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Objectives The rat experimental model of continuous regional arterial infusion of protease inhibitor (CRAI) on acute pancreatitis has yet to be established. Therefore, the aims of this study were (1) to establish the rat experimental model of CRAI and (2) to evaluate the effects of nafamostat on rat severe acute pancreatitis via different routes of administration. Methods The rat internal jugular vein or the celiac artery was infused with nafamostat, and the concentration of nafamostat in the lung and pancreas was measured. After the induction of severe acute pancreatitis, rats received intravenous or regional intraarterial infusion of nafamostat and then concentrations of trypsinogen activated peptide (TAP) and serum interleukin (IL-6), and histologic sections of the pancreas were examined and the 96-hour survival rate was evaluated. Results CRAI rats had higher concentrations of nafamostat in the pancreas than those infused intravenously. However, CRAI rats had lower concentrations of nafamostat in the lung that those infused intravenously. CRAI significantly reduced the levels of TAP and pancreatic necrosis. Moreover, the levels of serum IL-6 and the mortality rate were significantly reduced after CRAI compared with the intravenous infusion of nafamostat. Conclusion The effectiveness of the rat experimental model of CRAI on acute pancreatitis was clearly demonstrated. The concentration of nafamostat in the lung and pancreas and the effects of nafamostat differ according to the route of administration.

It has recently been recognized that anandamide (arachidonylethanolamide), which is an endogeneous-cannabinoid (endocannabinoid), mediates septic shock. Cannabinoid means a mind-active material in cannabis (marijuana). Anandamide is mainly produced by macrophages. Cannabinoid 1 (CB1) receptor, which is one of the cannabiniod receptors, is also known to mediate hypotensive shock. The role of endocannabinoids in the progression of acute pancreatitis is unclear. The aims of this study are to clarify their relationship and to find a new therapeutic strategy by regulating the endocannabinoid signaling in acute pancreatitis. Male Wistar rats were injected with caerulein intravenously to induce mild edematous pancreatitis or injected with 5% sodium taurocholate to the bilio-pancreatic duct to induce severe necrotizing pancreatitis. The animals in the latter group were also injected with a CB1 receptor antagonist, AM251, or vehicle solution to see if the inhibition of endocannabinoids improves their survival. Plasma anandamide level was measured by the liquid chromatography/tandem mass spectrometry method. In both models of acute pancreatitis, the plasma anandamide levels were increased, and the levels were significantly higher in rats with severe necrotizing pancreatitis than those in rats with mild edematous pancreatitis. The mean arterial pressure and survival rate were significantly improved by the treatment with AM251, despite that the local inflammatory changes in the pancreas and various parameters (white blood cells, hematocrit, serum amylase, and serum interleukin-6) were similar. This is the first report to show that endocannabinoids are involved in the deterioration of acute pancreatitis and that the down-regulation of endocannabinoid signaling may be a new therapeutic strategy for severe acute pancreatitis.

The interaction of immature dendritic cells (DC) with irradiated pancreatic cancer cells was examined. Flow cytometric analysis using annexin V and propidium iodide revealed that ionizing radiation (25–35 Gy X-ray) induced both apoptosis and necrosis in pancreatic cancer cell lines. After irradiation, PK-1 and Panc-1 cells were likely to undergo necrosis, whereas MIAPaCa-2 cells underwent apoptosis. When DiO-stained immature DCs were co-incubated with DiI-stained irradiated MIAPaCa-2, it was observed under fluorescent microscopy that DCs phagocytized dead tumor cells as early as 4 h after co-incubation. The DCs’ phagocytosis of irradiated tumor cells was also confirmed by flow cytometry. These results suggest that irradiated pancreatic cancer cells, which undergo both apoptosis and necrosis, could be a good source of tumor-associated antigens for cross-presentation by DCs.

Small pancreatic cancers, intractable diseases, offer the possibility of cure. Can this be true? Through the National Pancreatic Cancer Registry, the Japan Pancreas Society (JPS) has collected 822 cases of invasive cancer with tumors

症例は64歳の女性で, 糖尿病の悪化と体重減少が出現し, 精査にて膵頭部癌として当科紹介となった. 術前画像評価にて血管浸潤などから根治切除術は困難と判断された. 術中所見においても総肝動脈・固有肝動脈への腫瘍浸潤を認め, 手術診断はStage IVa, 胆道・消化管バイパス術を施行した. 術後5-FU併用放射線療法 (Chemoradiation; 以下, CRTと略記) を施行し, その後外来にてGemcitabine (以下, GEMと略記) 投与を行った. その結果, 原発腫瘍の縮小とCA19-9の著明な減少を認め, 初回手術から9か月後に膵頭十二指腸切除術を施行した. さらに外来でのGEM 投与を継続し, 初回手術から1年7か月経過した2003年4月現在, 画像上再発は認めていない. 根治切除術が施行できない局所進行膵癌に対し, down stagingを視野に入れてCRT とGEM の併用を行うことも選択肢の一つと考えられた.

On March 1, 1999, a 71-year-old woman was diagnosed as having cholecystolithiasis, for which she underwent laparoscopic cholecystectomy at a local hospital. Intraoperative cholangiography was not performed. No malignant lesion was detected in the gallbladder. In March 2000, a subcutaneous tumor was pointed out at the port site in her abdomen, and resected. Histological examination revealed metastatic adenocarcinoma. On detailed examination, endoscopic retrograde cholangiopancreatography (ERCP) revealed a tumor, about 2 cm in diameter, in the lower bile duct. On June 1, she underwent pylorus-preserving pancreatoduodenectomy at our institute, and several disseminated lesions were detected at the port site and in the abdominal cavity. There have been few reports of bile duct carcinoma that developed peritoneal dissemination caused by leakage of bile during cholecystectomy. Leakage of bile should be prevented during laparoscopic cholecystectomy, even in patients not diagnosed as having cancer preoperatively.

The mortality associated with severe acute pancreatitis is still high, and death in the later stage of the disease is chiefly due to bacterial infection and sepsis. However, objective parameters for the risk of sepsis in acute pancreatitis have not been established.To investigate the value of human leukocyte antigen-DR (HLA-DR) on peripheral monocytes for predicting the development of sepsis during acute pancreatitis.The expression of HLA-DR on peripheral monocytes was measured in 64 patients by flow cytometry at admission and 7 and 14 days after the onset of acute pancreatitis. Twenty-eight patients with severe acute pancreatitis and 36 with mild acute pancreatitis, as determined by the Atlanta classification, were enrolled.Six patients had sepsis, and two of them died during the hospital stay. At admission, the percentage of HLA-DR-expressing cells in the monocyte population was significantly lower in the patients who had sepsis in the later course than in the patients who did not have sepsis. A percentage lower than 80% at admission was observed in 17 patients, and the patients who had persistently low percentages of HLA-DR-expressing monocytes throughout the observation period had sepsis in the later clinical course, whereas the patients in whom expression recovered to the normal range were spared the development of sepsis.In acute pancreatitis, the low percentage of HLA-DR-expressing cells in the monocyte population is a reliable predictor of the development of sepsis. Monitoring of monocyte HLA-DR expression may be a useful marker for identifying the patients who are at high risk of sepsis in acute pancreatitis.

Seasonal allergic rhinitis (SAR) is an inflammatory disease of the nose and eyes that follows sensitization to air-born pollens. We conducted a genome-wide linkage screening of 48 Japanese families (188 members) with orchard grass (OG)-sensitive SAR children (67 affected sib-pairs) in a farming community in central Japan where OG was planted for apple farming and OG pollen is a major cause of SAR. We used the GENEHUNTER program to performed nonparametric multipoint linkage analysis for OG-sensitive SAR as a qualitative trait and for log total serum IgE levels and OG-RAST IgE levels as quantitative traits. Genotyping data of 400 microsatellite markers suggested linkage of SAR to chromosomes 1p36.2, 4q13.3, and 9q34.3 (P < 0.001), linkage of serum total IgE levels to 3p24.1, 5q33.1, 12p13.1, and 12q24.2 (P < 0.001), and linkage of OG-RAST IgE levels to 4p16.1, 11q14.3, and 16p12.3 (P < 0.001). Weak evidence for linkage of SAR to 5q33.1 was also observed (P = 0.01). All these regions, with the exception of 9q34.3, have been previously reported to be linked to asthma and/or atopy. These data suggest that, although loci linked to SAR are likely to be common to asthma, a strong contribution by specific gene(s) to OG-sensitive SAR is unlikely.

The mechanism of metastasis formation remains still largely unknown. Many studies underline the importance and complexity of the initial arrest of the circulating tumour cells in the target organ, a key stage in metastasis occurrence. In our study, we evaluated by visual means the metastasis formation using an in vivo microscopy system in a murine model. Moreover, we investigated the involvement of P-selectin in these processes using immunohistochemistry and P-selectin knockout mice. The present study offers direct evidence of distinct pathways for tumour metastasis formation by a lymphoma cell – EL-4 and a solid tumour cell – C26. Off-line analysis of the images and histological data confirmed that mechanical entrapment of the solid tumour cell, which had a bigger diameter than that of the liver sinusoids, promoted metastasis without any detectable involvement of adhesion molecules. On the other hand, we observed that lymphoma cells, in spite of their smaller diameter as compared to the sinusoids, promoted liver metastasis as well, but with the essential participation in their arrest of P-selectin, indicating an adhesion molecule-mediated pathway. © 2001 Cancer Research Campaign http://www.bjcancer.com

The clinical manifestations of acute pancreatitis (AP) vary significantly from mild to lethal in form, the severity of the disease being largely determined by the actions of various kinds of inflammatory mediators, including cytokines, reactive oxygen species, proteolytic enzymes, and lipids, as well as gaseous mediators. Despite increasing knowledge implicating the involvement of cytokines in the progression of AP, no clinical trials pertaining to cytokine modulation have been performed so far. Progress in intensive care technologies has contributed to the improvement of mortality and morbidity rates in severe AP in the past decade; however, it appears to be reasonable for clinicians to "line up their sights" on the modulation of cytokines as a direct treatment. In contrast to the large body of experimental studies demonstrating the beneficial effects of cytokine modulation on the amelioration of the disease, direct extrapolation from these successful experiments to the clinical situation seems to be extremely difficult.

In clinical settings, the effectiveness of protease inhibitors in the treatment of acute pancreatitis has been still controversial. With the concept that sufficient tissue concentration of protease inhibitor in the pancreas has to be included to achieve its potent inhibitory effect, we applied a continuous regional intra-arterial (CRI) application of low-molecular-weight protease inhibitor, nafamostat mesilate (FUT-175), for closed duodenal loop obstruction model in mongrel dogs. The use of CRI application led to a higher concentration of FUT-175 in the pancreatic tissue (4,453 ± 758 ng/g) when compared with that applied intravenously (905 ± 48 ng/g). Consequently, pancreatic parenchyma in CRI application animals was remarkably preserved, as assessed by the lower extent of pancreatic necrosis (12.4 ± 2.6% in CRI vs. 25.6 ± 1.9% in intravenous). Additionally, the elevation of trypsin-like activity in the pancreas was significantly inhibited in CRI animals. Based on these findings, the dose as well as the route of protease inhibitors should be carefully considered to achieve its beneficial effect.

Background IL-4 gene cluster on chromosome 5 contains several candidate genes for atopy and asthma. Several independent studies have shown evidence for linkage between the markers flanking IL-4 gene cluster and asthma and/or asthma-related traits. Interferon regulatory factor 1 (IRF-1) is located approximately 300 kb telomeric to IL-4 and recent study reveals that IRF-1 deficiency results in an elevated production of Th2-related cytokines and a compensatory decrease in the expression of native cell- and Th1-related cytokines. Objective To determine if there are any mutations associated with the development of atopy and asthma present in the coding exons and 5′ flanking region of the IRF-1 gene. Methods and results We have screened the promoter and coding regions of the IRF-1 gene in atopic asthmatics and controls by SSCP method. We found three novel nuclear variants (the −300G/T and 4396 A/G polymorphisms and the 6355G > A rare variant) in the IRF-1 gene. No variants causing amino acid alterations of IRF-1 were detected. The −300G/T polymorphism was in nearly complete linkage disequilibrium with the 4396 A/G polymorphism. An association between the 4396 A > G polymorphism and atopy/asthma was examined by transmission disequilibrium test in 81 asthmatic families. Either of 4396 A or 4396G alleles was not significantly preferentially transmitted to atopy- or asthma-affected children. Conclusion The IRF-1 gene is less likely to play a substantial role in the development of atopy and asthma in the Japanese population.

Background. The Japanese Pancreas Society Registry Committee obtained data on 16 071 patients with pancrea-tic cancer diagnosed from 1981 to 1996. This is the largest multi-institutional retrospective study of the Japanese experience to describe the extent of disease and survival.

Interleukin 12 (IL-12) is a heterodimeric cytokine that exerts a potent antitumor effect through its pleiotropic actions. It was recently reported that IL-12 has also a potent antiangiogenic effect through the induction of IFN-gamma, which triggers the production of chemokines such as IP-10 that has been shown to have antiangiogenesis properties. In this study we transfected the IL-12 gene into a human pancreatic adenocarcinoma cell line (PK-1). PK-1 cells transfected with the green fluorescence protein (gfp) gene were used as positive controls. The in vitro growth curve and in vivo tumor growth of transfectants (IL-12/PK-1 and gfp/PK-1) were compared with those of parental cells. The SCID mice used in this study were administered antiasialo GM-1 Ab (100 microg, i.p., twice weekly) to deplete the remaining immunoeffector cells, NK cells. Using a skinfold chamber model, we observed and recorded tumor angiogenesis by intravital microscopy. In vitro growth of IL-12/PK-1 and gfp/PK-1 cells was not different from that of wild-type PK-1 cells (wt/PK-1). However, IL-12 transfected PK-1 cells did not develop into tumors as did the wt/PK-1 cells after subcutaneous inoculation in antiasialo GM-1 Ab administered SCID mice. The growth of IL-12/PK-1 tumors was restored in mice treated with anti-IL-12 antibody. We found that IL-12/PK-1, in contrast to gfp/PK-1 and wt/PK-1, failed to initiate an angiogenic response, as observed in the skinfold chamber model. These results indicate that the antiangiogenesis effect of IL-12 alone, without immune system involvement, is sufficient to block the growth of human pancreatic cancer.

This study was conducted as part of an international evaluation on transgenic mouse models as potential alternatives to the standard two-year bioassay. Methapyrilene hydrochloride (MP), a non-genotoxic rat-specific hepatocarcinogen, in the diet was given to male and female transgenic CB6F1 mice carrying copies of a human prototype c-Ha-ras gene (rasH2 mice) at doses of 0, 1, 750, 3, 500, and 7, 000 ppm and to male and female non-transgenic littermates (non-Tg mice) at 0 and 7000 ppm for 26 weeks and subsequently sacrificed. N-methyl-N-nitrosourea (MNU) was used as a positive control compound to confirm that a positive response is elicited in the rasH2 model. Complete autopsies were performed and all organs of mice were histologically examined. Lung alveolar/bronchiolar adenomas and carcinomas, a thymic lymphoma, splenic hemangiosarcomas, skin squamous cell papillomas/carcinomas and hemangiosarcoma, a Harderian gland adenoma, and uterus and testicular hemangiosarcomas were detected in rasH2 mice receiving MP or basal diet. Only one neoplasm was found in the non-Tg group, in a non-treated male. However, there were no effects of MP on tumor incidence or multiplicity, although rasH2 mice were sensitive to the carcinogenic activity of MNU. Slight hepatotoxicity, as evidenced by hepatocyte hypertrophy and small bile duct proliferation, was noted in rasH2 and non-Tg mice treated with MP, but no hepatic foci were noted in any mice. The results indicate that negative carcinogenicity of MP was confirmed even at doses higher than those employed earlier in B6C3F1 mice, and suggest that this non-genotoxic rat specific carcinogen may not be a human carcinogen. Thus, the rasH2 mouse model has utility as an alternative for the detection of carcinogenicity of environmental chemicals.

Clinical indicators set forth in the guidelines have been found to contribute to the improvement in compliance with the guidelines. On the other hand, it has been shown that clinical indicators are more effective when individual indicators are presented in the form of a bundle than when they are given separately. Accordingly, in the JPN Guidelines 2010 for management of acute pancreatitis, those indicators that are judged to be important on the basis of a recommendation classification of "A or B" are presented as a pancreatitis bundle. Each item includes assessment of severity after a diagnosis of pancreatitis has been made, differentiation of pathogenesis, management of gallstone-induced pancreatitis, a sufficient dose of fluid replacement and monitoring, pain control, prophylactic administration of wide-spectrum antibiotics and cholecystectomy following resolution of pancreatic symptoms caused by cholecystolithiasis. Hereafter, the efficacy of these indicators and the significance of their achievement should be examined carefully. Then, the assessment of the compliance rate with the guidelines as well as the assessment of the guidelines and pancreatitis itself should become possible.

Leukocyte infiltration in the pancreas is involved in the aggravation of acute pancreatitis from edematous phase into necrotic change, and mild disease into severe disease; however, the mechanism responsible for leukocyte accumulation is not fully understood. This study was designed to clarify the mechanism underlying leukocyte accumulation into the pancreas and to elucidate the therapeutic efficacy of a novel diamino-pyridine derivative, IS-741 on leukocyte-endothelial cell interaction using rat necrotizing pancreatitis model. The number of adherent leukocytes to pancreatic collecting venules assessed by in vivo fluorescence microscopy increased significantly in necrotizing pancreatitis animals in a time-dependent manner. The expression of CD11b on circulating neutrophils determined by flow cytometric analysis was enhanced to approximately 500% after 2 h. IS-741 attenuated the leukocyte adherence significantly, accompanied by a lower up-regulation of CD11b. These findings were further supported by the histological examination that the accumulation of leukocytes in the pancreas was remarkably inhibited by IS-741. These results suggest that the leukocyte accumulation in the early phase of acute necrotizing pancreatitis may be mediated by leukocyte-endothelial cell interaction via leukocyte integrin CD11b/18. IS-741 attenuated the leukocyte endothelial cell interaction as a consequence of its inhibitory effect on CD11b upregulation.

This paper reviewed our experience with the nonsurgical management of acute necrotizing pancreatitis (ANP) by continuous regional arterial infusion (CRAI) of protease inhibitor (nafamostat mesilate, 240 mg/day) and antibiotic (imipenem, 0.5 g every 12 h). 47 patients with ANP admitted within 7 days were treated with intensive care and CRAI for 5 days prospectively. 40 patients responded to CRAI therapy and the mortality rate in these patients was 2.5%. 7 patients (14.9%) did not respond to CRAI. 5 of 7 nonresponders died of multiple organ failure although pancreatic necrosis was persistently sterile. The remaining 2 patients who underwent necrosectomy for infected pancreatic necrosis recovered after surgery. In 34 patients treated with CRAI in the early stage within 72 h after the onset, 31 (91.2%) responded. The mortality rate was 5.9% and the incidence of infected pancreatic necrosis was 2.9% in these 34 patients. These results demonstrated that most patients with ANP responded to conservative management combined with CRAI with nafamostat and imipenem when employed within 72 h after the onset. Early intervention of CRAI with protease inhibitor and antibiotic has a significant role in the nonsurgical management of ANP.

Objectives It is known that prophylaxis with imipenem reduces the risk of infection accompanying severe acute pancreatitis. In this study,we modified a rat experimental model of severe acute pancreatitis for antibiotic evaluation, and the effect of biapenem was compared with that of imipenem to determine the usefulness of biapenem. Methods Severe acute pancreatitis was induced by 5% sodium taurocholate. Antibiotics were subcutaneously administered at 3 and 6 hours and evaluated at 12 hours after the pancreatitis induction. For pharmacokinetic evaluation, antibiotics were subcutaneously administered at 3 hours after the pancreatitis induction. Results From 3 hours after the induction, bacteria were detected from the pancreas. The total bacterial count increased in a time-dependent manner for 12 hours. Biapenem administration reduced the total bacterial count in the pancreas, as observed in imipenem administration. The plasma concentration of biapenem was almost equivalent to that of imipenem; however, the pancreatic penetration of biapenem was approximately twice that of imipenem in this model. Conclusions Biapenem was suggested to be effective in prophylactic treatment of infectious complications as much as imipenem because of its superior penetration to the pancreas in severe acute pancreatitis.

We present a review of the microvascular morphology of the pancreas and microstructure of the pancreatic lobule, and report our experimental results of the investigation of pancreatic microcirculation following acute pancreatitis. Impairment of pancreatic microcirculation in the early phase of acute pancreatitis may play a key role in the progression of this disease. Possible contributory mechanisms include increased vascular permeability, reduced blood flow, leukocyte-endothelial cell interaction and intravascular thrombus formation. Using an in-vivo microscope system and off-line computer analysis, we achieved direct visualization and quantification of changes in microvascular permeability and leukocyte behavior in pancreas with acute pancreatitis. Bradykinin and oxygen radicals have been demonstrated to be involved in the increase of vascular permeability in the early stage of caerulein pancreatitis. Leukocyte adherence to the vessels in the pancreatic microcirculation is a secondary event following permeability changes in acute pancreatitis. Leukocyte infiltration during exacerbation of acute pancreatitis is mediated by leukocyte-endothelial cell interaction via leukocyte integrin CD11b/18.

The Japanese grading system for severity of acute pancreatitis has evolved from results of a national survey on 2,553 patients managed in 523 major medical centers in Japan between 1982 and 1986. It was devised to embrace the predictive factors that would offer high sensitivity and specificity in rendering an accurate diagnosis. In this system, computed tomographic (CT) examination is used for estimating the severity of acute pancreatitis. Combining criteria from laboratory data, clinical signs, and CT findings, the system appears cumbersome. However, it is actually more flexible in that only few criteria, from the wide range of findings actually covered, are needed to predict severity. Its rationale stems from a national effort to improve the outcome of this life-threatening disease. Further prospective studies are needed to determine its accuracy and superiority.

The levels of naturally occurring IgG, IgGl and lgG2 antibodies against polyvalent pneumococcal capsular polysaccharide antigen (Pneumovax®) were compared between atopic and nonatopic children with different ages, 6–12 months and 1, 2, 3, 4, 5–9 and 10–15 years, by enzyme-linked immunosorbent assay. Children with asthma, atopic dermatitis, food allergy or a combination of these, and those having serum IgE levels exceeding 50 IU/mL at 6–12 months old and 100 IU/mL at more than 1-year-old were included as atopic groups. Asymptomatic children whose serum IgE levels were less than these atopic standards and those not having detectable IgE antibodies to Dermatophagoides farinae comprised the nonatopic groups. Geometric mean levels of IgG and IgG 1 antibodies against pneumococcal antigen increased steadily with age, and that of IgG2 antibodies was low until 3 years of age and then gradually increased age-dependently up to 15 years of age. The levels of IgG antibody as well as IgG 1 and IgG 2 antibodies were not significantly different between atopic and nonatopic children in any age group. This suggests that the immune response to the most common bacterial pathogen in the respiratory tract does not influence atopic status.

Susceptibility to the development of asthma and other atopic diseases is known to be associated with genetic components, and several candidate genes have been reported to be linked to atopy and asthma. We have examined a linkage between traits of specific IgE responses to the house dust mite and its purified allergens, high total serum IgE levels and asthma, and the markers at the T-cell receptor (TCR) alpha chain gene (TCR-alpha) and beta chain gene (TCR-beta) in Japanese families ascertained through asthmatic children. Affected sib-pair analyses provided evidence for linkage between TCR-beta and nearby markers (D7S684) on chromosome 7q35 and both IgE and asthmatic phenotypes, but no evidence for linkage of IgE responses nor asthma phenotype to TCR-alpha was detected. The results suggest the presence of major gene(s) controlling atopy and asthma susceptibility in TCR-beta and the nearby region.

The health insurance system in Japan is based upon the Universal Medical Care Insurance System, which gives all citizens the right to join an insurance scheme of their own choice, as guaranteed by the provisions of Article 25 of the Constitution of Japan, which states: “All people shall have the right to maintain the minimum standards of wholesome and cultured living.” The health care system in Japan includes national medical insurance, nursing care for the elderly, and government payments for the treatment of intractable diseases. Medical insurance provisions are handled by Employee’s Health Insurance (Social Insurance), which mainly covers employees of private companies and their families, and by National Health Insurance, which provides for the needs of self-employed people. Both schemes have their own medical care service programs for retired persons and their families. The health care system for the elderly covers people 75 years of age and over and bedridden people 65 years of age and over. There is also a system under which the government pays all or part of medical expenses, and/or pays medical expenses not covered by insurance. This is referred to collectively as the “medical expenses payment system” and includes the provision of medical assistance for specified intractable diseases. Because severe acute pancreatitis has a high mortality rate, it is specified as an intractable disease. In order to lower the mortality rate of various diseases, including severe acute pancreatitis, the specification system has been adopted by the government. The cost of treatment for severe acute pancreatitis is paid in full by the government from the date the application is made for a certificate verifying that the patient has an intractable disease.

Susceptibility to the development of asthma and other atopic diseases is known to be associated with genetic components, and several candidate genes have been reported to be linked to atopy in Caucasian populations. We conducted a study of linkage between asthma and markers on chromosomes 5q31-q33 and 11q13 in 68 Japanese families (306 members) by affected sib-pair analysis. Families for the linkage study were ascertained through asthmatic children visiting the allergy clinic. The results provide supportive evidence for linkage between asthma and gene markers in or near the interleukin-4 (IL-4) gene, the IL-9 gene, and D5S393 on chromosome 5q31-q33 (p = 0.0013, p = 0.018, and p = 0.0077, respectively). Linkage between atopic phenotype and these genetic markers was also suggested (p = 0.006, p = 0.01, and p0.0001 for atopy, respectively). However, we failed to find evidence for linkage of asthma or atopy to the IgE high-affinity receptor gene on 11q13 (p0.1). These findings indicate that beyond ethnicity, there are specific loci that contribute to susceptibility to atopy on chromosome 5q31-q33. In addition, our findings suggest that loci on chromosome 5q31-q33 are linked to the development of asthma in childhood.

To evaluate appropriate surgical treatment and to predict prognosis for mucin-producing tumors (MPTs) of the pancreas, we conducted a retrospective clinicopathological study in 25 patients with MPT. Eight patients who had mild dysplasia of the pancreas were diagnosed with benign disease and 17 patients with ductal lesions of the pancreas with severe dysplasia/carcinoma in situ or with invasive foci were diagnosed as malignant. Clinical symptoms and histories, tumor markers, cytological examination, and radiological and gross pathological features were compared in the benign and malignant groups. Clinical symptoms, history, and tumor markers were of no value for predicting prognosis. Cytological examination results were ambiguous because of too many falsenegatives. Radiological features, including the diameters of the cystic space and of the main pancreatic duct (MPD) were shown to be valuable. The significant maximal diameters, above which malignancy was seen, were 30mm for the diameter of the cystic space and 10mm for the MPD. In regard to gross features, the uniformly dilated main duct-type and focally dilated main duct-type were significant indicators of malignancy. Long term follow-up was available in 22 patients. Seven patients died of recurrence of the tumor or other malignancies. We could have predicted prognosis by the radiological features and gross appearance. Surgical treatment should be considered the primary choice for MPT. Total pancreatectomy would be ideal for patients with the uniformly dilated main duct-type. Because of the probability of multicentricity and the transforming potential of mild dysplasia, very careful follow-up is necessary for patients with MPT.

Summary To understand the relevance of allergy to the development of asthma in children, we examined basophil hislamine release (HR) with Df antigen, blood cosinophii counts, serum eosinophil cationic protein (ECP) levels, and bronchial responsiveness to methacholine (PC20) in three groups of children, including 36 asthmatics with high RAST titre for Df (group 1), 36 non-asthmatics with similarly high RAST titre for Df (group 2) and 21 non-asthmatics with negative RAST titre for Df (group 3). The amount of Df antigen inducing 50% HR from basophils did not vary significantly between group 1 and 2 (P>0.05), while none of the cells responded to higher concentrations of Df in group 3. The mean number of blood eosinophils and level of serum ECP were highest in group 1, and lowest in group 3, with group 2 being intermediate, and the differences were significant between all three groups (P

A new strategy for the treatment of acute necrotizing pancreatitis (ANP) is reported. In this prospective study, all patients received intensive medical support. Surgery was performed in patients with infected pancreatic necrosis and/or sepsis. Continuous regional arterial infusion (CRAI) of the protease inhibitor, nafamostat mesilate, and the antibiotic imipenem was initiated in patients with ANP referred to our hospital within 7 days of the onset of the disease. Sixty patients with ANP were allocated to three groups: group I, no CRAI (n =16); group II, CRAI of nafamostat only (n=22); and group III, CRAI of nafamostat mesilate and imipenem (n=22). The mortality rate was 43.3% in group I, 13.6% in group II (P

s / Pancreatology 16 (2016) S1eS130 S109 than 70 years showed pancreas volume over 80 ml, but in those over that age a reduction was observed below 70 ml. Conclusion:We have not found differences related to sex. People older than 70 years showed a decrease in pancreas volume.

The findings in 35 surgically treated patients with insulinoma and 43 tumors of these patients were analyzed to confirm the efficacy of diagnostic modalities and surgical interventions. The rate of accurate preoperative tumor localization was 72% by angiography, 53% by computed tomographic scan, 55% by ultrasonography, and 83% by percutaneous transhepatic portal vein sampling. Extensive operative exposure and palpation detected 81% of the tumors and intraoperative ultrasonography demonstrated 96% of the tumors. Intraoperative ultrasonography was significantly better than any other diagnostic procedure and was able to demonstrate the anatomical relationship of the insulinoma to the essential structures of the pancreas. Intraoperative ultrasonography also helped determine the safest route for enucleating the insulinomas. Five patients (14%) in our series had metastatic diseases; 2 of these patients with metastases beyond the lymph nodes died due to the growth of tumors. The other 33 patients were free of insulinoma syndrome after the removal of the insulinomas. Streptozotocin was used in 1 patient with recurrent malignant insulinoma, with encouraging results.

Infected pancreatic necrosis which spreads extensively in the retroperitoneal space requires open drainage to prevent the formation of residual abscess. With open drainage and repeated debridement, we often encountered patients who suffered from abdominal complications such as prolapse of the small intestine through the wound and injury to the intestine. In order to improve the open drainage method, we combined diverting ileostomy with open drainage. Diverting ileostomy was effective in decompressing the small intestine; this prevented prolapse and reduced the incidence of paralytic ileus. Prophylactic diverting ileostomy appears to result in the reduction of complications during open drainage and has advantages in the subsequent management of critically ill patients with infected pancreatic necrosis.

The relation between non-specific bronchial responsiveness and allergic sensitivity was evaluated in children with asthma. Bronchial responsiveness was determined by methacholine inhalation challenge test, and was expressed as a provocative concentration of methacholine causing a 20% fall in FEV1 (PC20). RAST titre for Dermatophagoides farinae and serum IgE level were evaluated as parameters of allergic sensitivity. When the PC20 values, RAST titres for D. farinae, and serum IgE levels of 47 asthmatic children and 16 normal controls were compared, the asthmatic children had significantly lower PC20 values and higher D. farinae-RAST titres and serum IgE levels than the normal controls. The correlation analyses in 47 asthmatic children have shown that there is no significant correlation between PC20 values and RAST titres for D. farinae (r = 0.04, P > 0.1) or between PC20 values and serum IgE levels (r = 0.03, P > 0.1). These results suggest that although both bronchial hyperresponsiveness and allergic sensitization may be in some way related to one another in children with asthma, the magnitude of allergic sensitization does not influence the degree of the non-specific bronchial responsiveness.