Accumulating evidence has shown that the risk of osteoporotic fractures is increased in patients with diabetes mellitus (DM). Thus, DM-induced bone fragility has been recently recognized as a diabetic complication. Because the fracture risk is independent of the reduction in bone mineral density, deterioration of the bone quality may be the main cause of bone fragility. Although its mechanism remains poorly understood, accumulated collagen cross-links of advanced glycation end-products (AGEs) and dysfunctions of osteoblast and osteocyte may be involved. Previous studies have suggested that various diabetes-related factors, such as chronic hyperglycemia, insulin, insulin-like growth factor-I, AGEs, and homocysteine, are associated with the risk of bone fragility caused by impaired bone formation and bone remodeling. Furthermore, several anti-diabetic drugs are known to affect bone metabolism and fracture risk. We herein review the association between DM and fracture risk as well as the mechanism of DM-induced bone fragility based on recent evidence.

Objective Dietary antigens are common luminal antigens in the gastrointestinal tract and have been considered to contribute to the pathogenesis of inflammatory bowel disease (IBD). We analyzed the levels of food-specific IgGs against a variety of dietary antigens, explored the clinical relevance of food allergy to the pathogenesis of IBD, and investigated whether or not infliximab (IFX) treatment could regulate the immune responses induced by dietary antigens.

Methods A total of 301 IBD patients, including 201 patients with Crohn's disease (CD) and 100 patients with ulcerative colitis (UC), were recruited, and their serum food-specific IgGs against 14 food antigens were detected by a semi-quantitative enzyme linked immunosorbent assay (ELISA). Total serum IgG and IgE levels were measured by immunonephelometry and fluorescent enzyme immunoassay, respectively. Simultaneously, the relevant medical records and clinical data were collected for further analyses.

Results Food-specific IgGs against egg, milk, wheat, corn, rice, tomato, codfish, and soybean antigens were found to be significantly increased in the sera of CD patients compared with UC patients and healthy controls (p<0.01). The levels of total serum IgG and IgE were also significantly higher in CD patients than in healthy controls (p<0.01). The titers of corn- and tomato-specific IgGs were found to be significantly correlated with total serum IgG in CD patients (p<0.05), while the titers of egg-, milk-, and wheat-specific IgGs were correlated with total serum IgE (p<0.05). Interestingly, IFX therapy was able to down-regulate the food-specific IgG-mediated immune response markedly in active CD patients.

Conclusion Food-specific IgGs against egg, milk, wheat, corn, rice, tomato, codfish, and soybean are highly increased in the sera of CD patients. IFX treatment was able to down-regulate the levels of food-specific IgGs by suppressing intestinal inflammation and promoting mucosal healing. Therefore, food-specific IgGs may serve as an important approach in the diagnosis and management of food allergy in IBD.

Objective Low urine pH is associated with several metabolic diseases, such as dyslipidemia, diabetes, and metabolic syndrome. However, the association between low urine pH and non-alcoholic fatty liver disease (NAFLD) remains unknown. Therefore, we conducted a community-based cross-sectional study to investigate this association.

Methods Between April 2013 and March 2014, the records of 4,945 Japanese subjects who had undergone annual health checkups were reviewed to identify subjects who met the diagnostic criteria for NAFLD.

Patients Based on urine pH, the participants were classified into four groups; a low urine pH was defined as ≤5.5. Of the 3,411 subjects who qualified for enrollment, 1,028 met the diagnostic criteria for NAFLD.

Results The prevalence of NAFLD was significantly increased with decreasing urine pH in both men and women (p<0.01 and p=0.02, respectively). A multivariate analysis, including adjustments for age, metabolic markers, and the renal function, showed a significant association between low urine pH and NAFLD in men and women (odds ratio, 1.37; 95% confidence interval, 1.01-1.85, p=0.04 and odds ratio, 1.73; 95% confidence interval, 1.15-2.62, p<0.01, respectively).

Conclusion Our study indicates that NAFLD is associated with a low urine pH in both sexes, findings that might help clinicians identify patients at high risk for NAFLD.

Objective There are few reports on the outcomes of 12-week paritaprevir, ombitasvir, and ritonavir (PTV/OBV/r) treatment in real-world clinical settings. We aimed to evaluate the efficacy and safety of 12-week treatment with ritonavir-boosted paritaprevir and ombitasvir in patients with hepatitis C virus (HCV) genotype 1 infection in a real-world setting.

Methods Fifty-eight patients with chronic hepatitis or compensated hepatic cirrhosis and genotype-1 HCV infection were treated with PTV/OBV/r and followed for 24 weeks after the completion of treatment in 10 centers in northern Tohoku. The efficacy and safety of this 12-week treatment regimen was analyzed.

Results Among the 58 treated patients, 18 (31%) had compensated liver cirrhosis, while 11 (19%) patients had experienced treatment failure with another treatment regimen. NS5A resistance-associated variants (RAVs) were detected at baseline in 3 patients (5.2%), including Y93H in two patients and L31M in two patients. One patient had NS5A RAVs at both positions 93 and 31. The overall sustained virological response (SVR) 24 rate was 96.6%. Three patients with NS5A RAVs also achieved an SVR24. The SVR24 rate was not significantly affected by age, sex, prior treatment, prior history of HCC, or liver stiffness. The mean alanine aminotransferase (ALT) levels decreased significantly during this treatment. Adverse events occurred in 15 patients (26%), 26% of which were grade 1 or 2. No severe adverse events occurred.

Conclusion In this real-world study, 12-week PTV/OBV/r treatment was effective and safe for treating patients with HCV-1 infection who had chronic hepatitis or compensated hepatic cirrhosis.

Objective Pirfenidone (PFD) is often used for years, but the efficacy and safety of long-term PFD therapy in patients with idiopathic pulmonary fibrosis (IPF) are not fully understood.

Methods and Patients We retrospectively evaluated 46 patients with IPF who received PFD between February 2009 and August 2014. The efficacy and safety of PFD therapy were compared between 2 groups: long-term therapy patients who received PFD for over 1 year (group L, n=30, 65%) and short-term therapy patients who could not receive PFD for more than 1 year due to worsening of their condition or side effects (group S, n=16, 35%).

Results The median age of the 46 patients was 70.5 years, and the median baseline % predicted forced vital capacity (%FVC) was 70.0%. The changes in the FVC in group L were -120 mL and -170 mL at 12 and 24 months after receiving PFD, respectively. The respective median survival times after PFD therapy in groups L and S were 1,612 days and 285 days (p<0.001). The patients in group L experienced a longer time free of acute exacerbation of IPF than those in group S (947 days vs. 145 days, p=0.001). A multivariate analysis revealed that %FVC <60% was a predictor of the inability to receive PFD for over 1 year (odds ratio 0.240, 95% confidence interval 0.060-0.958; p=0.043). With regard to grade 3-5 adverse events, only one patient exhibited grade 3 hyponatremia.

Conclusion Long-term PFD therapy is effective, with few severe adverse events.

A 51-year-old man visited our hospital with a main complaint of precordial pain, difficulty swallowing, and pyrexia. The patient was diagnosed with esophageal carcinosarcoma, based on the characteristic morphology noted on upper gastrointestinal endoscopy and histology tests, and he underwent surgical treatment. His preoperative blood granulocyte-colony stimulating factor (G-CSF) and interleukin-6 (IL-6) levels were high, and the surgical specimens were positive in both immunohistochemical tests; therefore, he was diagnosed with a G-CSF- and IL-6-producing tumor. When pyrexia is seen as a paraneoplastic symptom, it is important to consider and investigate the possibility of a cytokine-producing tumor.

Aberrant pancreas is defined as pancreatic tissue present outside of the pancreas and is often found incidentally during esophagogastroduodenoscopy. Obtaining sufficient tissue to differentiate aberrant pancreas from other subepithelial lesions is sometimes difficult. Due to the lack of a definitive diagnosis, patients often undergo unnecessary surgery. We herein report the first case of aberrant pancreas in which the concomitant use of needle-based probe confocal laser endomicroscopy and fine-needle aspiration supported the final diagnosis. Needle-based probe confocal laser endomicroscopy provides a real-time in vivo histopathology evaluation and may be a feasible means of diagnosing aberrant pancreas.

A 1-year-old female toddler who was under a great amount of psychological stress presented with acute hematemesis. She had no significant medical history; she displayed lethargy and was anemic. Although blood transfusion and famotidine were administered for upper gastrointestinal bleeding (UGIB), the anemia did not improve. Thus, early endoscopy was performed under general anesthesia, revealing a gastric ulcer with exposed vessels in the supra-angular region. Cauterization via bipolar hemostatic forceps was performed on the exposed vessels, and the bleeding was controlled successfully. We diagnosed the patient with hemorrhagic stress-induced gastric ulcer due to psychological stress. Three months later, endoscopy revealed that the gastric ulcer had healed.

Endoscopic submucosal dissection (ESD) of lesions using expanded indications for early gastric cancer (EGC) has been accepted as an alternative treatment for cases without lymph node metastasis. We herein report a rare case of metastatic lymph node tissue in mixed adenoneuroendocrine carcinoma (MANEC) after curative ESD using the expanded pathological criteria. A 70-year-old man underwent ESD for two EGC lesions. A pathological examination revealed lesions that required curative resection based on the expanded pathological criteria of the Japanese classification of gastric carcinoma. However, lymph node metastasis was detected at 26 months after ESD. Additional surgical resection was performed and MANEC was pathologically diagnosed in the metastatic lymph node. The patient subsequently underwent additional chemotherapy and remains alive at 2 years after surgery. Even though MANEC is a rare tumor, this case suggests that periodic follow-up is important when patients undergo curative resection by ESD based on the expanded indications because of the high malignant potential and the poor prognosis.

The optimum retreatment strategy for chronic hepatitis C virus (HCV) patients who failed directly-acting antiviral agents (DAA)-based therapy is unknown. We herein report the outcomes of an HCV genotype (GT) 2a-infected patient with virologic failure following treatment with sofosbuvir plus ribavirin (SOF+RBV) who was successfully retreated with ombitasvir/paritaprevir/ritonavir plus ribavirin (OBV/PTV/r+RBV).

A 73-year-old woman with massive ascites associated with a giant hepatic mass accompanied by arterio-portal (AP) shunt was admitted to our hospital. Based on contrast-enhanced computed tomography (CT) and angiography findings, hepatic hemangioma with AP shunt and ascites due to portal hypertension was diagnosed. Transcatheter arterial embolization (TAE) by N-butyl-2-cyanoacrylate (NBCA) was performed without complications. The patient's ascites disappeared, and her liver function test results improved after the treatment. The patient has maintained a steady state for two years. This case indicates that TAE with NBCA is a safe and effective treatment for hepatic hemangioma accompanied by AP shunt.

A 75-year-old man was admitted to our hospital for follow-up coronary angiography. Just after starting coronary angiography, his electrocardiogram showed ST-segment elevation in the V1-6, I, II, and aVF leads, and he fell into catastrophic cardiogenic shock. His left coronary arteriogram showed proximal total obstruction in the left anterior descending artery and proximal subtotal occlusion in the left circumflex artery. Because pulseless electrical activity arrest was recognized, cardiopulmonary support was started. After more than 15 minutes' cardiac massage, his blood pressure gradually returned to baseline. During the cardiogenic shock due to pulseless electrical activity arrest, neither ventricular fibrillation nor ventricular tachycardia was recognized.

The patient was a 32-year-old Japanese woman who was given a 75-g oral glucose tolerance test at the 35th week of pregnancy and was normoglycemic. She had excessive thirst and polyuria from 15 days after delivery. When she visited for the 1-month postpartum checkup, her plasma glucose level was 479 mg/dL, HbA1c was 7.4%, and urinary C-peptide was 1.1 μg/mL; she was therefore diagnosed with fulminant type 1 diabetes mellitus associated with pregnancy. All physicians should be aware of this disease so as to provide a prompt diagnosis and emergency treatment and consequently improve the maternal prognosis.

This is a 10-year follow-up study of a family with ferroportin disease A. The proband, a 59-year-old man showed no noteworthy findings with the exception of an abnormal iron level. The proband's 90-year-old father showed reduced abilities in gait and cognition; however, with the exception of his iron level, his biochemistry results were almost normal. Brain imaging showed age-matched atrophy and iron deposition. In both patients, the serum levels of ferritin and hepcidin25, and liver computed tomography scores declined over a 10-year period. These changes were mainly due to a habitual change to a low-iron diet. The iron disorder in this family was not associated with major organ damage.

A 58-year-old man with type 1 autoimmune pancreatitis was referred to nephrologists for severe proteinuria. Laboratory data revealed a high serum IgG4 level, hypoalbuminemia, and massive proteinuria, which were compatible with nephrotic syndrome. The renal pathological findings confirmed the diagnosis of secondary membranous nephropathy concurrent with IgG4-related tubulointerstitial nephritis. Despite the improvement of interstitial markers, the proteinuria was refractory to prednisolone, requiring cyclosporine to achieve complete remission. Membranous nephropathy is a rare manifestation of IgG4-related kidney disease. This case shows that the therapeutic response to prednisolone significantly differs between glomerular lesions and interstitial lesions of IgG4-related kidney disease.

A 61-year-old man was admitted to our hospital because of decreased visual acuity. On admission, he had marked blepharoedema, conjunctival injection, exophthalmos, diplopia, and blurred vision. He also had bronchial asthma and urinary retention requiring urethral catheterization. His serum immunoglobulin (Ig) G4 level was elevated to 1,830 U/mL. Fluorodeoxyglucose-positron emission tomography revealed an abnormal uptake in multiple organs. A histopathological examination of the salivary gland revealed IgG4-positive plasma cell infiltration, leading to a diagnosis of IgG4-related ophthalmic disease. After initiating steroid therapy, his longstanding ophthalmic, respiratory, and urinary symptoms dramatically improved. In IgG4-related disease, steroid therapy should be considered even if patients have longstanding symptoms.

A 60-year-old man was admitted to our hospital because of abdominal pain and disturbed consciousness. Head magnetic resonance imaging showed right vertebral artery dissection and abdominal enhanced computed tomography showed dissection of the superior mesenteric artery. The patient was diagnosed as having fibromuscular dysplasia (FMD) based on conventional angiography. Although multiple vascular bed involvement is observed in approximately 40% of FMD patients, reports of sequential symptomatic dissections in various vascular beds are rare. Patients with FMD and dissection require close observation, and hemodynamic stabilization may prevent not only the further development of dissection, but also subsequent dissection of other arteries.

An 81-year-old Japanese man presented with constitutional symptoms and anemia and was diagnosed with giant cell arteritis (GCA) and myelodysplastic syndrome (MDS) simultaneously. His symptoms and anemia improved promptly with steroids; however, the MDS rapidly progressed to overt leukemia. While MDS patients are at an increased risk of autoimmune diseases, an association with GCA has rarely been reported. This case illustrates the importance of considering GCA as a cause of anemia in elderly patients if MDS is already diagnosed, even in countries where the prevalence of GCA is very low. The simultaneous development of GCA and MDS suggests a common pathogenetic link between these two diseases.

Axitinib has emerged as a promising antineoplastic agent for the treatment of advanced renal cell carcinoma. Although the administration of axitinib was well-tolerated in clinical trials, the real-world safety and tolerability remain unverified. We herein report a patient with metastatic renal cell carcinoma who suddenly developed life-threatening hyperkalemia following the initiation of axitinib treatment. Although hyperkalemia has been reported with an incidence of <10%, acute severe hyperkalemia may be a considerably critical adverse event of axitinib therapy, especially in patients with risk factors for hyperkalemia. An abundance of caution for unusual and unpredictable toxicities is warranted when using axitinib.

Familial Mediterranean fever (FMF), the most common autoinflammatory disorder, is characterized by recurrent febrile attacks and polyserositis. FMF is caused by mutations in MEFV, which encodes pyrin. In this report, we present an atypical FMF case with E148Q/L110P mutations in MEFV. The patient experienced periodic episodes of systemic pain originating from prostate cancer bone metastases. The pain attacks were prevented by continuous prophylactic therapy with colchicine. In this case, the presence of atypical FMF may have modulated the clinical manifestations of cancer bone metastases. To our knowledge, this is the first report to demonstrate the potential modulatory effect of MEFV mutations on cancer manifestations.