Objective The aim of this pilot study was to determine the safety and efficacy of natural human interferon β (nIFNβ) plus ribavirin (RBV) in patients with chronic hepatitis C who did not respond to pegylated interferon alpha (PEG-IFN), with special emphasis on the incidence of mental disorders or refusal for fear of adverse effects.
Methods We studied 19 patients with HCV genotype 1b, 2a or 2b and a high viral load, including 8 patients with mental disorders. They were treated with nIFNβ-RBV. Eleven patients with HCV genotype 1b of these patients were treated with nIFNβ-RBV for 48 weeks (group A), and compared with 22 matched controls treated with PEG-IFN plus RBV for 48 weeks (group B). The other 8 patients with HCV genotype 2 were treated with nIFNβ-RBV for 24 weeks.
Results Six of 8 patients with mental disorders and 9 of 11 patients without mental disorders completed nIFNβ-RBV therapy; 1 patient with mental disorder dropped out due to exacerbation of depression, and 3 patients suspended the therapy due to insufficient response. The sustained virological response (SVR) was 27% (3/11) in group A and 41% (9/22) in group B (p = 0.70). During treatment, platelet count increased in group A but not in group B. SVR was 88% (7/8) in patients of genotype 2 and high viral load treated with nIFNβ plus RBV.
Conclusion nIFNβ-RBV therapy offers sufficient safety and efficacy for patients with mental disorders, and thus could represent an excellent second-line therapy for subpopulations that are not suitable for PEG-IFN-RBV.

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Background The coronary artery calcification (CAC) score as determined by multi-detector row computed tomography (MDCT) is known to predict coronary artery disease (CAD). Chronic kidney disease (CKD) is also known to be a risk factor for CAD. Little is known about the relationship between CKD and the severity of coronary artery stenosis or CAC as determined by MDCT, a non-invasive method for screening.
Methods and Results The subjects included 313 consecutive patients who underwent MDCT angiography. We quantified the number of significantly stenosed vessels in coronary vessel disease (VD) and CAC score using MDCT and measured body mass index (BMI), waist circumference and blood pressure. We also analyzed plasma levels of lipid profile, hemoglobin A1c, uric acid, and creatinine. Furthermore, we calculated the estimated glomerular filtration rate (eGFR), and defined CKD as GFR <60 mL/min/1.73 m². eGFR levels in the 3-VD group were significantly lower than those in patients without stenosed vessels. In the two classifications that were based on the CAC score [low (L, 0-444) and high (H, ≥445)] in our previous report, the H group was significantly associated with age, number of VD, incidence of hypertension and CKD. Multivariate logistic regression analysis revealed that the high CAC score group was significantly correlated with age (p=0.0023), CKD (p=0.0109) and number of VD (p=0.0470).
Conclusion CKD may contribute to the severity of CAD associated with the progression of CAC. Therefore, therapeutic intervention for CKD, in addition to the improvement of conventional risk factors, is needed to prevent CAD when MDCT is performed.

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Objrctive Obstructive sleep apnea syndrome (OSAS) is frequently complicated by metabolic syndrome, including diabetes and hypertension. Both OSAS and metabolic syndrome are strongly associated with obesity. Recently, adiponectin and leptin, which are secreted by adipose tissue, have been considered to play important roles in the progression of these diseases. Thus, to examine the association between leptin, adiponectin and OSAS, we measured the serum level of these adipocytokines in the same OSAS patients.
Methods and Patients Sixty-eight consecutive Japanese men, who recorded all-night polysomnography, were enrolled in this study, and were divided into three groups, control (n=15), moderate OSAS (n=21) and severe OSAS (n=32). We measured serum levels of adiponectin and leptin by ELISA.
Results Serum leptin levels were positively correlated with apnea hypopnea index (AHI) (r=0.552, p<0.001), the percentage of time with less than 90% hemoglobin saturation level in total sleep time (%T<90) (r=0.399, p<0.001) and body mass index (BMI) (r=0.807, p<0.0001). These parameters were suggested as the determinant factor for the serum leptin level by stepwise multiple regression analysis. On the other hand, serum adiponectin levels showed a positive correlation with age (r=0.361, p=0.005) and HDL-cholesterol level (r=0.274, p=0.039). Although there was no significant correlation between serum adiponectin levels and AHI or %T<90, serum adiponectin levels were chosen at a determinant factor of %T<90.
Conclusion These results suggested that the increasing severity of OSAS induces an increase in setum leptin concentration, but the serum adiponectin levels may be regulated independently of the degree of OSAS, obesity and serum leptin levels in patients with OSAS.

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Objective The aim of the study was to evaluate the effect of valsartan/amlodipine combination on insulin sensitivity in overweight-obese hypertensive patients.
Methods After a 4-week placebo period, 58 overweight-obese (BMI ≥25 kg/m²) patients, with mild to moderate essential hypertension (DBP >95 and <110 mmHg, SBP >140 mmHg) were treated with amlodipine 5 mg od or valsartan 160 mg od or amlodipine 5 mg plus valsartan 160 mg od for 8 weeks according to a randomized, open-label, blinded end-point, cross-over study. At the end of the placebo period and each treatment period, blood pressure (BP) and insulin sensitivity (IS) (by euglycemic hyperinsulinemic clamp technique) were evaluated. IS was expressed as the amount of glucose infused during the last 30 min (glucose infusion rate, GIR) in mg/kg/min.
Results Valsartan/amlodipine combination produced a significantly greater decrease in SBP/DBP values (-22.3/16.7 mmHg, p<0.001 vs baseline) than valsartan (-15.2/11.7 mmHg, p<0.01 vs baseline) and amlodipine monotherapy (-16.1/12.6 mmHg, p<0.01 vs baseline). Both valsartan and amlodipine provided a significant increase in GIR (+1.24 mg/kg/min, p=0.036 vs baseline and +1.02 mg/kg/min, p=0.047, respectively), but such an increase was significantly greater with their combination (+1.82 mg/kg/min, p<0.01 vs baseline). These greater changes in IS were not related to BP changes.
Conclusion Valsartan/amlodipine combination improved IS more than respective monotherapy beyond affording greater BP reductions. This strengthens the rationale to use valsartan/amlodipine combination in the treatment of overweight-obese hypertensives.

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Objective Chronic kidney disease (CKD) is an important worldwide health problem. The incidence of end-stage renal disease (ESRD) is increasing steadily around the world, however few studies have discussed the risk factors for progression in patients with early-stage CKD. Therefore, we designed a retrospective cohort study of patients with early-stage CKD to identify the risk factors influencing the annualized slope of the estimated glomerular filtration rate (eGFR).
Methods and Patients In this longitudinal cohort study, baseline examination was conducted in 2012 outpatients treated at the Kidney Center, Tokyo Women's Medical University. Follow-up examinations were completed in 485 patients with stage 1 and stage 2 CKD within the study period (2002-2007). The conventional risk factors for CKD progression, such as proteinuria, blood pressure, serum triglyceride, serum HDL, fasting plasma glucose, smoking habit, hypertension or treatment with antihypertensive medication and body mass index, were examined. The annualized eGFR slope was calculated at the start and end of the study period. Multivariate analysis was performed to determine the associations of the eGFR slope with the predisposing risk factors.
Results The mean annualized eGFR slope was -1.64 mL/min/1.73 m²/year. Concerning the relationship between etiology and the GFR decreasing slope, IgA nephropathy was defined as the worst (-1.80 mL/min/year) due to the high ratio of proteinuria. Proteinuria (-2.13 mL/min/1.73 m²/year, p=0.005), smoking habit (-2.06 mL/min/1.73 m²/year, p=0.014), low serum HDL (-1.95 mL/min/1.73 m²/year, p=0.035), and hypertension (-1.73 mL/min/1.73 m²/year, p=0.045) were all significantly related to the eGFR slope. The estimated GFR for the highest BMI quartile was significantly higher than that of the eGFR for the lowest BMI.
Conclusion Proteinuria, smoking habit, hypertension and low HDL were clearly related to accelerated disease progression in patients with early-stage CKD. Therefore, aggressive treatment of these risk factors is essential in the early stages of CKD.

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Objective The effect of clinical pathway (CP) care and early switch from intravenous to oral antibiotics therapy on community-acquired pneumonia (CAP) has been well documented. However, limited studies have evaluated the effects of CP on reducing time taken for attaining clinical stability and duration of antibiotics prescriptions. This study was aimed to investigate the use of a CP and its implication for CAP in a community hospital.
Methods We conducted a retrospective cohort study of CAP patients hospitalized between November 2005 and January 2007. The patients were divided into two groups, those for whom CP was adopted and those for whom CP was not adopted on admission. We compared the outcomes of three risk classes assessed using the severity scoring system (A-DROP). CP included switching from an intravenous β-lactam plus a macrolide to an oral respiratory fluoroquinolone, when the patients exhibited risk factors for drug-resistant pneumococci.
Results One hundred thirty-five patients were evaluated, and sixty received CP care. Patients in the CP group had a lower A-DROP score. Although clinical cure proportions were similar, the CP group in the mild and moderate classes (A-DROP score, ≤2) required significantly less time to achieve clinical stability and had a reduced duration of total antibiotics prescriptions, length of hospital stay, and hospital charges. These effects were absent in the severe class.
Conclusion Implementation of this CP would lead to effective care, may serve to reduce time for attaining clinical stability and reduce the use of unnecessary antibiotics without worsening clinical outcomes in mild and moderate CAP.

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Objective To evaluate the affective state biochemically and quantitatively in amyotrophic lateral sclerosis (ALS) patients using salivary chromogranin A (CgA) measurement.
Subjects and Methods Twelve moderate and 12 terminal ALS patients defined using the ALS Health State Scale were studied. The correlation between salivary CgA levels and the 40-item ALS assessment questionnaire (ALSAQ-40) scores was investigated in 12 moderate ALS patients. Moreover, salivary CgA levels in 12 terminal ALS patients, in whom the emotional functioning score could not be assessed, were compared with those in 12 moderate ALS patients, 7 patients with tube-fed vascular dementia, and in 26 healthy volunteers.
Results There were individual differences in salivary CgA levels in spite of similar severity of disease; however, mean salivary CgA levels in terminal ALS patients, in whom the emotional functioning score based on interview could not be assessed, was significantly higher (12.58±2.79 pmol/mL) than in patients with moderate ALS (6.36±1.62 pmol/mL, p<0.05), tube-fed vascular dementia (4.04±2.04 pmol/mL, p<0.01), and healthy volunteers (3.77±1.90 pmol/mL, p<0.01). Moreover, a statistically significant positive correlation was observed between salivary CgA levels and emotional functioning scores on ALSAQ-40 in moderate patients (r=0.892, p<0.01).
Conclusion Salivary CgA may be a useful and quantitative biochemical marker of the affective state, not only in moderate, but also in terminal ALS. Periodic salivary CgA measurements over the long term and/or in various situations could have therapeutic implications for the quality of life of these patients.

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Objective To clarify the incidence and clinical significance of HTLV-I associated myelopathy/tropical spastic paraparesis (HAM/TSP) showing T2 hyperintensity in the spinal cord on magnetic resonance images (MRI).
Patients and Methods We reviewed the spinal cord MRI of 38 HAM/TSP patients and analyzed them in relation to clinical and laboratory findings. Analyzed data were: age at onset, disease duration, disability status, responsiveness to interferon therapy, brain abnormalities on MRI, serum anti-HTLV-I titers, and cerebrospinal fluid (CSF) findings.
Results MRI findings of the spinal cord were classified into 3 types, "normal" (n=22, 57.9%), "atrophy" (n=13, 34.2%) and "T2-hyperintensity" (n=3, 7.9%). Patients in the normal and atrophy types showed slowly progressive paraparesis. Significant differences were not found between the normal and atrophy types in any clinical or laboratory data, including disease duration, disability status and responsiveness to interferon-alpha therapy. Meanwhile, all patients showing T2-hyperintensity had severe paraparesis of a rapid progressive nature, with CSF IgG elevation.
Conclusion HAM/TSP with T2-hyperintensity on spinal MRI shows a rapid progressive clinical course with severe motor impairment. The incidence of this malignant form of HAM/TSP is estimated to be around 7.9%.

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Objective The purpose of the present study was to clarify the olfactory functions of Japanese patients with idiopathic Parkinson's disease (IPD) using the odor stick identification test for Japanese (OSIT-J).
Methods Fifty-four non-demented IPD patients (33 men and 21 women), ranging in age from 43 to 81 years (69.7±8.1 years) and 50 age- and gender-matched healthy controls who reported having no olfactory complaints were enrolled. OSIT-J consisted of 12 odorants familiar to Japanese subjects. Each subject sniffed each odor that was applied to paraffin paper. Next the subject chose 1 of 6 answers: 4 pictures associated with the odors labeled with their names, one of which was correct, and 2 other ones ("unknown" and "not detected").
Results The number of correct answers was significantly lower in the IPD group (4.4±2.7) than in the normal group (8.3±2.2) (p<0.0001). Even in IPD patients who could smell normal strength odors in subjective symptom, the number of correct answers decreased. The number of correct answers was not correlated with motor function, disease duration, or medication.
Conclusion The present study demonstrated that the smell identification ability of Japanese IPD patients was impaired based on the OSIT-J.

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Objective To investigate the relationship between heart rate variability and hypercapnia.
Patients and Methods We measured the coefficient of variation of R-R interval (CVrr) and arterial blood gas pressures in 73 patients with Duchenne muscular dystrophy.
Results CVrr was negatively correlated with arterial partial pressure of carbon dioxide (PaCO₂). In patients whose CVrr was larger than 5%, 84% of them had no hypercapnia while the other 16% had hypercapnia (PaCO₂ >45 mmHg). In contrast, 27% of those with CVrr smaller than 3% had no hypercapnia, 73% had hypercapnia and 47% had severe hypercapnia (PaCO₂ >50 mmHg).
Conclusion We first showed that CVrr was negatively correlated with PaCO₂, and propose that abnormally low CVrr indicates respiratory insufficiency in patients with Duchenne muscular dystrophy.

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A case of 22 mm hypervascular nodule in segment two of the liver but without hepatitis B or C virus infection in a 32-year-old Japanese woman with a history of alcohol abuse is presented. Imaging studies such as contrast-enhanced ultrasound, computed tomography and magnetic resonance imaging showed hypervascularity in the early phase and venous washout in the late phase. Histologically, stellate scar-like fibrous septa, pericellular fibrosis, fatty change, neutrophilic infiltration, slight increase of cell density, and diffuse capillarization of the sinusoids together with small unpaired arteries were observed. The nodule was diagnosed as focal nodular hyperplasia-like lesion in alcoholic liver cirrhosis.

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We report a patient with superior mesenteric venous thrombosis presenting as diabetic ketonuria and bacteremia. The patient was a 65-year-old man with a history of diabetes mellitus, and was admitted to our hospital due to high fever. Tests revealed diabetic ketonuria and Bacteroides fragilis bacteremia. Abdominal computed tomographic scan and Doppler sonography revealed an old thrombus in the superior mesenteric vein with good flow through collateral vessels, causing the patient to have an absence of abdominal symptoms. There was no evidence of hereditary thrombophilia. The thrombus was secondary to a combination of comorbidities, including dehydration, hyperosmolarity, and diabetes mellitus.

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Autoimmune hypercalcemia has been reported in only a few cases, and never in the context of autoimmune polyglandular syndrome.
A patient with type 1, insulin-dependent diabetes mellitus, Graves' disease, and antiparietal cell antibodies presented with persistent hypercalcemia with inappropriate PTH secretion. Other causes of hypercalcemia were excluded.
In this context of two associated organ-specific autoimmune diseases we searched for autoantibodies directed to parathyroid tissue and to calcium-sensing receptor. Anti-parathyroid autoantibodies were detected by indirect immunofluorescence on parathyroid adenomas, and autoantibody against a peptide of the extracellular domain of the calcium-sensing receptor were detected by immunoblotting.
Autoimmune hypercalcemia may be another organ-specific feature of autoimmune polyglandular syndrome.

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We herein report an extremely rare case of a patient with IgD-lambda positive multiple myeloma presenting with myelomatous pleural effusion and ascites. A 58-year-old man visited our hospital with dyspnea as his initial symptom. His chest radiograph findings on admission revealed a left pleural effusion, and later, bilateral involvement. Computed tomography (CT) of the chest showed a paraspinal tumor with extension from the upper mediastinum to the abdomen. The cytological examination demonstrated myeloma cells in the pleural effusion and ascites, and histologically, in the pleura, an abdominal subcutaneous tumor and bone was observed. The pleural effusion was an exudate and slightly bloody. The ADA was 70 IU/L. Pleural effusion accompanying myeloma or primary pleural myeloma is very rare and, furthermore, the extremely rare findings of both myeloma cells in the ascites (although the ascites was mainly caused by liver cirrhosis) and a high ADA activity in the pleural fluid were also observed in this case.

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A 56-year-old man complained of fever, anemia, thrombocytopenia and lymph node swelling. Biopsy of the lymph node demonstrated angioimmunoblastic T cell lymphoma (AITL) with the loss of normal architecture, proliferation of neoplastic T cells, small vessels mixed with eosinophils and plasma cells. Aspiration of bone marrow was dry tap, and biopsy demonstrated myelofibrosis with increased proliferation of reticulin fiber. Markedly elevated plasma levels of transforming growth factor β1 (TGF-β1) and soluble interleukin-2 receptor (sIL-2R) were observed, and that of platelet growth factor (PDGF) AB was slightly elevated. After chemotherapy, remission of lymphoma was achieved. The aspiration of bone marrow became possible, and the level of TGF-β1 and PDGF AB showed normalization; thus, myelofibrosis was reversible.

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We report severe brain calcification in a case of LEOPARD syndrome that has not been reported in the literature. A 53-year-old Japanese man presented with generalized lentigines, arrhythmia, gonadal hypoplasia, endocrine abnormality, mental retardation and skeletal abnormalities, and was consequently diagnosed as LEOPARD syndrome. Brain computed tomography demonstrated surprisingly dense and symmetric calcifications in the cerebellar dentate nuclei, cerebral basal ganglia, thalamus, and cerebral white matter. It may be an incidental idiopathic calcification. Alternatively it may be a rare clinical manifestation of LEOPARD syndrome.

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A 32-year-old man with an atypical form of reversible leukoencephalopathy syndrome (RPLS) caused by thrombotic thrombocytopenic purpura (TTP) is reported. In this particular case, a timely diagnosis of TTP was established primarily on the clinical findings, which led to the early initiation of plasmapheresis and resulted in excellent clinical recovery. The pathophysiological aspects of the relationship between TTP and RPLS are discussed in light of the clinical and radiological features (including diffusion- and perfusion-weighted magnetic resonance imaging studies) of this case. The mechanism for TTP-associated, or TTP-induced, leukoencephalopathy is suggested to be independent of hypertension and vasoconstriction. TTP-associated endothelial injury can play a major role as the inciting mechanism for the development of RPLS.

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Cutaneous ulcers associated with vasculitis are rarely reported in adult-onset dermatomyositis (DM), and are often resistant to treatment, resulting in a poor prognosis. There is no general treatment strategy and the effects of various treatments have never been confirmed histopathologically. A 43-year old man with DM developed refractory multiple cutaneous ulcers which were revealed as vasculitis by skin biopsy. Repeated intravenous cyclophosphamide pulse therapy (IV-CY) without high-dose corticosteroid therapy resulted in complete resolution of the ulcers without adverse effects or severe complications. A repeat biopsy confirmed complete remission of vasculitis. Repeated IV-CY is a useful treatment for induction of clinical remission of DM with cutaneous vasculitis.

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Here, we present the case of an extremely subtle peripheral graft infection caused by Staphylococcus aureus. The lack of local signs and the negativity of all imaging studies, including ^99mTc-HMPAO-Labelled-Leukocyte Scan which is reported to have 100% sensitivity, delayed the diagnosis and therapy, which were both provided by surgery.

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