Objective Nighttime onset of atrial fibrillation (AF) is sometimes associated with obstructive sleep apnea accompanied by a characteristic heart rate (HR) pattern known as cyclical variation of HR. The aim of this study was to evaluate whether cyclical variation of HR is prevalent in patients with nocturnal AF.
Methods The subjects consisted of 34 patients (68±12 years) with paroxysmal AF, including 14 patients with daytime AF and 20 patients with nighttime AF. Holter electrocardiogram (ECGs) were examined for the presence of cyclical variation in HR and to quantify the HR variability within the 40-minute period preceding each AF episode using a fast Fourier transform (FFT) methods.
Results Cyclical variation in HR was observed in 12 of 20 (60%) nighttime episodes and in only two of 14 (14%) daytime episodes. The prevalence of cyclical variation in HR was significantly greater in the nighttime AF episodes than in the daytime AF episodes (Chi=5.34, p<0.05). The mean frequency of cyclical variation in HR was 0.015±0.003 Hz. The mean power of the VLF (very low frequency) component (0.008-0.04 Hz) before the onset of AF was significantly greater in the nighttime AF episodes than in the daytime AF episodes. Among the nighttime AF episodes, the power of the HF (high frequency), LF (low frequency) and very low frequency (VLF) components increased significantly just before the onset of AF compared with that observed 40 minutes before onset.
Conclusion The high prevalence of cyclical variation in HR observed before nocturnal AF episodes suggests that sleep apnea may play a role in the onset of nighttime AF.

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Objective Endothelial dysfunction plays an important role in the development of diabetic retinopathy. The aim of this study was to evaluate endothelial dysfunction using different approaches in patients with type 1 diabete mellitus with early stages of diabetic retinopathy. For this purpose, we investigated the serum levels of cellular adhesion molecules, including intercellular adhesion molecule (ICAM-1), vascular cell adhesion molecule (VCAM-1) and endothelin-1 (ET-1), which have emerged as specific markers of endothelial dysfunction, and measured the flow-mediated dilatation (FMD), a noninvasive technique used to evaluate endothelial dysfunction.
Methods The study group included 59 patients with type 1 diabetes mellitus (DM) and 30 age-matched healthy control subjects. The diabetic patients were divided into two groups according to the ophthalmoscopic findings: Group 1, composed of type 1 diabetic patients having no signs of diabetic retinopathy (DRP), and Group 2, composed of type 1 diabetic patients having findings of the early stages of nonproliferative diabetic retinopathy (NPDR).
Results The serum levels of ET-1 (fmol/mL), ICAM-1 (ng/mL) and VCAM-1 (ng/mL) were 8.52±0.699 vs. 478.39±46.22 vs. 728.64±35.081 in the patients without retinopathy, 8.91±1.354 vs. 451.79±48.262 vs. 863.59±62.37 in the diabetic patients with NPDR and 10.73±1.04 vs. 608.15±74.92 vs. 872.95±57.63 in the control group. There were no significant differences in the serum levels of the three molecules between the groups. The FMD values were 6.51±0.46% in the diabetic patients without retinopathy, 6.66±0.29% in the diabetic patients with NPDR and 6.68±0.51% in the control group. No significant differences were found between the groups.
Conclusion The early stages of diabetic retinopathy cannot be considered in the evaluation of systemic markers of endothelial dysfunction.

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Objective The effects of dipeptidyl peptidase-4 (DPP-4) inhibition on adipose tissue inflammation remain obscure. The aim of this study was to evaluate the effects of the addition of sitagliptin on the β-cell function and various inflammatory biomarkers in type 2 diabetic patients.
Methods After a run-in period of taking metformin, 178 diabetic patients with poor glycemic control were randomized to take sitagliptin at a dose of 100 mg once a day or a placebo in addition to metformin for 12 months. We evaluated the following parameters at three, six, nine and twelve months: body mass index (BMI), glycemic control, the homeostasis model assessment insulin resistance index (HOMA-IR), the homeostasis model assessment β-cell function index (HOMA-β), the proinsulin/fasting plasma insulin ratio (Pr/FPI ratio) and the levels of fasting plasma insulin (FPI), fasting plasma proinsulin (FPPr), C-peptide, glucagon, resistin, vaspin, omentin-1 and tumor necrosis factor-α (TNF-α). Before and twelve months after the addition of sitagliptin, the patients underwent combined euglycemic hyperinsulinemic and hyperglycemic clamping with subsequent arginine stimulation to assess insulin sensitivity and secretion.
Results Treatment with sitagliptin + metformin was more effective than placebo + metformin in improving glycemic control, the HOMA-IR and the glucagon level and increasing the HOMA-β and all β-cell measurements after combined euglycemic hyperinsulinemic and hyperglycemic clamping with subsequent arginine stimulation. Regarding inflammatory biomarkers, sitagliptin + metformin more effectively reduced the levels of resistin, vaspin and omentin-1 than placebo + metformin.
Conclusion When treatment with metformin alone is not adequate for obtaining glycemic control, the addition of sitagliptin can be considered due to its actions in preserving the β-cell function and reducing the levels of biomarkers of inflammation.

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Objective Prolonged air leaks in patients with spontaneous pneumothorax are not infrequent. The aim of this study was to assess the duration of air leaks and define the clinical variables associated with the therapeutic success of chest tube drainage for spontaneous pneumothorax.
Methods A total of 441 patients with spontaneous pneumothorax treated with chest tube drainage between 2008 and 2012 were retrospectively evaluated. The clinical differences between the patients successfully treated with drainage and those who required more invasive procedures were analyzed.
Results Invasive procedures, such as video-assisted thoracic surgery (n=121), fibrin glue administration through a chest tube (n=8) and pleurodesis with OK-432 (n=21), were performed in 34% (150/441) of the patients. The treatment rate of chest drainage alone was higher in the patients with initial pneumothorax (72%; 124/170) than in those with recurrent pneumothorax (62%; 167/271) (p=0.015). In addition, this rate was higher in the patients with moderate lung collapse (70%; 167/237) than in those with severe lung collapse (61%; 124/204) (p=0.032).
Conclusion Patients with recurrent pneumothorax or severe lung collapse associated with prolonged air leakage are more likely to receive invasive procedures.

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Objective The development of myeloid malignancies is a concern when administering thrombopoietin receptor (or the myeloproliferative leukemia virus proto-oncogene product, MPL) agonists. Progression from myelodysplastic syndrome (MDS) to acute myelogenous leukemia [AML, 9 (6.12%) AML patients among 147 MDS subjects] was reported in a clinical trial. However, only one (0.15%) case of AML among 653 immune thrombocytopenic purpura (ITP) subjects was reported. Our objective was to determine whether there is currently a safety signal in the FDA files termed Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) for AML in ITP patients who receive MPL agonists.
Methods We conducted a case-controlled study using the FAERS as a source of case and control data. We compared demographic characteristics, such as gender, age and exposure to MPL agonists between AML patients and others among ITP subjects registered between 2002 and 2011.
Results Total of 4,821 ITP subjects were identified, including 62 AML patients. The number of patients treated with romiplostim and eltrombopag was 54 (1.74%) AML patients among 3,102 ITP subjects and nine (1.52%) AML patients among 594 ITP subjects, respectively. It should be noted that all AML patients were exposed to one or more MPL agonists. Another factor associated with AML was male gender.
Conclusion We herein report an association between AML and MPL agonist use in ITP subjects. Due to various biases and the incompleteness of the FAERS data, further studies are warranted to determine whether the detected signal is a real risk. Physicians should not alter their prescribing behaviors based on this single preliminary analysis.

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Objective The concentrations of neopterin and osteopontin in the cerebrospinal fluid (CSF) were measured in patients with HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP) in order to evaluate their utility as biomarkers for the treatment response.
Methods Seven HAM/TSP patients were treated intravenously with high-dose methylprednisolone (1,000 mg/day) for 3 days. CSF samples were collected before and after the treatment. The neopterin and osteopontin concentrations were determined using high-performance liquid chromatography (HPLC) and an enzyme immunoassay, respectively. The clinical symptoms were evaluated using the Osame Motor Disability Score and the Urinary Disturbance Score.
Results Four out of the seven patients showed an improvement in motor function with the treatment, and were therefore classed as responders. The pre-treatment CSF neopterin concentration exceeded the upper limit of normal in all seven of the patients, and tended to be higher in treatment responders as compared to non-responders. The CSF neopterin concentration was reduced following treatment in all patients. The mean CSF neopterin concentration significantly (p<0.01) decreased following treatment by almost 60% (from 124.1±79.9 nmol/L to 49.2±29.8 nmol/L). The mean CSF osteopontin concentration was significantly (p<0.01) higher in the HAM/TSP patients in comparison to the 18 HTLV-1-seronegative patients who were designated as controls (9.54±4.53 mg/L vs. 3.72±3.04 mg/L). No significant (p=0.47) reduction of the CSF osteopontin concentration was observed following the intravenous administration of high-dose methylprednisolone.
Conclusion These results indicate that the CSF neopterin concentration, but not the osteopontin concentration, is a potentially valuable biomarker for monitoring the treatment response in HAM/TSP patients. Furthermore, high pre-treatment CSF neopterin concentrations may be a predictive biomarker for a response to intravenous high-dose methylprednisolone therapy.

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Objective No studies have so far sufficiently investigated the risk factors for drug-induced liver injury (DILI) with an elevated serum bilirubin concentration.
Methods We conducted a historical cohort study observing inpatients admitted to two hospitals in Japan. A decreased level of activities of daily living (ADL) was defined as a Barthel Index score of <80. The patients were treated with standard regimens under a directly observed treatment short-course strategy.
Results The cohort of 356 patients comprised 244 men (68.5%) and 112 women (31.5%), with a mean age of 63.8±20.2 years. Compared with the patients who did not experience DILI with a bilirubin level of ≥2.0 mg/dL, the patients who experienced DILI with a bilirubin level of ≥2.0 mg/dL more often had a decreased level of ADLs, were more likely to suffer from chronic cardiac disease, had lower serum albumin levels and were less often treated with four-drug regimens involving pyrazinamide (PZA). In a logistic regression analysis in which these five factors acted as independent variables, a decreased level of ADLs was the strongest predictor for DILI with a bilirubin level of ≥2.0 mg/dL, with an odds ratio of 16.5 (95%CI: 1.7-159; p=0.015), followed by chronic cardiac disease, with an odds ratio of 4.0 (95%CI: 1.2-12.6; p=0.020).
Conclusion A decreased level of ADLs and chronic cardiac disease are strong risk factors for DILI with a bilirubin level of ≥2.0 mg/dL resulting from the use of antituberculous drugs. Physicians should pay close attention to the possibility of DILI with a bilirubin level of ≥2.0 mg/dL when treating tuberculosis patients with a decreased level of ADLs and/or chronic heart disease.

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We herein report the case of a 43-year-old man with distinct gastropathy and hypoproteinemia treated with H. pylori eradication therapy. Most reported cases of protein-losing gastropathy are divided into Ménétrier's disease (MD) and diffuse varioliform gastritis (DVG). Our patient presented with leg edema due to marked hypoalbuminemia, which we ascribed to distinct gastropathy with novel endoscopic findings resembling cap polyposis in the colon, apparently different from both MD and DVG. H. pylori eradication therapy promptly induced the normalization of laboratory data and mucosal healing. Our case together with two previously published similar cases may contribute to establishing an association between cap-polyposis-like-gastropathy with hypoproteinemia and H. pylori.

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Hepatic xanthoma is an extremely rare lesion worldwide. We herein present a case of hepatic xanthoma that developed in a 27-year-old Taiwanese man who had participated in a clinical trial of pasireotide. This is, to the best of our knowledge, the first case of pasireotide-induced hepatic xanthoma. Following discontinuation of the drug, the tumor continued to decrease in size (98.2% decrease in tumor volume). We suggest that, in patients receiving pasireotide, the liver should be checked using periodic radiological examinations, even if the patient does not exhibit any risk factors, and that medical or surgical intervention may not be needed.

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A 64-year-old Japanese woman with a history of bronchiectasis presented with multiple hypervascular nodules in both lobes of the liver without hepatitis B or C virus infection. Imaging studies, including ultrasound, contrast-enhanced computed tomography and magnetic resonance imaging, showed hypervascularity in the early phase. Histologically, no lipid degeneration was observed; however, there was a mild increase in cell density, miniaturization of nuclei, increased chromatin content, partial sinusoidal dilatation and congestion. No unpaired arteries were evident. The diagnosis based on the pathology and diagnostic radiology findings was multiple hypervascular focal nodular hyperplasia (FNH)-like lesions with no history of alcohol abuse or chronic liver disease.

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Nocardiosis is an uncommon infection that occurs primarily in immunocompromised patients. We herein report an extremely rare case of Nocardia farcinica (N. farcinica) pericarditis. A 53-year-old man with nephrotic syndrome that required chronic corticosteroid therapy presented with pleuritic chest pain and cardiac tamponade. Pericardiocentesis revealed purulent pericardial effusion and a bacteriological examination showed the characteristic branching filamentous bacteria identified as N. farcinica. Aggressive surgical drainage and a trimethoprim-sulfamethoxazole based regimen resulted in clinical improvement. To the best of our knowledge, this is the first reported case of N. farcinica pericarditis in Thailand.

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Although spontaneous cervical artery dissection (SCAD) is generally a rare contributor to a stroke, this condition triggers a considerable percentage of the strokes that are observed in young to middle-aged patients. We herein report the findings of a patient who presented with a stroke and a severe headache. A diagnosis of SCAD was made following a series of examinations. The patient had high-grade stenosis in the cervical artery and received carotid angioplasty along with stenting. A diagnosis of SCAD should be suspected if a patient who is less than 50 years of age presents with a stroke and a severe headache, and CT or an MRI scan rules out hemorrhage.

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The following three case reports present the effects of 6-month continuous positive airway pressure (CPAP) therapy on blood pressure (BP) in severe obstructive sleep apnea patients with resistant hypertension.
Case 1 A 58-year-old woman exhibited a decreased 24-hour BP and changes in the nocturnal BP dipping pattern from non-dipper to dipper. Case 2 A 64-year-old man showed no improvements in nocturnal BP. Case 3 A 78-year-old man with ischemic cardiomyopathy exhibited changes in the nocturnal BP dipping pattern from non-dipper to dipper. These results suggest that 6-month CPAP therapy improves the nocturnal BP dipping status in some patients with obstructive sleep apnea and resistant hypertension.

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An 82-year-old woman with type 2 diabetes mellitus, hypertension, and unstable angina presented with severe lactic acidosis and acute kidney injury (AKI) accompanied by acute pancreatitis. Her medical history revealed that she had taken cimetidine for two weeks while taking other medications, including metformin. Continuous veno-venous hemodiafiltration (CVVHDF) was initiated under diagnosis of lactic acidosis due to metformin and AKI caused by cimetidine-induced acute pancreatitis. In three days of CVVHDF, the levels of serum biochemical markers of lactic acidosis and AKI improved and the patient's urine output reached over 1 L/day. The pancreatitis improved over time.

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A 56-year-old woman was admitted to our hospital because a chest X-ray and thoracic computed tomography (CT) scan revealed a heterogeneous tumor in the middle mediastinum during a visit to a nearby clinic for a consultation regarding a persistent cough and body weight loss. However, the tumor spontaneously decreased on thoracic CT performed on admission. Subsequently, a biopsy of the tumor using video-assisted thoracoscopy was performed. The pathological findings disclosed the tumor to be small-cell lung cancer with infiltration of CD8-positive T-cells exhibiting spontaneous regression. Cell-mediated immunity, including CD8-positive T-cells, may have relevance to the spontaneous regression of malignant tumors.

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The classification of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) has limitations because the condition includes disorders with similar general clinical features, similar characteristics of lung and renal involvement and a positive ANCA serology. A 40-year-old woman was admitted to our hospital for hemoptysis and dyspnea. She had no history of bronchial asthma. Laboratory examinations revealed hypereosinophilia, positive anti-myeloperoxidase antibodies, hematuria and proteinuria. The patient was ultimately diagnosed with AAV associated with diffuse alveolar hemorrhage, rapidly progressive glomerulonephritis and hypereosinophilia without bronchial asthma. Obtaining a definitive diagnosis of ANCA vasculitis can be very difficult, and the characteristics of this case were not compatible with the findings of typical AVV. We herein report a rare case of AVV.

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The prognosis is poor for patients with advanced pleomorphic carcinoma of the lung due to the generally limited response to chemotherapy and/or radiotherapy. It has been suggested the production of granulocyte colony-stimulating factor (G-CSF) by cancer cells may aggravate the disease progression. We herein report a case of a 73-year-old Japanese man with advanced G-CSF-producing pleomorphic carcinoma of the lung. First-line chemotherapy with carboplatin and paclitaxel had been suspended. Subsequent radiotherapy achieved a moderate volume reduction and an amelioration of the excessive G-CSF-related complications. Six cycles of second-line chemotherapy with docetaxel administered with good results. These combined treatments resulted in long term survival without progression of the disease.

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Immune reconstitution inflammatory syndrome (IRIS) is associated with clinical manifestations that can overlap with the patients with acquired immunodeficiency disease (AIDS)-related non-Hodgkin's lymphoma. We herein report a case of AIDS-related Burkitt lymphoma which was successfully treated with dose-adjusted etoposide, doxorubicin, cyclophosphamide, vincristine, and prednisone (EPOCH). However, the patient developed a lymphoma-like clinical presentation shortly after the conclusion of chemotherapy. The patient's symptoms were identical to the initial symptoms characteristic of lymphoma; however, the laboratory data revealed no evidence of a relapse of Burkitt lymphoma. A bone marrow examination showed T-cell clonality, even though there were no signs of any progression of the lymphoma. The patient was diagnosed with IRIS, and the clinical manifestations rapidly improved following treatment.

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Neuronal ceroid lipofuscinosis (NCL) is a rare disease with onset typically during childhood; however, that developing during adulthood can lead to early-onset dementia. We report a 54-year-old man whose onset coincided with speech impairment, amnesia and dyscalculia. On brain MRI, marked diffuse leukoencephalopathy with periventricular predominance was observed. On a skin biopsy, characteristic fingerprint images were noted, and the patient was diagnosed with NCL. The differential diagnosis of cognitive impairment with leukoencephalopathy is wide ranging; however, when marked symmetrical periventricular-predominant leukoencephalopathy is prevalent and no peripheral neuropathy or gait disorders are evident, a diagnosis of NCL should be suspected and a skin biopsy should be performed.

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A 22-year-old Japanese woman was diagnosed with hemophagocytic lymphohistiocytosis and subsequently was treated with etoposide and cyclophosphamide. On Day 22, multiple nodular lesions appeared in the bilateral lungs. Neither the administered antibiotics nor the antifungal agent were effective, and she died suddenly of respiratory failure on Day 35. An autopsy revealed disseminated zygomycosis and a pulmonary infarction due to the embolization of an angioinvasive fungus, which was later identified as Cunninghamella bertholletiae using in situ hybridization of 18S rRNA. C. bertholletiae is aggressive as well as resistant to antifungal agents. This rare species should therefore be taken into consideration as a potential causative agent of zygomycosis.

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