Impact of Preoperative Environmental Enrichment on Prevention of Development of Cognitive Impairment following Abdominal Surgery in a Rat Model.

BACKGROUND: Sustained neuroinflammation may contribute to the pathogenesis of postoperative cognitive dysfunction (POCD). Here, the authors evaluated the preventive effect of preoperative environmental enrichment (PEE) on the development of neuroinflammation and concomitant POCD in a rat abdominal surgery model. METHODS: Young and aged rats were assigned to one of four groups using a 2 × 2 experimental design: PEE versus sedentary condition for 14 days, by abdominal surgery versus anesthesia alone (n = 8 in each group). After a 7-day postsurgical recovery period, cognitive function was assessed using a novel object recognition test, followed by measurement of hippocampal levels of proinflammatory cytokines. Under identical conditions, microglia were isolated from the hippocampus for assessment of cytokine response to lipopolysaccharide. RESULTS: In the sedentary group, aged, but not young, rats receiving surgery showed memory deficits (novel object preference during testing phase of 54.6 ± 7.8% vs. 76.9 ± 11.3% in nonsurgery group, P < 0.05) and increased hippocampal levels of cytokines compared with nonsurgical rats. PEE had no effects on novel object preference in nonsurgery animals (78.6 ± 10.7%), whereas it attenuated surgery-induced impairment of novel object preference (70.9 ± 15.0%, P < 0.05 vs. sedentary/surgery group) as well as increase of cytokine levels in hippocampus. Furthermore, upon ex vivo stimulation with lipopolysaccharide, cytokines release from hippocampal microglia isolated from aged rats before intervention was significantly higher in comparison with young rats. PEE resulted in reduction of these age-related microglial phenotypic changes. CONCLUSIONS: PEE could prevent the development of neuroinflammation and related POCD in aged rats by reversion of a proinflammatory phenotype of hippocampal microglia.

Differentiation of infiltrative cardiomyopathy from hypertrophic cardiomyopathy using high-sensitivity cardiac troponin T: a case-control study.

BACKGROUND: Because infiltrative cardiomyopathy and hypertrophic cardiomyopathy (HCM) share clinical and hemodynamic features of left ventricular (LV) hypertrophy and abnormal diastolic function, it is often difficult to distinguish these entities. METHODS: We investigated the potential role of high-sensitivity cardiac troponin T (hs-cTnT) for differentiation of infiltrative cardiomyopathy from HCM. RESULTS: The study group consisted of 46 consecutive patients with infiltrative cardiomyopathies or HCM in whom sarcomere protein gene mutations were identified at Kochi Medical School Hospital; of these, there were 11 patients with infiltrative cardiomyopathy (cardiac amyloidosis in 8 patients and Fabry disease in 3 patients) and 35 HCM patients. Serum hs-cTnT level was significantly higher in patients who had infiltrative cardiomyopathy than in those who had HCM (0.083 ± 0.057 ng/ml versus 0.027 ± 0.034 ng/ml, p < 0.001), whereas brain natriuretic peptide levels did not differ between the two groups. In two age-matched the 2 cohorts (patients evaluated at > 40 years at age), hs-cTnT level, maximum LV wall thickness, posterior wall thickness, peak early (E) transmitral filling velocity, peak early diastolic (Ea) velocity of tissue Doppler imaging at the lateral corner and E/Ea ratios at both the septal and lateral corners were significantly different between the two groups. As for diagnostic accuracy to differentiate the two groups by using receiver operating characteristic analysis, hs-cTnT was the highest value of area under the curve (0.939) and E/Ea (lateral) was second highest value (0.914). CONCLUSIONS: Serum hs-cTnT is a helpful diagnostic indicator for accurate differentiation between infiltrative cardiomyopathy and HCM.

Thromboembolic events in paroxysmal vs. permanent non-valvular atrial fibrillation. Subanalysis of the J-RHYTHM Registry.

BACKGROUND: It is disputed whether the risk of cardiogenic embolism varies with type of atrial fibrillation (AF). Although several studies have found that the risk of cardiogenic embolism was similar among paroxysmal and persistent/permanent AF, a few studies have found that patients with paroxysmal AF had a lower rate of stroke and systemic embolism than those with persistent/permanent AF. In the present study, post-hoc analysis of the J-RHYTHM Registry was done to compare the risk of thromboembolic events among 3 types of non-valvular AF (NVAF). METHODS AND RESULTS:A total of 7,406 NVAF patients were followed up prospectively for 2 years. At baseline, warfarin was used for 78.6%, 90.0%, and 91.8% of patients with paroxysmal, persistent, and permanent AF, respectively. There were 126 thromboembolic events during the follow-up period. The crude event rate was 2-fold higher among the patients with permanent NVAF (2.29%) than among those with paroxysmal (1.16%) or persistent (1.20%) NVAF (P=0.001). After adjusting for warfarin use and CHA2DS2-VASc score components, however, the hazard ratio for thromboembolism did not differ between paroxysmal (reference) and permanent NVAF (1.007; 95% confidence interval: 0.955-1.061). CONCLUSIONS: The crude rate of thromboembolic events was higher in permanent NVAF than in paroxysmal NVAF, but after adjusting for warfarin use and CHA2DS2-VASc score components, paroxysmal and permanent NVAF patients had similar risk of thromboembolism.

Effects of ketoprofen for prevention of postoperative cognitive dysfunction in aged rats.

Postoperative cognitive dysfunction is a common geriatric complication that may be associated with increased mortality. Here, we investigated the effects of postoperative analgesia with ketoprofen on cognitive functions in aged animals and compared its effectiveness to morphine. Rats were randomly allocated to one of four groups: isoflurane anesthesia without surgery (group C), isoflurane anesthesia with laparotomy (group IL), and isoflurane anesthesia with laparotomy plus postoperative analgesia with ketoprofen or morphine. There was no difference in postoperative locomotor activity among groups. In group IL, postoperative pain levels assessed by the Rat Grimace Scale significantly increased until 8 h after surgery, which was similarly inhibited by both ketoprofen and morphine. Cognitive function was assessed using radial arm maze testing for 12 consecutive days from postoperative day 3. Results showed that the number of memory errors in group IL were significantly higher than those in goup C. However, both ketoprofen and morphine could attenuate the increase in memory errors following surgery to a similar degree. Conversely, ketoprofen showed no effect on cognitive function in the nonsurgical rats that did not experience pain. Our findings suggest that postoperative analgesia with ketoprofen can prevent the development of surgery-associated memory deficits via its pain-relieving effects.

Target international normalized ratio values for preventing thromboembolic and hemorrhagic events in Japanese patients with non-valvular atrial fibrillation: results of the J-RHYTHM Registry.

BACKGROUND: Target anticoagulation levels for warfarin in Japanese patients with non-valvular atrial fibrillation (NVAF) are unclear. METHODS AND RESULTS: Of 7,527 patients with NVAF, 1,002 did not receive warfarin (non-warfarin group), and the remaining patients receiving warfarin were divided into 5 groups based on their baseline international normalized ratio (INR) of prothrombin time (≤1.59, 1.6-1.99, 2.0-2.59, 2.6-2.99, and ≥3.0). Patients were followed-up prospectively for 2 years. Primary endpoints were thromboembolic events (cerebral infarction, transient ischemic attack, and systemic embolism), and major hemorrhage requiring hospital admission. During the follow-up period, thromboembolic events occurred in 3.0% of non-warfarin group, but at lower frequencies in the warfarin groups (2.0, 1.3, 1.5, 0.6, and 1.8%/2 years for INR values of ≤1.59, 1.6-1.99, 2.0-2.59, 2.6-2.99, and ≥3.0, respectively; P=0.0059). Major hemorrhage occurred more frequently in warfarin groups (1.5, 1.8, 2.4, 3.3, and 4.1% for INR values ≤1.59, 1.6-1.99, 2.0-2.59, 2.6-2.99, and ≥3.0, respectively; P=0.0041) than in non-warfarin group (0.8%/2 years). These trends were maintained when the analyses were confined to patients aged ≥70 years. CONCLUSIONS: An INR of 1.6-2.6 is safe and effective at preventing thromboembolic events in patients with NVAF, particularly patients aged ≥70 years. An INR of 2.6-2.99 is also effective, but associated with a slightly increased risk in major hemorrhage. (UMIN Clinical Trials Registry UMIN000001569)

Evaluation of two- and three-dimensional visualization for endoscopic endonasal surgery using a novel stereoendoscopic system in a novice: a comparison on a dry laboratory model.

BACKGROUND: Three-dimensional (3-D) stereoscopic vision is theoretically superior to two-dimensional (2-D) vision in endoscopic endonasal surgery. However, only few reports have quantitatively compared endoscopic performance under the two visual conditions. We introduced a newly designed stereoendoscopic system with a "dual-lens and single camera" for endoscopic endonasal surgery and objectively compared the performances under 3-D and high-definition 2-D visualizations on a dry laboratory model. METHODS: Thirty subjects without experience performing endoscopic surgery, computer-simulated training or any 3-D video system were recruited and divided into two groups (Group A and Group B) for performing two different tasks. The novel 4.7-mm-diameter stereoendoscope provided high-definition (HD) images. In Task 1, Group A started the task under the 3-D condition followed by the 2-D condition, and Group B vice versa. In Task 2, Group A started the task under the 2-D condition followed by the 3-D condition, and Group B vice versa. The performance accuracy and speed under the two visual conditions were analyzed. RESULTS: Significant improvement in performance accuracy and speed was seen under 3-D conditions in the both "3-D first" and "2-D first" subgroups during both tasks (P < .001). Regardless of order, the inaccuracy rate and performance time under 3-D conditions was significantly lower than that under 2-D conditions in each subject. CONCLUSIONS: We demonstrated the advantage of 3-D visualization over 2-D visualization for inexperienced subjects. Further quantitative clinical studies are required to confirm whether stereoendoscopy actually provides benefits in clinical settings.

Prognostic significance of smoking in patients with acute ischemic stroke within 3 months of onset.

BACKGROUND: Various factors that have been implicated in recovery after the acute phase of stroke have not been well evaluated. METHODS: To identify prognostic factors affecting outcomes at 90 days after stroke from the viewpoint of recovery patterns, we enrolled 660 patients from the Edaravone and Argatroban Stroke Therapy for Acute Ischemic Stroke study database. Fourteen groups of patients were identified based on an analysis of their recovery patterns according to changes in their National Institutes of Health Stroke Scale scores during the first 21 days. These groups were then divided into 2 groups: favorable recovery trend (patterns 1-3; n = 486) and poor recovery trend (patterns 4-14; n = 174). Patterns with >80% of the patients experiencing a favorable outcome (National Institutes of Health Stroke Scale score of ≤ 4 at 90 days) were defined as the favorable recovery trend group, whereas patterns that included ≤ 80% favorable outcomes were defined as the poor recovery trend group. RESULTS: Using the poor recovery trend group, logistic regression analysis found that after controlling for covariates, lower scores at admission, fewer ischemic lesions, and nonsmoking were significant prognostic factors for a favorable outcome at 90 days. CONCLUSIONS: Based on a detailed analysis of the relationship between recovery patterns after stroke and clinical outcomes in the chronic stage of stroke, smoking cessation may improve the prognosis of patients after stroke.

Flat and roll-type translucent anodic porous alumina molds anodized in oxalic acid for UV nanoimprint lithography.

There is much interest in UV nanoimprinting as a fabrication method for various functional devices because of its suitability for efficient fine patterning. To form patterns on opaque substrates by UV nanoimprinting, it is essential to use molds through which UV light can pass. In this study, translucent anodic porous alumina (APA) molds for UV nanoimprinting were fabricated by the anodization of an Al substrate. To fabricate a translucent APA mold, an ordered APA film used as a mold for UV nanoimprinting was formed on the surface side of the Al substrate, and then anodization was continued from the back surface of the Al substrate to increase its transparency in the UV spectral range. A gradient change of Al thickness is necessary for the production of a large-area translucent mold, since it lowers the thickness of opaque defects remaining in the mold. The resulting translucent mold was effective for UV nanoimprinting to prepare ordered polymer nanopillar arrays on the surfaces of opaque substrates because the transmittance of the resulting translucent APA mold was 40% at a wavelength of 365 nm, which was confirmed to be sufficiently translucent to polymerize the photocurable monomer used in this study. In addition, it was possible to fabricate roll-type translucent APA molds by using Al pipes as a starting material. A seamless ordered nanopillar array can be effectively formed on a substrate by continuous UV nanoimprinting using the resulting roll-type translucent APA molds. Ordered nanopillar arrays formed on opaque substrates by UV nanoimprinting using translucent APA molds have various potential applications, such as those for forming antireflective and water-repellent surfaces.

Risk score for predicting recurrence in patients with ischemic stroke: the Fukuoka stroke risk score for Japanese.

BACKGROUND: Currently, there are only a few risk scores to predict long-term recurrence of ischemic stroke and no risk score has been developed for the Asian population. The aim of the present study was to develop a new risk score to predict 1-year recurrence in Japanese patients with ischemic stroke and compare it with the other ones. METHODS: Data used in this analysis were extracted from the Fukuoka stroke registry (FSR) database, including 3,067 Japanese patients who experienced ischemic stroke. FSR is a multicenter, hospital-based, prospective registry of Japanese patients with acute stroke. Associations between potential clinical variables that could be involved in the increase of risk and recurrence of ischemic stroke within 1 year after initial stroke onset were evaluated using univariate and multivariate analyses. To calculate risk scores, weighted points proportionally based on standardized coefficient values were assigned to variables that were identified to be significant risks for recurrence by multivariate analysis. The Hosmer-Lemeshow goodness-of-fit test was used to test agreement between a predicted outcome using a model and an actual observed outcome. Kaplan-Meier analysis was used to estimate average cumulative recurrence rates within three risk groups. Intergroup comparisons in recurrence rate among the risk groups were performed using a log-rank test. RESULTS: Univariate and multivariate analyses identified nine significant predictors for 1-year recurrence, to which we assigned the following points: age (65-74 years, 1 point; ≥75 years, 2 points), hypertension (1 point), diabetes mellitus (1 point), smoker (1 point), atrial fibrillation (1 point), cardiac diseases (1 point), chronic kidney disease (1 point), nonlacunar stroke (1 point), and previous ischemic stroke (2 points). The Hosmer-Lemeshow goodness-of-fit test demonstrated good agreement between the observed and predicted recurrence rate (χ(2) = 2.30, p = 0.97). The ROC curve for the risk score models showed acceptable discriminant power with a C-statistic of 0.636 (95% confidence interval: 0.573-0.698). Trends toward increased risk of recurrence with higher scores were observed. The 1-year recurrence rates were 2.93, 5.83 and 7.96% in low- (≤3 points), intermediate (4-5 points), and high-risk groups (≥6 points), respectively. Kaplan-Meier curves with log-rank test showed a significant difference in recurrence among the three risk groups (p < 0.0001). CONCLUSIONS: A new risk score was developed and successfully validated. Our results suggest that this simple risk score enables clinicians to assess 1-year recurrence risk in Japanese patients with ischemic stroke.

Influences of donepezil on cardiovascular system--possible therapeutic benefits for heart failure--donepezil cardiac test registry (DOCTER) study.

To study prospectively influences of donepezil, an acetylcholinesterase inhibitor against Alzheimer disease, on cardiovascular system, we evaluated cardiovascular changes occurring during new initialized treatment with donepezil in 49 dementia patients over 6 months. No patient suffered from cardiovascular events. In clinical changes between baseline and the first evaluation after donepezil treatment, heart rate and plasma brain natriuretic peptide (BNP) levels as a marker for heart failure did not change (BNP: 59.62 ± 62.71 pg/mL at baseline to 53.18 ± 42.34 pg/mL at first evaluation; P = 0.262). We further examined plasma BNP levels in 2 groups into which the patients were divided at baseline according to the cut-off plasma BNP level of 60 pg/mL. In patients with high level of BNP, the BNP levels decreased after administration of donepezil (116.39 ± 76.58 pg/mL at baseline to 82.24 ± 46.64 pg/mL at first evaluation; P = 0.011) with the tendency to be reduced in the follow-up period. BNP did not change in patients with low level of BNP. Donepezil seemed to be safe in patients with dementia without symptomatic heart disease and significantly decreased plasma BNP levels in patients with subclinical chronic heart failure.

Clinical significance of flow-mediated dilation, brachial intima-media thickness and pulse wave velocity in patients with and without coronary artery disease.

BACKGROUND: Little is known about the interrelationships among brachial flow-mediated vasodilatation (bFMD), brachial-ankle pulse wave velocity (baPWV) and brachial intima-media thickness (bIMT) in patients with and without coronary artery disease (CAD). METHODS AND RESULTS: Two-hundred consecutive patients with stable angina pectoris (SAP) were enrolled as the CAD group and 50 age-, sex- and body mass index-matched patients without CAD were selected as the non-CAD group. bFMD, diastolic blood pressure (DBP) and high-density lipoprotein cholesterol (HDL-C) in the CAD group were significantly lower. The CAD group showed significantly higher levels of hemoglobin A(1c)(HbA(1c)) and low-density lipoprotein cholesterol (LDL-C), but not baPWV. CAD was independently associated with bFMD, DBP, HbA(1c) and HDL-C. bFMD and HDL-C significantly decreased and LDL-C increased as the number of diseased vessels with significant stenosis increased. The number of diseased vessels was independently associated with bFMD and HDL-C. In addition, bFMD, bIMT, the time constant of the shear rate and the time constant of the flow rate as assessed by a new program, Trend Plus(®), were associated with the presence of CAD. Among these parameters, the presence of CAD was independently associated with bIMT as well as bFMD. CONCLUSIONS: bFMD was a better predictor of the severity of CAD than either baPWV or coronary risk factors in patients with SAP. In addition, bIMT may be a critical predictor of CAD.

Biophysical and pharmacological properties of glucagon-like peptide-1 in rats under isoflurane anesthesia.

BACKGROUND: Glucagon-like peptide-1 (GLP-1) increases insulin secretion and has an important role in maintaining glucose homeostasis. In this study, we evaluated the biophysical and pharmacological properties of GLP-1 by performing in vivo and in vitro experiments to determine the applicability of GLP-1 in glycemic control in rats under isoflurane anesthesia. METHODS: Levels of portal GLP-1, insulin, and glucose and dipeptidyl peptidase-4 activity were measured in the basal fasting state and after gastric glucose load before, during, and after exposure to 30% O(2) in air (control) or 1.4% isoflurane in a mixture of 30% O(2) and air. The direct effects of isoflurane on GLP-1 secretion were assessed in human enteroendocrine NCI-H716 cells. Insulin release from isolated pancreatic islets was measured using a radioimmunoassay. Single pancreatic ß-cell membrane potentials were recorded using whole-cell current-clamp patches perforated by ß-escin. RESULTS: In fasting rats, inhalation of isoflurane led to a decrease in the basal levels of GLP-1 but did not affect insulin and glucose levels. Levels of GLP-1, insulin, and glucose increased after gastric administration of glucose in control rats. However, isoflurane attenuated the glucose-induced increase in GLP-1 and insulin levels and increased plasma glucose levels. In contrast, isoflurane did not affect dipeptidyl peptidase-4 activity before or after gastric glucose loading. Isoflurane (0.35 mM) inhibited GLP-1 release in NCI-H716 cells; this finding was similar to that observed in in vivo studies. In perifusion experiments, isoflurane (0.35 mM) inhibited glucose-induced insulin release, whereas exogenous GLP-1 (10 nM) enhanced insulin release. Importantly, combined administration of isoflurane and GLP-1 enhanced both phases of glucose-induced insulin release to an extent similar to that achieved with GLP-1 alone. Whole-cell patches showed that exposure to GLP-1 (10 nM) led to nearly complete restoration of glucose-stimulated depolarization that had been suppressed by isoflurane (0.35 mM). CONCLUSIONS: GLP-1 secretion is impaired during isoflurane anesthesia. However, our study showed that the insulinotropic action of GLP-1 was not affected by isoflurane. Furthermore, exposure to GLP-1 increased the membrane activity of pancreatic ß-cells, preventing isoflurane-induced impairment of glucose-induced insulin secretion. These results support the hypothesis that GLP-1-based therapy may be a useful approach for achieving intraoperative glycemic control.

Decreased CXCR3 expression in CD4+ T cells exposed to asbestos or derived from asbestos-exposed patients.

Asbestos causes malignant tumors such as lung cancer and malignant mesothelioma (MM). To determine whether asbestos exposure causes reduction of antitumor immunity, we established an in vitro T-cell line model of low-dose and continuous exposure to asbestos using an human adult T-cell leukemia virus-1 immortalized human polyclonal T-cell line, MT-2, and revealed that MT-2 cells exposed continuously to asbestos showed resistance to asbestos-induced apoptosis. In addition, the cells presented reduction of surface CXCR3 chemokine receptor expression and IFN-γ production. In this study, to confirm that these findings are suitable for clinical translation, surface CXCR3 and IFN-γ expression were analyzed using freshly isolated human CD4(+) T cells derived from healthy donors and patients with pleural plaque (PP) or MM. The results revealed that CXCR3 and IFN-γ expression in the ex vivo model were reduced in some cases. Additionally, CXCR3 expression in CD4(+) T cells from PPs and MMs was significantly reduced compared with that from healthy donors, and CD4(+) T cells from patients with MMs exhibited a marked reduction in IFN-γ mRNA levels after stimulation in vitro. Moreover, CD4(+)CXCR3(+) T cells in lymphocytes from MMs showed a tendency for an inverse correlation with its ligand CXCL10/IP10 in plasma. These findings show reduction of antitumor immune function in asbestos-exposed patients and indicate that CXCR3, IFN-γ, and CXCL10/IP10 may be candidates to detect and monitor disease status.

Reduction of CXC chemokine receptor 3 in an in vitro model of continuous exposure to asbestos in a human T-cell line, MT-2.

Because patients with silicosis who are chronically exposed to silica particles develop not only pulmonary fibrosis, but also complications involving autoimmune diseases such as rheumatoid arthritis and systemic sclerosis, exposure to asbestos may affect the human immune system. This immunologic effect may impair antitumor immune function because cancer complications such as lung cancer and malignant mesothelioma are found in patients exposed to asbestos. To elucidate the antitumor immune status caused by CD4(+) T cells exposed to asbestos, an in vitro T-cell model of long-term and low-level exposure to chrysotile asbestos was established from a human adult T-cell leukemia virus-1-immortalized human polyclonal T cell line, MT-2, and the resulting six sublines showed resistance to asbestos-induced apoptosis after more than 8 months of continuous exposure. The results of DNA microarray analysis showed that the expression of 139 genes was altered by long-term and low-level exposure to asbestos, and the profile was almost similar among the six sublines when compared with the original MT-2 cells that had never been exposed to asbestos. Pathway and network analysis indicated a down-regulation of IFN-γ signaling and expression of CXC chemokine receptor 3 (CXCR3) in the sublines, whereas ELISA and flow cytometry analysis demonstrated a reduction in Th1-related IFN-γ production and cell-surface CXCR3 expression. These findings suggest that chronic exposure to asbestos may reduce antitumor immune status in CD4(+) T cells, and that an in vitro T-cell model may be useful in identifying molecules related to the impairment of antitumor immune function.

Present status of anticoagulation treatment in Japanese patients with atrial fibrillation: a report from the J-RHYTHM Registry.

BACKGROUND: Underuse and an inadequate range for the international normalized ratio (INR) for warfarin use are still problems in the management of the patients with atrial fibrillation (AF) in Japan. METHODS AND RESULTS: From January to July 2009, a total of 7,937 AF patients [5,468 men (68.6 ± 10.0 years) and 2,469 women (72.2 ± 9.0 years)] were registered from 158 institutions for the J-RHYTHM Registry. Overall, 34.2% of the patients were over the age of 75. The associated cardiovascular diagnoses were hypertension in 59.1%, coronary artery disease in 10.1%, cardiomyopathy in 8.3%, valvular heart disease in 13.7% and artificial cardiac valves in 3.1% of the patients. The type of AF was paroxysmal in 37.1%, persistent in 14.4%, and permanent in 48.5%. Overall, 87.3% of patients were taking warfarin (2.9 ± 1.2mg/day), of whom 66.0% had an INR between 1.6 and 2.6, and 35.4% were in the INR range from 2.0 to 3.0 at the time of registration. Aspirin was prescribed in 22.3% of cases. The CHADS2 score was 0 in 15.7% of patients, 1 in 34.0%, and ≥ 2 in 50.3%. CONCLUSIONS: At present, warfarin is used extensively in patients with AF whose stroke risk is relatively low (ie, in Japan) and half of them had CHADS2 scores of 0 to 1 (UMIN Clinical Trials Registry UMIN000001569).

Role of the neurosteroid allopregnanolone in the hyperalgesic behavior induced by painful nerve injury in rats.

The neurosteroid allopregnanolone (AP) influences the excitability of the central nervous system by acting as a positive allosteric modulator of γ-aminobutyric acid type A (GABA(A)) receptors. Here, we investigated the role of AP and its therapeutic potential in rats that showed hyperalgesic behavior after undergoing spinal nerve ligation (SNL). AP levels measured in the spinal cord and brain of rats that underwent SNL were greater than the corresponding levels in control animals. More importantly, spinal AP levels in hyperalgesic rats were lower than those in the rats that did not develop hyperalgesia following SNL; in contrast, brain AP levels were comparable among these groups. No differences in serum AP levels were observed among the groups. In addition, intrathecal exogenous administration of AP showed the antihyperalgesic effects in hyperalgesic rats after SNL. These findings suggest that changes in spinal AP biosynthesis are involved in the pathogenesis of neuropathic pain following peripheral nerve injury, and pharmacological manipulation of this phenomenon may provide a potential therapeutic target for neuropathic pain.

[Archives of "comprehensive approach on asbestos-related diseases" supported by the "special coordination funds for promoting science and technology (H18-1-3-3-1)"-- overview of group research project, care and specimen registration, cellular characteristics of mesothelioma and immunological effects of asbestos].

The research project entitled "Comprehensive approach on asbestos-related diseases" supported by the "Special Coordination Funds for Promoting Science and Technology (H18-1-3-3-1)" began in 2006 and was completed at the end of the Japanese fiscal year of 2010. This project included four parts; (1) malignant mesothelioma (MM) cases and specimen registration, (2) development of procedures for the early diagnosis of MM, (3) commencement of clinical investigations including multimodal approaches, and (4) basic research comprising three components; (i) cellular and molecular characterization of mesothelioma cells, (ii) immunological effects of asbestos, and (iii) elucidation of asbestos-induced carcinogenesis using animal models. In this special issue of the Japanese Journal of Hygiene, we briefly introduce the achievements of our project. The second and third parts and the third component of the fourth part are described in other manuscripts written by Professors Fukuoka, Hasegawa, and Toyokuni. In this manuscript, we introduce a brief summary of the first part "MM cases and specimen registration", the first component of the fourth part "Cellular and molecular characterization of mesothelioma cells" and the second component of the fourth part "Immunological effects of asbestos". In addition, a previous special issue presented by the Study Group of Fibrous and Particulate Substances (SGFPS) (chaired by Professor Otsuki, Kawasaki Medical School, Japan) for the Japanese Society of Hygiene and published in Environmental Health and Preventive Medicine Volume 13, 2008, included reviews of the aforementioned first component of the fourth part of the project. Taken together, our project led medical investigations regarding asbestos and MM progress and contributed towards the care and examination of patients with asbestos-related diseases during these five years. Further investigations are required to facilitate the development of preventive measures and the cure of asbestos-related diseases, particularly in Japan, where asbestos-related diseases are predicted to increase in the next 10 to 20 years.

SCN5A mutation is associated with early and frequent recurrence of ventricular fibrillation in patients with Brugada syndrome.

BACKGROUND: Mutations in SCN5A are reportedly linked to Brugada syndrome (BS), but recent observations suggest that they are not necessarily associated with ventricular fibrillation (VF) in BS patients. Therefore, the clinical importance of SCN5A mutations in BS patients was examined in the present study. METHODS AND RESULTS: The 108 BS patients were examined for SCN5A mutations and various parameters were compared between patients with and without mutations. An implantable cardioverter defibrillator (ICD) was implanted in 49 patients and a predictor of appropriate ICD shock was investigated. The existence of a SCN5A mutation was not associated with initial VF episodes (21.7% vs 20.0%, P=0.373). In the secondary prevention group, appropriate shock-free survival rate was significantly lower in patients with spontaneous type 1 ECG than in those without (41.1% vs 85.7% at 2 years, P=0.014). The appropriate shock-free survival rate was also significantly lower in patients with SCN5A mutations than in those without (28.6% vs 83.3% at 1 year, P=0.040). Appropriate shock was more frequent in patients with SCN5A mutations than in those without (6.6±6.2 vs 1.7±3.0, P=0.007). CONCLUSIONS: SCN5A mutations are associated with early and frequent VF recurrence, but not with initial VF episodes. This is the first report on the genotype-phenotype interaction and clinical significance of this mutation.

[Immunological effects of silica/asbestos].

Silica and asbestos cause pneumoconioses known as silicosis and asbestosis, respectively, that are each characterized by progressive pulmonary fibrosis. On the other hand, silicosis patients often suffer from a type of immunological dysregulation that gives rise to autoimmunity. These epidemiological findings suggest that silica may affect the immune system in humans. In addition, as asbestos itself is a mineral silicate, it may possess generalized immunotoxicological effects similar to those associated with silica particles. Because asbestos-exposed patients are well-known to often develop malignant diseases such as lung cancer and mesothelioma, one silica-like dysregulatory outcome that needs to be considered (apart from autoimmunity) is an alteration in host tumor immunity. In this review, the immunotoxicological effects of both silica and asbestos are presented and discussed in terms of immune system dysregulation as manifested by the onset of autoimmunity or alterations in host tumor immunity.

The senescence-accelerated mouse (SAM): a higher oxidative stress and age-dependent degenerative diseases model.

The SAM strain of mice is actually a group of related inbred strains consisting of a series of SAMP (accelerated senescence-prone) and SAMR (accelerated senescence-resistant) strains. Compared with the SAMR strains, the SAMP strains show a more accelerated senescence process, a shorter lifespan, and an earlier onset and more rapid progress of age-associated pathological phenotypes similar to human geriatric disorders. The higher oxidative stress status observed in SAMP mice is partly caused by mitochondrial dysfunction, and may be a cause of this senescence acceleration and age-dependent alterations in cell structure and function. Based on our recent observations, we discuss a possible mechanism for mitochondrial dysfunction resulting in the excessive production of reactive oxygen species, and a role for the hyperoxidative stress status in neurodegeneration in SAMP mice. These SAM strains can serve as a useful tool to understand the cellular mechanisms of age-dependent degeneration, and to develop clinical interventions.