Reduced blood glucose levels by the combination of vadadustat in an elderly patient with chronic kidney disease who was receiving mitiglinide and sitagliptin: a case report.

BACKGROUND: Our case is the first report showing the development of hypoglycemia following the administration of vadadustat in a patient with chronic kidney disease being treated with mitiglinide and sitagliptin, possibly due to drug-drug interaction between vadadustat and sitagliptin under the administration of mitiglinide. CASE PRESENTATION: A 72-year-old man with type 2 diabetes mellitus had received sitagliptin 50 mg once daily and mitiglinide 10 mg three times daily over the last 3 years. He initiated vadadustat 300 mg once daily orally on day X owing to renal anemia (hemoglobin A1c: 7.4% and estimated glomerular filtration rate: 28.0 mL/min/1.73 m2). On day 23, he developed hypoglycemia with a blood glucose level of 67 mg/dL. The mean blood glucose level ± standard deviation was lower in the first 24 days of co-administration of vadadustat (before breakfast: 94 ± 14 mg/dL, before lunch: 109 ± 24 mg/dL, and before dinner: 126 ± 39 mg/dL) than in the last 2 weeks (before breakfast: 108 ± 14 mg/dL, before lunch: 122 ± 24 mg/dL, and before dinner: 158 ± 39 mg/dL). Considering the timing of the concomitant administration of vadadustat, hypoglycemia may have been caused by the drug-drug interaction between sitagliptin and vadadustat, and he discontinued treatment with vadadustat. The mean blood glucose levels improved two weeks after the discontinuation of vadadustat (before breakfast: 121 ± 25 mg/dL, before lunch: 147 ± 38 mg/dL, and before dinner: 161 ± 36 mg/dL). The drug interaction probability scale was classified as "Probable" (5 points). CONCLUSIONS: Hypoglycemia was observed when sitagliptin, mitiglinide, and vadadustat were concomitantly administered, which may have resulted in a drug-drug interaction between vadadustat and sitagliptin via OAT3 inhibition in the renal tubules.

Associated factors and effects of comorbid atrial fibrillation in hypertensive patients due to primary aldosteronism.

The incidence of atrial fibrillation (AF) and risk of cardiovascular events are reportedly higher in patients with primary aldosteronism (PA) than essential hypertension. However, associated factors of comorbid AF and cardiovascular events in PA patients after PA treatment remain unclear. This nationwide registration study included PA patients ≥20 years old. Incident cardiovascular events were observed with a mean follow-up of approximately 3 years. A total of 3654 patients with PA were included at the time of analysis. Prevalence of AF was 2.4%. PA patients with AF were older, more frequently male and had longer duration of hypertension than those without AF. No significant difference in basal plasma and adrenal venous aldosterone concentration, renin activity, potassium concentration, confirmatory tests of PA, laterality or surgery rate were seen between groups. Logistic regression analysis showed age, male sex, cardiothoracic ratio, past history of coronary artery disease and heart failure were independent factors associated with AF. PA patients with AF showed a higher frequency of cardiovascular events than those without AF (P < 0.001). Multivariate Cox analyses demonstrated AF in addition to older age, duration of hypertension, body mass index and chronic kidney disease as independent prognostic factors for cardiovascular events after PA treatment. Incidence of cardiovascular events were significantly lower in PA patients with AF than AF patients from the Fushimi registry during follow-up after adjusting age, sex and systolic blood pressure. Early diagnosis of PA may prevent AF and other cardiovascular events in PA patients by shortening the duration of hypertension and appropriate PA treatment.

Adrenocorticotropic hormone-secreting pancreatic neuroendocrine carcinoma with multiple organ infections and widespread thrombosis: A case report.

BACKGROUND: Ectopic adrenocorticotropic hormone (ACTH)-secreting neuroendocrine tumors are rare diseases. Patients with ACTH-secreting pancreatic neuroendocrine carcinomas have a poor prognosis. Infections and coagulopathies have been reported as the cause of death. However, detailed clinical descriptions of the morbid complications of ACTH-secreting neuroendocrine carcinomas have not been reported. CASE SUMMARY: A 78-year-old Japanese woman consulted a medical center due to systemic edema and epigastric discomfort. Laboratory analysis revealed hypercortisolemia with increased ACTH secretion without diurnal variation in serum cortisol level. An enhanced computed tomography (CT) scan revealed a 3-cm tumor in the pancreatic head. The cytological material from endoscopic ultrasound-guided fine-needle aspiration was compatible with ACTH-secreting pancreatic neuroendocrine carcinoma. The Ki-67 index was 40%. She was transferred to Mie University Hospital for surgical treatment. The patient was diagnosed with urinary tract infection, cytomegalovirus hepatitis, esophageal candidiasis, pulmonary infiltrates suspicious for Pneumocystis carinii pneumonia, peripheral deep vein thrombosis, pulmonary embolism, and disseminated intravascular coagulation. The multiple organ infections and thromboses responded well to antimicrobial and anticoagulant therapy. Radioisotope studies disclosed a pancreatic tumor and a metastatic lesion in the liver, whereas somatostatin receptor scintigraphy showed negative findings, suggesting the primary and metastatic tumors were poorly differentiated. A CT scan before admission showed no metastatic liver lesion, suggesting that the pancreatic tumor was rapidly progressing. Instead of surgery, antitumor chemotherapy was indicated. The patient was transferred to another hospital to initiate chemotherapy. However, she died four months later due to the rapidly progressive tumor. CONCLUSION: ACTH-secreting pancreatic neuroendocrine neoplasm is a rare disease with a very poor prognosis. The clinical course and acute complications of the tumor remain unreported. Here we report the clinical course of a rapidly progressive case of ACTH-secreting pancreatic neuroendocrine tumor that developed infectious complications due to many types of pathogens in multiple organs, widespread thromboses, pulmonary embolism, and disseminated intravascular coagulation.

Inhibition of lung microbiota-derived proapoptotic peptides ameliorates acute exacerbation of pulmonary fibrosis.

Idiopathic pulmonary fibrosis is an incurable disease of unknown etiology. Acute exacerbation of idiopathic pulmonary fibrosis is associated with high mortality. Excessive apoptosis of lung epithelial cells occurs in pulmonary fibrosis acute exacerbation. We recently identified corisin, a proapoptotic peptide that triggers acute exacerbation of pulmonary fibrosis. Here, we provide insights into the mechanism underlying the processing and release of corisin. Furthermore, we demonstrate that an anticorisin monoclonal antibody ameliorates lung fibrosis by significantly inhibiting acute exacerbation in the human transforming growth factorß1 model and acute lung injury in the bleomycin model. By investigating the impact of the anticorisin monoclonal antibody in a general model of acute lung injury, we further unravel the potential of corisin to impact such diseases. These results underscore the role of corisin in the pathogenesis of acute exacerbation of pulmonary fibrosis and acute lung injury and provide a novel approach to treating this incurable disease.

The Fairy Chemical Imidazole-4-carboxamide Inhibits the Expression of Axl, PD-L1, and PD-L2 and Improves Response to Cisplatin in Melanoma.

The leading cause of death worldwide is cancer. Many reports have proved the beneficial effect of mushrooms in cancer. However, the precise mechanism is not completely clear. In the present study, we focused on the medicinal properties of biomolecules released by fairy ring-forming mushrooms. Fairy chemicals generally stimulate or inhibit the growth of surrounding vegetation. In the present study, we evaluated whether fairy chemicals (2-azahypoxanthine, 2-aza-8-oxohypoxanthine, and imidazole-4-carboxamide) exert anticancer activity by decreasing the expression of Axl and immune checkpoint molecules in melanoma cells. We used B16F10 melanoma cell lines and a melanoma xenograft model in the experiments. Treatment of melanoma xenograft with cisplatin combined with imidazole-4-carboxamide significantly decreased the tumor volume compared to untreated mice or mice treated cisplatin alone. In addition, mice treated with cisplatin and imidazole-4-carboxamide showed increased peritumoral infiltration of T cells compared to mice treated with cisplatin alone. In vitro studies showed that all fairy chemicals, including imidazole-4-carboxamide, inhibit the expression of immune checkpoint molecules and Axl compared to controls. Imidazole-4-carboxamide also significantly blocks the cisplatin-induced upregulation of PD-L1. These observations point to the fairy chemical imidazole-4-carboxamide as a promising coadjuvant therapy with cisplatin in patients with cancer.

Case Report: A Difficult-to-Diagnose Case of Hyperinsulinemic Hypoglycemia Surgically Treated After Developing Acute Pancreatitis.

The patient is a 28-year-old Japanese man diagnosed with severe congenital hyperinsulinemic-hypoglycemia six months after birth. Clinical records revealed no imaging evidence of pancreatic tumor at the time of diagnosis. Subsequently, he had developmental disorders and epilepsy caused by recurrent hypoglycemic attacks. The patient's hypoglycemia improved with oral diazoxide. However, he developed necrotizing acute pancreatitis at 28 years of age, thought to be due to diazoxide. Discontinuation of diazoxide caused persistent hypoglycemia, requiring continuous glucose supplementation by tube feeding and total parenteral nutrition. A selective arterial secretagogue injection test revealed diffuse pancreatic hypersecretion of insulin. He underwent subtotal distal (72%) pancreatectomy and splenectomy. There was no intraoperative visible pancreatic tumor. His hypoglycemia improved after the surgical procedure. The histopathological study revealed a high density of islets of Langerhans in the pancreatic body and tail. There were large islets of Langerhans and multiple neuroendocrine cell nests in the whole pancreas. Nests of neuroendocrine cells were also detected in lymph nodes. The pathological diagnosis was grade 1 neuroendocrine tumor (microinsulinomas) with lymph node metastases. This patient is a difficult-to-diagnose case of hyperinsulinemic hypoglycemia surgically treated after developing acute pancreatitis. We believe this is a unique case of microinsulinomas with lymph metastases diagnosed and treated as congenital hyperinsulinemic hypoglycemia for almost 28 years.

Protective Role of Recombinant Human Thrombomodulin in Diabetes Mellitus.

Diabetes mellitus is a global threat to human health. The ultimate cause of diabetes mellitus is insufficient insulin production and secretion associated with reduced pancreatic ß-cell mass. Apoptosis is an important and well-recognized mechanism of the progressive loss of functional ß-cells. However, there are currently no available antiapoptotic drugs for diabetes mellitus. This study evaluated whether recombinant human thrombomodulin can inhibit ß-cell apoptosis and improve glucose intolerance in a diabetes mouse model. A streptozotocin-induced diabetes mouse model was prepared and treated with thrombomodulin or saline three times per week for eight weeks. The glucose tolerance and apoptosis of ß-cells were evaluated. Diabetic mice treated with recombinant human thrombomodulin showed significantly improved glucose tolerance, increased insulin secretion, decreased pancreatic islet areas of apoptotic ß-cells, and enhanced proportion of regulatory T cells and tolerogenic dendritic cells in the spleen compared to counterpart diseased mice treated with saline. Non-diabetic mice showed no changes. This study shows that recombinant human thrombomodulin, a drug currently used to treat patients with coagulopathy in Japan, ameliorates glucose intolerance by protecting pancreatic islet ß-cells from apoptosis and modulating the immune response in diabetic mice. This observation points to recombinant human thrombomodulin as a promising antiapoptotic drug for diabetes mellitus.

Missed diagnosis and delayed treatment of acromegaly in a patient with severe diabetes: A case report.

The early stages of acromegaly are characterized by slow and progressive acral overgrowth without major systemic complications. Failure to diagnose acromegaly at an early stage may have devastating consequences on patient care. The case in the present report was a 44-year-old Japanese man, referred to Kuwana City Medical Center due to severe hyperglycemia detected in a general checkup. The patient had no acromegaly-related complaints. Laboratory data revealed high blood levels of hemoglobin A1c and glucose. Careful physical examination revealed enlargement of extremities and soft tissues. Laboratory investigation indicated a high blood concentration of growth hormone, and magnetic resonance imaging disclosed an enhanced pituitary tumor. The diagnosis was pituitary tumor-associated acromegaly with severe diabetic complications. The pituitary tumor became large and unresectable following 10 years of misdiagnosis. The patient was treated with somatostatin receptor ligands (lanreotide and pasireotide), as well as bromocriptine in Mie University Hospital. The tumor size was reduced following treatment, though it was still unresectable at the time of this report. The case highlights the importance of hyperglycemia and abnormal manifestations of the feet in patients with acromegaly. In addition, these findings highlight the need for a thorough examination of the feet in diabetic patients, and the critical importance of the early diagnosis of acromegaly for preventing the consequences of inappropriate patient care.

Thrombomodulin ameliorates transforming growth factor-ß1-mediated chronic kidney disease via the G-protein coupled receptor 15/Akt signal pathway.

Kidney fibrosis is the common consequence of chronic kidney diseases that inexorably progresses to end-stage kidney disease with organ failure treatable only with replacement therapy. Since transforming growth factor-ß1 is the main player in the pathogenesis of kidney fibrosis, we posed the hypothesis that recombinant thrombomodulin can ameliorate transforming growth factor-ß1-mediated progressive kidney fibrosis and failure. To interrogate our hypothesis, we generated a novel glomerulus-specific human transforming growth factor-ß1 transgenic mouse to evaluate the therapeutic effect of recombinant thrombomodulin. This transgenic mouse developed progressive glomerular sclerosis and tubulointerstitial fibrosis with kidney failure. Therapy with recombinant thrombomodulin for four weeks significantly inhibited kidney fibrosis and improved organ function compared to untreated transgenic mice. Treatment with recombinant thrombomodulin significantly inhibited apoptosis and mesenchymal differentiation of podocytes by interacting with the G-protein coupled receptor 15 to activate the Akt signaling pathway and to upregulate the expression of anti-apoptotic proteins including survivin. Thus, our study strongly suggests the potential therapeutic efficacy of recombinant thrombomodulin for the treatment of chronic kidney disease and subsequent organ failure.

A Staphylococcus pro-apoptotic peptide induces acute exacerbation of pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a chronic and fatal disease of unknown etiology; however, apoptosis of lung alveolar epithelial cells plays a role in disease progression. This intractable disease is associated with increased abundance of Staphylococcus and Streptococcus in the lungs, yet their roles in disease pathogenesis remain elusive. Here, we report that Staphylococcus nepalensis releases corisin, a peptide conserved in diverse staphylococci, to induce apoptosis of lung epithelial cells. The disease in mice exhibits acute exacerbation after intrapulmonary instillation of corisin or after lung infection with corisin-harboring S. nepalensis compared to untreated mice or mice infected with bacteria lacking corisin. Correspondingly, the lung corisin levels are significantly increased in human IPF patients with acute exacerbation compared to patients without disease exacerbation. Our results suggest that bacteria shedding corisin are involved in acute exacerbation of IPF, yielding insights to the molecular basis for the elevation of staphylococci in pulmonary fibrosis.

Irregularly branched microvessels as visualized by magnifying endoscopy: a reliable marker for predicting deep submucosal invasion of superficial esophageal squamous cell carcinoma.

Background and study aims Magnifying endoscopy with narrow-band imaging (M-NBI) is reported to be useful in diagnosing invasion depth of superficial esophageal squamous cell carcinoma (SCC), but accurate diagnosis of deep submucosal invasion (SM2) has remained difficult. However, we discovered that irregularly branched microvessels observed with M-NBI are detected in SM2 cancers with high prevalence. Thus, this retrospective study aimed to investigate the diagnostic performance of irregularly branched microvessels as visualized by M-NBI for predicting SM2 cancers. Patients and methods Patients with superficial esophageal SCC lesions that were endoscopically or surgically resected at our hospital between September 2005 and December 2014 were included. Endoscopic findings by M-NBI of these lesions were presented to an experienced endoscopist who was unaware of the histopathological diagnosis and who then judged whether irregularly branched microvessels were present. Using the invasion depth according to postoperative histopathological diagnosis as the gold standard, we determined the diagnostic performance of the presence of irregularly branched microvessels as an indicator for SM2 cancers. Results A total of 302 superficial esophageal SCC lesions (228 patients) were included in the analysis. When irregularly branched microvessels were used as an indicator of SM2 cancers, the diagnostic accuracy was 94.0 % (95 % confidence interval [CI]: 91.1-96.1 %), sensitivity was 79.4 % (95 % CI: 66.6-88.4 %), specificity was 95.9 % (95 % CI: 94.3-97.0 %), positive predictive value was 71.1 % (95 % CI: 59.6-79.1 %), and negative predictive value was 97.3 % (95% CI: 95.7-98.5 %). Conclusions Irregularly branched microvessels may be a reliable M-NBI indicator for the diagnosis of cancers with deep submucosal invasion.

Predictors of confirmatory test results for the diagnosis of primary hyperaldosteronism in hypertensive patients with an aldosterone-to-renin ratio greater than 20. The SHRIMP study.

It remains unknown which surrogate markers can predict diagnostic test results for primary hyperaldosteronism (PA). The Secondary Hypertension Registry Investigation in Mie Prefecture (SHRIMP) study has sequentially and prospectively recruited 128 patients with hypertension with an aldosterone-to-renin ratio (ARR) greater than 20, evaluated the differences among essential hypertension (EHT), idiopathic hyperaldosteronism (IHA), and aldosterone-producing adenoma (APA), and analyzed the predictors for the confirmatory tests. The patients underwent saline-loading, captopril-challenge, and upright furosemide-loading tests. Carotid, renovascular, and cardiac echography, brachial ankle pulse wave velocity (baPWV), endothelial function, nocturnal blood pressure decline, and the apnea hypopnea index were evaluated. Multivariate regression analyses showed that the plasma aldosterone concentration (PAC) at screening was a strong predictor of the saline and captopril test results. The plasma renin activity (PRA) at screening, urine ß2-microglobulin, and left ventricular mass index (LVMI) were independent predictors for the captopril test. The estimated saline PAC and captopril 60 and 90 min ARRs predicted by the equations were highly correlated with the real values. The ROC curve analysis showed PAC at screening among each of predictors for the diagnostic tests and PAC after the saline-loading test had the highest diagnostic abilities of APA. Patients with IHA were older and had glucose intolerance and increased U-Alb/gCre and resistive indices. In patients with APA, the levels of U-Alb/gCre and urine ß2-microglobulin were increased, and levels of insulin and the HOMA-IR were decreased. In conclusion, our proposed equations may be useful for estimating saline PAC and captopril ARR. Diagnostic predictors may differ for each confirmatory test.

Crohn's disease-specific mortality: a 30-year cohort study at a tertiary referral center in Japan.

BACKGROUND: In this study, survival and cause of death were investigated in patients with Crohn's disease (CD) at a tertiary referral center. METHODS: A database was created based on the medical records of 1108 CD patients who had a history of visiting our hospital to investigate background characteristics, cumulative survival rates from diagnosis, causes of death, and the standardized mortality ratio (SMR) for each cause of death. A follow-up questionnaire survey of patients followed up inadequately was also conducted. The cumulative survival rate from diagnosis was determined using the life table method and compared with that of a sex- and age-matched population model from the year 2000. RESULTS: The study included 1108 patients whose mean age at diagnosis was 25.6 ± 10.8 years. The mean duration of follow-up was 14.6 ± 9.4 years, and there were 52 deaths. The cumulative survival rate was significantly lower 25 years after the diagnosis of CD (91.7%) than in the standard population model (95.7%). SMRs for both all causes [3.5; 95% confidence interval (CI): 2.7-4.6] and CD-specific causes (36.7; 95% CI 26.1-51.6) were high. Among the CD-specific causes, SMRs were especially high for small intestine and colorectal cancers, gastrointestinal diseases including intestinal failure (IF), perioperative complications, and amyloidosis. CONCLUSION: The SMRs for both all causes and CD-specific causes were high in CD patients. CD-specific causes including intestinal cancer, IF, perioperative complications, and amyloidosis showed especially high SMRs.

Canagliflozin improves obesity and insulin resistance in a diabetic patient with Cushings disease undergoing postoperative steroid therapy: A case report.

A 47-year-old woman with diabetes treated with high-dose insulin was admitted to Mie University Hospital, Tsu, Japan, for screening of secondary diabetes mellitus and obesity. Laboratory tests and imaging studies were consistent with Cushing's disease (CD). The patient underwent trans-sphenoidal pituitary surgery. The patient exhibited loss of body weight (85.9 to 80.0 kg), improved glycated hemoglobin (HbA1c) (11.2 to 7.8%) and required lower doses of insulin (112 to 46 U/day) 6 months after surgery. The patient's body weight and daily insulin dose remained stable during the following 5 months (6-11 months after surgery). At that point, the patient was administered with canagliflozin, a sodium-glucose cotransporter 2 inhibitor. The patient required lower daily insulin dose without decreasing the dose of postoperative hydrocortisone concurrent to the administration of canagliflozin (100 mg/day). The patient's body weight decreased to 69.5 kg and withdrawal of insulin therapy was possible 8 months after initiation of canagliflozin. Despite withdrawal of insulin therapy, the HbA1c levels remained at <7.0%. Although surgical treatment is the first-choice treatment for CD, obesity-related metabolic disorders including diabetes are frequent in CD patients following surgery. Canagliflozin may be an effective treatment to reduce body weight and improve insulin resistance following surgical treatment of CD.

Anti-apoptotic activity of human matrix metalloproteinase-2 attenuates diabetes mellitus.

BACKGROUND: Chronic progression of diabetes is associated with decreased pancreatic islet mass due to apoptosis of ß-cells. Patients with diabetes have increased circulating matrix metalloproteinase-2 (MMP2); however, the physiological significance has remained elusive. This study tested the hypothesis that MMP2 inhibits cell apoptosis, including islet ß-cells. METHODS: Samples from diabetic patients and newly developed transgenic mice overexpressing human MMP2 (hMMP2) were harnessed, and diabetes was induced with streptozotocin. RESULTS: Circulating hMMP2 was significantly increased in diabetic patients compared to controls and significantly correlated with the serum C-peptide levels. The diabetic hMMP2 transgenic mice showed significant improvements in glycemia, glucose tolerance and insulin secretion compared to diabetic wild type mice. Importantly, the increased hMMP2 levels in mice correlated with significant reduction in islet ß-cell apoptosis compared to wild-type counterparts, and an inhibitor of hMMP2 reversed this mitigating activity against diabetes. The increased activation of Akt and BAD induced by hMMP2 in ß-cells compared to controls, links this signaling pathway to the anti-apoptotic activity of hMMP2, a property that was reversible by both an hMMP2 inhibitor and antibody against integrin-ß3. CONCLUSION: Overall, this study demonstrates that increased expression of hMMP2 may attenuate the severity of diabetes by protecting islet ß-cells from apoptosis through an integrin-mediated activation of the Akt/BAD pathway.

A case of type 2 diabetes mellitus with metformin-associated lactic acidosis initially presenting the appearance of a sulfonylurea-related hypoglycemic attack.

Case: A 64-year-old Japanese woman with diabetes mellitus was admitted for hypoglycemia. Her diabetes had been under good control with glimepiride, voglibose, exenatide, and metformin for a few years. Although overt proteinuria was observed, the serum creatinine values were within normal range during the routine outpatient follow-up. Hypoglycemic attack caused by glimepiride and loss of appetite by urinary tract infection were diagnosed. Then, metformin-associated lactic acidosis with acute renal failure caused by dehydration was detected. Outcome: Her condition was improved by continuous veno-venous hemodiafiltration and hemodialysis, known to be useful to remove metformin. Conclusion: We reported a case of metformin-associated lactic acidosis with hypoglycemia during routine treatment of diabetes that was successfully rescued by early renal replacement therapy.

Retrospective Analysis of Growth Speed of 54 Lesions of Colitis-associated Colorectal Neoplasia.

AIM: This study used a multicenter questionnaire survey to evaluate the morphology and progression of the initial lesion in cases of colitis-associated colorectal neoplasia (CRN). PATIENTS AND METHODS: Endoscopic images of lesions that had been definitively diagnosed as CRN by pathological examination were retrospectively reviewed. RESULTS: This resulted in the identification of 54 initial lesions in 49 patients. The 54 initial lesions fell into the following categories: 22 endoscopically visible localized lesions consisting of 18 elevated lesions and 4 depressed lesions, as well as 32 lesions that were not endoscopically visible as localized and consisted of 20 active-phase mucosal lesions and 12 remission-phase mucosal lesions. Nineteen of the lesions eventually became advanced cancers, while 35 lesions eventually became early-stage cancers. The final lesions were 40 elevated lesions, 5 flat or depressed lesions and 9 stenotic lesions. The form of growth of the advanced cancers was progressive stenosis or increased elevation. For approximately 69% of the early-stage cancers, the growth form was increasing elevation or development of elevation. For 73.6% of the advanced cancers, the initial lesion underwent rapid growth and became advanced cancer within 3 years; they accounted for 25.9% of the total cancers. Approximately 40% of the initial lesions of CRN were endoscopically visible as localized lesions, while approximately 60% were judged to be inflammatory mucosal lesions. CONCLUSION: It will be necessary to proactively take biopsy inflammatory mucosal lesions in order to discover tumors early and periodic surveillance should be performed with the knowledge that tumors may grow very quickly.

Long-term course of Crohn's disease in Japan: Incidence of complications, cumulative rate of initial surgery, and risk factors at diagnosis for initial surgery.

BACKGROUND AND AIMS: Intestinal complications of stenosis or fistula may occur during the course of Crohn's disease (CD), and surgery is performed in a fair number of patients. The risk factors for initial surgery in a Japanese hospital-based cohort of CD patients were evaluated. METHODS: This study was a single-center, retrospective, cohort study. The subjects were 520 patients who underwent inpatient and outpatient treatment at our hospital, had a definitive diagnosis of CD, and no previous surgery. Three parameters were investigated: (i) cumulative incidence of stenosis and fistula; (ii) cumulative rate of initial surgery for each disease type; and (iii) risk factors at diagnosis for initial surgery. RESULTS: (i) Stenosis and fistula increased with time, with stenosis or fistula appearing in about half of the patients after 5 years. (ii) The cumulative rate of initial surgery was about 50% after 10 years. (iii) The patient factors at diagnosis of current smoker, upper gastrointestinal disease, stricturing, penetrating, moderate to severe stenosis of the jejunum, moderate to severe stenosis of the ileum, and moderate to severe stenosis of the terminal ileum were risk factors for initial surgery. CONCLUSIONS: Stenosis or fistula appeared in about half of the patients after 5 years from diagnosis. When upper gastrointestinal disease or complicated small intestinal lesions are seen at the time of diagnosis, the cumulative rate of initial surgery is significantly higher.

Amelioration of Atherosclerosis by the New Medicinal Mushroom Grifola gargal Singer.

The beneficial effects of edible mushrooms for improving chronic intractable diseases have been documented. However, the antiatherogenic activity of the new medicinal mushroom Grifola gargal is unknown. Therefore, we evaluated whether Grifola gargal can prevent or delay the progression of atherosclerosis. Atherosclerosis was induced in ApoE lipoprotein-deficient mice by subcutaneous infusion of angiotensin II. Grifola gargal extract (GGE) was prepared and intraperitoneally injected. The weight of heart and vessels, dilatation/atheroma formation of thoracic and abdominal aorta, the percentage of peripheral granulocytes, and the blood concentration of MCP-1/CCL2 were significantly reduced in mice treated with GGE compared to untreated mice. By contrast, the percentage of regulatory T cells and the plasma concentration of SDF-1/CXCL12 were significantly increased in mice treated with the mushroom extract compared to untreated mice. In vitro, GGE significantly increased the secretion of SDF-1/CXCL12, VEGF, and TGF-ß1 from fibroblasts compared to control. This study demonstrated for the first time that Grifola gargal therapy can enhance regulatory T cells and ameliorate atherosclerosis in mice.

Prevalence and clinicopathological features of autoimmune pancreatitis in Japanese patients with inflammatory bowel disease.

OBJECTIVES: The purpose of this study was to clarify the clinicopathological characteristics of autoimmune pancreatitis (AIP) in Japanese patients with inflammatory bowel disease (IBD). METHODS: The clinicopathological findings of 7 patients with IBD whose definite AIP was diagnosed in our hospital according to the International Consensus Diagnostic Criteria were reviewed. RESULTS: Five (0.5%) of 961 patients with ulcerative colitis (UC) and 2 (0.3%) of 790 patients with Crohn disease had AIP. All of 7 patients whose AIP was diagnosed were type 2. The rate of elevated values of serum immunoglobulin G4 was 0%. Most patients with the diagnosis of IBD preceded that of AIP, and disease activity of IBD were active. Granulocyte epithelial lesion is similar to the cryptitis seen in colonic tissue of UC. All of 7 patients were given corticosteroids, immunomodulators, and/or biological agents for IBD. One patient had a recurrence. CONCLUSIONS: The frequency of AIP in Japanese patients with IBD was low. All cases were type 2 and responded well to corticosteroids, immunomodulators, and biological agents. Autoimmune pancreatitis in UC patients may be an extraintestinal manifestation of UC.