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Elevated levels of arginine vasopressin (AVP) have been reported to be involved in the pathogenesis of heart failure (HF). Recent evidence has shown the role of copeptin, the C-terminal fragment of pro-AVP, as a biomarker in patients with HF. However, the relevant information is still limited. Therefore, we evaluated 39 Japanese patients admitted for HF between 2013 and 2015 (23 males and 16 females with an average age of 79.2 years). They were treated according to the Japanese acute HF guideline. Plasma copeptin levels were measured on admission and about 1 week later. The median plasma copeptin levels on admission were 0.5 (0.1-50.6) pmol/L, higher than the normal values (0.24 ± 0.06 pmol/L). Despite the similar clinical severity on admission, the patients showed great variability in plasma copeptin levels. They were divided into three groups (13 patients/group) according to plasma copeptin levels on admission: highest (> 30.8 pmol/L), midrange, and lowest (< 0.2 pmol/L) groups. Initial treatment improved HF symptoms in 37 of 39 patients, with the two unresponsive patients in the lowest group. Notably, plasma copeptin responses to initial treatment were different, depending on admission copeptin levels. The initial treatment significantly decreased copeptin levels in the highest group, but increased copeptin levels in the lowest group. By contrast, patients in the midrange group showed no significant changes. Thus, the treatment appears to restore the plasma copeptin levels. In conclusion, HF is a complex syndrome with the differential integration of stimulatory and inhibitory inputs to the AVP/copeptin secretory system.

Although inflammatory markers, such as the white blood cell (WBC) count, erythrocyte sedimentation rate (ESR) and levels of C-reactive protein (CRP) and procalcitonin, are widely used to differentiate causes of fever of unknown origin (FUO), little is known about the usefulness of this approach. We evaluated relationships between the causes of classical FUO and the levels of inflammatory markers.A nationwide retrospective study including 17 hospitals affiliated with the Japanese Society of Hospital General Medicine was conducted.This study included 121 patients ≥18 years old diagnosed with "classical FUO" (axillary temperature ≥38.0°C at least twice over a ≥3-week period without elucidation of the cause on three outpatient visits or during three days of hospitalization) between January and December 2011.The causative disease was infectious diseases in 28 patients (23.1%), non-infectious inflammatory disease (NIID) in 37 patients (30.6%), malignancy in 13 patients (10.7%), other in 15 patients (12.4%) and unknown in 28 patients (23.1%). The rate of malignancy was significantly higher for a WBC count of4,000/μL than for a WBC count of 4,000-8,000/μL (p=0.015). Among the patients with a higher WBC count, the rate of FUO due to NIID tended to be higher and the number of unknown cases tended to be lower. All FUO patients with malignancy showed an ESR of40 mm/h. A normal ESR appeared to constitute powerful evidence for excluding a diagnosis of malignancy. In contrast, the concentrations of both serum CRP and procalcitonin appeared to be unrelated to the causative disease.The present study identified inflammatory markers that should be considered in the differential diagnosis of classical FUO, providing useful information for future diagnosis.

Nicorandil (NCR), a KATP channel opener, has been reported to preserve microvascular integrity in patients with reperfused myocardial infarction. We tested the hypothesis that NCR suppresses myocardial ischemia and reperfusion injury via the attenuation of cytokine production. Forty patients who underwent coronary artery bypass graft surgery were studied. The patients were randomly divided into two groups, i.e., the patients with NCR (4-6 mg/h; N group, n = 20) or without NCR (C group, n = 20). Cardiac surgery was performed under anesthesia using fentanyl and propofol. Blood were sampled at the time of induction of anesthesia, pre-cardiopulmonary bypass, 60 min after aortic occlusion, and 60, 120, and 180 min after declamping the aorta. The activation of NF-kappaB, expression of adhesion molecules, and cytokine production were evaluated in blood samples from the control volunteers by flow cytometric analysis with or without lipopolysaccharide (LPS) stimulation in vitro. Serum IL-6 and IL-8 levels in both groups increased 60 min after declamping the aorta compared with the preoperative value (P < 0.001); the increases of these parameters in N group were lower than those in C group (P < 0.05). Serum creatine kinase with muscle and brain subunits and troponin-T levels increased 60 min after declamping the aorta in two groups (P < 0,001), but the increases of both parameters in N group were lower than those in C group (P < 0.05). NF-kappaB activation, CD11b/CD18 expression, and the production of TNF-alpha, IL-8, and IL-6 in monocytes and granulocytes were inhibited by NCR in vitro. NCR suppressed the increase of inflammatory cytokines such as IL-6 and IL-8 levels, and reduced myocardial reperfusion injury. The inhibition on NF-kappaB activation, adhesion molecule expression, and cytokine production may be one of the important mechanisms of myocardial protection of NCR.

In the dystrophin-mutant mdx mouse, an animal model for Duchenne muscular dystrophy (DMD), damaged skeletal muscles are efficiently regenerated and thus the animals thrive. The phenotypic differences between DMD patients and the mdx mice suggest the existence of factors that modulate the muscle wasting in the mdx mice. To identify these factors, we searched for mRNAs affected by the mdx mutation by using cDNA microarrays with newly established skeletal muscle cell lines from mdx and normal mice. We found that in the mdx muscle cell line, 12 genes, including L-arginine:glycine amidinotransferase and thymosin beta4, are up-regulated, whereas 7 genes, including selenoprotein P and a novel regeneration-associated muscle protease (RAMP), are down-regulated. Northern blot analysis and in situ hybridization revealed that RAMP mRNA is predominantly expressed in normal skeletal muscle and brain, and its production is enhanced in the regenerating area of injured skeletal muscle in mice. RAMP expression was much lower in individual muscle cell lines derived from biopsies of six DMD patients compared to a normal muscle cell line. These results suggest that RAMP may play a role in the regeneration of skeletal muscle and that its down-regulation could be involved in the progression of DMD in humans.

Background The beneficial effect of inhaled nitric oxide (NO) on pulmonary hypertension is well known. However, the indications for NO inhalation therapy for pulmonary hypertension associated with congenital heart lesions are still unclear. The aim of the current study was to seek a measure that would predict the effectiveness of inhaled NO in infants undergoing cardiac surgery. Methods Forty-six infants with pulmonary hypertension were studied. Pulmonary vascular resistance (PVR) measured at the time of cardiac catheterization was used as an indicator and compared with pulmonary arterial pressure/systemic blood pressure ratio (Pp/Ps) at the time of weaning from cardiopulmonary bypass. The effect of 40 ppm of inhaled NO for 15 min was evaluated in patients whose Pp exceeded systemic values. Results Preoperative PVR correlated positively with Pp/Ps at the time of weaning from cardiopulmonary bypass (r2 = 0.86; P < 0.05; n = 46). A Pp/Ps greater than or equal to 1 was not observed in any cases in which the preoperative PVR values were less than 7 Wood units m2; Pp/Ps ratio greater than or equal to 1 occurred in four patients. Each of these had PVR values greater than 7 Wood units m2. Three of these patients who had PVR values in the 7-12 Wood units m2 range were responsive to inhaled NO. The fourth patient, whose PVR value was greater than 15 Wood units m2, was unresponsive. Lung biopsy specimens were obtained in two patients whose preoperative PVR values were greater than 10 Wood units m2. Conclusion Preoperative PVR correlates reasonably well with postbypass Pp/Ps.

Objective Fever of unknown origin (FUO) can be caused by many diseases, and varies depending on region and time period. Research on FUO in Japan has been limited to single medical institution or region, and no nationwide study has been conducted. We identified diseases that should be considered and useful diagnostic testing in patients with FUO. Design A nationwide retrospective study. Setting 17 hospitals affiliated with the Japanese Society of Hospital General Medicine. Participants This study included patients ≥18 years diagnosed with ‘classical fever of unknown origin’ (axillary temperature ≥38°C at least twice over a ≥3-week period without elucidation of a cause at three outpatient visits or during 3 days of hospitalisation) between January and December 2011. Results A total of 121 patients with FUO were enrolled. The median age was 59 years (range 19–94 years). Causative diseases were infectious disease in 28 patients (23.1%), non-infectious inflammatory disease in 37 (30.6%), malignancy in 13 (10.7%), other in 15 (12.4%) and unknown in 28 (23.1%). The median interval from fever onset to evaluation at each hospital was 28 days. The longest time required for diagnosis involved a case of familial Mediterranean fever. Tests performed included blood cultures in 86.8%, serum procalcitonin in 43.8% and positron emission tomography in 29.8% of patients. Conclusions With the widespread use of CT, FUO due to deep-seated abscess or solid tumour is decreasing markedly. Owing to the influence of the ageing population, polymyalgia rheumatica was the most frequent cause (9 patients). Four patients had FUO associated with HIV/AIDS, an important cause of FUO in Japan. In a relatively small number of cases, cause remained unclear. This may have been due to bias inherent in a retrospective study. This study identified diseases that should be considered in the differential diagnosis of FUO.

Many human leukocyte antigen (HLA)-class I (mainly A*0201)-restricted peptide-specific cytotoxic T cells (CTLs) have been derived from peripheral blood lymphocytes (PBLs) of melanoma patients. However, few studies regarding HLA-A*2402-restricted melanoma-associated peptides have been performed, because HLA-A24 is not a common allele in Caucasians. In this study, we investigated the specific CTL-inducing activity of 5 HLA-A*2402-restricted peptides derived from gp100, tyrosinase, MAGE1, MAGE2 and MAGE3. A CTL induction culture was performed using PBLs and cultured dendritic cell (DC) pulsed with HLA-A*2402-restricted melanoma peptide cocktail. The CTLs derived from volunteers killed the A24 peptide-pulsed TISI cells and even HLA-A*2402-positive melanoma cells, but not HLA-A*0201-positive cells. IFN-gamma levels produced by the melanoma patients' CTLs were obviously low in each peptide group compared with those produced by the volunteers' CTLs, which indicated the presence of immunosuppressive factors in metastatic melanoma. These results suggested that polyvalent immunotherapy using multiple epitopes from melanoma antigens might be a better way of improving the efficacy of treatment.