Pancreatic stone protein (PSP; reported in 1979), pancreatitis-associated protein (PAP; 1984) and regenerating protein (Reg I; 1988) were discovered independently in the fields of the exocrine (pancreatitis) and endocrine (diabetes) pancreas. Subsequent analysis revealed that PSP and Reg I are identical and PAP belongs to the same protein family. PSP/Reg I and PAP share a selective and specific trypsin cleavage site and result in insoluble fibrils (PTP, PATP). Search for a functional role of PSP had led to the idea that it might serve as an inhibitor in pancreatic stone formation and PSP was renamed lithostathine. Inhibitory effects of lithostathine in stone formation have been questioned. Evidence so far obtained can support a lithogenic role rather than a lithostatic role of PSP. PAP and its isoforms have been investigated mainly regarding responses to inflammation and stress. Reg I and its isoforms have been examined on regeneration, growth and mitogenesis in gastrointestinal neoplastic diseases as well as diabetes. Evidence obtained can be applied in the prediction of prognosis and therapy for inflammatory and neoplastic diseases.

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Objective Quality of life (QOL) impairment of patients who visit an outpatient clinic for abdominal symptoms has not been clarified. We investigated symptom-related QOL impairment that led patients to seek medical care.
Patients and Methods Abdominal symptom-related QOL was determined using the Izumo scale instrument in 172 patients who visited a clinic for their abdominal symptoms and in 961 healthy subjects who attended an annual health check.
Results QOL was more strongly impaired in the patients with abdominal symptoms than in subjects who attended health checks. Patients with heartburn consulted physicians even when QOL impairment was minimal, while those with epigastric fullness tended to consult a physician only when QOL impairment was significant.
Conclusion Abdominal symptom-related QOL impairment is considered to lead patients to seek medical care, though different symptoms have varying levels of influence.

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Background Recent studies have suggested that a higher body mass index (BMI) is associated with an improved prognosis in heart failure (HF). Adropin is a recently identified protein that has been implicated in the maintenance of energy homeostasis. In the present study, we investigated plasma adropin levels in patients with HF and evaluated the relationship between the levels and the severity of HF.
Methods and Results The study group comprised 56 patients with HF and 20 control subjects, who were divided into 4 subgroups according to New York Heart Association (NYHA) functional classification. Plasma levels of adropin, brain natriuretic peptide (BNP) and cardiac hemodynamics were determined. Plasma adropin levels were significantly increased according to the severity of NYHA class in the patients with HF; control: 6.0 ± 0.3; NYHA functional Class II: 7.6 ± 0.4; NYHA functional Class III: 9.8 ± 0.5; NYHA functional Class IV: 12.4 ± 0.6 ng/mL (p<0.01). Similarly, plasma BNP levels were significantly increased in accordance with the NYHA class. Plasma adropin levels were correlated positively with BNP (r=0.723, p<0.001), interleukin-6 (IL-6) (r=0.326, p=0.007) and body mass index (BMI) (r=0.295, p=0.014), and negatively with left ventricular ejection fraction (LVEF) (r=-0.710, p<0.001).
Conclusion Plasma adropin levels were significantly increased according to the severity of HF, and BNP and BMI had independent impact on the plasma adropin level. These findings suggest that the augmented release of adropin may be involved in the pathogenesis of HF and further study is necessary to explain the precise role of adropin in HF.

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Background Increased levels of selectins, adhesion molecules, hs-CRP and homocysteine are considered important as indicators of atherosclerosis. There is a significant amount of evidence that high LDL-C levels are a risk factor for coronary artery disease, whereas the relevance of isolated triglycerides is controversial. The present study aims to compare the levels of homocysteine, hs-CRP, E-selectin, sP-selectin, VCAM-1, ICAM-1 in patients with isolated hypertriglyceridemia and polygenic hypercholesterolemia.
Methods The following three groups were formed: polygenic hypercholesterolemia group (n=30), isolated hypertriglyceridemia group (n=30) and control group (n=30). These three groups were matched in terms of BMI, waist circumference and gender. Plasma high sensitive CRP, homocysteine, sVCAM-1, sICAM-1, sP-selectin, sE-Selectin levels of patients in these three groups were measured.
Results In the present study, mean values for sE-selectin, sVCAM-1 and sICAM-1 in the polygenic hypercholesterolemia group were significantly higher than in the other two groups (p<0.001). Homocysteine and hs-CRP levels were higher in the polygenic hypercholesterolemia group, compared to the isolated hypertriglyceridemia group (p=0.019, p<0.001; respectively) and the control group (p<0.001, p<0.001; respectively). Comparison of patients with hypertriglyceridemia to individuals in the control group did not yield a significant difference in terms of sE-selectin, sP-selectin, sVCAM-1, sICAM and homocysteine (p>0.05), where as the hs-CRP value was significantly higher in patients with isolated hypertriglyceridemia compared to the control group (p=0.001).
Conclusion The increase of adhesion molecules, homocysteine and hs-CRP in polygenic hypercholesterolemia subjects compared to the isolated hypertriglyceridemia group reflects their high cardiovascular risk.

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Background To date, there is very limited longitudinal data on COPD and incidence estimates in Japan. The aim of this study was to investigate the 12-year cumulative incidence of airflow obstruction (COPD) in Japanese males.
Methods This study included 913 male subjects, aged 30-76 years, who underwent lung function tests at a medical check-up in 1994 (baseline), 1999, and 2006. The study group consisted of 263 persistent never smokers, 296 early quitters, 117 late quitters, and 237 persistent smokers without airflow obstruction at baseline. The 12-year cumulative incidence of airflow obstruction was estimated. The spirometric criteria for diagnosis of airflow obstruction were forced expiratory volume in 1 second (FEV₁)/forced vital capacity (FVC) of <0.7 and 5th percentile lower limit of normal (FEV₁/FVC<LLN).
Results The 12-year cumulative incidences of airflow obstruction using fixed criteria and LLN criteria were 5.3%, 7.6% in persistent never smokers, 10.5%, 10.1% in early quitters, 12.0%, 14.5% in late quitters, 13.5%, 17.3% in persistent smokers, respectively. In logistic regression models, the odds ratio (OR) of developing airflow obstruction defined using the fixed criteria and the LLN criteria increased with a history of smoking status and increasing pack-years of smoking. When using the LLN criteria to define obstruction compared with fixed criteria, higher incidence rates among aged <60 and lower incidence rates among aged ≥60 were observed.
Conclusion The cumulative incidence of airflow obstruction defined using the fixed ratio and LLN criteria was strongly associated with smoking status. This study suggested that early cessation of smoking may prevent the development of airflow obstruction among smokers.

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Background Many primary care physicians begin treatment of asthma patients on the basis of their subjective symptoms. We hypothesized that patients diagnosed as having intermittent asthma on the basis of subjective symptoms by a primary care physician may have their asthma severity underestimated.
Methods We investigated 293 patients who were in their 20s and diagnosed as having asthma. Two hundred and fifteen patients with intermittent asthma diagnosed on the basis of subjective symptoms were chosen. We evaluated their asthma severity using FEV₁ (% predicted), airway hyperresponsiveness to histamine dihydrochloride, and exhaled nitric oxide level as factors that determine asthma severity.
Results Among these patients, 27.8% were determined to have moderate or severe asthma by the pulmonary function test. History of childhood asthma was the only significant risk factor for a low pulmonary function. Among the patients, 60.9% showed moderate or severe airway hyperresponsiveness. History of childhood asthma was the only significant risk factor for the increase in airway hyperresponsiveness. Moreover, 53.8% showed a high exhaled nitric oxide level. History of childhood asthma was associated with an increased risk of a high eNO level as determined by univariate analysis, but no significant difference was observed in the comparison by multiple logistic regression analysis. The percentage of subjects classified into the mild group by all of the results of the three tests was only 20.6%.
Conclusion We showed that asthma severity classified on the basis of only subjective symptoms may be underestimated in young adults. We showed that the diagnosis of mild intermittent asthma needs to be determined carefully.

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Objective To determine the prevalence of fatigue and factors associated with fatigue in patients with Parkinson's disease (PD).
Methods Fatigue was evaluated using the PD Fatigue Scale, a self-report questionnaire consisting of 16 statements describing the severity of fatigue symptoms. Patients were also evaluated using the Unified PD Rating Scale, Zung Depression Scale, the Epworth Sleepiness Scale, the PD Questionnaire-39 (PDQ-39) for assessing quality of life (QOL), and the Apathy Scale.
Patients We examined 46 consecutive outpatients clinically diagnosed with PD, excluding patients with cognitive impairment.
Results Fatigue was present in 22 (48%) patients. Multiple logistic regression analysis indicated that only QOL-scores and Apathy Scale scores were significant independent variables related to the presence of fatigue.
Conclusion Fatigue is a common symptom in patients with PD, and it is a symptom closely related to impaired QOL.

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Objective Several reports have indicated that cilostazol is effective in the prevention of recurrence after cerebral infarction. However, cilostazol is inferior in tolerability for the adverse events than other anti-platelet agents. The goal of this study was to determine whether cilostazol escalation oral administration affects its tolerability.
Methods One hundred sixty-eight patients hospitalized for brain infarction with cilostazol treatment in our stroke center from 2006 to 2008 were enrolled in this study. During this term, we had two teams in our center and used different regimens. One of which used 100 mg b.i.d. regimen of cilostazol (Standard group) and the other used 50 mg b.i.d. for the initial 4 days, followed by a dose of 100 mg b.i.d. of it (Escalation group). Patient's information such as baseline characteristics, adverse events, were collected and statistically analyzed retrospectively.
Results Seventy-nine patients were enrolled in Standard group and 87 patients in Escalation group. Comparison between these groups demonstrated that Escalation group had fewer patients who discontinued treatment (p=0.001) and a lower incidence of headache (p=0.004).
Conclusion This type of dose escalation regimen of cilostazol may be superior to the standard regimen in tolerability.

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Objective The lag in the approval and development of neurological drugs between Japan and other countries has been a major issue for patients with neurological diseases. The objective of this study was to analyze the factors contributing to the delay in the launching of neurological drugs in Japan.
Methods We analyzed data from Japan and the US for the approval of 36 standard neurological drugs and examined the potential factors that may cause the delay of their launch.
Results Of the 36 standard neurological drugs, all of which were approved in the US, only 21 were introduced in Japan from June 1999 to April 2010, whereas the other 15, whose indications were Alzheimer disease, epilepsy, migraine, multiple sclerosis, and Parkinson disease, remained unapproved. The US led Japan in the number of introductions (20 versus 1), with introductions in Japan occurring at a median of 87 months after introductions in the US. Japan's review time of new drug applications (23 months) could not explain this lag. In 15 of the 21 approved drugs, the application data package included overseas data. The mean review time of these 15 drugs was significantly shorter than that of the other 6 drugs without overseas data. The maximum daily doses of 7 of the drugs were higher in the US than in Japan.
Conclusion These results show that there is still a large gap between Japan and the US with regard to access to standard neurological drugs, despite several important reforms in the Japanese drug approval system.

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Objective To evaluate the effects of periodontal intervention on inflammatory cytokines, adiponectin, insulin resistance (IR), and metabolic control and to investigate the relationship between type 2 diabetes mellitus (T2DM) and moderately poor glycemic control and chronic periodontitis.
Methods and Patients A total of 190 moderately poorly controlled (HbA1c between 7.5% and 9.5%) T2DM patients with periodontitis were randomly divided into two groups according to whether they underwent periodontal intervention: T2DM-NT and T2DM-T group. The levels of serum adiponectin, C-reactive protein (CRP), tumor necrosis factor α (TNF-α), interleukin-6 (IL-6), lipid profile, glucose, insulin, homeostasis model of assessment - insulin resistance (HOMA-IR) and homeostasis model assessment of β-cell function (HOMA-β) were measured at baseline and after 3 months.
Results The levels of clinical periodontal variables, the probing depth, attachment loss, bleeding index, and plaque index were improved significantly in T2DM-T group after 3 months compared to T2DM-NT group (all p<0.01). After 3 months, the serum levels of hsCRP, TNF-α, IL-6, fasting plasma glucose (FPG), glycosylated hemoglobin (HbA1c), fasting insulin (FINS) and HOMA-IR index decreased, and adiponectin was significantly increased in T2DM-T group compared to those in the T2DM-NT group (p<0.05 or p<0.01).
Conclusion Periodontal intervention can improve glycemic control, lipid profile and IR, reduce serum inflammatory cytokine levels and increase serum adiponectin levels in moderately poorly controlled T2DM patients.

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Primary renal synovial sarcomas (SS) are rare tumors of the kidney. Faria et al first described primary renal synovial sarcoma in 1999 (Mod Pathol 12:94A). In this paper we present a primary renal synovial sarcoma case and review the 41 primary renal synovial sarcoma cases reported to date. Primary renal synovial sarcomas can exist in either a monophasic or a biphasic pattern. The monophasic variant of primary renal synovial sarcoma is more common and tends to have a better prognosis than the biphasic variant. We present in this paper, a 68-year-old woman with primary renal synovial sarcoma. She presented with right flank pain and abdominal distention. Postoperative pathology of the 20 cm mass on magnetic resonance imaging showed histologic and immunochemical features of synovial sarcoma with coexisting spindle and epithelial cells. She underwent adjuvant ifosfamide and doxorubicin chemotherapy and was free of disease at 1 year after diagnosis. As a conclusion, physicians should be aware of the possibility of malignancy in cystic renal masses and that synovial sarcoma is one of the possibilities.

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Takayasu's arteritis (TA) and Crohn's disease (CD) are chronic inflammatory diseases of uncertain etiology. Although co-existence of these rare diseases is estimated to occur in 1 in 10 billion individuals, a theoretically unexpected association has been reported in several patients and it is suggested that those associations may have been more than an unusual coincidence. Herein, we report a case of TA associated with clinically inactive CD. A Japanese woman was diagnosed with colonic CD at the age of 15, developed aortic valve regurgitation at 19, and then presented with general fatigue, low grade fever, and painful sensations in her left arm at 25. She was diagnosed with TA based on computed tomography scanning and magnetic resonance angiography findings, and treatments with prednisolone and cyclosporine were started. Thereafter, valve replacement and right coronary artery bypass graft surgery were performed. The possible pathophysiological mechanism responsible for concurrent existence of TA and CD may be associated with immune disorders. Early diagnosis of vascular lesions for patients with inflammatory bowel disease is highly encouraged.

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A 68-year-old woman with fecal occult blood was referred to Dokkyo Medical School Hospital. Colonoscopy demonstrated a flat lesion in the rectum, and endoscopic mucosal resection of the lesion was performed. Histologic examination revealed that it contained ectopic gastric mucosa, which had a gastric foveolar and glandular mucinous phenotype, as demonstrated by immunohistochemistry. Moreover, the lesion also contained CA19-9- and CK7-positive pancreatic duct-like components in the submucosal layer. The present case is the first report to describe ectopic gastric mucosa and pancreatic ducts concurrently arising in the rectum.

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Granulocyte and monocyte adsorption apheresis (GMA) is one therapeutic option for induction of remission in patients with inflammatory bowel diseases. Recently intensive GMA (2 sessions per week) was reported to be strikingly better than weekly GMA, both in remission rate and time to remission. Here we report two cases of Crohn's disease refractory to weekly GMA who responded to intensive GMA. One patient had not received immunosuppressive therapy while the other had been refractory to combination therapy with infliximab and azathioprine. Intensive GMA induced remission in these 2 patients. Intensive GMA may represent a therapeutic choice for remission induction and maintenance with infliximab.

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A 53-year-old man presented with angina pectoris and ST-segment elevation in V₁-V₄ leads. Electrocardiogram changes and chest pain were completely resolved with nitroglycerine infusion. Coronary angiogram revealed normal epicardial vessels. These findings suggest that the acute myocardial ischemia was secondary to coronary vasospasm. From his medical history we learned that he was taking L-thyroxine and the dose had been increased two months previously. He was found to be in thyrotoxic state at admission. L-thyroxine treatment was withheld and diltiazem was given. He had no further symptoms. In conclusion we think that acute myocardial ischemia was likely secondary to L-thyroxine-induced coronary spasm.

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A 40-year-old man with microscopic polyangiitis developed both myeloperoxidase anti-neutrophil cytoplasmic antibodies (90 EU) and anti-glomerular basement membrane antibodies (134 EU)-positive rapidly progressive glomerulonephritis and heparin-induced thrombocytopenia. Although the patient initially showed no signs of improvement, persistent therapy including 1 g/day intravenous methylprednisolone, 50 mg/day oral prednisolone, plasma exchange, and 900 mg/day intravenous cyclophosphamide resulted in the normalization of both titers, recovery of renal function, and discontinuation of dialysis. Though previous studies showed poor outcomes in such "double-positive" patients, aggressive immunosuppression in younger patients may result in the recovery of renal function, even in those with severe renal dysfunction.

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Neuromyelitis optica (NMO) is an inflammatory demyelinating disorder characterized by optic neuritis and acute myelitis. A parainfectious pathogenesis may play a partial role in the development of this disorder. Several viral infections are known to cause NMO. Here we report the case of a 15-year-old girl diagnosed with postinfluenza monophasic NMO. The patient developed sudden fever and chills, and the rapid diagnostic test for influenza was positive. She was diagnosed as influenza A and was treated with zanamivir hydrate (10 mg/day, inhalation). Three days later, she complained of dysuria and dysesthesia in the lower extremities. After nine days, she experienced blurred vision bilaterally. Neurological examination revealed visual disturbance, dysuria, dysesthesia and hyperreflexia in the lower extremities. Her visual acuity was counting fingers in OD and 2/100 in OS. Pupillary size was 4.0 mm and light reflexes were sluggish on both sides. Ophthalmoscopy showed marked edema of the optic discs. Serum influenza immunoglobulin M antibodies were elevated and serum anti-aquaporin 4 (AQP4) antibodies were undetectable. Spinal cord magnetic resonance imaging (MRI) displayed longitudinally extensive lesions in the thoracic cord. Brain MRI disclosed three subcortical lesions. The patient fulfilled the revised diagnostic criteria for NMO (2006). After methylprednisolone pulse therapy followed by oral administration of prednisolone, visual dysfunction, dysuria, limb dysesthesia and hyperreflexia were improved. Subsequently, she experienced no attacks for 3 years. This is the first case report of influenza A-associated NMO with such features of postinfectious NMO as a pediatric onset, monophasic course and anti-AQP4 antibody-seronegative status.

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We herein present the first reported case of reversible cerebral vasoconstriction syndrome (RCVS) in Takayasu's arteritis (TA), in a patient with severe thunderclap headache and generalized tonic-clonic seizure. Magnetic resonance imaging and angiography revealed posterior reversible encephalopathy syndrome, followed by severe vasoconstriction in multiple arteries. RCVS should be included in the differential diagnosis of thunderclap headache attacks with radiologic intracranial vascular abnormalities in connective tissue diseases, including TA.

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Primary HIV infection (PHI) is associated with various neurological disorders. However, acute transverse myelitis (ATM) complicating PHI has not been reported after the introduction of the combination antiretroviral therapy (cART). We encountered one patient with known PHI with clinical presentation of ATM. Treatment with cART and corticosteroids successfully improved symptoms, and no recurrence was noted after discontinuation of cART. In conclusion, concurrent use of cART and corticosteroids was effective against PHI accompanied by ATM and could be withdrawn after improvement of ATM.

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