Tetsunori Saikawa

Plasma HHV-6 viral load-guided preemptive therapy against HHV-6 encephalopathy after allogeneic stem cell transplantation: a prospective evaluation

Human herpesvirus 6 (HHV-6) causes life-threatening encephalopathy in recipients of allogeneic SCT, but no consensus has been reached regarding appropriate preventive methods. This study evaluated a plasma HHV-6 viral load-guided preemptive approach against HHV-6-associated encephalopathy. Plasma real-time PCR assay was performed once a week. Among 29 patients, 19 developed positive plasma HHV-6 DNA. Median maximum plasma HHV-6 DNA was 4593.5 copies/ml plasma (range, 150.0–127 891.0 copies/ml plasma). In one of eight events with low-level HHV-6 DNA (defined as <1000 copies/ml plasma) and four of seven events with mid-level HHV-6 DNA (1000–9999.5 copies/ml plasma), HHV-6 loads in plasma subsequently continued increasing. Ganciclovir was administered against six of nine patients with high-level HHV-6 DNA (⩾10 000 copies/ml plasma). High-level HHV-6 DNA resolved similarly in both groups with or without ganciclovir therapy. Among the nine patients with high-level HHV-6 DNA two developed encephalopathy. As encephalopathy developed before the detection of high-level HHV-6 DNA in plasma, these two patients had not received preemptive ganciclovir therapy. In conclusion, our preemptive approach against HHV-6-associated encephalopathy cannot prevent all cases of HHV-6 encephalopathy in SCT recipients due to the dynamic kinetics of plasma HHV-6 viral load.

Correlations of HHV-6 viral load and plasma IL-6 concentration with HHV-6 encephalitis in allogeneic stem cell transplant recipients

This study investigated factors associated with the development of human herpesvirus (HHV)-6 encephalitis. Among 111 enrolled subjects, 12 patients developed central nervous system (CNS) dysfunction. CNS dysfunction in four patients was found to have no association with HHV-6. The remaining eight patients displayed HHV-6 encephalitis (n=3), limbic encephalitis (HHV-6 DNA in cerebrospinal fluid was not examined; n=3) or CNS dysfunction because of an unidentified cause (n=2). Real-time PCR showed CNS dysfunction in the latter eight patients, which developed concomitant with the appearance of high plasma levels of HHV-6 DNA (⩾104 copies/ml). Overall, eight of the 24 patients with high-level HHV-6 DNA developed CNS dysfunction, whereas no patients developed CNS dysfunction potentially associated with HHV-6 infection if peak HHV-6 DNA was <104 copies/ml. We next analyzed plasma concentrations of IL-6, IL-10 and tumor necrosis factor-α among patients who displayed high-level plasma HHV-6 DNA and found elevated IL-6 concentrations preceding HHV-6 infection in patients who developed CNS dysfunction. (Mean±s.d.: 865.7±1036.3 pg/ml in patients with CNS dysfunction; 56.5±192.9 pg/ml in others; P=0.01). These results suggest that high-level HHV-6 load is necessary for the development of HHV-6 encephalitis, and systemic inflammatory conditions before HHV-6 infection form the preparatory conditions for progression to encephalopathy.

Recombinant thrombomodulin prevents heatstroke by inhibition of high-mobility group box 1 protein in sera of rats.

Heatstroke, a severe inflammatory response disease, is a medical emergency characterized by high body temperature. The protein C anticoagulant system inhibits inflammation resulting from various causes. Thrombomodulin (TM), a widely expressed glycoprotein originally identified in vascular endothelium, is an important cofactor in the protein C anticoagulant system. We tested the hypothesis that TM could prevent acute inflammation induced by heat stress in a rodent model. Male Wistar rats received a bolus of 1 mg · kg−1 of body weight of TM or saline injected into the tail vein, followed by heat-stress treatment (exposure to 42°C for 30 min). Serum concentrations of cytokines (IL-1&bgr;, IL-6, and TNF-&agr;), NO, and high-mobility group box 1 (HMGB1) protein were measured at various time points after treatment. We observed a decrease in the levels of cytokines and HMGB1 protein in sera of TM-treated animals over time. Inhibition of NO overproduction by recombinant TM was observed during heat stress-induced inflammation. Because of the decline in inflammatory marker levels, TM ameliorated injury to various organs in the rat model of heat stress-induced acute inflammation. As TM exhibited a strong anti-inflammatory effect in a rat model of acute inflammation induced by heat stress, TM represents a potential therapeutic for heatstroke prevention or management in patients.

Abdominal visceral fat accumulation is associated with hippocampus volume in non-dementia patients with type 2 diabetes mellitus

Obesity is associated with cognitive dysfunction, for which changes in the hippocampus plausibly play a pivotal role. We tested the hypothesis that an elevated level of visceral fat accumulation (VFA) correlates with hippocampus volume and insulin resistance in non-dementia patients with type 2 diabetes. Subjects included 48 non-dementia patients with type 2 diabetes, who were divided into two groups, high VFA group (mean+/-standard deviation: age=65+/-6 years, n=30) and normal VFA group (65+/-5 years, n=18). Hippocampus volume has been quantitated with computer-assisted analysis using a magnetic resonance imaging (MRI) voxel-based specific regional analysis system developed for the study of Alzheimers disease (VSRAD), which yields a Z-score as the end point for assessment of hippocampal volume. The Z-score was higher in the high VFA group than in the normal VFA group (p<0.0001). The fasting plasma glucose (p<0.05) and insulin concentrations (p<0.0001) and the homeostasis model assessment (HOMA) index (p<0.0001) were higher in the high VFA group than in the normal VFA group. Multiple regression analysis showed that VFA levels were independently predicted by Z-score and HOMA index. Our results indicate that the elevated level of VFA in Japanese non-dementia patients with type 2 diabetes is characterized by increased hippocampus volume and insulin resistance, and that the Z-score and HOMA index are independent predictors of VFA.

Classification and assessment of computerized diagnostic criteria for Brugada-type electrocardiograms

BACKGROUND Although a Brugada-type electrocardiogram (ECG) is occasionally detected in mass health screening examinations in apparently healthy individuals, the automatic computerized diagnostic criteria for Brugada-type ECGs have not been established. OBJECTIVE This study was performed to establish the criteria for the computerized diagnosis of Brugada-type ECGs and to evaluate their diagnostic accuracy. METHODS We examined the ECG parameters in leads V1 to V3 in patients with Brugada syndrome and cases with right bundle branch block. Based on the above parameters, we classified the ECGs into 3 types of Brugada-type ECGs, and the conditions for defining each type were explored as the diagnostic criteria. The diagnostic effectiveness of the proposed criteria was assessed using 548 ECGs from 49 cases with Brugada-type ECGs and the recordings from 192,673 cases (36,674 adults and 155,999 school children) obtained from their annual health examinations. RESULTS The Brugada-type ST-segment elevation in V1 to V3 was classified into 3 types, types 1, 2/3, and a suggestive Brugada ECG (type S). The automatic diagnostic criteria for each type were established by the J-point amplitude, ST-segment elevation with its amplitude and configuration, as well as the T-wave morphology in leads V1 to V3. CONCLUSION The proposed criteria demonstrated a reasonable accuracy (type 1: 91.9%, type 2/3: 86.2%, type S: 76.2%) for diagnosing Brugada-type ECG in comparison to the macroscopic diagnosis by experienced observers. Moreover, the automatic criteria had a comparable detection rate (0.6% in adults, 0.16% in children) of Brugada-type ECGs to the macroscopic inspection in the health screening examinations.

Diabetic retinopathy is associated with visceral fat accumulation in Japanese type 2 diabetes mellitus patients.

The presence of diabetic retinopathy (DR) and increased of visceral fat accumulation (VFA) are associated with high mortality in type 2 diabetes mellitus patients. This preliminary study was therefore designed to test the hypothesis that DR is associated with insulin resistance and VFA in type 2 diabetes mellitus patients without insulin treatment. A total of 102 type 2 diabetes mellitus patients were divided into 2 groups: DR group (age, 60 +/- 6 years [mean +/- SD]; n = 31) and no diabetic retinopathy (NDR) group (59 +/- 5 years, n = 71). The level of blood glucose was assessed by fasting plasma glucose, fasting immunoreactive insulin, homeostasis model assessment index, and hemoglobin A(1c). The fat distribution was evaluated by measuring the VFA by abdominal computed tomography at the umbilical level. The body mass index and waist circumference were higher in the DR group than in the NDR group (P < .001 and P < .0005, respectively). Plasma levels of triglyceride were higher, whereas high-density lipoprotein cholesterol was lower, in the DR group than in the NDR group (P < .005 and P < .0001, respectively). Fasting plasma glucose (P < .0005), insulin concentrations (P < .0001), homeostasis model assessment index (P < .0001), and VFA (P < .0001) levels were higher in the DR group than in the NDR group. Multivariate logistic analysis revealed that DR was independently predicted by high VFA and insulin resistance. The results of this preliminary study indicate that the presence of DR was associated with high VFA and insulin resistance in Japanese patients with type 2 diabetes mellitus.

High-glucose condition reduces cardioprotective effects of insulin against mechanical stress-induced cell injury

AIMS Mechanical stress induces cardiomyocyte injury and contributes to the progression of heart failure in patients with hypertension. In this study, we investigated whether insulin exerts cardioprotective effects against mechanical stretching-induced cell injury, and whether the protective effect is influenced by high-glucose condition. MAIN METHODS Cultured neonatal rat cardiomyocytes were plated on silicone chambers, and the cells were mechanically stretched by 15% to induce cell injury. KEY FINDINGS Mechanical stretching increased reactive oxygen species (ROS) and decreased mitochondrial inner membrane potential (DeltaPsi(m)), eventually leading to cell death by apoptosis and necrosis. Insulin activated the phosphoinositide 3 (PI3) kinase/Akt pathway and reduced apoptosis and necrosis by suppressing ROS increase and preserving DeltaPsi(m). However, high-glucose condition attenuated the insulin-induced Akt phosphorylation and cardioprotection. To investigate the mechanisms that attenuated the effects of insulin in high-glucose condition, we examined the expression of tensin homologue deleted on chromosome 10 (PTEN), which is a negative regulator of the PI3 kinase/Akt pathway. The expressions of PTEN and phosphorylated PTEN were significantly decreased by insulin, and those effects were attenuated in high-glucose condition. SIGNIFICANCE The present results suggest that insulin prevents mechanical stress-induced cell injury which otherwise lead to heart failure. Furthermore, we found that high-glucose condition prevented the decrease in PTEN expression and the cardioprotective effects induced by insulin.

New lipoic acid derivative drug sodium zinc dihydrolipoylhistidinate prevents cardiac dysfunction in an isolated perfused rat heart model

Objective:Myocardial ischemia/reperfusion injury is a life-limiting condition. Reactive oxygen species are released upon reperfusion, resulting in damage to myocardial cells. Accordingly, antioxidant drugs have been shown to protect the myocardium against ischemia/reperfusion injury. The purpose of the present study was to determine the cardioprotective effects of the new lipoic acid-derivative drug sodium zinc dihydrolipoylhistidinate in a global ischemia isolated perfused rat heart model. Design:Animals were randomly divided into five groups: 1) normal group, 2) control ischemia/reperfusion group, 3) high-dose sodium zinc dihydrolipoylhistidinate (1 ng/mL) plus ischemia/reperfusion group, 4) medium-dose sodium zinc dihydrolipoylhistidinate (0.1 ng/mL) plus ischemia/reperfusion group, or 5) low-dose sodium zinc dihydrolipoylhistidinate (0.01 ng/mL) plus ischemia/reperfusion group. Setting:University medical center research laboratory. Subjects:Male Sprague-Dawley rats weighing 250–300 g. Measurements and Main Results:Hearts underwent ischemia/reperfusion after isolation with or without sodium zinc dihydrolipoylhistidinate treatment. We then conducted cardiac histopathology and transmission electron microscopy analyses and assessed cardiac function. In addition, we examined the effects of sodium zinc dihydrolipoylhistidinate on ischemia/reperfusion-induced mitochondrial dysfunction. We found that cardiac dysfunction and mitochondrial damage were significantly reduced after reperfusion by sodium zinc dihydrolipoylhistidinate treatment. However, only rats treated with high-dose sodium zinc dihydrolipoylhistidinate showed improved cardiac function. Furthermore, treatment with sodium zinc dihydrolipoylhistidinate significantly improved mitochondrial function in vitro. Conclusions:These findings suggest that sodium zinc dihydrolipoylhistidinate attenuates ischemia/reperfusion-induced myocardial dysfunction in rats. Furthermore, sodium zinc dihydrolipoylhistidinate exerted cardioprotective effects via preservation of mitochondrial function. Taken together, our results strongly support the potential therapeutic role of sodium zinc dihydrolipoylhistidinate in the treatment of ischemia/reperfusion injury.

Is the reno-protective effect of valsartan dose dependent? A comparative study of 80 and 160 mg day −1

Whether the reno-protective effect of angiotensin receptor blockers is dose dependent is unknown for the Japanese population. We sought to elucidate the dose-dependent reno-protective effects of valsartan in Japanese hypertensive patients with albuminuria. This was a multi-center, open-label, parallel-group trial. A total of 181 patients were randomized to receive either 80 (n=89) or 160 mg day−1 (n=92) of valsartan for 24 weeks. Then, the effects on blood pressure, urinary albumin excretion (UAE), type IV collagen and β2-microglobulin (β2MG) were determined. Systolic and diastolic blood pressures decreased substantially by almost the same extent in the low-dose and high-dose groups, showing no inter-group difference during the treatment. The UAE value decreased significantly by 35% in both groups. Urinary excretion of β2MG was significantly decreased in the high-dose group (17%), but not in the low-dose group (13%), although the decrease was not significantly different between the two groups (P=0.74). Urinary excretion of type IV collagen decreased non-significantly by 10% in the low-dose group and by 8% in the high-dose group, showing no significant inter-group difference (P=0.78). Low (80 mg day−1) and high (160 mg day−1) doses of valsartan showed a similar effect of lowering blood pressure. The high dose of valsartan resulted in a slightly greater decrease in urinary β2MG, but it was inconclusive whether the high dose was more reno-protective as compared with the low dose.