Hidehiro Takekawa

Fluvastatin upregulates endothelial nitric oxide synthase activity via enhancement of its phosphorylation and expression and via an increase in tetrahydrobiopterin in vascular endothelial cells.

BACKGROUND An HMG-CoA reductase inhibitor, fluvastatin, appears to act directly on the blood vessel wall to stabilize plaques in situ, agents that share this property have been termed vascular statins. METHODS We investigated the effects of fluvastatin on endothelial nitric oxide synthase (eNOS) phosphorylation and expression, as well as terahydrobiopterin (BH4) metabolism, in human umbilical vein endothelial cells (HUVEC). RESULTS Fluvastatin was observed to enhance eNOS phosphorylation at Ser-1177 and Ser-633 through the PI3-kinase/Akt and PKA pathways, respectively. Inhibition of eNOS phosphorylation using inhibitors of these pathways attenuated acute NO release in response to fluvastatin. The mRNA of GTP cyclohydrolase I (GTPCH), the rate-limiting enzyme of the first step of de novo BH4 synthesis, as well as eNOS, was upregulated in HUVEC treated with fluvastatin. In parallel with this observation, fluvastatin increased intracellular BH4. Pre-treatment of HUVEC with the selective GTPCH inhibitor, 2,4-diamino-6-hydroxypyrimidine, reduced intracellular BH4 and decreased citrulline formation following stimulation with ionomycin. Furthermore, the potentiating effect of fluvastatin was reduced by limiting the cellular availability of BH4. CONCLUSIONS Our data demonstrate that fluvastatin phosphorylates and activates eNOS, and increases eNOS expression in vascular endothelial cells. In addition to modulating eNOS, fluvastatin potentiates GTPCH gene expression and BH4 synthesis, thereby increasing NO production and preventing relative shortages of BH4.

Circadian Variation of Core Body Temperature in Parkinson Disease Patients with Depression: A Potential Biological Marker for Depression in Parkinson Disease

Background: The biological rhythm in comorbidity of depression and Parkinson disease (PD) is still unclear. For early diagnosis or clarification of the pathologic condition of comorbidity of depression and PD, the present study investigated the presence of circadian rhythm abnormalities in patients with depression. Methods: We measured the rectal temperature (RT) in 30 PD patients with or without depression during 48 consecutive hours using the maximum entropy method (MEM) and least-squares method (COSINOR). The presence of major or minor depression was evaluated by the Mini International Neuropsychiatric Interview based on the 4th edition of the Diagnostic and Statistical Manual of Mental Disorders, and the Hamilton Depression Scale. Results: The RT rhythms of patients without depression predominately showed a circadian rhythm. However, 2 of 6 patients with depression showed an infradian rhythm using MEM. COSINOR revealed that PD patients with depression showed lower amplitudes of core body temperature (p = 0.012) and higher minimum RT (p = 0.031) relative to those of patients without depression. Conclusion: PD patients with depression show an altered RT circadian rhythm. The results suggest that the characteristics of core body temperature could be potentially used as a biological marker for depression in PD.

Effects of Stroke Education of Junior High School Students on Stroke Knowledge of Their Parents Tochigi Project

Background and purpose— Educating the youth about stroke is a promising approach for spreading stroke knowledge. The aim of this study was to verify communication of stroke knowledge to parents by educating junior high school students about stroke. Methods— We enrolled 1127 junior high school students (age, 13–15 years) and their parents in the Tochigi prefecture, Japan. All students received a stroke lesson, watched an animated cartoon, and read the related Manga comic as educational aids. The students took back home the Manga and discussed what they learned with their parents. Questionnaires on stroke knowledge were given to all at baseline and immediately after the lesson. Results— A total of 1125 students and 915 parents answered the questionnaires. In the students, the frequency of correct answers increased significantly for all questions on stroke symptoms except for headache, and for all questions on risk factors after the lesson. In the parents, the correct answer rates increased for stroke symptoms except for headache and numbness in one side of the body, and for all questions on risk factors except for hypertension. Ninety-one percent of students and 92.7% of parents correctly understood the Face, Arm, Speech, and Time (FAST) mnemonic after the lesson. Conclusions— Improvement of stroke knowledge immediately after the stroke lesson was observed in parents as well as their children, which indicated that our teaching materials using the Manga was effective in delivering the stroke knowledge to parents through their children.

Amyotrophic lateral sclerosis associated with insomnia and the aggravation of sleep‐disordered breathing

A case of amyotrophic lateral sclerosis (ALS) diagnosed by sleep‐disordered breathing is described. The patient’s chief complaints were insomnia and nocturnal dyspnea after taking a hypnotic drug. On examination, he showed restrictive ventilatory impairment, alveolar hypoventilation and hypoxia. Polysomnographic examination revealed marked hypoxia during REM sleep periods, decreased duration of REM sleep periods, and increased sleep disruption. Amyotrophic lateral sclerosis was diagnosed by the neurological finding of paraspinal muscle weakness and neurogenic changes revealed by needle electromyography and muscle biopsy. The daytime and nocturnal respiratory insufficiency improved after nasal bilevel positive airway pressure therapy. Amyotrophic lateral sclerosis should be suspected as a cause of insomnia and nocturnal dyspnea.

A comparison of middle latency auditory-evoked response in obstructive sleep apnea syndrome before and after treatment.

The ascending reticular activating system seems to be affected by nocturnal hypoxia in obstructive sleep apnea syndrome (OSAS) patients so that their vigilance level is decreased. To evaluate the change in vigilance level in OSAS patients, polysomnography, the Epworth Sleepiness Scale and middle latency auditory‐evoked responses (MLR) were measured before and after treatment in seven men with OSAS (mean age 45.4 ± 12.9 years, mean body mass index 33.3 ± 7.6 kg/m2). After treatment there was significant improvement of nocturnal hypoxia in OSAS. Peak amplitude of P1 in MLR increased after treatment. There was also improvement of the electrical field distribution of MLR on the scalp. The results suggest that the decreased vigilance level in OSAS patients is reversible with treatment.

PHANTOM ARM AND LEG AFTER PONTINE HEMORRHAGE

The phantom limb appears not only after limb amputation1 but also after brain damage (known as supernumerary phantom limb [SPL]).2 A previous review1 on phantom limb following limb amputation proposed the remapping hypothesis of topographic reorganization of somatosensory cortex in which the referred sensation from the neighboring receptive field to phantoms is one of at least five possible sources for phantom sensation. On the other hand, the current theories of SPL emphasize the dissociation between established sensorimotor limb representation and marked changes in afferent and efferent signals in brain–limb communication.3,4 There is little information about SPL in patients with brainstem damage,5 which has somewhat different characteristics from phantom sensations following supratentorial cerebral lesions, as well as from phantoms following limb amputation. Here we address the contribution of the brainstem to SPL. ### Case reports. A 47-year-old woman (Case 1) and a 55-year-old man (Case 2) developed acute pontine hemorrhage (figure, A [a, b] and B [a, b]). They survived a locked-in period with complete paralysis except for vertical eye movements. The neurologic examination …

Circadian rhythm abnormalities in the acute phase of cerebral infarction correlate with poor prognosis in the chronic phase.

The aim of this study was to determine circadian rhythm abnormalities in patients with acute cerebral infarction and their relationship with prognosis in the chronic phase. The subjects were 50 patients who were admitted within 48 h of onset. Rectal temperature and wrist motor activity were recorded during the acute phase. Time-series data were assayed by MEM spectral analysis. Functional prognosis (degree of handicap) was assessed at 3 months after stroke onset by the modified Rankin Scale. Ambulatory patients tended to exhibit circadian rhythm in rectal temperature and/or wrist activity rhythms, whereas non-ambulatory patients did not (P < 0.001) in the acute phase of ischemic stroke. Our findings suggest the biological rhythms of rectal temperature and wrist activity during the acute stroke phase might be a possible prognostic indicator of their chronic phase.

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.

Alteration of circadian periodicity in core body temperatures of patients with acute stroke

Abstract The effect of brain damage on body temperature rhythm was investigated by spectral analysis using the maximum entropy method. The rectal temperatures of 56 patients with acute stroke were recorded for 1–3 days by actigraphy. Many patients with disturbance of consciousness showed infradian rhythm. Ambulatory patients tended to have circadian rhythm, and non‐ ambulatory patients tended to show infradian rhythm. The study’s findings suggest that impaired physical activity and disturbance of consciousness affect body temperature rhythm in patients with acute stroke.

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.