Initial experience in Japan with HeartWare ventricular assist system

We describe the first clinical experiences in Japan with the HeartWare ventricular assist device (HVAD: HeartWare Inc., Miami Lakes, FL, USA) in patients awaiting heart transplantation. Nine patients (6 males, 3 females; mean 33.5 ± 7.8 years; New York Heart Association class III or IV) received the HVAD as a bridge to transplantation between 2011 and 2012. Six had dilated cardiomyopathy, 2 secondary cardiomyopathy, and 1 dilated phase hypertrophic cardiomyopathy. All operations were uneventful, with a mean operation time of 269 ± 77 min and cardiopulmonary bypass time of 121 ± 40 min. One required a temporary right ventricular assist device and was weaned on postoperative day 20, while another required pump exchange due to foreign tissue in the inflow. Mean support duration was 245 ± 162 days (range: 50–535 days) and mean pump blood flow at 1 month postoperatively was 4.8 ± 0.8 l/min. There was no mortality after 30 days, though 1 patient died during support due to cerebral hemorrhage. Presently, the others are waiting for heart transplantation without problems, except 1 who suffered from an active infection. There was no pump mechanical failure in any case. The HeartWare pump enables quick implantation with acceptable morbidity and mortality. Our preliminary results indicate that this left ventricular assist device is safe for circulatory assistance for heart transplant candidates in Japan.     

Preoperative oral rehydration therapy with 2.5 % carbohydrate beverage alleviates insulin action in volunteers

Preoperative carbohydrate loading enhances insulin action by approximately 50 %. In some Japanese hospitals, preoperative oral rehydration therapy is performed for preventing dehydration during surgery. We hypothesized that preoperative oral rehydration therapy with a 2.5 % carbohydrate beverage that is widely used in Japan can enhance insulin action. Therefore, we investigated the effect of this 2.5 % carbohydrate beverage on insulin action in volunteers. Six healthy volunteers participated in this crossover randomized study. The participants were segregated into 2 groups: an oral rehydration therapy with 2.5 % carbohydrate beverage group (group A) and a control group (group B). Subjects in group B were allowed to drink only water from 9 pm the day before the test; conversely, group A fasted from 9 pm onward and drank 500 ml of the beverage containing 2.5 % carbohydrate (OS-1; Otsuka Pharmaceutical Factory, Tokushima, Japan) between 9 and 12 pm and again at 6.30 am. At 8.30 am, a hyperinsulinemic normoglycemic clamp was initiated using an artificial pancreas STG-22 (Nikkiso, Tokyo, Japan). Insulin action was evaluated in both groups using the glucose infusion rate. Blood glucose levels at the initiation of the clamp procedure were similar. However, the glucose infusion rate for group A was significantly higher than that of group B (8.6 ± 1.5 vs. 6.8 ± 2.0 mg/kg/min, p = 0.009). In conclusion, the hyperinsulinemic normoglycemic clamp using an artificial pancreas showed that the administration of a 2.5 % carbohydrate oral rehydration solution for preoperative oral rehydration therapy improves insulin action in volunteers.     

Multi-Step Regulation of Interferon Induction by Hepatitis C Virus

Acute hepatitis C virus (HCV) infection evokes several distinct innate immune responses in host, but the virus usually propagates by circumventing these responses. Although a replication intermediate double-stranded RNA is produced in infected cells, type I interferon (IFN) induction and immediate cell death are largely blocked in infected cells. In vitro studies suggested that type I and III IFNs are mainly produced in HCV-infected hepatocytes if the MAVS pathway is functional, and dysfunction of this pathway may lead to cellular permissiveness to HCV replication and production. Cellular immunity, including natural killer cell activation and antigen-specific CD8 T-cell proliferation, occurs following innate immune activation in response to HCV, but is often ineffective for eradication of HCV. Constitutive dsRNA stimulation differs in output from type I IFN therapy, which has been an authentic therapy for patients with HCV. Host innate immune responses to HCV RNA/proteins may be associated with progressive hepatic fibrosis and carcinogenesis once persistent HCV infection is established in opposition to the IFN system. Hence, innate RNA sensing exerts pivotal functions against HCV genome replication and host pathogenesis through modulation of the IFN system. Molecules participating in the RIG-I and Toll-like receptor 3 pathways are the main targets for HCV, disabling the anti-viral functions of these IFN-inducing molecules. We discuss the mechanisms that abolish type I and type III IFN production in HCV-infected cells, which may contribute to understanding the mechanism of virus persistence and resistance to the IFN therapy.     

Psychosocial factors associated with suicidal ideation in clinical patients with depression

Background

Depression is a major risk factor for suicide, but few studies have examined psychosocial risk factors for suicide in clinical patients with depression. The purpose of this study was to investigate psychosocial factors which could be associated with suicidal ideation in clinical patients with depression including: sick-leave, help-seeking behavior, and reluctance to admit mental health problems.

Methods

A multi-center cross-sectional survey using self-report questionnaire was conducted at 54 outpatient psychiatric clinics in Tokyo in 2012. Adult outpatients who were diagnosed by psychiatrists as mood disorders (F30–F39) in the International Classification of Diseases-10 (ICD-10) were included in the study. Those who met the criteria for current hypomanic or manic episode were excluded from the study.

Results

A total of 189 patients with depression participated in the survey. Multivariable logistic regression analysis showed that taking sick-leave and having sought help from family were associated with decreased odds of current suicidal ideation. Moderate or more severe depression was associated with increased odds of suicidal ideation, and reluctance to admit own mental health problem tended to increase odds of suicidal ideation.

Limitations

Living status and suicidal ideation before consultation with psychiatrist were not investigated. Severity of suicidal ideation and comorbid psychiatric disorders were not assessed.

Conclusions

Importance of treatment of more severe depression for suicide prevention was confirmed. Industrial health staffs should consider the possibility of positive effect of taking sick-leave when they see employees with depression. Promoting help-seeking for family and reducing stigma of mental illness may be effective for suicide prevention.     

Increased CD45RO CD62L CD4 T-cell subpopulation responsible for Th2 response in Kimura’s disease

Kimura’s disease is characterized by subcutaneous masses, eosinophilia, and markedly elevated serum immunoglobulin E, suggesting that T helper (Th)2 cells may play a role in the pathogenesis. We investigated Th2 cytokine synthesis by mononuclear cells and possible Th1/Th2 subpopulations in Kimura’s disease. Peripheral blood samples were obtained from seven patients with Kimura’s disease and CD4⁺ T-cell subpopulations separated by CD45RO and CD62L were isolated. Purified cells were stimulated with PHA or anti-CD3 mAb, and the cytokine levels were measured by Cytometric Bead Array kit. Peripheral blood mononuclear cells in the majority of the patients produced Th2 cytokines such as interleukin (IL)-3, IL-4, IL-5, IL-13 or GM-CSF higher than those of controls. The ratio of CD45RO⁺ CD62L⁺ cells in CD4⁺ T cells was increased in six out of seven patients compared to age-matched controls. Especially, patient 1 had remarkably increased levels of CD45RO⁺ CD62L⁺ population in CD4⁺ T cells. In addition, IL-4 production levels by CD45RO⁺ CD62L⁺ CD4⁺ T cells of patients 1 and 2 were higher than those of their CD45RO⁺ CD62L⁻ CD4⁺ T cells, in the same manner as those by a normal control. Taken together, the synthesis of Th2 cytokines and CD62L-positive subpopulation in CD45RO⁺ CD4⁺ T cells, which may represent characteristics of Th2, are increased in patients with Kimura’s disease, suggesting that deviation to Th2 may involve in pathogenesis of the disease.     

Longest neurite‐specific activation of Rap1B in hippocampal neurons contributes to polarity formation through RalA and Nore1A in addition to PI3‐kinase

In a developing nervous system, axon‐dendrite formation is instructed by extrinsic cues, and the mechanism whereby a developing neuron interprets these cues using intracellular signaling is particularly important. Studies using dissociated hippocampal neurons have identified many signaling pathways underlying neuronal polarization. Among the components of these pathways, Rap1B is essential for axon specification in hippocampal cultures. However, spatiotemporal regulation of Rap1B activity in polarizing neurons and how it affects neuronal polarization remain unclear. Herein, we investigated spatiotemporal activity‐change of Rap1B and its target molecules in hippocampal neurons. FRET imaging showed that specific activation of Rap1B was observed at the tip of a future axon. To dissect downstream signaling, we used three effector mutants of Rap1B. Expression of Rap1B‐G12V/E37G and G12V/Y40C mutants resulted in supernumerary axons. The targets of Rap1B‐G12V/E37G were RalA and Nore1A, whereas Rap1B‐G12V/Y40C activated PI3‐kinase. RalA was activated in the tip of stage 3 axons, and RalA‐S28N expression reduced the fraction of neurons with supernumerary axons induced by Rap1B‐G12V/E37G. Furthermore, Nore1A depletion reduced the number of cells without axons. These results indicate that specific activation of Rap1B contributes to neuronal polarization via interaction with RalA and Nore1A in addition to PI3‐kinase.     

Relationship between Plasma Fibrinogen Levels and Pulmonary Function in the Japanese Population: The Takahata Study

Background:Plasma fibrinogen is considered a biomarker of respiratory disease, owing to the relationship between plasma fibrinogen and pulmonary function established in Western populations. However, such a relationship has not yet been confirmed in an Asian population. We assessed this relationship in the general Japanese population.Methods:Totally, 3,257 men and women aged ≥40 years who participated in a community-based annual health checkup in Takahata, Japan, from 2004 to 2006, underwent spirometry, and their plasma fibrinogen levels were determined.Results:We found an inverse relationship between spirometric measures (percent predicted forced vital capacity [%FVC] and forced expiratory volume in 1s [%FEV₁], and FEV₁/FVC) and plasma fibrinogen levels in men, but not in women. The plasma fibrinogen levels were significantly higher in subjects with restrictive, obstructive, and mixed ventilatory disorders than in those with normal spirometry results. Multiple linear regression analysis revealed that in men, plasma fibrinogen levels were predictive for %FVC and %FEV₁ (independent of age, body mass index, and cigarette smoking) but not for FEV₁/FVC.Conclusions:Plasma fibrinogen was significantly associated with pulmonary function in Japanese men, and as such, plasma fibrinogen might be a potent biomarker for pulmonary dysfunction in men.