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Polyunsaturated fatty acids (PUFAs) are essential FAs for human health. Cytochrome P450 oxygenates PUFAs to produce anti-inflammatory and pain-resolving epoxy fatty acids (EpFAs) and other oxylipins whose epoxide ring is opened by the soluble epoxide hydrolase (sEH/Ephx2), resulting in the formation of toxic and pro-inflammatory vicinal diols (dihydroxy-FAs). Pharmacological inhibition of sEH is a promising strategy for the treatment of pain, inflammation, cardiovascular diseases, and other conditions. We tested the efficacy of a potent, selective sEH inhibitor, 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) urea (TPPU), in an animal model of multiple sclerosis (MS), experimental autoimmune encephalomyelitis (EAE). Prophylactic TPPU treatment significantly ameliorated EAE without affecting circulating white blood cell counts. TPPU accumulated in the spinal cords (SCs), which was correlated with plasma TPPU concentration. Targeted lipidomics in EAE SCs and plasma identified that TPPU blocked production of dihydroxy-FAs efficiently and increased some EpFA species including 12(13)-epoxy-octadecenoic acid (12(13)-EpOME) and 17(18)-epoxy-eicosatrienoic acid (17(18)-EpETE). TPPU did not alter levels of cyclooxygenase (COX-1/2) metabolites, while it increased 12-hydroxyeicosatetraenoic acid (12-HETE) and other 12/15-lipoxygenase metabolites. These analytical results are consistent with sEH inhibitors that reduce neuroinflammation and accelerate anti-inflammatory responses, providing the possibility that sEH inhibitors could be used as a disease modifying therapy, as well as for MS-associated pain relief.

BACKGROUND Rapid urinary trypsinogen-2 dipstick test and levels of urinary trypsinogen-2 and trypsinogen activation peptide (TAP) concentration have been reported as prognostic markers for the diagnosis of acute pancreatitis. AIM To reconfirm the validity of all these markers in the diagnosis of acute pancreatitis by undertaking a multi-center study in Japan. METHODS Patients with acute abdominal pain were recruited from 17 medical institutions in Japan from April 2009 to December 2012. Urinary and serum samples were collected twice, at enrollment and on the following day for measuring target markers. The diagnosis and severity assessment of acute pancreatitis were assessed based on prognostic factors and computed tomography (CT) Grade of the Japanese Ministry of Health, Labour, and Welfare criteria. RESULTS A total of 94 patients were enrolled during the study period. The trypsinogen-2 dipstick test was positive in 57 of 78 patients with acute pancreatitis (sensitivity, 73.1%) and in 6 of 16 patients with abdominal pain but without any evidence of acute pancreatitis (specificity, 62.5%). The area under the curve (AUC) score of urinary trypsinogen-2 according to prognostic factors was 0.704, which was highest in all parameter. The AUC scores of urinary trypsinogen-2 and TAP according to CT Grade were 0.701 and 0.692, respectively, which shows higher than other pancreatic enzymes. The levels of urinary trypsinogen-2 and TAP were significantly higher in patients with extended extra-pancreatic inflammation as evaluated by CT Grade. CONCLUSION We reconfirmed urinary trypsinogen-2 dipstick test is useful as a marker for the diagnosis of acute pancreatitis. Urinary trypsinogen-2 and TAP may be considered as useful markers to determine extra-pancreatic inflammation in acute pancreatitis.

IntroductionGiven an increasing use of dipeptidyl peptidase-4 (DPP-4) inhibitors to treat patients with type 2 diabetes mellitus in the real-world setting, we conducted a prospective observational study (Japan-based Clinical Research Network for Diabetes Registry: J-BRAND Registry) to elucidate the safety and efficacy profile of long-term usage of alogliptin.Research design and methodsWe registered 5969 patients from April 2012 through September 2014, who started receiving alogliptin (group A) or other classes of oral hypoglycemic agents (OHAs; group B), and were followed for 3 years at 239 sites nationwide. Safety was the primary outcome. Symptomatic hypoglycemia, pancreatitis, skin disorders of non-extrinsic origin, severe infections, and cancer were collected as major adverse events (AEs). Efficacy assessment was the secondary outcome and included changes in hemoglobin A1c (HbA1c), fasting blood glucose, fasting insulin and urinary albumin.ResultsOf the registered, 5150 (group A: 3395 and group B: 1755) and 5096 (3358 and 1738) were included for safety and efficacy analysis, respectively. Group A patients mostly (>90%) continued to use alogliptin. In group B, biguanides were the primary agents, while DPP-4 inhibitors were added in up to ~36% of patients. The overall incidence of AEs was similar between the two groups (42.7% vs 42.2%). Kaplan-Meier analysis revealed the incidence of cancer was significantly higher in group A than in group B (7.4% vs 4.8%, p=0.040), while no significant incidence difference was observed in the individual cancer. Multivariate Cox regression analysis revealed that the imbalanced patient distribution (more elderly patients in group A than in group B), but not alogliptin usage per se, contributed to cancer development. The incidence of other major AE categories was with no between-group difference. Between-group difference was not detected, either, in the incidence of microvascular and macrovascular complications. HbA1c and fasting glucose decreased significantly at the 0.5-year visit and nearly plateaued thereafter in both groups.ConclusionsAlogliptin as a representative of DPP-4 inhibitors was safe and durably efficacious when used alone or with other OHAs for patients with type 2 diabetes in the real world setting.

Neuropathic pain (NP) is a complex chronic pain state with a prevalence of almost 10% in the general population. Pharmacological options for NP are limited and weakly effective, so there is a need to develop more efficacious NP attenuating drugs. Activation of the type 1 lysophosphatidic acid (LPA(1)) receptor is a crucial factor in the initiation of NP. Hence, it is conceivable that a functional antagonism strategy could lead to NP mitigation. Here we describe a new series of LPA(1) agonists among which derivative (S)-17 (UCM-05194) stands out as the most potent and selective LPA(1) receptor agonist described so far (E(max) = 118%, EC(50) = 0.24 µM, K(D) = 19.6 nM; inactive at autotaxin and LPA(2-6) receptors). This compound induces characteristic LPA(1)-mediated cellular effects and prompts the internalization of the receptor leading to its functional inactivation in primary sensory neurons and to an efficacious attenuation of the pain perception in an in vivo model of NP.

Cerebral edema is a life-threatening neurological condition characterized by brain swelling due to the accumulation of excess fluid both intracellularly and extracellularly. Fulminant hepatic failure (FHF) develops cerebral edema by disrupting blood-brain barrier (BBB). However, the mechanisms by which mediator induces brain edema in FHF remain to be elucidated. Here, we assessed a linkage between brain edema and lysophosphatidic acid (LPA) signaling by utilizing an animal model of FHF and in vitro BBB model. Azoxymethane-treated mice developed FHF and hepatic encephalopathy, associated with higher autotaxin (ATX) activities in serum than controls. Using in vitro BBB model, LPA disrupted the structural integrity of tight junction proteins including claudin-5, occludin, and ZO-1. Furthermore, LPA decreased transendothelial electrical resistances in in vitro BBB model, and induced cell contraction in brain endothelial monolayer cultures, both being inhibited by a Rho-associated protein kinase inhibitor, Y-27632. The brain capillary endothelial cells predominantly expressed LPA6 mRNA, whose knockdown blocked the LPA-induced endothelial cell contraction. Taken together, the up-regulation of serum ATX in hepatic encephalopathy may activate the LPA-LPA6-G12/13-Rho pathway in brain capillary endothelial cells, leading to enhancement of BBB permeability and brain edema.

Posthemorrhagic hydrocephalus (PHH) in premature infants is a common neurological disorder treated with invasive neurosurgical interventions. Patients with PHH lack effective therapeutic interventions and suffer chronic comorbidities. Here, we report a murine lysophosphatidic acid (LPA)–induced postnatal PHH model that maps neurodevelopmentally to premature infants, a clinically accessible high-risk population, and demonstrates ventriculomegaly with increased intracranial pressure. Administration of LPA, a blood-borne signaling lipid, acutely disrupted the ependymal cells that generate CSF flow, which was followed by cell death, phagocytosis, and ventricular surface denudation. This mechanism is distinct from a previously reported fetal model that induces PHH through developmental alterations. Analyses of LPA receptor–null mice identified LPA1 and LPA3 as key mediators of PHH. Pharmacological blockade of LPA1 prevented PHH in LPA-injected animals, supporting the medical tractability of LPA receptor antagonists in preventing PHH and negative CNS sequelae in premature infants.

Glutamate is the principal excitatory neurotransmitter in the human brain. Following neurotransmission, astrocytes remove excess extracellular glutamate to prevent neurotoxicity. Glutamate neurotoxicity has been reported in multiple neurological diseases including multiple sclerosis (MS), representing a shared neurodegenerative mechanism. A potential modulator of glutamate neurotoxicity is the bioactive lysophospholipid sphingosine 1-phosphate (S1P) that signals through five cognate G protein-coupled receptors (GPCRs), S1P1 - S1P5, however, a clear link between glutamate homeostasis and S1P signaling has not been established. Here, S1P receptor knock-out mice, primary astrocyte cultures, and receptor-selective chemical tools were used to examine the effects of S1P on glutamate uptake. S1P inhibited astrocytic glutamate uptake in a dose-dependent manner and increased mitochondrial oxygen consumption, primarily through S1P2. Primary cultures of wild-type mouse astrocytes expressed S1P1,2,3 transcripts, and selective deletion of S1P1 and/or S1P3 in cerebral cortical astrocytes, did not alter S1P-mediated, dose-dependent inhibition of glutamate uptake. Pharmacological antagonists, S1P2-null astrocytes, and Gα12 hemizygous-null astrocytes indicated that S1P2-Gα12-Rho/ROCK signaling was primarily responsible for the S1P-dependent inhibition of glutamate uptake. In addition, S1P exposure increased mitochondrial oxygen consumption rates (OCRs) in wild-type astrocytes, and reduced OCRs in S1P2-null astrocytes, implicating receptor selective metabolic consequences of S1P-mediated glutamate uptake inhibition. Astrocytic S1P-S1P2 signaling increased extracellular glutamate, which could contribute to neurotoxicity. This effect was not observed with the FDA-approved S1P receptor modulators, siponimod and fingolimod. Development and use of S1P2-selective antagonists may provide a new approach to reduce glutamate neurotoxicity in neurological diseases. Significance statement Extracellular glutamate is excitotoxic and its levels are controlled by astrocyte uptake. Sphingosine 1-phosphate (S1P) is a bioactive lipid originating from cell membrane sphingolipids that associates with carrier molecules like albumin, ApoM, and ApoA4 to produce cellular effects. S1P signals extracellularly through five GPCRs and it is found in higher concentrations in neurological diseases like multiple sclerosis where excitotoxic neurodegeneration has been implicated. Here we show that astrocytic S1P2 activation by S1P results in glutamate uptake inhibition to promote excitotoxic damage. S1P receptor modulators, including approved drugs for treating multiple sclerosis (e.g., fingolimod (FTY720) and siponimod (BAF312)), do not engage S1P2, thus avoiding glutamate uptake inhibition. S1P2 antagonists may provide a means to reduce S1P-induced glutamate neurotoxicity and ameliorate neurological diseases.

Fingolimod (FTY720, Gilenya) was the first US Food and Drug Administration–approved oral therapy for relapsing forms of multiple sclerosis (MS). Research on modified fungal metabolites converged with basic science studies that had identified lysophospholipid (LP) sphingosine 1-phosphate (S1P) receptors, providing mechanistic insights on fingolimod while validating LP receptors as drug targets. Mechanism of action (MOA) studies identified receptor-mediated processes involving the immune system and the central nervous system (CNS). These dual actions represent a more general theme for S1P and likely other LP receptor modulators. Fingolimod's direct CNS activities likely contribute to its efficacy in MS, with particular relevance to treating progressive disease stages and forms that involve neurodegeneration. The evolving understanding of fingolimod's MOA has provided strategies for developing next-generation compounds with superior attributes, suggesting new ways to target S1P as well as other LP receptor modulators for novel therapeutics in the CNS and other organ systems.

Bioactive lipids, or lipid mediators, are utilized for intercellular communications. They are rapidly produced in response to various stimuli and exported to extracellular spaces followed by binding to cell surface G protein-coupled receptors (GPCRs) or nuclear receptors. Many drugs targeting lipid signaling such as non-steroidal anti-inflammatory drugs (NSAIDs), prostaglandins, and antagonists for lipid GPCRs are in use. For example, the sphingolipid analog, fingolimod (also known as FTY720), was the first oral disease-modifying therapy (DMT) for relapsing-remitting multiple sclerosis (MS), whose mechanisms of action (MOA) includes sequestration of pathogenic lymphocytes into secondary lymphoid organs, as well as astrocytic modulation, via down-regulation of the sphingosine 1-phosphate (S1P) receptor, S1P1, by in vivo-phosphorylated fingolimod. Though the cause of MS is still under debate, MS is considered to be an autoimmune demyelinating and neurodegenerative disease. This review summarizes the involvement of bioactive lipids (prostaglandins, leukotrienes, platelet-activating factors, lysophosphatidic acid, and S1P) in MS and the animal model, experimental autoimmune encephalomyelitis (EAE). Genetic ablation, along with pharmacological inhibition, of lipid metabolic enzymes and lipid GPCRs revealed that each bioactive lipid has a unique role in regulating immune and neural functions, including helper T cell (TH1 and TH17) differentiation and proliferation, immune cell migration, astrocyte responses, endothelium function, and microglial phagocytosis. A systematic understanding of bioactive lipids in MS and EAE dredges up information about understudied lipid signaling pathways, which should be clarified in the near future to better understand MS pathology and to develop novel DMTs.

Dimethyl fumarate is an orally bioavailable compound for the treatment of multiple sclerosis and psoriasis. A mechanism involving nuclear factor erythroid 2-like 2 activation has been proposed to account for its efficacy in multiple sclerosis. Here, we report that dimethyl fumarate inhibits expression of integrin α4 on circulating lymphocytes in experimental autoimmune encephalomyelitis mice and also on activated human Jurkat T cells in a manner distinct from nuclear factor erythroid 2-like 2 activation. Our results offer an alternative mechanism for the efficacy of dimethyl fumarate in multiple sclerosis.

Chest computed tomography image of a 23-year-old man. Image shows right-sided middle and lower lobe consolidation and multiple cystic bronchiectasis.

Sagittal T2-weighted fat saturation magnetic resonance imaging reveals erosion and a high-intensity area around the C3-C4 facet joint.

Fingolimod is the first oral disease-modifying therapy approved for relapsing forms of multiple sclerosis (MS). Following phosphorylation in vivo, the active agent, fingolimod phosphate (fingolimod-P), acts as a sphingosine 1-phosphate (S1P) receptor modulator, binding with high affinity to four of the five known S1P receptors (S1P1, S1P3, S1P4 and S1P5). The mechanism of action of fingolimod in MS has primarily been considered as immunomodulatory, whereby fingolimod-P modulates S1P1 on lymphocytes, selectively retaining autoreactive lymphocytes in lymph nodes to reduce damaging infiltration into the central nervous system (CNS). However, emerging evidence indicates that fingolimod has direct effects in the CNS in MS. For example, in the MS animal model of experimental autoimmune encephalomyelitis (EAE), fingolimod is highly efficacious in both a prophylactic and therapeutic setting, yet becomes ineffective in animals selectively deficient for S1P1 on astrocytes, despite maintained normal immunologic receptor expression and functions, and S1P-mediated immune activities. Here, we review S1P signalling effects relevant to MS in neural cell types expressing S1P receptors, including astrocytes, oligodendrocytes, neurons, microglia and dendritic cells. The direct effects of fingolimod on these CNS cells observed in preclinical studies are discussed in view of the functional consequences of reducing neurodegenerative processes and promoting myelin preservation and repair. The therapeutic implications of S1P modulation in the CNS are considered in terms of the clinical outcomes of MS, such as reducing MS-related brain atrophy, and other CNS disorders. Additionally, we briefly outline other existing and investigational MS therapies that may also have effects in the CNS.

ObjectiveCorticosteroid has been established as the standard therapy for autoimmune pancreatitis (AIP), but the requirement for maintenance corticosteroid therapy is controversial. We conducted a randomised controlled trial to clarify the efficacy of maintenance corticosteroid therapy in patients with AIP.DesignWe conducted a multicentre, tertiary setting, randomised controlled trial. After the induction of remission with the initial oral prednisolone (PSL) treatment, maintenance therapy with PSL at 5–7.5 mg/day was continued for 3 years or withdrawn at 26 weeks. The primary endpoint was relapse-free survival over 3 years and the secondary endpoint was serious corticosteroid-related complications. All analyses were performed on an intention-to-treat basis.ResultsBetween April 2009 and March 2012, 49 patients with AIP were randomly assigned to the maintenance therapy group (n=30) or the cessation group (n=19). Baseline characteristics were not different between the two groups. Relapses occurred within 3 years in 11 out of 19 (57.9%) patients assigned to the cessation group, and in 7 of 30 (23.3%) patients in the maintenance therapy group. The relapse rate over 3 years was significantly lower in the maintenance therapy group than that in the cessation group (p=0.011). The relapse-free survival was significantly longer in the maintenance therapy group than that in the cessation group (p=0.007). No serious corticosteroid-related complications requiring discontinuation of PSL were observed.ConclusionsMaintenance corticosteroid therapy for 3 years may decrease relapses in patients with AIP compared with those who discontinued the therapy at 26 weeks.Trial registration numberUMIN000001818; Results.

A nationwide survey was conducted to clarify the epidemiological features of patients with chronic pancreatitis (CP) in Japan.Two sequential surveys were conducted. In the first survey, both the prevalence and incidence of CP in Japan in 2007 were estimated by a questionnaire, which was mailed to 3027 randomly chosen Japanese facilities. In the second survey, the second questionnaire was then mailed to 1110 facilities selected by the first survey to clarify the clinicoepidemiological features of the patients.The estimated annual prevalence of CP was 36.9 per 100,000; 53.2 in males and 21.2 in females. The estimated annual incidence was 11.9 per 100,000. The prevalence and the incidence of CP gradually increased in Japan as compared to former surveys. The sex ratio (male/female) of definitive and probable CP patients was 4.5, with a mean age of 59.4 years; 59.2 years in males and 60.2 years in females. Alcoholic (69.7%) was most the common and idiopathic (21.0%) was the second most common cause of CP. The proportion of alcoholic CP increased as compared to the 55.5% found in 1994. The clinical features of overall Japanese patients with CP were: abdominal pain (60.6%), malabsorbtion (12.2%), diabetes mellitus (39.7%) and pancreatolithiasis (75.7%). Alcoholic patients were characterized by high morbidity as compared to nonalcoholic patients: abdominal pain (alcoholic 65.0% vs nonalcoholic 53.0%, p0.0001), diabetes mellitus (44.8% vs 31.4%, p0.0001) and pancreatolithiasis (84.0% vs 60.8%, p0.0001).The prevalence and the incidence of CP, especially alcoholic CP, have been increasing in Japan.

Poorly differentiated neuroendocrine carcinoma is a very rare malignancy, but it is characterized by agressive histological features and a poor clinical prognosis. We report a 42-year-old man who had poorly differentiated neuroendocrine carcinoma of the pancreas with multiple liver metastases. We administrated combined chemotherapy with S-1 and gemcitabine. This treatment was efficacious and well tolerated, and then this patient obtained objective partial response for 7 months and survived for 13 months after the diagnosis. This case suggests that S-1 and gemcitabine combination produce beneficial responses for patients with this disease.

Little is known about the etiopathogenesis of chronic pancreatitis, due mainly to the lack of simple animal models suitable to study inflammatory and fibrogenetic processes in the pancreas. The purpose of this study was to examine whether transient congestion of pancreatic fluid flow alone or slight ductal injury alone is sufficient, or where both are required, to induce chronic pancreatic injury. Three different models of pancreatitis were tested in rats induced by retrograde intraductal infusion of 40 μl/100 g body weight of 0.01% agarose (group A), 40 μl/100 g body weight of 0.1% sodium taurocholate (group T), or a mixture of the two solutions (group M). Histological alterations of the pancreas were examined by hematoxylin-eosin staining, changes in type IV collagen structure were studied by immunostaining, and the gelatinolytic activity of latent and active matrix metalloproteinase-2 (MMP-2) was analyzed by zymography. In group A and T rats, histological alterations of the pancreas and the gelatinolytic activity of MMP-2 returned to baseline levels by day 14, and immunoreactivity for type IV collagen appeared as continuous lines along the basement membrane. In group M rats, however, acinar damage, fibrosis and fatty degeneration were observed even on day 56, and type IV collagen was detected as discontinuous lines until day 56. MMP-2 was significantly elevated from day 5 to day 42. Co-existence of transient stasis of pancreatic fluid flow, together with mild damage to the pancreatic duct and acinar cells, exert synergistic effects on the development of persistent pancreatic injury with continuous disorganization of type IV collagen in the basement membrane of the ducts.

Astrocytes have prominent roles in central nervous system (CNS) function and disease, with subpopulations defined primarily by morphologies and molecular markers often determined in cell culture. Here, we identify an in vivo astrocyte subpopulation termed immediate-early astrocytes (ieAstrocytes) that is defined by functional c-Fos activation during CNS disease development. An unbiased screen for CNS cells showing c-Fos activation during experimental autoimmune encephalomyelitis (EAE), a mouse model for multiple sclerosis (MS), was developed by using inducible, TetTag c-Fos reporter mice that label activated cells with a temporally stable, nuclear green fluorescent protein (GFP). Four-dimensional (3D over time) c-Fos activation maps in the spinal cord were produced by combining tissue clearing (iDISCO) and confocal microscopy that identified onset and expansion of GFP+ cell populations during EAE. More than 95% of the GFP+ cells showed glial fibrillary acidic protein (GFAP) immunoreactivity-in contrast to absent or rare labeling of neurons, microglia, and infiltrating immune cells-which constituted ieAstrocytes that linearly increased in number with progression of EAE. ieAstrocyte formation was reduced by either astrocyte-specific genetic removal of sphingosine 1-phosphate receptor 1 (S1P1) or pharmacological inhibition by fingolimod (FTY720), an FDA-approved MS medicine that can functionally antagonize S1P1. ieAstrocytes thus represent a functionally defined subset of disease-linked astrocytes that are the first and predominant CNS cell population activated during EAE, and that track with disease severity in vivo. Their reduction by a disease-modifying agent supports their therapeutic relevance to MS and potentially other neuroinflammatory and neurodegenerative diseases.

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 epidemiology of pancreatic diabetes in Japan in 2005 by using a nationwide stratified random-sampling method. Especially, we focused on newly developed diabetes in association with the occurrence of pancreatic disease (true pancreatic diabetes).A total of 19,500 individuals received treatment for true pancreatic diabetes, accounting for 0.8% of patients with diabetes. Prevalence was estimated to be 15.2 per 100,000 with an annual onset incidence of 1.1 per 100,000. With regard to the complications in true pancreatic diabetes, the incidence of retinopathy was lower than that in types 1 and 2 diabetes. Among true pancreatic diabetes with chronic pancreatitis, alcoholic pancreatitis was found in the largest sector. Furthermore, as many as 53.7% were continuous drinkers, and 66.7% received insulin therapy. The frequency of hypoglycemia was high in regular drinkers treated with insulin. Hypoglycemia was a major cause of death in patients who were on insulin and continuous drinkers.We clarified the epidemiology of pancreatic diabetes in Japan. Patients with chronic pancreatitis-associated pancreatic diabetes should receive lifestyle guidance focused on drinking cessation.

Platelet-activating factor (PAF; 1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine) plays a critical role in inflammatory disorders including experimental allergic encephalomyelitis (EAE), an animal model for multiple sclerosis (MS). Although PAF accumulation in the spinal cord (SC) of EAE mice and cerebrospinal fluid of MS patients has been reported, little is known about the metabolic processing of PAF in these diseases. In this study, we demonstrate that the activities of phospholipase A2 (PLA2) and acetyl-CoA:lyso-PAF acetyltransferase (LysoPAFAT) are elevated in the SC of EAE mice on a C57BL/6 genetic background compared with those of naive mice and correlate with disease severity. Correspondingly, levels of groups IVA, IVB, and IVF cytosolic PLA2s, group V secretory PLA2, and LysoPAFAT transcripts are up-regulated in the SC of EAE mice. PAF acetylhydrolase activity is unchanged during the disease course. In addition, we show that LysoPAFAT mRNA and protein are predominantly expressed in microglia. Considering the substrate specificity and involvement of PAF production, group IVA cytosolic PLA2 is likely to be responsible for the increased PLA2 activity. These data suggest that PAF accumulation in the SC of EAE mice is profoundly dependent on the group IVA cytosolic PLA2/LysoPAFAT axis present in the infiltrating macrophages and activated microglia.

The aim of the study was to clarify clinicopathological features of type 2 autoimmune pancreatitis (AIP) in Japan; a multicenter survey was carried out.The first screening collected patients with pancreatitis whose pancreatic tissue samples were available and who fulfilled at least 1 of the following 3 criteria as possible type 2 AIP: (1) histological presence of granulocytic epithelial lesion, (2) age of 50 years or younger, and (3) association of ulcerative colitis, Sjogren syndrome, and/or primary biliary cirrhosis. Patients with histologically confirmed type 1 AIP were also collected as a control. Clinical information was gathered by questionnaire.A histological re-evaluation identified 8 patients with type 2 AIP and 20 with type 1 AIP. Three of the latter had intralobular neutrophilic infiltration. Factors more frequent in type 2 included age younger than 40 years, abdominal pain, and elevation of serum amylase and lipase, whereas patients with type 1 more frequently showed jaundice, elevated serum IgG and IgG4, presence of autoantibodies, association of IgG4-related disease, sclerosing cholangitis and diabetes mellitus, and imaging findings of intrapancreatic biliary stenosis and extrapancreatic biliary dilatation.The clinical features of type 2 AIP in Japan were similar to those of western countries. Intralobular neutrophilic infiltration in type 1 is a potential pitfall, especially in the biopsy-based diagnosis.

「急性膵炎の診療ガイドライン」が上梓され3年が経過し，予後改善が期待される．実際，ガイドライン発刊前でも全国調査結果の致死率には着実に改善傾向が見られており，初期治療方針の啓蒙により早期死亡が減少した結果と考えられる．しかし，感染に起因する後期死亡の比率はかえって増加している．感染と外科治療に関連するガイドラインの項目を検討すると，感染性膵壊死の診断におけるFNA，非感染性膵壊死に対する壊死部切除，膵膿瘍に対する治療方針などに検討の余地があると考えられる．そこで，2003年の症例を対象として行われた急性膵炎全国調査における重症549例の外科治療成績を，1995年から1998年に行われた調査結果の成績と比較解析した．その結果，手術施行率の低下と手術施行例の致死率の低下が確認された．さらに，外科治療における壊死部切除の比率が16％から35％に上昇しており，胆石膵炎に対するESTなどの内視鏡治療や経皮的ドレナージなどが積極的に導入された結果であると考えられた．一方，壊死部切除症例の25例中7例は術前診断が膵膿瘍であり，膵膿瘍の診断と治療に改善すべき問題があると考えられた．2003年の調査症例では，膵膿瘍と診断された症例の致命率は23％で，感染性膵壊死と診断された症例の致命率（25％）とほぼ同等で，決して低くないことが判明した．これは，膵膿瘍と診断されても，その後，壊死部切除や外科的ドレナージが必要であった症例の予後が不良で，さらに経皮的ドレナージのみで治療した症例の致死率も20％と高いことに起因していた．膵膿瘍の診断は安易につけるべきではなく，感染合併例に対しては常に感染性膵壊死を念頭に置くべきであること，経皮的ドレナージ症例でも，感染性膵壊死を疑えば手術を躊躇することなく選択すべきことを示している．現行ガイドラインにおいても，「経皮的ドレナージで改善が見られない場合の外科的ドレナージ」が推奨度Bとなっているが，ガイドライン改定に際して，このことを一層強調する必要があると考えられた．

Background and aims 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. Methods Three different models of pancreatitis were induced in rats by repetitive intraperitoneal injections of 500 mg/100 g body weight of arginine (Arg) or 20 microg/kg body weight of caerulein (Cn) or a single retrograde intraductal infusion of 40 microL/100 g body weight of 3% sodium taurocholate (NaTc). We examined the changes in type IV collagen structure by immunostaining, and the serial changes in the gelatinolytic activity of pro- and active matrix metalloproteinase-2 by zymography in these models of pancreatitis. Results The pancreas appeared to be histologically normal on day 35 after the first intraperitoneal Cn injection and on day 42 after intraductal infusion of NaTc, whereas 85% to 90% of acinar tissue was replaced by fatty tissue and dilated pancreatic ducts on day 54 after the first intraperitoneal Arg injection. Immunoreactivity for type IV collagen appeared as a discontinuous line along the BM of ducts, vessels, tubular complexes, and acinar cells on day 40 in Arg-induced pancreatitis, whereas it was detected as a continuous line along the BM on day 35 in Cn-induced pancreatitis and on day 42 in NaTc-induced pancreatitits. Gelatinolytic activity of active MMP-2 increased significantly from day 13 to day 40 after the first intraperitoneal Arg injection, whereas it decreased to the baseline level on day 35 after the first intraperitoneal Cn injection and on day 42 after intraductal infusion of NaTc. Conclusions Our findings indicate that a long-term increase in gelatinolytic activity of active MMP-2 in Arg-induced pancreatitis causes continuous disorganization of type IV collagen in the BM and progressive acinar atrophy, whereas a transient increase in gelatinolytic activity of active MMP-2 is involved in the regeneration of type IV collagen structure in the BM and recovery from acinar injury.

OBJECTIVES 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. METHODS Female C57 BL/6J mice weighing 20 to 22 g were fed a CDE diet for 3 days to induce pancreatitis. Female C3H/HEJ mice were used as controls. Mice were killed on days 1, 2, and 3 after the onset of the CDE diet. The severity of pancreatitis was evaluated by survival rate, plasma PLA2 activity, serum amylase level, histologic changes in the pancreas and lung, and myeloperoxidase activity in the lung. RESULTS The survival rate of C57 BL/6J mice was 100% up to day 3 after the onset of the CDE diet, whereas that of the control mice was 42% on day 3. Plasma PLA2 activity in control mice increased on day 3 but did not increase in C57 BL/6J mice. Serum amylase activity on day 3 in C57 BL/6J mice was 15,480 +/- 3036 SU/dL, which was significantly lower than that in the control mice (43,760 +/- 8657 SU/dL, P < 0.01). Histologic changes in the pancreas of C57 BL/6J mice were markedly milder than in control mice. The degree of alveolar membrane thickening and infiltration of inflammatory cells in the lung of C57 BL/6J mice were overtly less than those of the controls. Myeloperoxidase activity in the lung of C57 BL/6J mice was lower, albeit insignificant, than in C3H/HEJ mice. CONCLUSIONS Natural disruption of the group 2 PLA2 gene protects against CDE diet-induced acute pancreatitis and associated lung injury. These findings support the view that group 2 PLA2 is one of the factors in the exacerbation of severe acute pancreatitis.

重症急性膵炎は平成3年1月に特定疾患治療研究事業の対象疾患 (難病) に指定され, 平成10年度には特定疾患治療研究事業の改正が行われたが, 重症急性膵炎は引き続き医療費自己負担分の全額が公費で負担される重症患者として取り扱われることになった. しかし, 医療受給者証の有効期限は, 改訂前の1年から6カ月に短縮された. 本制度の運用実態を明らかにするため, 重症急性膵炎の医療受給者証申請状況とその問題点を検討した. 平成15年度の新規受給者数は1,433人で, 平成10年度の718人に比べ2倍に増加していたが, 重症急性膵炎の推定患者数の28%と少なかった. 一方, 更新受給者が平成10年度の456人から, 平成14年度には152人まで減少した. 平成15年度には更新受給者が再び183人にまで増加していた. しかし, 更新受給者の増加は当該年度のみで, 複数年度に及ぶ更新受給者数は減少しており, 平成15年度から採用された更新用の臨床個人調査票が有効に機能していると考えられた.

Experimental allergic encephalomyelitis (EAE) serves as a model for multiple sclerosis and is considered to be a CD4+ Th1 cell–mediated autoimmune disease. To investigate the role of platelet-activating factor (PAF) in this disease, PAF receptor (PAFR) KO (PAFR-KO) and wild-type (WT) mice, on a C57BL/6 genetic background, were immunized with myelin oligodendrocyte glycoprotein 35–55. The levels of PAF production and PAFR mRNA expression in the spinal cord (SC) correlated with the EAE symptoms. PAFR-KO mice showed lower incidence and less severe symptoms in the chronic phase of EAE than WT mice. However, no difference was observed in T cell proliferation, Th1-cytokine production, or titer of IgG2a between both genotypes. Before onset, as revealed by microarray analysis, mRNAs of inflammatory mediators and their receptors—including IL-6 and CC chemokine receptor 2—were down-regulated in the SC of PAFR-KO mice compared with WT mice. Moreover, in the chronic phase, the severity of inflammation and demyelination in the SC was substantially reduced in PAFR-KO mice. PAFR-KO macrophages reduced phagocytic activity and subsequent production of TNF-α. These results suggest that PAF plays a dual role in EAE pathology in the induction and chronic phases through the T cell–independent pathways.

Kihara Y, Hori H, Murakami H, Hatakeyama Y, Yoshikawa I, Hamada T, Otsuki M (University of Occupational and Environmental Health, Japan, School of Medicine, Kitakyushu, Japan). A case of POEMS syndrome associated withreactive amyloidosis and Waldenstrom's macroglobulinaemia (Case report). J Intern Med 2002; 252: 255–258. A72-year-old Japanese man presented with a 5-year history of fatigue, night sweats, oedema of dorsum of foot, muscle weakness, and paresthesia of the lower extremities. On examination, the patient fulfilled the diagnostic criteria for POEMS syndrome, but was unusual in that he also had underling Waldenstrom's macroglobulinaemia with IgM κ. The M protein of POEMS syndrome is usually IgG and IgA with λ light chains. To our knowledge, there are only three cases of POEMS syndrome with IgM κ including our case. Autopsy findings revealed that small lymphocytes were more prominent than plasma cells in the bone marrow. These plasma cells were stained with IgM κ. Amyloid deposits identified by Congo red stain were detected predominantly in the vascular walls of the gastrointestinal tract, pancreas and kidney. This amyloid protein was classified as amyloid associated protein. This is the first case of POEMS syndrome associated with reactive amyloidosis and Waldenstrom's macroglobulinaemiae.

Arteriovenous malformation (AVM) of the pancreas is a rare condition that may cause severe gastrointestinal bleeding. We describe a 54-year-old man with a 7-year history of recurrent duodenal ulcer due to AVM in the pancreatic head. We recommended pancreatoduodenectomy because of recurrent haemorrhage from the duodenal ulcer, but the patient refused surgery on several occasions. He was admitted to our hospital complaining of severe upper abdominal pain radiating to the back and was diagnosed with acute pancreatitis. He agreed at that stage to the surgical treatment. The resected specimen contained a highly vascular malformation in the pancreatic head and ulceration in the adjacent descending duodenum. Histopathological examination revealed numerous vascular structures with dilated and tortuous vessels in the pancreatic head, confirming the presence of AVM. Moreover, oedema, inflammatory cell infiltration, haemorrhage and necrosis were evident, confirming the presence of acute pancreatitis.

Recently established Otsuka Long-Evans Tokushima Fatty (OLETF) rats, a model of naturally occurring obesity diabetes, exhibit progressive accumulation of connective tissue in the pancreas. The present study was designed to determine the pathogenic role of transforming growth factor-beta1 (TGF-beta1) in the development of pancreatic fibrosis in OLETF rats by investigating the serial changes in the expression of TGF-beta1 and extracellular matrix (ECM) in the pancreas. Progressive proliferation of connective tissue arose from the interstitial region surrounding islets at 20 wk of age and extended to the exocrine pancreas adjacent to the islets. TGF-beta1 mRNA levels in the pancreas increased at 20 wk of age and reached a peak value at 30 wk of age. Fibronectin (FN) and procollagen types I and III mRNAs peaked at 20 wk of age and remained at higher levels than those in the nondiabetic counterparts Long-Evans Tokushima Otsuka rats until 50 wk of age. Immunoreactivities for TGF-beta1 and FN were found in islets of OLETF rats at 20 wk of age and were seen in acinar and interstitial cells at 50 wk of age. Moreover, alpha-smooth muscle actin was located at interstitial region surrounding the islets. Proliferation of the connective tissue in the pancreas of OLETF rats closely correlated with expression of TGF-beta1 and ECM. Our results suggest that the development of pancreatic fibrosis in OLETF rats extends from endocrine to exocrine pancreas and that TGF-beta1 is involved in pancreatic fibrosis of OLETF rats.

INTRODUCTION 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)-beta 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. AIMS To elucidate the role of TGF-beta, ECM, and matrix metalloproteinase (MMP) in the process of regeneration occurring after acute necrotizing pancreatitis. METHODOLOGY Acute necrotizing pancreatitis was induced by intraperitoneal injection of 500 mg/100 g body weight of L-arginine in male Wistar rats. Expression of TGF-beta1 and ECM messenger RNA (mRNA) was determined by Northern blot analysis, and that of MMP-1 and MMP-2 mRNA was examined by the reverse transcription polymerase chain reaction (RT-PCR). Immunoreactivity for ECM components, TGF-beta1, and MMP-2 in the pancreas was assessed by using a monoclonal antibody. RESULTS TGF-beta1 mRNA expression reached a peak value on day 2.5, with a decrease on day 3, and reached the control level on day 7. Procollagen types III and IV and fibronectin mRNA reached a peak value on day 2.5, whereas the expression level of procollagen type I mRNA was maximal on day 3, and gradually decreased to control levels by day 7. MMP-2 mRNA was significantly elevated on day 3, and peaked on day 5, whereas MMP-1 mRNA levels did not change throughout the observation period. Immunoreactivity for MMP-2 was observed around disrupted acinar cells and interstitial spaces on day 3, and maximally on day 7. Immunoreactivity for fibronectin was detected around disrupted acinar cells and interstitial spaces. On day 7, it was less than on day 5 around disrupted acinar cells and interstitial spaces, whereas in the regenerated acinar cells, it was undetected. CONCLUSION Our results show that TGF-beta1 mRNA expression peaked earlier than that of ECM mRNA. Furthermore, increased level of the MMP-2 transcript was followed by disappearance of fibronectin. Our findings suggest that TGF-beta1 plays an important role in ECM production in the early phase of acute pancreatitis, and that MMP-2 is involved in the subsequent healing process.

The recently developed Otsuka Long-Evans Tokushima Fatty (OLETF) rat is known to develop insulinopenic diabetes after a prolonged period in a condition resembling non—insulin-dependent diabetes mellitus (NIDDM). We examined the effect of pharmacological intervention with a potent intestinal α-glucosidase inhibitor, acarbose, on the metabolic and histopathologic changes in this rat model. The first two groups of rats received an acarbose-rich diet (150 mg/100 g normal chow) from 12 weeks of age (ie, before the onset of diabetes) or from 28 weeks of age (ie, after the onset of diabetes), while a third group received the acarbose-rich diet for the initial 16 weeks only (from 12 to 28 weeks of age). A control group received standard rat chow. Acarbose-fed rats gained less weight or lost weight despite increased food intake when switched to the acarbose-rich diet. Acarbose also reduced visceral adipose depots and fasting triglyceride (TG), glucose, and insulin levels. At the end of the study at 72 weeks, the pancreatic wet weight and insulin content were significantly higher in the treated groups versus control rats. The morphological changes observed in control rats, such as atrophy of the pancreas and reduced number and size of islets, were not present in acarbose-treated rats. Rats fed acarbose from 12 to 28 weeks of age gradually gained weight after switching to standard chow, and hyperinsulinemia, hyperglycemia, and hyperlipidemia appeared (in that order). The pancreatic insulin content in these rats was significantly higher and the visceral adipose depot was significantly smaller than in control rats. Our study demonstrates that acarbose prevented and reversed the metabolic derangement and histopathological changes in genetically diabetic rats. Moreover, treatment with acarbose even for a short period produced a marked delay in the development of insulin insensitivity and frank diabetes.

We examined the effects of treatment with cholecystokinin (CCK) octapeptide (CCK-8) and the CCK receptor antagonist loxiglumide on the recovery of exocrine pancreas in post-acute pancreatitic rats. Acute pancreatitis was induced in rats by intravenous infusion of 20 microg/kg/h cerulein for 4 h. At 24 h after the start of cerulein infusion, rats were divided into nine treatment groups: oral administration of saline (control), or oral administration of 10 or 50 mg/kg body weight loxiglumide twice daily for the first 3 days, followed by saline administration (Loxi-1 and Loxi-2), 10 or 50 mg/kg body weight loxiglumide twice daily for 6 days (Loxi-3 and Loxi-4), oral administration of saline or 10 or 50 mg/kg body weight loxiglumide twice daily for the first 3 days, followed by subcutaneous injection of 2.5 microg/kg body weight CCK-8 twice daily for the next 3 days (CCK-1, CCK-2, and CCK-3), and subcutaneous injection of 2.5 microg/kg body weight CCK-8 twice daily for 6 days (CCK-4). Pancreatic wet weight and biochemical changes were evaluated on day 8 at 12 h after the last treatment. Treatment with loxiglumide (Loxi-3 and Loxi-4) or CCK-8 for 6 days (CCK-4) or with a high dose of loxiglumide for the first 3 days (Loxi-2) significantly suppressed the recovery of pancreatic weight and DNA content compared to saline treatment or to the untreated normal control rats. However, when loxiglumide treatment was followed by 3 days of CCK-8 injections (CCK-2 and CCK-3), pancreatic protein and DNA content recovered to levels comparable to or above the control levels. The most remarkable increase in enzyme content was obtained in postpancreatitic rats treated with high-dose loxiglumide for the first 3 days, followed by CCK-8 injection (CCK-3). On the other hand, 6 days of CCK-8 treatment (CCK-4) had no significant influences on pancreatic enzyme contents. These results suggest that the most favorable strategy for the treatment of acute pancreatitis is to give high-dose loxiglumide during the early stage for only a short period, followed by CCK-8 administration.

Glucose intolerance and diabetes mellitus are both prevalent in patients with chronic liver diseases. We examined the efficacy and systemic safety of therapy with an alpha-glucosidase inhibitor, acarbose, in diabetes mellitus associated with chronic liver diseases. Twenty patients with chronic hepatitis or liver cirrhosis and overt diabetes mellitus received acarbose (taken orally) for 8 weeks. The initial dosage of acarbose was 50 mg three times daily, taken before meals; this was increased to 100 mg three times daily after 2 weeks. The mean fasting plasma glucose level was 173.7 +/- 18.6 mg/dl (mean +/- SE) at entry, and was significantly decreased to 132.9 +/- 7.5 mg/dl (P0.05) after 8 weeks of acarbose treatment. The improved glycemic control was reflected by a significant decrease in glycosylated hemoglobin (HbA1c) from 7.2 +/- 0.3% at entry to 6.3 +/- 0.2% (P0.05) after 8 weeks. Serum levels of both aspartate and alanine aminotransferases fluctuated during acarbose treatment, probably due to the natural course of chronic liver diseases, but the mean values had decreased after 8 weeks of treatment. Plasma ammonia levels increased, from 61.3 +/- 10.7 micrograms/dl to 71.1 +/- 9.6 micrograms/dl after 8 weeks of acarbose treatment but the increase was not significant. Clinically significant elevation of plasma ammonia concentration was seen in 2 cirrhotic patients (121 and 124 micrograms/dl); this was asymptomatic and gradually returned to the normal range despite continuous acarbose treatment in one patient, and was reversed after the withdrawal of acarbose with the concomitant administration of lactulose in the other patient. No other blood tests results, including albumin, cholinesterase, and prothrombin time, or lipid profile and nutritional status, in terms of rapid turnover proteins, prealbumin, retinol binding protein, and transferin, were altered throughout the study period. These results indicate that diabetes mellitus associated with chronic liver diseases may be safely and effectively treated with acarbose. However, clinicians must be aware of the possibility of hyperammonemia when they prescribe acarbose for patients with diabetes mellitus and advanced liver cirrhosis.

Leukotriene B(4) (LTB(4)) is a potent chemoattractant and activator of neutrophils, macrophages and T cells. These cells are a key component of inflammation and all express BLT1, a high affinity G-protein-coupled receptor for LTB(4). However, little is known about the neuroimmune functions of BLT1. In this study, we describe a distinct role for BLT1 in the pathology of experimental autoimmune encephalomyelitis (EAE) and T(H)1/T(H)17 immune responses. BLT1 mRNA was highly upregulated in the spinal cord of EAE mice, especially during the induction phase. BLT1(-/-) mice had delayed onset and less severe symptoms of EAE than BLT1(+/+) mice. Additionally, inflammatory cells were recruited to the spinal cord of asymptomatic BLT1(+/+), but not BLT1(-/-) mice before the onset of disease. Ex vivo studies showed that both the proliferation and the production of IFN-gamma, TNF-alpha, IL-17 and IL-6 were impaired in BLT1(-/-) cells, as compared with BLT1(+/+) cells. Thus, we suggest that BLT1 exacerbates EAE by regulating the migration of inflammatory cells and T(H)1/T(H)17 immune responses. Our findings provide a novel therapeutic option for the treatment of multiple sclerosis and other T(H)17-mediated diseases.

慢性膵炎は膵のび漫性進行性線維化を主体とする経過の長い疾患で,一般に頑固で反復する疼痛で始まり,次第に膵外内分泌機能が低下する.慢性膵炎の病因としてはアルコール性が最も多く,次いで特発性,胆石性である.アルコール性慢性膵炎では膵外分泌機能高度障害例が多く,改善しにくい.疼痛は慢性膵炎が進行すると軽減することが多い.膵内分泌機能障害によって起こる膵性糖尿病ではインスリン分泌だけではなく,グルカゴン分泌も低下することから血糖が変動しやすい.

The arachidonic acid (AA) cascade produces eicosanoids, such as prostaglandins (PGs), that regulate physiological and pathological functions. Although various nonsteroidal anti-inflammatory drugs have been developed, blocking upstream components (cyclooxygenase-1 and -2) of the AA cascade leads to severe side effects, including gastrointestinal ulcers and cardiovascular events, respectively, due to the complexity of the AA cascade. Here, using an AA cascade-targeted lipidomics approach, we report that microsomal PGE synthase 1 (mPGES-1) plays a key role in experimental autoimmune encephalomyelitis (EAE). Eicosanoids (mainly PGD 2 ) are produced constitutively in the spinal cord of naive mice. However, in EAE lesions, the PGE 2 pathway is favored and the PGD 2 , PGI 2 , and 5-lipoxygenase pathways are attenuated. Furthermore, mPGES-1 −/− mice showed less severe symptoms of EAE and lower production of IL-17 and IFN-γ than mPGES-1 +/+ mice. Expression of PGE 2 receptors (EP1, EP2, and EP4) was elevated in EAE lesions and correlated with clinical symptoms. Immunohistochemistry on central nervous systems of EAE mice and multiple sclerosis (MS) patients revealed overt expression of mPGES-1 protein in microglia/macrophages. Thus, the mPGES-1-PGE 2 -EPs axis of the AA cascade may exacerbate EAE pathology. Our findings have important implications for the design of therapies for MS.

In 2002, the Japan Pancreas Society (JPS) was the first in the world to propose diagnostic criteria for autoimmune pancreatitis (AIP). Since the concept of AIP has changed with the accumulation of AIP cases, the Research Committee of Intractable Pancreatic Diseases (RCIPD) provided by the Ministry of Health, Labour and Welfare of Japan and the JPS issued revised clinical diagnostic criteria of AIP in 2006. The Asan Medical Center of Korea also proposed diagnostic criteria for AIP in 2006. However, there are subtle but clinically challenging differences between the Japanese and Korean criteria. This inconsistency makes it difficult to compare data in studies from different centers and elucidate the characteristics of AIP. To reach a consensus on AIP, the RCIPD and the Korean Society of Pancreatobiliary Diseases established the following Asian criteria for the diagnosis of AIP: I-1. Imaging studies of pancreatic parenchyma show a diffuse/segmental/focally enlarged gland, occasionally with a mass and/or a hypoattenuation rim. I-2. Imaging studies of pancreaticobiliary ducts show diffuse/segmental/focal pancreatic ductal narrowing, often with stenosis of the bile duct. (Both I-1 and I-2 are required for diagnosis). II. Elevated level of serum IgG or IgG4, and detection of autoantibodies. III. Common lymphoplasmacytic infiltration and fibrosis, with abundant IgG4-positive cell infiltration. AIP should be diagnosed when criterion I and one of the other two criteria are satisfied, or when histology shows the presence of lymphoplasmacytic sclerosing pancreatitis in the resected pancreas. A diagnostic trial of steroid therapy can be applied carefully by expert pancreatologists only in patients fulfilling criterion I alone with negative diagnostic work-up results for pancreatobiliary cancer.

OBJECTIVE—To determine the association between nonalcoholic fatty liver disease and the risk for development of diabetes. RESEARCH DESIGN AND METHODS—We conducted an observational cohort study in male workers ≥40 years old in a Japanese company from 1997 to 2005. We excluded workers with alcohol intake ≥20 g/day and those with impaired glucose tolerance by a 75-g oral glucose tolerance test. The remaining 3,189 workers were classified into fatty liver (FL) and non-FL group based on the findings of abdominal ultrasonography. Both groups were followed for the development of diabetes. Hazard ratio (HR) was determined in Cox proportional hazard analysis. A nested case-control study was conducted to determine the odds ratio (OR). RESULTS—The average age of participants was 48.0 years at the entry, and the average follow-up period was 4.0 years. The incidence of diabetes in the FL group was 2,073 per 100,000 person-years (65 cases), whereas 452 per 100,000 person-years (44 cases) in the non-FL group. The age- and BMI-adjusted HR of diabetes associated with FL was 5.5 (95% CI 3.6–8.5, P < 0.001). In the nested case-control analysis, the OR adjusted for age and BMI was 4.6 (3.0–6.9, P < 0.001). CONCLUSIONS—Nonalcoholic fatty liver disease significantly increases the risk of diabetes in middle-aged Japanese men.

Platelet-activating factor (PAF), a potent lipid mediator with various biological activities, plays an important role in inflammation by recruiting leukocytes. In this study we used platelet-activating factor receptor (PAFR)-deficient mice to elucidate the role of PAF in inflammatory renal injury induced by folic acid administration. PAFR-deficient mice showed significant amelioration of renal dysfunction and pathological findings such as acute tubular damage with neutrophil infiltration, lipid peroxidation observed with antibody to 4-hydroxy-2-hexenal (day 2), and interstitial fibrosis with macrophage infiltration associated with expression of monocyte chemoattractant protein-1 and tumor necrosis factor-alpha in the kidney (day 14). Acute tubular damage was attenuated by neutrophil depletion using a monoclonal antibody (RB6-8C5), demonstrating the contribution of neutrophils to acute phase injury. Macrophage infiltration was also decreased when treatment with a PAF antagonist (WEB2086) was started after acute phase. In vitro chemotaxis assay using a Boyden chamber demonstrated that PAF exhibits a strong chemotactic activity for macrophages. These results indicate that PAF is involved in pathogenesis of folic acid-induced renal injury by activating neutrophils in acute phase and macrophages in chronic interstitial fibrosis. Inhibiting the PAF pathway might be therapeutic to kidney injury from inflammatory cells.

Diabetes mellitus (DM) is frequently observed in patients with chronic hepatitis caused by hepatitis C virus infection (CHC). The present study was designed to determine the pathogenic factors responsible for glucose intolerance in CHC patients.A total of 131 patients with CHC were enrolled in this study. Insulin resistance and beta-cell function were determined after 75 g oral glucose tolerance tests.Glucose intolerance was detected in 27.5% (36/131) of CHC patients; 10 had DM and 26 impaired glucose tolerance. HOMA-R [insulin 0xglucose 0/22.5] was greater in patients with both impaired glucose tolerance and DM than in those with normal glucose tolerance (P0.01). Matsuda index [10(4)/ (square root) (mean insulinxmean glucosexglucose 0xinsulin 0)] was lower in diabetic patients than in those with normal glucose tolerance (P0.05). The insulinogenic index [Deltainsulin 30-0/Deltaglucose 30-0] and DeltaC-peptide 30 [DeltaC-peptide 30-0/Deltaglucose 30-0] were significantly lower even in patients with impaired glucose tolerance than in patients with normal glucose tolerance (P0.01).Both insulin resistance and beta-cell dysfunction contribute to glucose intolerance in CHC patients.

INTRODUCTION AND AIMS 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)-beta1 and identified their production sites in the pancreas following pancreatitis. METHODOLOGY Pancreatitis was induced in rats by a single intraductal infusion of oleic acid. Gene expression of TGF-betas and ECM components was studied by northern blotting. Pancreatic stellate cell activation was assessed by immunostaining for alpha-smooth muscle actin (alphaSMA) and desmin. RESULTS Gene expression of TGF-betas and ECM components was increased in association with pancreatic fibrosis after 1-2 weeks and remained higher than the control levels for the ensuing 12 weeks. Both alphaSMA and desmin were strongly immunostained around small vessels and faintly stained in mesenchymal cells and tubular complexes at 1 week. The combination of staining for alphaSMA plus in situ hybridization for procollagen type III mRNA revealed that procollagen type III mRNA was expressed in both alphaSMA-positive and alphaSMA-negative cells in the mesenchyma. CONCLUSIONS Our findings demonstrate that expression of genes for both TGF-betas and ECM components was increased and that both alphaSMA-positive myofibroblasts and mesenchymal cells are the major sources of ECM components after pancreatitis.

Recent diagnostic and therapeutic progress for severe acute pancreatitis (SAP) remarkably decreased the case-mortality rate. To further decrease the mortality rate of SAP, it is important to precisely evaluate the severity at an early stage, and initiate appropriate treatment as early as possible. Research Committee of Intractable Diseases of the Pancreas in Japan developed simpler criteria combining routinely available data with clinical signs. Severity can be evaluated by laboratory examinations or by clinical signs, reducing the defect values of the severity factors. Moreover, the severity criteria considered laboratory/clinical severity scores and contrast-enhanced computed tomography (CE-CT) findings as independent risk factors. Thus, CE-CT scans are not necessarily required to evaluate the severity of acute pancreatitis. There was no fatal case in mild AP diagnosed by the CE-CT severity score, whereas case-mortality rate in those with SAP was 14.8%. Case-mortality of SAP that fulfilled both the laboratory/clinical and the CE-CT severity criteria was 30.8%. It is recommended, therefore, to perform CE-CT examination to clarify the prognosis in those patients who were diagnosed as SAP by laboratory/clinical severity criteria. Because the mortality rate of these patients with SAP is high, such patients should be transferred to advanced medical units.

A 62-year-old male was referred to our hospital because of liver dysfunction, diffuse pancreatic swelling, and trachelophyma. At admission, the patient was free of pain. Physical examination showed enlarged and palpable bilateral submandibular masses, but no palpable mass or organomegaly in the abdomen. Laboratory findings were as follows: total protein 90 g/L with gamma-globulin of 37.3% (33 g/L), total bilirubin 4 mg/L, aspartate aminotransferase 39 IU/L, alanine aminotransferase 67 IU/L, gamma-glutamyl transpeptidase 1 647 IU/L, and amylase 135 IU/L. Autoantibodies were negative, and tumor markers were within the normal range. Serum IgG4 level was markedly elevated (18 900 mg/L). Computed tomography (CT) showed diffuse swelling of the pancreas and dilatation of both common and intra-hepatic bile ducts. Endoscopic retrograde pancreatography (ERP) revealed diffuse irregular and narrow main pancreatic duct and stenosis of the lower common bile duct. Biopsy specimens from the pancreas, salivary gland and liver showed marked periductal IgG4-positive plasma cell infiltration with fibrosis. We considered this patient to be autoimmune pancreatitis (AIP) with fibrosclerosis of the salivary gland and biliary tract, prescribed prednisolone at an initial dose of 40 mg/d. Three months later, the laboratory data improved almost to normal. Abdominal CT reflected prominent improvement in the pancreatic lesion. Swelling of the salivary gland also improved. At present, the patient is on 10 mg/d of prednisolone without recurrence of the pancreatitis. We present here a case of AIP with fibrosclerosis of salivary gland and biliary tract.