly suppressed hepatocyte death induced by antimycin A; however, it did not suppress hepatic stellate cell activation.

Conclusion: We conclude that hydrogen water protects hepatocytes from injury by scavenging hydroxyl radicals and thereby suppresses liver fibrogenesis in mice.
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http://dx.doi.org/10.1111/hepr.12165DOI Listing
June 2014

Effect of olprinone on liver microstructure in rat partial liver transplantation.

J Surg Res 2013 Jul 8;183(1):391-6. Epub 2012 Dec 8.

Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

Background: Donor safety is a major concern in living-donor liver transplantation. However, partial grafts do not meet the functional demands of recipients and lead to small-for-size syndrome (SFSS). In a previous study, we showed that olprinone (OLP), a selective phosphodiesterase ІІІ inhibitor, up-regulates endothelial nitric oxide synthase level in the liver and attenuates shear stress, sinusoidal endothelial cell injury, and hepatocyte apoptosis after excessive liver resection in a rat model. We aimed to examine whether OLP treatment has beneficial effects on SFSS in a rat model of partial liver transplantation (PLT).

Methods: We performed experiments in a rat model of 30% PLT. In the OLP group, we inserted an osmotic pump with OLP into the peritoneal cavity 48 h before liver graft sampling. Recipient rats were not treated with OLP. We examined the liver microstructure by electron microscopy and biochemical examination, and determined the 7-d survival of recipients.

Results: In the OLP group 1 h after PLT, the sinusoidal endothelial cells of the liver were well preserved and we observed few vacuolar structures in hepatocytes. The total serum bilirubin level 1 wk after PLT tended to be lower in the OLP group than in the controls, and the liver microstructures were also well preserved in the OLP group. The probability of survival in the OLP group (100%; 14 of 14 rats) was significantly higher than that in the control group (75%; 15 of 20 rats).

Conclusions: Olprinone treatment was demonstrated to have therapeutic potential to overcome SFSS.
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http://dx.doi.org/10.1016/j.jss.2012.11.033DOI Listing
July 2013

[Is the GIRK channel a possible target in the development of a novel therapeutic drug of urinary disturbance?].

Yakugaku Zasshi 2011 Apr;131(4):523-32

Department of Environmental and Molecular Health Sciences, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan.

Clinically, both overactive bladder (OAB) and dysuria are known to occur in patients with cerebral infarction (CI). A few anticholinergic drugs are used to treat OAB in such patients, although the effect is not satisfactory. On the other hand, little or no therapeutic drug is available for dysuria after CI. We previously reported that dextromethorphan (DM) and cloperastine (CP), centrally acting antitussives, reduce the frequency of micturition reflex and increase the threshold pressure in anesthetized rats. In this article, we describe the effects of DM and CP on urinary disturbances at 24 h after CI, induced by occlusion of the left middle cerebral artery in conscious rats. We also briefly review the structure, function, and distribution of G-protein-coupled inwardly rectifying K(+) (GIRK) channels in the brain, since both drugs have potent inhibitory effect on GIRK channel-activated currents in brain neurons. Of the two drugs, CP at antitussive-effective doses ameliorated both OAB and dysuria 24 h after CI in rats. On the other hand, DM aggravated the dysuria, although it significantly ameliorated the OAB. These results suggest that CP may have some therapeutic value for the treatment of OAB and dysuria after CI. At the present time, mechanisms of the effect of CP are unknown. However, several lines of evidence including pharmacological findings support the idea that the effects of CP may be produced at least partly by an increase in the level of 5-HT in the brain through an inhibitory effect on GIRK channel-activating currents.
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http://dx.doi.org/10.1248/yakushi.131.523DOI Listing
April 2011

Ameliorating effects of cloperastine on dysfunction of the urinary bladder caused by cerebral infarction in conscious rats.

Can J Physiol Pharmacol 2009 Nov;87(11):893-9

Department of Environmental and Molecular Health Sciences, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto 862-0973, Japan.

We investigated the effects of the centrally acting antitussives dextromethorphan and cloperastine on urinary bladder dysfunction 24 h after cerebral infarction in rats using the cystometry technique. First, cystometrography was performed in conscious male Sprague-Dawley rats. Cerebral infarction was then induced by occlusion of the left middle cerebral artery. Twenty-four hours after cerebral infarction, the effect of each drug on micturition disorder was estimated for 5 parameters: bladder capacity, maximum voiding pressure, micturition latency, flow rate, and urethral resistance. Cerebral infarction markedly reduced bladder capacity, micturition latency, and flow rate and increased urethral resistance. After cerebral infarction, intravenous dosing of saline had no effect on these parameters. Dextromethorphan (20 mg/kg) and cloperastine (2.5 and 5.0 mg/kg) at antitussive effective doses significantly increased bladder capacity and micturition latency. Unlike dextromethorphan, cloperastine ameliorated decreases in flow rate and increases in urethral resistance caused by cerebral infarction. These results suggest that cloperastine may have therapeutic value for the treatment of disorders of the micturition reflex associated with cerebral infarction, and that the drug may become a base compound from which to develop more active drugs for such disorders.
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http://dx.doi.org/10.1139/y09-078DOI Listing
November 2009
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