Sodium-glucose cotransporter 2 (SGLT2), which is specifically expressed on the apical side of proximal tubular cells, is involved in the reabsorption of most of the glucose filtered by the glomeruli, and its inhibitors are gaining publicity as potent antihyperglycemic drugs. In some clinical trials, SGLT2 inhibitors exerted cardiovascular and kidney protective effects, which appeared to be partly independent of the original glucose-lowering effect. SGLT2 inhibitors have both direct and indirect renoprotective effects. The direct effects involve the suppression of hyperplasia/hypertrophy, inflammation, and fibrosis in the proximal tubular cells, utilization of ketone bodies, restored tubuloglomerular feedback, decreased oxygen consumption, improvement in anemia, and preconditioning against ischemia/reperfusion. The indirect effects involve a reduction in insulin levels and resistance, uric acid concentration, body weight, and blood pressure. However, safety concerns remain, including consequences of an enhanced glucose load in the lower nephron, leg amputation, bone fractures, and therapeutic efficacy in patients with advanced chronic kidney disease.

Objective The aim of this study was to clarify the safety of colorectal endoscopic submucosal dissection (ESD) during the era of health insurance coverage starting from April 2012 in Japan.

Methods Between April 2012 and May 2016, ESD was applied to 398 lesions in 373 patients. Risk factors for serious complications of colorectal ESD, perforation and post-ESD bleeding, were evaluated focusing on the resected specimen size, location, growth pattern, invasion depth, histopathology, postoperative clipping, and procedure time. In addition, the relationship between serious complications and patients' background characteristics was analyzed.

Results Among 373 patients, perforation occurred in 12 patients and post-ESD bleeding in 19 patients. A univariate analysis showed that the risk factors for perforation were the lesion size, the resected specimen size, and a long operation time. A multivariate analysis showed that a long operation time was a risk factor for perforation during colorectal ESD. A univariate analysis indicated that significant risk factors for postoperative bleeding were a long operation time, rectal lesion, and cancer. All patients with serious complications were treated by an endoscopic procedure without blood transfusion or the need to convert to open surgery.

Conclusion The present study suggests that colorectal ESD may be accepted with relative safety in Japan as a common therapeutic approach for early colorectal cancer.

Objective An infectious hepatic cyst (IHC) is a hepatic cyst complicated with secondary infection and is generally assumed to be rare. However, we have experienced no small number of patients with IHC in recent clinical practice. We therefore examined the incidence and clinical characteristics of IHC.

Methods The medical records of patients with IHC who were hospitalized at our institution between January 2012 and December 2016 were retrospectively reviewed. Their demographic factors, biochemical, bacteriological, imaging, and treatment results were explored and compared with those of patients with pyogenic liver abscess (PLA).

Patients Twelve patients with IHC and 39 with PLA were identified.

Results The IHCs were significantly larger in diameters than the PLAs, and patients with IHCs tended to be older and more often women than those with PLAs. IHCs showed characteristic imaging features, including heterogeneous contents with occasional fluid-debris levels, a thickened cystic wall with rim enhancement, perilesional edema and hyperaemia. Patients with IHCs had a significantly shorter hospital stay than those with PLAs.

Conclusion Physicians should note that IHCs are not rare. A careful imaging evaluation can suggest an IHC, and the timely aspiration of the content can lead to an accurate diagnosis. The cystic wall may keep the infectious material confined within the IHC, resulting in the observed good treatment outcome with catheter drainage.

Objective and methods There is little information concerning the influence of the heart rhythm on the vascular endothelial function in patients with non-valvular atrial fibrillation (AF) compared with studies concerning sinus rhythm (SR). The present study included paroxysmal (n=184) or chronic (n=53) AF patients without heart failure and control subjects with SR (n=79) matched for age, gender and the CHA₂DS₂-VASc score. Paroxysmal AF was defined as episodes that terminated spontaneously within 7 days, while chronic AF was defined as longstanding AF that was refractory to cardioversion for 12 months or longer. There were no significant differences in the numbers of patients receiving renin-angiotension-aldosterone system inhibitors or statins among the three groups.

Results Among the 237 AF patients (155 men, mean age 64±9 years, mean CHA₂DS₂-VASc score 1.8±1.4), the flow-mediated dilatation (FMD) was 5.4%±2.6% in the paroxysmal AF group, 4.3%±2.1% in the chronic AF group and 6.5%±3.5% in the SR group. There were significant differences among the 3 groups (all, p<0.05). Nitroglycerin-induced dilatation (NMD) was noted in 14.6%±6.5% of the paroxysmal AF group, 16.5%±9.1% of the chronic AF group and 12.7%±5.9% of the SR group, with no significant differences among the 3 groups. There was a significant negative correlation between the CHA₂DS₂-VASc scores and the FMDs value in all 3 groups (paroxysmal AF group:r=-0.322, p<0.01; chronic AF group:r=-0.291, p<0.05; SR group:r=-0.326, p<0.01).

Conclusion In comparison with SR, the frequency and duration of AF episodes appear to cause deterioration of the vascular endothelial function.

Objective We conducted a retrospective study on the epidemiological and clinical features of patients with acute caffeine poisoning in Japan.

Methods Letters requesting participation were sent to 264 emergency departments of hospitals, and questionnaires were mailed to those that agreed to participate.

Patients Participants were patients transported to emergency departments of hospitals between April 2011 and March 2016 after consuming large or massive amounts of caffeinated supplements and/or energy drinks (caffeine dose ≥1.0 g).

Results We surveyed 101 patients from 38 emergency departments. Since April 2013, the number of patients has markedly increased. Of these young patients (median age, 25 years), 53 were men, and 97 had consumed caffeine in tablet form. Estimated caffeine doses (n=93) ranged from 1.2 to 82.6 g (median, 7.2 g). Serum caffeine levels on admission (n=17) ranged from 2.0 to 530.0 μg/mL (median level, 106.0 μg/mL). Common abnormal vital signs and laboratory data on admission included tachypnea, tachycardia, depressed consciousness, hypercreatinekinasemia, hyperglycemia, hypokalemia, hypophosphatemia, and hyperlactatemia. Common signs and symptoms in the clinical course included nausea, vomiting, excitement/agitation, and sinus tachycardia. Seven patients (6.9%) who had consumed ≥6.0 g of caffeine, or whose serum caffeine levels on admission were ≥200 μg/mL, developed cardiac arrest. Ninety-seven patients (96.0%) recovered completely, but 3 patients (3.0%) died.

Conclusion The present analysis of data from more than 100 emergency patients revealed clinical features of moderate to fatal caffeine poisoning. We recommend highlighting the toxicity risks associated with ingesting highly caffeinated tablets.

Objective Sodium-glucose co-transporter 2 (SGLT2) inhibitors reduce cardiovascular events and decrease the body fat mass in patients with type 2 diabetes mellitus (T2DM). We examined whether or not the SGLT2-inhibitor dapagliflozin can improve the endothelial function associated with a reduction in abdominal fat mass.

Methods We prospectively recruited patients with uncontrolled [hemoglobin A1c (HbA1c) >7.0%] T2DM who were not being treated by SGLT2 inhibitors. Patients were treated with add-on dapagliflozin (5 mg/day) or non-SGLT2 inhibitor medicines for 6 months to improve their HbA1c. We measured the peripheral microvascular endothelial function as assessed by reactive hyperemia peripheral arterial tonometry (RH-PAT) and calculated the natural logarithmic transformed value of the RH-PAT index (LnRHI). We then investigated changes in the LnRHI and abdominal fat area using computed tomography (CT).

Results The subjects were 54 patients with uncontrolled T2DM (72.2% men) with a mean HbA1c of 8.1%. The HbA1c was significantly decreased in both groups, with no significant difference between the groups. Dapagliflozin treatment, but not non-SGLT2 inhibitor treatment, significantly increased the LnRHI. The changes in the LnRHI were significantly greater in the dapagliflozin group than in the non-SGLT2 inhibitor group. Dapagliflozin treatment, but not non-SGLT2 inhibitor treatment, significantly decreased the abdominal visceral fat area, subcutaneous fat area (SFA), and total fat area (TFA) as assessed by CT and significantly increased the plasma adiponectin levels. The percentage changes in the LnRHI were significantly correlated with changes in the SFA, TFA, systolic blood pressure, and adiponectin.

Conclusion Add-on treatment with dapagliflozin significantly improves the glycemic control and endothelial function associated with a reduction in the abdominal fat mass in patients with uncontrolled T2DM.

Objective Sleep apnea syndrome is more prevalent among men than women and is frequently accompanied by metabolic syndrome (MetS). However, gender differences in the effect of sleep-disordered breathing (SDB) leading to the risk of MetS remain unclear. The aim of our study was to investigate the clinical characteristics of SDB in women and the differential influence of SDB on MetS between genders.

Methods In a single-center retrospective study, we compared the data of 1,809 consecutive SDB patients by gender to clarify the characteristics of sleep disorders in women. We also compared the prevalence of MetS and its related abnormalities by gender. A logistic regression analysis was used to determine the contributory factors for MetS.

Results The mean age and proportion of patients over 50 years of age were higher in women than in men. SDB was milder in women than in men according to polysomnography findings. Elevated Hemoglobin A1c levels and hyperlipidemia were less frequent in women than in men. The MetS prevalence was similar in women and men (30.0% vs. 35.2%). A logistic regression analysis showed that the apnea-hypopnea index (AHI) was an independent risk factor for MetS in both genders, but that female gender was independently associated with a decreased prevalence of MetS and its related abnormalities.

Conclusion Female SDB patients tend to be older with milder apnea and sleepiness than male SDB patients. A higher AHI is a significant risk factor for MetS in both genders, although female gender is an independent inhibitory factor for developing MetS in SDB patients.

Objective Diabetes commonly affects the bladder nerves. However, the relationship among bladder, periarterial and somatic neuropathy in diabetes is not well known. In the present study we investigated these relationships.

Methods A total of 110 diabetic subjects were enrolled in the study. All were referred for screening for diabetic neuropathy, irrespective of their symptoms. The patients included 61 men and 49 women; the mean age was 59.3 years (31-85 years); the mean disease duration was 14.0 years (5-30 years); and the mean HbA1c value was 10.1% (5.1-16.3%). We performed a nerve conduction study (NCS, A-alpha/beta and B fiber), ultrasound-based measurement of the post-void residual (PVR) volume (abnormal, >50 mL, mainly A-delta/C fiber) and postural blood pressure measurement (abnormal, >-20 mmHg, A-delta/C fiber). Fisher's exact probability test and Student's t-test were used to analyze the significance of differences.

Results NCS abnormality, an abnormal PVR volume, and postural hypotension were noted in 74, 19, and 36 of the subjects, respectively. There were clear relationships between NCS and an abnormal PVR volume (p<0.05), postural hypotension and an abnormal PVR volume (p<0.05), or NCS and postural hypotension (p<0.01). There were also subjects who had NCS abnormality alone, a high PVR volume alone or postural hypotension alone. An abnormal PVR volume was not associated with the HbA1c value, but was clearly related to the duration of diabetes (p<0.05).

Conclusion Bladder dysfunction was correlated with somatic and periarterial neuropathy. On the other hand, 16% of the cases of bladder dysfunction occurred in patients without somatic or periarterial neuropathy; thus, the regular measurement of the PVR volume is necessary.

Objective To investigate the efficacy of minodronate in the treatment of glucocorticoid-induced osteoporosis (GIO).

Methods The study population included patients in whom the administration of minodronate (50 mg, once every 4 weeks) had been newly started for the treatment of GIO in Niigata Rheumatic Center from 2012 to 2015. Patients who were bisphosphonate-naïve and those who switched from other bisphosphonates were classified into the naïve and switch groups, respectively. The changes in the bone mineral density (BMD) and bone metabolic markers after one year of minodronate treatment were retrospectively evaluated. We also compared the BMD and bone turnover marker changes of minodronate-naïve patients with those in whom alendronate or risedronate had been prescribed as a first bisphosphonate (control group).

Results Minodronate was prescribed to 142 patients, and data were successfully obtained from 120 patients. New vertebral fractures were observed in 5 of the 142 patients; 1 fracture occurred during the cessation of minodronate for dental treatment, and 3 patients already had multiple vertebral fractures before the initiation of minodronate. The patients' tartrate-resistant acid phosphatase 5b (TRACP-5b) (-27.0%, p<0.001) and bone alkaline phosphatase (BAP) (-15.7%, p<0.01) levels were decreased, but no patients showed a decrease to below the normal range. One year of treatment with minodronate significantly increased the lumbar BMD in the naïve (+3.9%, p<0.001) and switch (+2.3%, p<0.001) groups. Although the femoral BMD did not change to a significant extent overall, the patients with a low young adult mean (YAM) (<80%) at baseline showed a significant increase in their femoral BMD (+2.1%, p=0.034) values. Compared with the control group, the minodronate-naïve group showed a significant decrease in the TRACP-5b levels and a significant increase in the lumbar BMD.

Conclusion The administration of minodronate appears to be an effective treatment for GIO.

This case report refers to a 31-year-old patient with an 11-year history of Crohn's disease. The patient presented with an edematous elevated lesion in the splenic flexure. Two histological analyses revealed no signs of obvious dysplasia, and the patient subsequently began infliximab treatment. Nine months later, a worsening of the stricture of the edematous elevated lesion was observed in the splenic flexure, and transverse colonic resection was performed. A histological investigation of the lesion in the splenic flexure revealed advanced adenocarcinoma. Six months after the surgery, computed tomography revealed recurrent carcinoma and peritoneal metastases. The patient was administered palliative chemotherapy.

Phlegmonous gastritis is a rare but often fatal acute pyogenic infection of the stomach. We herein report three cases of phlegmonous gastritis with different causes: the long-term placement of a nasogastric feeding tube, bacteremia associated with cellulitis in a diabetic patient, and an adverse reaction to paclitaxel/carboplatin chemotherapy for cancer of unknown primary cause, which were classified as primary, secondary, and idiopathic types, respectively. Coping with the increasing morbidity rate associated with the diverse background of such patients requires a thorough understanding of the clinical features and image findings associated with this entity.

We herein report a unique case of hepatitis C virus (HCV)-associated renal disease without cryoglobulinemia that showed proteinuria, hypoproteinemia, ascites, and edema. Due to combination therapy with daclatasvir and asunaprevir, the patient achieved sustained virological response at week 24 of the therapy. Furthermore, the therapy caused marked amelioration of her proteinuria, ascites, edema, and hypoalbuminemia, and finally improved her estimated glomerular filtration rate. There were no adverse events, and the combination therapy was well-tolerated. We recommend that HCV eradication with antiviral therapy using direct-acting antiviral agents be attempted first for all renal disease with HCV infection, regardless of cryoglobulinemia, considering the existence of resistance-associated variants.

Intrahepatic cholangiocarcinoma (ICC) is the second-most common primary liver cancer, although its occurrence is relatively rare. Budd-Chiari syndrome (BCS) is characterized by outflow obstruction from the liver, with hepatocellular carcinoma being the most common cause of malignant BCS. In this case report, we describe the occurrence of an unrecognized ICC that induced BCS and esophageal achalasia.

We herein report a patient with a history of rheumatoid arthritis treated with methotrexate, which caused methotrexate-associated lymphoproliferative disorder and obstructive jaundice due to an enlarged lymph node. The obstructive jaundice was treated with endoscopic biliary stenting. A histopathological examination revealed features of Hodgkin's lymphoma, and chemotherapy with brentuximab vedotin was administered. Cholangiography and duodenoscopy after four rounds of chemotherapy revealed a choledochoduodenal fistula that developed in response to chemotherapy. It should be noted that, in cases of lymphoma infiltrating the gastrointestinal wall, fistulae can occur because of rapid regression due to regimens comprising monoclonal antibodies, such as rituximab and brentuximab vedotin.

Connective tissue disorders sometimes involve cardiovascular systems. This report describes the case of a middle-aged man with mitral regurgitation and heart failure. He had distinctive features of mucopolysaccharidosis type (MPS) III, but no gene mutations that were known to be associated with MPS. Meanwhile, he had a COL1A2 gene mutation that is associated with osteogenesis imperfecta (OI), and had some features that were compatible with OI. The patient might have had a rare connective tissue disorder with the characteristics of MPS III and OI, which was initially detected as a result of the cardiovascular manifestations.

We herein report a 42-year-old man with advanced lung adenocarcinoma and nivolumab-associated dermatomyositis. Nivolumab, an anticancer drug that is classified as an immune checkpoint inhibitor, often induces immune-related adverse events (irAEs). However, there have so far been no reports regarding nivolumab-associated dermatomyositis. This patient was diagnosed with dermatomyositis due to the presence of proximal muscle weakness with abnormal electromyography and magnetic resonance imaging findings; skin lesions, such as heliotrope rash, shawl sign, and periungual erythema; and an elevated serum aldolase level after nivolumab administration. It is important to consider drug-associated dermatomyositis in the differential diagnosis of patients presenting with skin lesions and muscle weakness after nivolumab treatment.

Pseudomesotheliomatous carcinoma of the lung is very rare, and reversible restrictive lung disease with pseudomesotheliomatous carcinoma has not yet been previously reported. We herein report a patient with HER2-positive non-small-cell lung cancer (NSCLC) showing pseudomesotheliomatous carcinoma who was successfully treated with bevacizumab combination chemotherapy. A 56-year-old Japanese woman with advanced NSCLC presented with dyspnea. We administered chemotherapy with cisplatin (75 mg/m²) plus pemetrexed (500 mg/m²) plus bevacizumab (15 mg/kg), followed by pemetrexed plus bevacizumab. After eight cycles of maintenance chemotherapy, chest CT demonstrated a marked tumor reduction and an improvement of the right lung volume. The vital capacity was thereafter found to have significantly increased according to pulmonary function tests.

A 68-year-old woman was admitted to our hospital with fever and pleural effusion. Her thoracentesis showed eosinophilic pleural effusion (EPE) without any evidence of malignancy, infection, or trauma. Pleural biopsy revealed pleuritis and intercostal myositis. Characteristic skin manifestations, including Gottron's sign, interstitial lung disease, and pericardial effusion, appeared later in the clinical course. She was finally diagnosed with anti-PL-7 antisynthetase syndrome (ASS) based on the presence of anti-PL-7 antibody, and she fulfilled the diagnostic criteria for dermatomyositis. These clinical manifestations improved with immunosuppressive therapy. EPE might therefore be one of the characteristic features of anti-PL-7 ASS.

Primary endobronchial mucosa-associated lymphoid tissue lymphoma (EML) is rare. We reviewed 20 cases of EML, including ours and case reports. We found that the location of tumor in 70% of these cases was limited to the trachea and main bronchus, and the form of tumor in 61% of these cases was several nodular protrusions. If a patient exhibits these characteristics, adequate specimen collection on bronchoscopy is important. Because the prognosis for patients with EML is good, tumors on the trachea and main bronchus should be treated, while those on the peripheral airway can be watched carefully.

Acquired hemophilia A (AHA) is a hemorrhagic disorder. Whether or not severe thrombotic events can develop without the use of bypassing agents in AHA patients is unclear. An 80-year-old woman with AHA underwent immunosuppressive therapy with prednisolone at 1 mg/kg daily. After achieving remission, she suddenly developed multiple organ failure due to acute systemic thrombosis and died within a few hours of the diagnosis. Patients with AHA, especially those with risk factors for thrombosis, have a considerable risk of developing thrombosis during the recovery phase of factor VIII activity and should be carefully monitored by coagulation testing.

Japanese encephalitis (JE) survivors often present with nigrostriatal aftereffects with parkinsonian features. A 67-year-old woman with JE showed right-dominant clinical parkinsonism and left-dominant substantia nigra lesions after magnetic resonance imaging (MRI). Dopamine transporter (DAT) imaging using ¹²³I-labeled 2β-carbomethoxy-3β-(4-iodophenyl)-N-(3-fluoropropyl)-nortropane (¹²³I-FP-CIT) revealed a corresponding left-dominant decrease. The present case is the first to reveal a clear match of laterality between clinical parkinsonism, MRI-based substantia nigra lesions, and impaired DAT in presynaptic dopaminergic neurons in JE.

A 72-year-old Japanese woman diagnosed with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis was admitted to our hospital with hearing loss, temporal pain, and sudden blindness. We finally diagnosed recurrent granulomatosis with polyangiitis and initiated methyl-prednisolone pulse therapy (1,000 mg) followed by prednisolone (30 mg/day) and rituximab (RTX). After the third RTX administration, she developed bloody stools along with acute thrombocytopenia and low complement levels. We diagnosed rituximab-induced acute thrombocytopenia (RIAT), and her platelet counts spontaneously recovered. This case suggests that after RTX therapy RIAT may sometimes cause severe thrombocytopenia, and that monitoring the complements may be useful for making an early diagnosis of RIAT.

An 81-year-old man was admitted with bilateral pleural effusion. A clinical examination showed lymphocytic pleura effusion and elevated serum IgG4 levels, so that IgG4-related disease was suggested, whereas tuberculous pleurisy was suspected because of high adenosine deaminase (ADA) levels in the pleural effusion. A surgical pleural biopsy revealed that there were large numbers of IgG4-positive cells and IgG4/IgG positive cell ratio exceeded 40% in several sites. Accordingly, we diagnosed IgG4-related pleuritis and treated with the patient with glucocorticoid therapy. The ADA levels in pleural effusion can increase in IgG4-related pleuritis, and it is therefore important to perform a pleural biopsy.

Thrombotic microangiopathies (TMAs) rarely accompany polymyositis/dermatomyositis. We treated three patients with dermatomyositis combined with TMA. A literature review identified 13 previously reported cases. Exacerbation of myositis at the time of the TMA onset was observed in 62.5% of all patients, suggesting that the TMA onset may be associated with autoantibody production. We also found that cases of TMA with polymyositis/dermatomyositis often had a poor treatment response rate (37.5%). Furthermore, even if treatment was effective, the mortality rate associated with subsequent complications was high, and the survival rate was low (18.8%). Therefore, careful attention should be paid to patient management after TMA treatment.