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Akira Yasuda,
Tsuyoshi Kurokawa,
Noiku Nakao,
Hiroyuki Fujisaki,
Keiichi Ando,
Nobuhiro Ito,
Norifumi Ohashi,
Takashi Arikawa,
Takahisa Tainaka,
Hiroshi Nagata,
Kazuyoshi Suzumura, Toshiaki Nonami
Digestive Diseases and Sciences 04/2013; · 2.12 Impact Factor
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ABSTRACT: The effect of pifithrin (PFT)-α, a pharmacological inhibitor of p53, on lipopolysaccharide (LPS)-induced nitric oxide (NO) production in RAW 264.7 macrophage-like cells was examined. PFT-α inhibited the production of NO but not tumor necrosis factor (TNF)-α in response to LPS. PFT-α inhibited LPS-induced NO production via reduced expression of an inducible NO synthase (iNOS). Moreover, PFT-α inhibited LPS-induced iNOS expression in p53-silenced cells. PFT-α inhibited the production of interferon (IFN)-β, characteristic of the MyD88-independent pathway of LPS signaling, whereas it did not affect the activation of nuclear factor (NF)-κB and mitogen-activated protein kinases in the MyD88-dependent pathway. PFT-α inhibited poly I:C-induced NO production whereas it did not inhibit IFN-β-induced NO production. Further, PFT-α reduced the expression of IFN regulatory factor 3 that leads to the IFN-β production in the MyD88-independent pathway. The most upstream event impaired by PFT-α was the reduced expression of TNF receptor-associated factor (TRAF) 3 in the MyD88-independent pathway. PFT-α also reduced the in vivo expression of iNOS in the livers of mice injected with LPS. Taken together, PFT-α was suggested to inhibit LPS-induced NO production via impairment of the MyD88-independent pathway and attenuated LPS-mediated inflammatory response.
International immunopharmacology 02/2013; · 2.21 Impact Factor
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ABSTRACT: Nitric oxide (NO) has been reported to be a key mediator in hepatocyte proliferation during liver regeneration. NO is the oxidative metabolite of L-arginine, and is produced by a family of enzymes, collective termed nitric oxide synthase (NOS). Thus, administration of L-arginine might enhance liver regeneration after a hepatectomy. Another amino acid, L-glutamine, which plays an important role in catabolic states and is a crucial factor in various cellular and organ functions, is widely known to enhance liver regeneration experimentally. Thus, the present study was undertaken to evaluate the effects of an L-arginine supplement on liver regeneration, and to compared this with supplementation with L-glutamine and L-alanine (the latter as a negative control), using a rat partial hepatectomy model.
Before and after a 70% hepatectomy, rats received one of three amino acid solutions (L-arginine, L-glutamine, or L-alanine). The effects on liver regeneration of the administered solutions were examined by assessment of restituted liver mass, staining for proliferating cell nuclear antigen (PCNA), and total RNA and DNA content 24 and 72 hours after the operation.
At 72 hours after the hepatectomy, the restituted liver mass, the PCNA labeling index and the DNA quantity were all significantly higher in the L-arginine and L-glutamine groups than in the control. There were no significant differences in those parameters between the L-arginine and L-glutamine groups, nor were any significant differences found between the L-alanine group and the control.
Oral supplements of L-arginine and L-glutamine enhanced liver regeneration after hepatectomy in rats, suggesting that an oral arginine supplement can clinically improve recovery after a major liver resection.
World Journal of Surgical Oncology 05/2012; 10:99. · 1.12 Impact Factor
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ABSTRACT: Background. Owing to recent advances in laparoscopic surgery, devascularization of the upper stomach with splenectomy (Spx) or Hassab's procedure (Has) as well as Spx for patients with portal hypertension have been attempted laparoscopically in some facilities, the results of which have been reported. This article describes the authors' surgical techniques and their results. Methods. Between August 1999 and August 2010, the authors treated 110 cases of portal hypertension with Spx or Has. Among these patients, 56 who simultaneously underwent additional major operations were eliminated from the study, leaving 54 patients eligible. They included 38 with open surgeries and 16 with laparoscopic surgeries, which consisted of 10 splenectomies and 6 Has operations. The perioperative data for the 2 groups were compared. Results. Purely laparoscopic Spx (L-Spx) was completed for 9 patients. Conversion from laparoscopic to hand-assisted laparoscopic surgery (HALS) was necessary for 1 patient because of poor visualization. Operative time was significantly longer in L-Spx than in the open method. Postoperative hospital stays were shorter for L-Spx. HALS was used for all 6 laparoscopic Has patients. There was no conversion from the laparoscopic to the open method. Operative time was significantly longer for laparoscopic Has than for open Has. Postoperative complication rates were significantly reduced, and postoperative hospital stays were significantly shorter for laparoscopic Has. Conclusions. Although the data are still preliminary, laparoscopic surgery for patients with portal hypertension may prove to be a successful strategy.
Surgical Innovation 01/2012; · 2.13 Impact Factor
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ABSTRACT: Peroxisome proliferator-activated receptor α (PPARα) regulates lipid metabolism in the liver. It is unclear, however, how this receptor changes in liver cancer tissue. On the other hand, mouse carcinogenicity studies showed that PPARα is necessary for the development of liver cancer induced by peroxisome proliferators, and the relationship between PPARα and the development of liver cancer have been the focus of considerable attention. There have been no reports, however, demonstrating that PPARα is involved in the development of human liver cancer.
The subjects were 10 patients who underwent hepatectomy for hepatocellular carcinoma. We assessed the expression of PPARα mRNA in human hepatocellular carcinoma tissue and non-cancerous tissue, as well as the expression of target genes of PPARα, carnitine palmitoyltransferase 1A and cyclin D1 mRNAs. We also evaluated glyceraldehyde 3-phosphate dehydrogenase, a key enzyme in the glycolytic system.
The amounts of PPARα, carnitine palmitoyltransferase 1A and glyceraldehyde 3-phosphate dehydrogenase mRNA in cancerous sections were significantly increased compared to those in non-cancerous sections. The level of cyclin D1 mRNA tends to be higher in cancerous than non-cancerous sections. Although there was a significant correlation between the levels of PPARα mRNA and cyclin D1 mRNA in both sections, however the correlation was higher in cancerous sections.
The present investigation indicated increased expression of PPARα mRNA and mRNAs for PPARα target genes in human hepatocellular carcinoma. These results might be associated with its carcinogenesis and characteristic features of energy production.
World Journal of Surgical Oncology 12/2011; 9:167. · 1.12 Impact Factor
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Jun An,
Guo-Gang Feng,
Lei Huang,
Tsuyoshi Kurokawa, Toshiaki Nonami,
Tatsuro Koide,
Fumio Kondo,
Toru Komatsu,
Koji Tsunekawa,
Yoshihiro Fujiwara,
Hidemi Goto,
Hiroshi Nishikawa,
Tokutaro Miki,
Satoru Sugiyama,
Naohisa Ishikawa
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ABSTRACT: Aim: The present study was undertaken to evaluate the effects of 1-O-hexyl-2,3,5-trimethylhydroquinone (HTHQ), a synthesized vitamin E derivative, on carbon tetrachloride (CCl(4))-induced cirrhosis. Methods: Rats were treated with hypodermic injections of CCl(4) twice a week to induce the hepatic cirrhosis, and given drinking water containing HTHQ or solvent. Primary cultures of rat hepatocytes were performed to evaluate the effects of HTHQ on the expression of inducible nitric oxide synthase (iNOS). Results: Masson's staining of rat livers showed fibrosis around pseudo-lobules in the CCl(4) group, the lesions being reduced in the CCl(4) HTHQ group. Increases in liver tissue hydroxyproline and alpha(1)(I) collagen, alpha-smooth muscle actin and iNOS induced by CCl(4), were also markedly diminished by HTHQ. Furthermore, both HTHQ and vitamin E attenuated interleukin-1beta-induced iNOS protein expression in cultured hepatocytes, the potency of HTHQ being 10-times higher than that of vitamin E. Conclusion: HTHQ may inhibit development of hepatic cirrhosis in rats, more potently than vitamin E, by inhibiting the iNOS expression in hepatocytes. Because vitamin E has a radical scavenging action, roles of NO and peroxynitrite will be discussed in the effects of HTHQ on the fibrosis.
Hepatology Research 04/2010; 40(6):566-73. · 2.20 Impact Factor
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ABSTRACT: Although an increasing number of reports and publications have dealt with the laparoscopic approach to liver resection, this procedure remains uncommon, and its feasibility, safety and effectiveness are still not established. There are few reports of the advantages of this approach on postoperative recovery.
From December 1997 to March 2007, laparoscopic hepatic resection were performed in 68 patients.
There were 52 malignant tumors (36 hepatocellular carcinomas, three intrahepatic cholangiocarcinomas, one cystadenocarcinoma, liver metastases from ten colorectal carcinomas and two other organs) and 16 benign lesions among our 68 patients. Fifteen patients with hepatocellular carcinoma had cirrhosis. The mean tumor size was 3.1 +/- 1.8 cm (range 1.0-14.0 cm), and the tumors were located in every liver segment except segment I. Liver resection was anatomical in 17 patients and consisted of a lobectomy in four patients and a lateral segmentectomy in 13 patients. Non-anatomical resections were performed in 51 patients. The operative time was 214 +/- 93 min. Mean blood loss was 393 +/- 564 g. A hand-assisted laparoscopic method or mini-laparotomy method was required in 35 patients (51.4%). Operative complications occurred mainly in our early cases and included three patients (4.4%) with operative bleeding, 2 of whom (2.9%) requiring a conversion to open surgery. Postoperative complications occurred in seven patients (10.0%), and two of then eventually required a re-operation. The mean hospital stay was 17 days. There were no complications in the more recent cases.
The laparoscopic approach for liver tumors is feasible, if the indication is carefully selected. The safety of this procedure depends on the surgical experience of the surgeon and team and the availability of the necessary technology.
Journal of Hepato-Biliary-Pancreatic Surgery 01/2009; 16(1):64-8. · 1.60 Impact Factor
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ABSTRACT: The effect of hydrogen peroxide (H(2)O(2)) on production of tumor necrosis factor (TNF)-alpha was examined in RAW 264.7 murine macrophage cells. H(2)O( 2) led to production of TNF-alpha up to 24 h after the treatment, but not nitric oxide in RAW 264.7 cells. H(2)O(2) induced TNF-alpha production in mouse peritoneal macrophages as well as RAW 264.7 cells. The H(2)O(2)induced TNF-alpha production was prevented by inhibitors of p38 and stress-activated protein kinase (SAPK/JNK), and H(2)O( 2) induced the phosphorylation of p38 and SAPK. Further, H(2)O( 2) significantly augmented the AP-1 activity, but not nuclear factor (NF)-kappaB activity in RAW 264.7 cells. A high level of intracellular reactive oxygen radicals (ROS) was detected in H(2)O(2)-exposed RAW 264.7 cells. Ebselen, a cell permeable antioxidant, prevented the H( 2)O(2)-induced TNFalpha production. H(2)O(2) significantly enhanced lipopolysaccharide (LPS)-induced TNF-alpha production. Therefore, H( 2) O(2) was suggested to induce TNF-alpha production in macrophages via activating p38 and SAPK/JNK as oxidative stress-related signal pathways.
Innate Immunity 07/2008; 14(3):190-6. · 4.00 Impact Factor
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Jun An,
Koji Tsunekawa,
Guo Gang Feng,
Chang Li,
Lei Huang,
Yoshitake Ito,
Satoru Sugiyama,
Tsuyoshi Kurokawa,
Tatsuro Koide, Toshiaki Nonami,
Naohisa Ishikawa
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ABSTRACT: Naofen (GenBank accession no. EF613262), a newly found intracellular protein in the WD-repeat-2 protein family, has been cloned as an anti-verotoxin II antibody immunoreactive substance, and the nucleotide- and amino acid-sequences have been clarified. The present study was undertaken to evaluate the roles of naofen especially in carbon tetrachloride (CCl4-induced cirrhosis model of rats, also in partial hepatectomy. Naofen mRNA expressions were observed from the early phases of cirrhosis development and during regenerative phases after partial hepatectomy, more remarkable in the former. Naofen immunoreactive fragments located in the vascular endothelial cells and peri-vascular spaces in normal livers especially in Glisson's areas, being strongly stained in the connective tissues 8 weeks after starting CCl4-injections, besides in the cytoplasm of hepatocytes in pseudo-lobules. In contrast, partial hepatectomy caused a small increase of naofen expressions in the whole hepatocytes, and significantly in the endothelial cells of portal veins and hepatic arterioles. Furthermore, in parallel to the degree of naofen mRNA and protein expressions, the rates of double-nuclei cells to total hepatocytes in the Glisson's areas increased in both cirrhosis and partial hepatectomy, suggesting a relationship between naofen expression and mitosis. In in-vitro studies with cell lines, vascular endothelial growth factor, a cell proliferation stimulant, increased the naofen mRNA expressions in HepG(2) cell lines, whereas paclitaxel, a cytotoxic anti-cancer drug, diminished them in NRK52E, both concentration-dependently. These results indicated that naofen immunoreactive fragments play an important role in the cell proliferation, relevant for analyzing the regenerative phases during cirrhosis developments and after partial hepatectomy.
European Journal of Pharmacology 07/2008; 587(1-3):285-90. · 2.52 Impact Factor
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ABSTRACT: A 63-year-old man had undergone a low anterior resection for rectal cancer with multiple liver metastases. Oral UFT (450 mg/day) administration alone was started after the operation. After 6 months post operatively, the patient was diagnosed as anastomosis recurrence because of ileus by abdominal X-ray. Transverse loop colostomy was performed by emergency surgery. After surgery, he suffered from paraplegia for lumbar vertebrae metastases. UFT+LV therapy was started. After chemotherapy a significant reduction of the lymph node and liver metastases and an apparent decrease in CEA and CA19-9 were observed. The patient left the hospital and showed no signs of tumor exacerbation for three months. The patient died of aggravation of primary disease afterwards. The therapy was safe and effective, and has successfully maintained the quality of life (QOL) of this patient.
Gan to kagaku ryoho. Cancer & chemotherapy 05/2008; 35(4):665-8.
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Li Shen,
Lisheng Zhuo,
Akihiko Okumura,
Tetsuya Ishikawa,
Masahiko Miyachi,
Yoshihiro Owa,
Tohko Ishizawa,
Nobuo Sugiura,
Yoshihisa Nagata, Toshiaki Nonami,
Shinichi Kakumu,
Koji Kimata
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ABSTRACT: Our previous study suggested that the serum-derived hyaluronan associated protein (SHAP)-hyaluronan (HA) complex in the sera of patients with rheumatoid arthritis is useful as a marker that directly correlates with the degree of inflammation. Here, we have investigated the serum levels of the SHAP-HA complex in patients at various clinical stages of chronic hepatitis (CH), liver cirrhosis (LC), and hepatocellular carcinoma (HCC) caused by infection with the hepatitis C or hepatitis B virus. Both serum levels of the SHAP-HA complex and HA in those patients were significantly higher than those of the controls and increased in the order of CH<LC<HCC. Different from the HA levels, there was a significant difference in the SHAP-HA complex levels between the LC and HCC groups in both HBV- and HCV-infected patients. In addition, the serum level of the SHAP-HA complex correlated with the well-known biomarkers for liver injury and function such as albumin and platelet, including the HCC indicator alpha-fetoprotein. In conclusion, the present data suggest that the SHAP-HA complex level is a better indicator for the progression of the stages of liver fibrosis, and that it could be a marker for HCC, in both HBV- and HCV-infected patients.
Hepatology Research 03/2006; 34(3):178-86. · 2.20 Impact Factor
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ABSTRACT: The elimination of endotoxin from the blood was studied in rats with D-galactosamine–induced liver failure and in normal controls after intravenous injection of various doses of endotoxin. Endotoxin was found to localize in liver tissue by immunohistochemical staining with factor C, which is derived from amebocyte lysate of the horseshoe crab and which reacts specifically with endotoxin. Before injection, the blood endotoxin concentrations were normal both in control rats and in rats with liver failure. The blood concentrations of endotoxin were significantly higher after intravenous injection of endotoxin in the D-galactosamine–induced liver failure group (p<0.05) and decreased much more slowly (p<0.05). Endotoxin concentrations were also significantly higher after in vitro incubation with plasma from rats with liver failure (p<0.05). After intravenous injection of endotoxin (1 mg/kg), endothelial and Kupffer cells in the liver sinusoids were positively stained for endotoxin in the control group, but not stained or faintly stained in the liver failure group. Endotoxemia in liver failure thus results from reduced inactivation of endotoxin in plasma and from impaired hepatic clearance. (HEPATOLOGY 1994;19:1251–1256.)
Hepatology 12/2005; 19(5):1251 - 1256. · 11.66 Impact Factor
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ABSTRACT: Significant evidence of the pharmacological and physiological effects of branched-chain amino acids (BCAA) has accumulated, attracting the interest of not only clinicians but also basic medical researchers. We summarize here the characteristic features of BCAA catabolism, focusing on the initial two enzymes in the pathway, branched-chain aminotransferase and branched-chain alpha-keto acid dehydrogenase complex. In addition, we describe a unique characteristic of the valine catabolic pathway. Finally, we present evidence obtained in animal studies that indicates that BCAA treatment may be appropriate for liver cirrhosis, but not acute liver failure.
Hepatology Research 01/2005; 30S:3-8. · 2.20 Impact Factor
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Hitoshi Inagaki,
Nobuhiro Ito,
Tsuyoshi Kurokawa,
Yoshihiro Owa,
Katsuhiro Kotake,
Takashi Arikawa,
Ichiro Horikoshi,
Mari Tsubamoto,
Hiroshi Nagata,
Kazuyoshi Suzumura, Toshiaki Nonami
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ABSTRACT: A 71-year-old man was diagnosed with giant hepatocellular carcinoma (HCC) and hepatitis C cirrhosis at a nearby hospital. Image diagnosis showed no other metastasis, but the tumor was very huge with daughter nodules in the bilateral lobe of the liver. He was thus treated by oral administration of UFT (300 mg/day). Two months later, the giant liver tumor had shrunk remarkably, and the daughter tumors had disappeared. Eight months later, the levels of serum AFP and PIVKA-II had also reduced remarkably. Twelve months following the first treatment, the levels of both serum AFP and PIVKA-II began increasing again, and he was referred to our hospital. CT showed 2 liver tumors, 1 of which showed viability with moderately differentiated hepatocellular carcinoma and the other evidencing necrosis histologically. Radio frequency ablation therapy was performed for 2 tumors by open laparotomy. It was considered that administration of UFT is a useful and safe therapy for far advanced HCC.
Gan to kagaku ryoho. Cancer & chemotherapy 10/2004; 31(9):1411-4.
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ABSTRACT: Branched-chain alpha-keto acid dehydrogenase (BCKDH) complex catalyzes the committed step of the catabolism of branched-chain amino acids (BCAA). The liver cirrhosis chemically induced in rats raised the activity of hepatic BCKDH complex and decreased plasma BCAA and branched-chain alpha-keto acid concentrations, suggesting that the BCAA requirement is increased in liver cirrhosis. Since the effects of liver cirrhosis on the BCKDH complex in human liver are different from those in rat liver, further studies are needed to clarify the differences between rats and humans. In the valine catabolic pathway, crotonase and beta-hydroxyisobutyryl-CoA hydrolase are very important to regulate the toxic concentration of mitochondrial methacrylyl-CoA, which occurs in the middle part of valine pathway and highly reacts with free thiol compounds. Both enzyme activities in human and rat livers are very high compared to that of BCKDH complex. It has been found that both enzyme activities in human livers were significantly reduced by liver cirrhosis and hepatocellular carcinoma, suggesting a decrease in the capability to dispose methacrylyl-CoA. The findings described here suggest that alterations in hepatic enzyme activities in the BCAA catabolism are associated with liver failure.
Biochemical and Biophysical Research Communications 02/2004; 313(2):381-5. · 2.48 Impact Factor
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ABSTRACT: Despite recent progress in trials with laparoscopic hepatectomy, it is still necessary to develop safe and stable techniques. We have performed laparoscopic hepatic resection for 30 patients with liver tumors to date. We have recently been applying a hand-assisted laparoscopic surgical technique for greater safety.
In the present study, we report techniques using a hand-assisted laparoscopic anatomical left-lateral segmentectomy for hepatocellular carcinoma with liver cirrhosis.
Direct feeling with the surgeon's hand makes possible a procedure that is almost identical to open surgery in which there is better visualization of the surgical field and transected margin, and immediate hemostasis is also achieved by manually depressing the bleeding point.
With this method, laparoscopic anatomical hepatectomy can be performed more safely for patients with cirrhosis than by the fully laparoscopic method, although a larger incision is necessary.
Journal of Hepato-Biliary-Pancreatic Surgery 02/2003; 10(4):295-8. · 1.60 Impact Factor
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ABSTRACT: Porcine skin (PS) gelatin showed antitumor effect in vitro on MH134 murine hepatoma cells. We analyzed the effect of PS gelatin on MH134 cells compared to the effect of Bovine bone (BB) gelatin, 5-Fluorouracil (5-FU) and 7-ethyl-10-hydroxycamptothecin (SN-38). We previously suggested that PS gelatin induces apoptosis in MH134 cells using flow cytometric analysis. We performed agarose gel electrophoresis and electron microscopic studies to ascertain apoptosis. Agarose gel electrophoresis showed the typical DNA ladder pattern and electron microscopic findings revealed characteristic features in the case of apoptosis on PS gelatin. SN-38 also showed DNA ladder pattern and ultrastructural changes in apoptosis. 5-FU didn't show DNA ladder pattern but electron microscope revealed changes in necrosis. On the other hand, BB gelatin didn't induce apoptosis or necrosis.
Cancer Biotherapy and Radiopharmaceuticals 09/2002; 17(4):379-84. · 1.79 Impact Factor
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Hitoshi Inagaki, Toshiaki Nonami,
Takatsugu Kawagoe,
Takaya Miwa,
Jiro Hosono,
Tsuyoshi Kurokawa,
Akio Harada,
Akimasa Nakao,
Hiroshi Takagi,
Harumi Suzuki,
Junichi Sakamoto
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ABSTRACT: A case of idiopathic portal hypertension (IPH) associated with systemic lupus erythematosus (SLE) is reported in a 38-year-old
man who had been diagnosed with SLE and treated for 18 years. Esophageal varices, found in 1994 on endoscopic examination,
had been followed up for 2 years. On July 16, 1996, he was admitted to Nagoya University Hospital because there was a high
risk of bleeding from the esophageal varices due to severe thrombocytopenia. As partial splenic embolization had temporarily
controlled the thrombocytopenia, splenectomy and devascularization of the stomach vessels were performed after endoscopic
ligation of the esophageal varices. Histological specimens of wedge biopsied liver showed chronic inactive hepatitis without
cirrhosis. The presence of anticardiolipin antibody, indicated by positivity for lupus anticoagulant, was suggestive of the
presence of a common immunological mechanism in the etiology of SLE and IPH.
Journal of Gastroenterology 02/2000; 35(3):235-239. · 4.16 Impact Factor
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ABSTRACT: Seven cases of pancreatic serous cystadenoma were examined immunohistochemically and molecular biologically. Six were benign tumors and one was clinically malignant. Immunohistochemical studies were performed with the avidin-biotin peroxidase complex technique on paraffinembedded tumor tissue and were stained with antibody to carcinoembryonic antigen (CEA), CA19-9, and p53 protein. Twostage polymerase chain reaction-restriction fragment length polymorphism analysis was used to detect K-ras oncogene mutation at codon 12. No tumor cells were stained with anti-CEA and anti-p53 protein, but two cases were stained focally with anti-CA19-9. One case was benign and one was clinically malignant. In the anti-CA19-9 staining, tumor cells of the benign case were positive only on the apical membrane and supranuclear cytoplasm of the cells, whereas those of the clinically malignant case were positive over the entire surface and cytoplasm of the cells. All seven cases were without K-ras gene mutation. So the features of serous cystadenoma of the pancreas suggest a tumor genesis different from that of ductal adenocarcinoma. They also suggest a relationship between immunohistochemical localizations of CA 19-9 in the tumor cells and the biological behavior of the tumor itself.
(C) Lippincott-Raven Publishers.
Pancreas 12/1997; 16(1). · 2.39 Impact Factor
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Journal of Clinical Gastroenterology 11/1997; 25(4):706-708. · 3.16 Impact Factor
