Naoko Kumagai

Significance of high-sensitivity cardiac troponin T in hypertrophic cardiomyopathy.

OBJECTIVES This study investigated the significance of the serum high-sensitivity cardiac troponin T (hs-cTnT) marker for prediction of adverse events in hypertrophic cardiomyopathy (HCM). BACKGROUND Although serum cardiac troponins as sensitive and specific markers of myocardial injury have become well-established diagnostic and prognostic markers in acute coronary syndrome, the usefulness of hs-cTnT for prediction of cardiovascular events in patients with HCM is unclear. METHODS We performed clinical evaluation, including measurements of hs-cTnT in 183 consecutive patients with HCM. RESULTS Of 183 HCM patients, 99 (54%) showed abnormal hs-cTnT values (>0.014 ng/ml). During a mean follow-up of 4.1 ± 2.0 years, 32 (32%) of the 99 patients in the abnormal hs-cTnT group, but only 6 (7%) of 84 patients with normal hs-cTnT values, experienced cardiovascular events: cardiovascular deaths, unplanned heart failure admissions, sustained ventricular tachycardia, embolic events, and progression to New York Heart Association functional class III or IV status (hazard ratio [HR]: 5.05, p < 0.001). Abnormal hs-cTnT value remained an independent predictor of these cardiovascular events after multivariate analysis (HR: 3.23, p = 0.012). Furthermore, in the abnormal hs-cTnT group, overall risk increased with an increase in hs-cTnT value (HR: 1.89/hs-cTnT 1 SD increase in the logarithmic scale, 95% confidence interval: 1.13 to 3.15; p = 0.015 [SD: 0.59]). CONCLUSIONS In patients with HCM, an abnormal serum concentration of hs-cTnT is an independent predictor of adverse outcome, and a higher degree of abnormality in hs-cTnT value is associated with a greater risk of cardiovascular events.

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.

Postoperative pain impairs subsequent performance on a spatial memory task via effects on N-methyl-d-aspartate receptor in aged rats

AIMS Pain may be associated with postoperative cognitive dysfunction (POCD); however, this relationship remains under investigated. Therefore, we examined the impact of postoperative pain on cognitive functions in aged animals. MAIN METHODS Rats were allocated to the following groups: control (C), 1.2 % isoflurane for 2 hours alone (I), I with laparotomy (IL), IL with analgesia using local ropivacaine (IL+R), and IL with analgesia using systemic morphine (IL+M). Pain was assessed by rat grimace scale (RGS). Spatial memory was evaluated using a radial maze from postoperative days (POD) 3 to 14. NMDA receptor (NR) 2 subunits in hippocampus were measured by ELISA. Finally, effects of memantine, a low-affinity uncompetitive N-methyl-d-aspartate (NMDA) receptor antagonist, on postoperative cognitive performance were tested. KEY FINDINGS Postoperative RGS was increased in Group IL, but not in other groups. The number of memory errors in Group I were comparable to that in Group C, whereas errors in Group IL were increased. Importantly, in Group IL+R and IL+M, cognitive impairment was not found. The memory errors were positively correlated with the levels of NMDA receptor 2 subunits in hippocampus. Prophylactic treatment with memantine could prevent the development of memory deficits observed in Group IL without an analgesic effect. SIGNIFICANCE Postoperative pain contributes to the development of memory deficits after anesthesia and surgery via up-regulation of hippocampal NMDA receptors. Our findings suggest that postoperative pain management may be important for the prevention of POCD in elderly patients.

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

Abstract: 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.

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 (χ2 = 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.

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 (GABAA) 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.

Heavy alcohol intake is a risk factor for esophageal squamous cell carcinoma among middle-aged men: A case-control and simulation study

Despite the advances in surgical techniques and treatments, the prognosis of esophageal cancer remains poor, since the disease is usually diagnosed at an advanced stage. Therefore, prevention plays an important role in reducing mortality. Smoking and alcohol intake are modifiable habits and are important risk factors for esophageal cancer. However, the number of large-scale studies that have investigated the association of the amount and duration of smoking and alcohol intake with esophageal cancer risk, while accounting for the effects of gender and cancer subtypes (squamous cell carcinoma and adenocarcinoma), is limited. Therefore, in this hospital-based matched case-control study we investigated this association while accounting for gender and subtype differences. Chinese male patients <60 years of age with esophageal squamous cell carcinoma (ESCC) from the Fourth Hospital of Hebei Medical University in China and healthy individuals were enrolled between January, 2002 and December, 2006. Each ESCC patient was age-matched to a control subject and a total of 535 pairs were enrolled in this study. The combined variables of amount and duration were created to elucidate their effect and association with ESCC. Multiple conditional logistic regression analysis was used to estimate the odds ratio (OR) and 95% confidence interval (CI) in this model, which included a family history of esophageal cancer, a combined smoking variable and a combined alcohol variable. A simulation study was subsequently performed to confirm the reliability of the results. The results of the present study demonstrated that a family history of esophageal cancer and the combined alcohol variable were significantly associated with ESCC risk. Heavy alcohol consumption and intake for ≤20 years increased the risk compared with no intake (OR=1.91, 95% CI: 1.25–2.92). Heavy alcohol consumption and intake for >20 years exhibited an even higher risk (OR=7.25, 95% CI: 3.12–16.83). These results were similar to those of the simulation. Heavy alcohol intake, even for a short duration, is a critical risk factor and may lead to the development of ESCC in Chinese males.

Effects of smoking on outcomes after acute atherothrombotic stroke in Japanese men

BACKGROUND The effects of smoking on clinical outcomes following acute stroke remain controversial. METHODS We evaluated the influence of smoking on 90-day outcomes after acute atherothrombotic stroke in 292 Japanese men extracted from the database of the Edaravone and Argatroban Stroke Therapy for Acute Ischemic Stroke randomized parallel-group trial that tested the safety and efficacy of edaravone and argatroban therapy in 814 patients in 2004-2008. Smokers were matched with non-smokers of the same age for identical age distribution in the smoker and non-smoker groups. Poor 90-day outcomes (defined as death, Barthel index<60, or modified Rankin score>3) were evaluated using a logistic regression model. Significant variables (P<0.05) in univariate analysis were further evaluated by multivariate logistic regression analysis using a forward-selection method. RESULTS Body temperature, age, National Institute of Health Stroke Scale score at admission, systolic blood pressure, and smoking status were selected in the final model. Smokers had significantly increased odds of poor 90-day functional outcomes independent of other statistically significant predictor variables (adjusted odds ratio, 2.28; 95% confidence interval, 1.15-4.55; P=0.019). CONCLUSIONS In Japanese men, smoking leads to poor functional outcomes at 3 months after acute atherothrombotic stroke.

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

BackgroundThree-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.MethodsThirty 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.ResultsSignificant 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.ConclusionsWe 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.

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% O2 in air (control) or 1.4% isoflurane in a mixture of 30% O2 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 &bgr;-cell membrane potentials were recorded using whole-cell current-clamp patches perforated by &bgr;-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 &bgr;-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.