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There have been few epidemiological studies on pancreatic diabetes. In this study, we determined the incidence and pathology of pancreatic diabetes in Japan.

We examined the effect of the overexpression of Smad6 on pancreatic fibrosis after chronic pancreatic injury.

Background: Excessive consumption of alcohol is involved in the onset of pancreatitis. However, most of heavy drinkers do not always develop chronic pancreatitis. Various genetic factors appear to be involved in these individual differences in onset of chronic alcoholic pancreatitis. Here we investigated a possible association of alcoholic pancreatitis with polymorphisms of the various genes belong to the phase II detoxification enzymes responsible for metabolism of the oxidative compounds, and the several genes that have relevance to inherited pancreatitis.

AbstractIn consequence of the close anatomical and functional links between the exocrine and endocrine pancreas, any disease affecting one of these parts will inevitably affect the other. Pancreatic conditions which might cause diabetes mellitus include acute and chronic pancreatitis, pancreatic surgery, cystic fibrosis and pancreatic cancer. The development of diabetes greatly influences the prognosis and quality of life of patients with exocrine pancreatic diseases. It may cause life-threatening complications, such as hypoglycemia, due to the lack of glucagon and the impaired absorption of nutrients, or the micro- and macrovascular complications may impair the organ functions. Diabetes mellitus is an independent risk factor of mortality in those with exocrine pancreatic diseases. The treatment of pancreatic diabetes, a distinct metabolic and clinical form of diabetes, requires special knowledge. Diet and pancreatic enzyme replacement therapy may be sufficient in the early stages. Oral antidiabetic drugs are not recommended. If the diet proves inadequate to reach the glycemic goals, insulin treatment with multiple injections is required. Impairments of the exocrine pancreatic function and morphology in diabetic patients are frequent and well known. Atrophy of the exocrine tissue may be caused by the lack of trophic insulin, whereas pancreatic fibrosis can result from activation of stellate cells by hyperglycemia, or from microangiopathy and neuropathy. The regulation of the exocrine pancreatic function is also damaged because of the impaired effect of islet hormones. In the event of a proven impairment of the pancreatic exocrine function in diabetes mellitus, pancreatic enzyme replacement therapy is indicated. This may improve the nutritional condition of the patient and decrease the metabolic instability.Copyright © 2009 S. Karger AG, Basel and IAP

In consequence of the close anatomical and functional links between the exocrine and endocrine pancreas, any disease affecting one of these parts will inevitably affect the other. Pancreatic conditions which might cause diabetes mellitus include acute and chronic pancreatitis, pancreatic surgery, cystic fibrosis and pancreatic cancer. The development of diabetes greatly influences the prognosis and quality of life of patients with exocrine pancreatic diseases. It may cause life-threatening com plications, such as hypoglycemia, due to the lack of glucagon and the impaired absorption of nutrients, or the micro- and macrovascular complications may impair the organ functions. Diabetes mellitus is an independent risk factor of mortality in those with exocrine pancreatic diseases. The treatment of pancreatic diabetes, a distinct metabolic and clinical form of diabetes, requires special knowledge. Diet and pancreatic enzyme replacement therapy may be sufficient in the early stages. Oral antidiabetic drugs are not recommended. If the diet proves inadequate to reach the glycemic goals, insulin treatment with multiple injections is required. Impairments of the exocrine pancreatic function and morphology in diabetic patients are frequent and well known. Atrophy of the exocrine tissue may be caused by the lack of trophic insulin, whereas pancreatic fibrosis can result from activation of stellate cells by hyperglycemia, or from microangiopathy and neuropathy. The regulation of the exocrine pancreaticfunction isal so damaged because of theim-paired effect of islet hormones. In the event of a proven impairment of the pancreatic exocrine function in diabetes meliitus, pancreatic enzyme replacement therapy is indicated. This may improve the nutritional condition of the patient and decrease the metabolic instability.

Cells of all living organisms have evolved complex mechanisms to maintain genome stability. There is increasing evidence that spontaneous genomic instability occurs primarily during DNA replication. RecQ DNA helicases function during DNA replication and are essential for the maintenance of genome stability. In human cells, there exist five RecQ DNA helicases, and mutations of three of these helicases, encoded by the BLM, WRN and RECQL4 genes, give rise to the cancer predisposition disorders, Bloom syndrome (BS), Werner syndrome (WS), and Rothmund-Thomson syndrome (RTS), respectively. Individuals suffering from WS and RTS also show premature aging phenotypes. Although the two remaining helicases, RECQL1 and RECQL5, have not yet been associated with heritable human diseases, a single nucleotide polymorphism of RECQL1 is associated with reduced survival of pancreatic cancer, and RecQl5 knockout mice show a predisposition to cancer. Here, we review the functions eukaryotic RecQ helicases, focusing primarily on BLM in the maintenance of genome stability through various pathways of nucleic acid metabolism and with special reference to DNA replication.

To elucidate the role of transforming growth factor (TGF) β1 and extracellular matrix (ECM) after acute necrotizing pancreatitis, we studied the regulation of TGF-β1 and ECM after induction of pancreatitis.

Hyperglycemia is implicated in fibrosis in many organs. Exocrine and endocrine pancreas are closely linked both anatomically and physiologically, and pathological conditions in the exocrine gland can cause impairment of endocrine function and vice versa. Chronic pancreatitis causes pancreatic fibrosis and sometimes results in diabetes mellitus. Pancreatic stellate cells (PSCs) play a pivotal role in pancreatic fibrogenesis. However, the effects of high glucose concentrations on PSC activation have not been fully elucidated.

A 50-year-old female was referred to our hospital because of postprandial epigastric pain and pancreatic head mass. On admission, an elastic hard mass with tenderness was palpable in the epigastric region. Laboratory findings showed no abnormalities, except for a slightly elevated C-reactive protein value and iron deficiency anemia. Serum levels of pancreatic enzymes and tumor markers were also within the reference range. Computed tomography (CT) demonstrated a 5-cm heterogenous mass at the head of the pancreas. Angiography showed that gastroduodenal artery was transformed and narrowed by the mass. Smooth stenosis of portal vein was also observed. Fusion CT-positron emission tomography with 2-deoxy-2-18Ffluoro-D-glucose demonstrated a focus of increased uptake in the pancreatic head mass. We suspected the mass of malignancy but, surprisingly, tumor size was gradually decreased without any therapies. Biopsy specimens from the mass of the pancreas showed marked inflammatory cell infiltration and marked interstitial fibrosis without malignant cells. Thereafter, we could isolate Corynebacterium coyleaefrom the biopsy specimen. We diagnosed the mass as a pancreatic abscess caused by C. coyleaeand started with the intravenous antibiotics therapy. Subsequent follow-up CT and ultrasonography showed dramatic improvement in pancreatic mass.

The aim of this study was to estimate the number of autoimmune pancreatitis (AIP) patients in Japan and evaluate the influence of steroid therapy on the course of diabetes mellitus (DM) in AIP.

Abstract: The diagnosis of acute pancreatitis is based on the following findings: (1) acute attacks of abdominal pain and tenderness in the epigastric region, (2) elevated blood levels of pancreatic enzymes, and (3) abnormal diagnostic imaging findings in the pancreas associated with acute pancreatitis. In Japan, in accordance with criteria established by the Japanese Ministry of Health, Labour, and Welfare, the severity of acute pancreatitis is assessed based on the clinical signs, hematological findings, and imaging findings, including abdominal contrast-enhanced computed tomography (CT) and magnetic resonance imaging (MRI). Severity must be re-evaluated, especially in the period 24 to 48 h after the onset of acute pancreatitis, because even cases diagnosed as mild or moderate in the early stage may rapidly progress to severe. Management is selected according to the severity of acute pancreatitis, but it is imperative that an adequate infusion volume, vital-sign monitoring, and pain relief be instituted immediately after diagnosis in every patient. Patients with severe cases are treated with broad-spectrum antimicrobial agents, a continuous high-dose protease inhibitor, and continuous intraarterial infusion of protease inhibitors and antimicrobial agents; continuous hemodiafiltration may also be used to manage patients with severe cases. Whenever possible, transjejunal enteral nutrition should be administered, even in patients with severe cases, because it seems to decrease morbidity. Necrosectomy is performed when necrotizing pancreatitis is complicated by infection. In this case, continuous closed lavage or open drainage (planned necrosectomy) should be the selected procedure. Pancreatic abscesses are treated by surgical or percutaneous drainage. Emergency endoscopic procedures are given priority over other methods of management in patients with acute gallstone-associated pancreatitis, patients suspected of having bile duct obstruction, and patients with acute gallstone pancreatitis complicated by cholangitis. These strategies for the management of acute pancreatitis are shown in the algorithm in this article.

Abstract: The basic principles of the initial management of acute pancreatitis are adequate monitoring of vital signs, fluid replacement, correction of any electrolyte imbalance, nutritional support, and the prevention of local and systemic complications. Patients with severe acute pancreatitis should be transferred to a medical facility where adequate monitoring and intensive medical care are available. Strict cardiovascular and respiratory monitoring is mandatory for maintaining the cardiopulmonary system in patients with severe acute pancreatitis. Maximum fluid replacement is needed to stabilize the cardiovascular system. Prophylactic antibiotic administration is recommended to prevent infectious complications in patients with necrotizing pancreatitis. Although the efficacy of the intravenous administration of protease inhibitors is still a matter of controversy, there is a consensus in Japan that a large dose of a synthetic protease inhibitor should be given to patients with severe acute pancreatitis in order to prevent organ failure and other complications. Enteral feeding is superior to parenteral nutrition when it comes to the nutritional support of patients with severe acute pancreatitis. The JPN Guidelines recommend, as optional measures, blood purification therapy and continuous regional arterial infusion of a protease inhibitor and antibiotics, depending on the patient’s condition.

Abstract: Acute pancreatitis represents a spectrum of disease ranging from a mild, self-limited course to a rapidly progressive, severe illness. The mortality rate of severe acute pancreatitis exceeds 20%, and some patients diagnosed as mild to moderate acute pancreatitis at the onset of the disease may progress to a severe, life-threatening illness within 2–3 days. The Japanese (JPN) guidelines were designed to provide recommendations regarding the management of acute pancreatitis in patients having a diversity of clinical characteristics. This article sets forth the JPN guidelines for the surgical management of acute pancreatitis, excluding gallstone pancreatitis, by incorporating the latest evidence for the surgical management of severe pancreatitis in the Japanese-language version of the evidence-based Guidelines for the Management of Acute Pancreatitis published in 2003. Ten guidelines are proposed: (1) computed tomography-guided or ultrasound-guided fine-needle aspiration for bacteriology should be performed in patients suspected of having infected pancreatic necrosis; (2) infected pancreatic necrosis accompanied by signs of sepsis is an indication for surgical intervention; (3) patients with sterile pancreatic necrosis should be managed conservatively, and surgical intervention should be performed only in selected cases, such as those with persistent organ complications or severe clinical deterioration despite maximum intensive care; (4) early surgical intervention is not recommended for necrotizing pancreatitis; (5) necrosectomy is recommended as the surgical procedure for infected pancreatic necrosis; (6) simple drainage should be avoided after necrosectomy, and either continuous closed lavage or open drainage should be performed; (7) surgical or percutaneous drainage should be performed for pancreatic abscess; (8) pancreatic abscesses for which clinical findings are not improved by percutaneous drainage should be subjected to surgical drainage immediately; (9) pancreatic pseudocysts that produce symptoms and complications or the diameter of which increases should be drained percutaneously or endoscopically; and (10) pancreatic pseudocysts that do not tend to improve in response to percutaneous drainage or endoscopic drainage should be managed surgically.

Abstract: The currently used diagnostic criteria for acute pancreatitis in Japan are presentation with at least two of the following three manifestations: (1) acute abdominal pain and tenderness in the upper abdomen; (2) elevated levels of pancreatic enzyme in the blood, urine, or ascitic fluid; and (3) abnormal imaging findings in the pancreas associated with acute pancreatitis. When a diagnosis is made on this basis, other pancreatic diseases and acute abdomen can be ruled out. The purpose of this article is to review the conventional criteria and, in particular, the various methods of diagnosis based on pancreatic enzyme values, with the aim of improving the quality of diagnosis of acute pancreatitis and formulating common internationally agreed criteria. The review considers the following recommendations: — Better even than the total blood amylase level, the blood lipase level is the best pancreatic enzyme for the diagnosis of acute pancreatitis and its differentiation from other diseases. — A pivotal factor in the diagnosis of acute pancreatitis is identifying an increase in pancreatic enzymes in the blood.— Ultrasonography (US) is also one of the procedures that should be performed in all patients with suspected acute pancreatitis.— Magnetic resonance imaging (MRI) is one of the most important imaging procedures for diagnosing acute pancreatitis and its intraperitoneal complications. — Computed tomography (CT) is also one of the most important imaging procedures for diagnosing acute pancreatitis and its intraabdominal complications. CT should be performed when a diagnosis of acute pancreatitis cannot be established on the basis of the clinical findings, results of blood and urine tests, or US, or when the etiology of the pancreatitis is unknown. — When acute pancreatitis is suspected, chest and abdominal X-ray examinations should be performed to determine whether any abnormal findings caused by acute pancreatitis are present. — Because the etiology of acute pancreatitis can have a crucial influence on both the treatment policy and severity assessment, it should be evaluated promptly and accurately. It is particularly important to differentiate between gallstone-induced acute pancreatitis, which requires treatment of the biliary system, and alcohol-induced acute pancreatitis, which requires a different form of treatment.

Abstract: The JPN Guidelines for the Management of Acute Pancreatitis are organized under the subject headings: epidemiology, diagnosis, management strategy, severity assessment and transfer criteria, management of gallstone pancreatitis, nonsurgical management, and surgical management. The Guidelines contain cutting-edge information on each of these subjects, as well as a section on the Japanese medical insurance system which provides information that should prove useful to physicians in other countries. The quality of the evidence was evaluated by the evidence-based classification method used at the Cochrane Library. The levels of recommendation of the individual management methods contained in the Guidelines were determined on the basis of the evaluation of evidence by the consensus of the members of the Working Group (see below). The Japanese Society for Abdominal Emergency Medicine, the Japan Pancreas Society, and the Research Group for Intractable Diseases and Refractory Pancreatic Diseases (which is sponsored by the Japanese Ministry of Health, Labour, and Welfare) were commissioned to produce the JPN Guidelines for the Management of Acute Pancreatitis. A Working Group of 20 physicians specializing in pancreatic diseases and emergency medicine investigated and analyzed 14821 cases retrieved by means of a Medline (1960–2004) search and discussed the available literature on acute pancreatitis (limited to human pancreatitis). The Working Group held many general discussions in order to reach a consensus on the content of the Guidelines. After producing a draft, the Publishing Committee of the JPN Guidelines for the Management of Acute Pancreatitis posted it on a website and asked for comments and criticisms. Subsequently, a final version of the Guidelines was published in Japanese in 2003. The Publishing Committee is now making the Guidelines available to a much wider readership by bringing out an English version.

Abstract: Gallstones, along with alcohol, are one of the primary etiological factors of acute pancreatitis, and knowledge of the etiology as well as the diagnosis and management of gallstones, is crucial for managing acute pancreatitis. Because of this, evidence regarding the management of gallstone-induced pancreatitis in Japan was collected, and recommendation levels were established by comparing current clinical practices with optimal clinical practices. The JPN Guidelines for managing gallstone-induced acute pancreatitis recommend two procedures: (1) an urgent endoscopic procedure should be performed in patients in whom biliary duct obstruction is suspected and in patients complicated by cholangitis (Recommendation A); and (2) after the attack of gallstone pancreatitis has subsided, a laparoscopic cholecystectomy should be performed during the same hospital stay (Recommendation B).

Abstract: Acute pancreatitis is a common disease with an annual incidence of between 5 and 80 people per 100 000 of the population. The two major etiological factors responsible for acute pancreatitis are alcohol and cholelithiasis (gallstones). The proportion of patients with pancreatitis caused by alcohol or gallstones varies markedly in different countries and regions. The incidence of acute alcoholic pancreatitis is considered to be associated with high alcohol consumption. Although the incidence of alcoholic pancreatitis is much higher in men than in women, there is no difference in sexes in the risk involved after adjusting for alcohol intake. Other risk factors include endoscopic retrograde cholangiopancreatography, surgery, therapeutic drugs, HIV infection, hyperlipidemia, and biliary tract anomalies. Idiopathic acute pancreatitis is defined as acute pancreatitis in which the etiological factor cannot be specified. However, several studies have suggested that this entity includes cases caused by other specific disorders such as microlithiasis. Acute pancreatitis is a potentially fatal disease with an overall mortality of 2.1%–7.8%. The outcome of acute pancreatitis is determined by two factors that reflect the severity of the illness: organ failure and pancreatic necrosis. About half of the deaths in patients with acute pancreatitis occur within the first 1–2 weeks and are mainly attributable to multiple organ dysfunction syndrome (MODS). Depending on patient selection, necrotizing pancreatitis develops in approximately 10%–20% of patients and the mortality is high, ranging from 14% to 25% of these patients. Infected pancreatic necrosis develops in 30%–40% of patients with necrotizing pancreatitis and the incidence of MODS in such patients is high. The recurrence rate of acute pancreatitis is relatively high: almost half the patients with acute alcoholic pancreatitis experience a recurrence. When the gallstones are not treated, the risk of recurrence in gallstone pancreatitis ranges from 32% to 61%. After recovering from acute pancreatitis, about one-third to one-half of acute pancreatitis patients develop functional disorders, such as diabetes mellitus and fatty stool; the incidence of chronic pancreatitis after acute pancreatitis ranges from 3% to 13%. Nevertheless, many reports have shown that most patients who recover from acute pancreatitis regain good general health and return to their usual daily routine. Some authors have emphasized that endocrine function disorders are a common complication after severe acute pancreatitis has been treated by pancreatic resection.

Abstract: This article addresses the criteria for severity assessment and the severity scoring system of the Ministry of Health and Welfare of Japan; now the Japanese Ministry of Health, Labour, and Welfare (the JPN score). It also presents data comparing the JPN score with the Acute Physiology and Chronic Health Evaluation (APACHE) II score and the Ranson score, which are the major measuring scales used in the United States and Europe. The goal of investigating these scoring systems is the achievement of earlier diagnosis and more appropriate and successful treatment of severe or moderate acute pancreatitis, which has a high mortality rate. This article makes the following recommendations in terms of assessing the severity of acute pancreatitis: (1) Severity assessment is indispensable to the selection of proper initial treatment in the management of acute pancreatitis (Recommendation A). (2) Assessment by a severity scoring system (JPN score, APACHE II score) is important for determining treatment policy and identifying the need for transfer to a specialist unit (Recommendation A). (3) C-reactive protein (CRP) is a useful indicator for assessing severity (Recommendation A).(4) Contrast-enhanced computed tomography (CT) scanning and contrast-enhanced magnetic resonance imaging (MRI) play an important role in severity assessment (Recommendation A). (5) A JPN score of 2 or more (severe acute pancreatitis) has been established as the criterion for hospital transfer (Recommendation A). (6) It is preferable to transfer patients with severe acute pancreatitis to a specialist medical institution where they can receive continuous monitoring and systemic management.

The imbalance between synthesis and degradation of extracellular matrix (ECM) proteins is a characteristic feature in chronic pancreatitis. We evaluated the relationship between type IV collagen structure in the basement membrane (BM) and the development of acinar atrophy or the regeneration from acinar injury.

Group 2 phospholipase A2 (PLA2) plays an important role in the pathogenesis of multiple organ failure associated with acute pancreatitis. C57 BL/6J mice are natural group 2 PLA2 knockout mice lacking group 2 PLA2 mRNA. To clarify the role of group 2 PLA2 in the exacerbation of acute pancreatitis, we studied the biologic and histologic alterations in choline-deficient and ethionine-supplemented (CDE) diet-induced pancreatitis in group 2 PLA2-deficient C57 BL/6J mice and compared them with those in wild-type mice.

Recent studies have demonstrated that synthetic protease inhibitors could ameliorate the progression of pancreatic fibrosis in some animal models. Since oral administration of protease inhibitors increases the plasma cholecystokinin (CCK) levels and causes hypertrophy of the pancreas in rats, there is a possibility that the protease inhibitor inhibits fibrosis in the pancreas via endogenous CCK release. We examined the effects of camostat, a synthetic protease inhibitor, on histopathologic changes in Otsuka Long-Evans Tokushima Fatty (OLETF) rat that has genetically no expression of CCK-1 receptor and displays inflammation and degeneration of the pancreas.

We examined the roles of cholecystokinin (CCK)-2 receptors in the regulation of pepsinogen secretion in the CCK-1 receptor deficient Otsuka Long–Evans Tokushima Fatty (OLETF) rats. Pepsinogen secretion was determined in fasted acute fistula OLETF and control Long–Evans Tokusima Otsuka (LETO) rats. Pepsinogen secretion in OLETF rats under basal conditions as well as in response to CCK-8 stimulation was significantly higher than that in LETO rats. CCK-1 receptor specific agonist ARL 15849 was unable to stimulate pepsinogen secretion in OLETF rats, whereas it elicited pepsinogen secretion in LETO rats to levels similar to those obtained with equimolar CCK-8 stimulation. CCK-2 receptor antagonist reduced basal pepsinogen secretion and completely abolished CCK-8-stimulated pepsinogen output in OLETF rats, whereas in LETO rats, it reduced basal pepsinogen secretion but augmented CCK-8-stimulated pepsinogen output. CCK-1 receptor antagonist loxiglumide also greatly decreased CCK-8-stimulated pepsinogen secretion in OLETF rat, which indicates that loxiglumide is not a specific CCK-1 receptor antagonist. Intravenous infusion of somatostatin antagonist significantly increased CCK-8-stimulated pepsinogen secretion in LETO rats, whereas it had no significant influence on CCK-8-stimulated pepsinogen secretion in OLETF rats. These results indicate that CCK-8 stimulates pepsinogen secretion via CCK-2 receptors in CCK-1 receptor deficient OLETF rats and that the higher CCK-8-stimulated as well as basal pepsinogen secretion in OLETF rats might result from an elimination of tonic inhibition by somatostatin that is released from D cells through mainly CCK-1 receptors.

Hereditary pancreatitis (HP) is the strongest known risk factor for pancreatic cancer. The aim of the present study is to establish diagnostic criteria for HP to predict and identify high-risk groups for pancreatic cancer.

Recent studies have suggested that CCK is not essential for normal pancreatic growth in mice. We examined whether the treatment of hyperglycemia participates in a non-CCK-1-receptor–mediated mechanism of pancreatic regeneration after partial (30) pancreatectomy (Px) with use of Otsuka Long-Evans Tokushima Fatty (OLETF) rats, an animal model for type 2 diabetes mellitus without CCK-1 receptor gene expression.

Background:Despite advances in endoscopic treatment methods for upper GI hemorrhage, hemostasis is often difficult to achieve, particularly when the endoscopic view at the site of hemorrhage is poor because of the presence of mucus and blood. The investigators developed an end hood that facilitates endoscopic hemostatic procedures while simultaneously allowing irrigation of the bleeding site. The usefulness of this end hood for treatment of upper GI hemorrhage, excluding hemorrhage from varices, was evaluated. Methods:The end-hood piece was fabricated by drilling a side hole in the cap portion of a conventional transparent hood. An irrigation tube then was glued to the exterior surface of the hole. The fabricated transparent hood was placed on the tip of an endoscope. With the hood piece in place, hemoclip placement and other endoscopic hemostatic procedures were performed in 15 patients with nonvariceal upper GI hemorrhage. Results:Hemostasis was successfully achieved in all cases. In all cases of active hemorrhage, hemostatic treatment was enhanced by simultaneous irrigation beneath the hood. The median time required for the hemostatic procedure with the attached hood was 4.8 minutes. Conclusion:The end-hood irrigation device and technique facilitate endoscopic hemostatic treatment of nonvariceal upper GI hemorrhage.

Damage to the exocrine pancreas has been observed in patients and animals with hyperlipidemia and hyperglycemia. Bezafibrate, a peroxisome proliferator-activated receptor (PPAR)- activator, has been shown to improve lipid and glucose metabolism, and to interfere with the inflammatory response.

Extracellular matrix (ECM) components participate in the process of tissue repair and development of fibrosis in the pancreas. We studied the production kinetics of ECM components and transforming growth factor (TGF)–1 and identified their production sites in the pancreas following pancreatitis.

Survivin is one of the inhibitors of the apoptosis family and has dual effects antiapoptotic effect and regulation of the cell cycle.

In 1997, a cooperative nationwide survey of 192 patients diagnosed with severe acute pancreatitis in 1996 was carried out.

A variety of treatments have recently been introduced to improve the prognosis of hepatocellular carcinoma (HCC). These anticancer therapies include the oily carcinostatic agent styrene maleic acid neocarzinostatin (SMANCS). SMANCS is a chemical conjugate of a synthetic copolymer of styrene maleic acid (SMA) and the proteinaceous anti-cancer agent neocarzinostatin (NCS), which dissolves in organic solvents such as pyridine and acetone, and particularly in Lipiodol. NCS is a simple protein capable of inhibiting DNA synthesis and inducing DNA degradation. Lipiodol is an ethyl ester of iodinated poppy seed oil in which most of the unsaturated double bonds in oleic, linoleic and linolenic acid are almost completely iodinated. When a homogeneous suspension of SMANCS with Lipiodol (SMANCS/Lipiodol) is administered intra-arterially, Lipiodol acts as a carrier of SMANCS. Many studies have demonstrated the clinical efficacy of SMANCS/Lipiodol in the treatment of HCC. We have shown that transcatheter arterial infusion (TAI) with SMANCS/Lipiodol has a more favorable focal therapeutic effect than does epirubicin in Lipiodol in the initial treatment of HCC. However, recent clinical studies have indicated that SMANCS causes severe adverse reactions and complications. We have also reported a case of HCC in which multifocal hepatic infarction developed after TAI with SMANCS/Lipiodol. Arterial administration of SMANCS/Lipiodol, therefore, should be given as peripherally as possible via the tumor feeding arteries, to enhance the efficacy of the agent and to reduce the adverse effects.

The pathogenesis and the mechanism of the development of severe acute pancreatitis are not clearly understood.

Pancreatic regeneration involves two pathways; proliferation and differentiation of pancreatic progenitor cells, which probably exist in pancreatic ductal epithelium, and replication of pre‐existing differentiated acinar, islet, and ductal epithelial cells. During pancreatic development, differentiated cells arise from the ductal progenitor cells expressing the pancreatic/duodenal homeobox‐1 (PDX‐1) homeodomain transcription factor. The aims of this study were to characterize cell proliferation and differentiation during regeneration after acute necrotizing pancreatitis and to evaluate the role of PDX‐1‐positive stem cells. Necrotizing pancreatitis was induced in rats by retrograde intraductal infusion of sodium taurocholate. Cell types were classified into five categories: main, large, and small ductal epithelial cells, tubular complexes and acinar cells. Each category was scored using a 5‐bromo‐2′‐deoxyuridine (BrdU) labelling index (LI) at various time points after induction of pancreatitis. Tissue sections were also immunostained for PDX‐1 to determine the source of pancreatic stem cells. Acinar necrosis was observed at 24 h after induction of pancreatitis and most lobules were filled with tubular complexes on day 5. Subsequently, newly formed acinar cells were observed on day 7, but the lobular architecture returned to normal appearance on day 28. Proliferation started in the main and large ducts at 24 h; marked mitotic activity was evident in small ductal epithelial cells and tubular complexes on day 3, and in acinar cells on day 7. At 24 h after induction of pancreatitis, epithelial cells of the main duct with PDX‐1‐positive nuclei were greatly increased, simultaneously with the peak LI of BrdU. These results suggest that regeneration after necrotizing pancreatitis involves proliferation and differentiation of pancreatic progenitor cells, and that ductal epithelial cells with PDX‐1‐positive nuclei may contribute to the differentiation of pancreatic stem cells in the main duct. Copyright © 2002 John Wiley & Sons, Ltd.

Dibutyltin dichloride (DBTC) is widely used as a stabilizer for polyvinylchloride plastics and is of particular toxicologic interest.

The matrix metalloproteinase (MMP) plays important roles in extracellular matrix turnover. However, little is known about the roles of MMP-2 and type IV collagen, and the relationship between MMP-2 and membrane type-1 matrix metalloproteinase (MT1-MMP) during progressive destruction of acinar cells in pancreatitis.

Peroxisome proliferator-activated receptors (PPARs) are a family of ligand-activated nuclear transcription factors belonging to the nuclear hormone receptors. Troglitazone, a specific ligand for PPAR- is shown to regulate not only lipids and glucose metabolism, but also cell cycle, differentiation, and apoptosis.

Pancreatic tissues are almost completely restored to normal after an attack of acute pancreatitis, once the cause of the disease is removed. Transforming growth factor (TGF)- and extracellular matrix (ECM) are known to play an important role in the process of wound healing in pathologic diseases. Tissue repair is a process regulated by a balance between synthesis and degradation of ECM.

It is well-known that chronic oral administration of trypsin inhibitors induces pancreatic hypertrophy and hyperplasia via stimulation of endogenous cholecystokinin (CCK) release. Because the growth-promoting effect of CCK on the pancreas is specifically mediated by the CCK-A receptor, we examined the plasma CCK concentrations, the expression of CCK mRNA in the intestine and CCK-A receptor mRNA in the pancreas, and pancreatic growth in rats after chronic oral administration of synthetic protease inhibitor (PI). PI at a dose of 100 mg/kg body weight was administered via an orogastric tube once daily for 20 days. Plasma CCK concentrations at 24 hours after the first PI administration were significantly higher than those in randomly fed rats (6.57 ± 0.67 pmol/L vs 4.31 ± 0.51 pmol/L;p< 0.001), and further increased to 14.24 ± 1.63 pmol/L after PI for 10 days and decreased to 10.05 ± 0.72 pmol/L after 15 days of PI administration. Treatment with PI for 20 days significantly increased the pancreatic weight, and the total pancreatic protein and DNA content by 190, 290, and 170, respectively, when compared to the control rats. Chronic oral administration of PI, however, reduced CCK-A receptor mRNA expression in the pancreas by 60. These findings suggest that chronic oral administration of PI induces an elevation of endogenous CCK release and stimulates pancreatic growth, but down-regulates the biosynthesis of CCK-A receptor at the transcriptional level in the pancreas.

Troglitazone has been shown to improve insulin sensitivity and thereby exert hypoglycemic effects in various animal models and humans with insulin resistance and diabetes. The recently established animal model of naturally occurring obese diabetes, the Otsuka Long-Evans Tokushima fatty (OLETF) rat, has many similarities with human type 2 diabetes mellitus and is characterized by a high degree of insulin resistance. In the present study, we examined the effect of pharmacologic intervention with troglitazone on metabolic and histopathologic changes in OLETF rats. Two groups of rats received a troglitazone-rich diet (200 mg/100 g normal chow) from age 12 weeks (ie, before the onset of diabetes) or 28 weeks (ie, after the onset of diabetes) to age 70 weeks, while a third group received standard rat chow. The addition of troglitazone to the diet did not alter food intake or body weight gain. Troglitazone had no influence on visceral adipose depots, but it significantly reduced fasting glucose, insulin, cholesterol, triglyceride (TG), and free fatty acid (FFA) levels. Troglitazone reduced the insulin resistance and maintained the postglycemic insulin response at a normal level, and thus inhibited the development of insulin insensitivity and frank diabetes in OLETF rats up to 70 weeks of age. The pancreatic wet weight and insulin content were significantly higher in the treated rat groups versus the control rats. The morphologic changes observed in the control rats, such as fibrosis and structural disarrangement of islets, were minimal in the troglitazone-treated rats. Our study demonstrates that troglitazone, albeit at a dosage 10 to 15 times higher than that in humans, not only prevents but also reverses the metabolic derangement and histopathologic changes in genetically determined obese diabetes.