Improving Acute In-Hospital Stroke Care by Reorganization of an In-Hospital Stroke Code Protocol.

BACKGROUND AND PURPOSE: Delays in recognition and assessment of in-hospital strokes (IHS) can lead to poor outcomes. The aim was to examine whether reorganized IHS code protocol can reduce treatment time. METHODS: IHS code protocol was developed, educational workshops were held for medical personnel. In the protocol, any medical personnel should directly consult a stroke neurologist before any diagnostic studies. Time intervals were compared between the pre- and post-implementation periods and between direct consultation with a stroke neurologist (DC group) and non-DC group in the post-implementation period. RESULTS: A total of 145 patients were included (pre, 42; post, 103). Time from recognition to stroke neurologist assessment (91 vs. 35 min, p = 0.002) and time from recognition to neuroimaging (123 vs. 74, p = 0.013) were significantly lower in the post-implementation period. Time from stroke neurologist assessment to groin puncture was significantly lower (135 vs. 81, p = 0.037). In the post-implementation period, DC group showed significant time savings from last known well (LKW) to recognition (93 vs. 260, p = 0.001), LKW to stroke neurologist assessment (145 vs. 378, p = 0.001), and recognition to stroke neurologist assessment (16 vs. 76, p < 0.001) compared with non-DC group. CONCLUSIONS: Reorganization of IHS code protocol reduced time from stroke recognition to assessment and treatment time. Reorganized IHS code and direct consultation with a stroke neurologist improved the initial response time.

Blonanserin, a novel atypical antipsychotic agent not actively transported as substrate by P-glycoprotein.

Although blonanserin, a novel atypical antipsychotic agent with dopamine D(2)/serotonin 5-HT(2A) antagonistic properties, displays good brain distribution, the mechanism of this distribution has not been clarified. P-glycoprotein [(P-gp) or multidrug resistance protein 1 (MDR1)] is an efflux transporter expressed in the brain and plays an important role in limiting drug entry into the central nervous system (CNS). In particular, P-gp can affect the pharmacokinetics and efficacy of antipsychotics, and exacerbate or soothe their adverse effects. In this study, we conducted in vitro and in vivo experiments to determine whether blonanserin is a P-gp substrate. Risperidone and its active metabolite 9-hydroxyrisperidone, both of which are P-gp substrates, were used as reference drugs. Affinity of blonanserin, risperidone, and 9-hydroxyrisperidone for P-gp was evaluated by in vitro transcellular transport across LLC-PK1, human MDR1 cDNA-transfected LLC-PK1 (LLC-MDR1), and mouse Mdr1a cDNA-transfected LLC-PK1 (LLC-Mdr1a). In addition, pharmacokinetic parameters in the brain and plasma (B/P ratio) of test compounds were measured in mdr1a/1b knockout (KO) and wild-type (WT) mice. The results of in vitro experiments revealed that P-gp does not actively transport blonanserin as a substrate in humans or mice. In addition, blonanserin displayed comparable B/P ratios in KO and WT mice, whereas B/P ratios of risperidone and 9-hydroxyrisperidone differed markedly in these animals. Our results indicate that blonanserin is not a P-gp substrate and therefore its brain distribution is unlikely to be affected by this transporter.

ZDHHC8 knockdown enhances radiosensitivity and suppresses tumor growth in a mesothelioma mouse model.

Mesothelioma is an aggressive tumor caused by asbestos exposure, the incidence of which is predicted to increase globally. The prognosis of patients with mesothelioma undergoing conventional therapy is poor. Radiation therapy for mesothelioma is of limited use because of the intrinsic radioresistance of tumor cells compared with surrounding normal tissue. Thus, a novel molecular-targeted radiosensitizing agent that enhances the radiosensitivity of mesothelioma cells is required to improve the therapeutic efficacy of radiation therapy. ZDHHC8 knockdown reduces cell survival and induces an impaired G(2) /M checkpoint after X-irradiation in HEK293 cells. In the present study, we further analyzed the effect of the combination of ZDHHC8 knockdown and X-irradiation and assessed its therapeutic efficacy in mesothelioma models. SiRNA-induced ZDHHC8 knockdown in 211H and H2052 mesothelioma cells significantly reduced cell survival after X-irradiation. In 211H cells treated with ZDHHC8 siRNA and X-irradiation, the G(2) /M checkpoint was impaired and there was an increase in the number of cells with micronuclei, as well as apoptotic cells, in vitro. In 211H tumor-bearing mice, ZDHHC8 siRNA and X-irradiation significantly suppressed tumor growth, whereas ZDHHC8 siRNA alone did not. Immunohistochemical analysis showed decreased cell proliferation and induction of apoptosis in tumors treated with ZDHHC8 siRNA and X-irradiation, but not with ZDHHC8 siRNA alone. These results suggest that ZDHHC8 knockdown with X-irradiation induces chromosomal instability and apoptosis through the impaired G(2) /M checkpoint. In conclusion, the combination of ZDHHC8 siRNA and X-irradiation has the potential to improve the therapeutic efficacy of radiation therapy for malignant mesothelioma.

Fluvoxamine and sigma-1 receptor agonists dehydroepiandrosterone (DHEA)-sulfate induces the Ser473-phosphorylation of Akt-1 in PC12 cells.

AIMS: The expression of brain-derived neurotrophic factor (BDNF) may be a downstream target of a variety of antidepressant treatments, and selective serotonin reuptake inhibitors (SSRIs) are used clinically for the treatment of depression. BDNF binds to and activates tyrosine kinases receptor (TrkB) to exert its effects. TrkB, after activation by ligands, stimulates phosphoinositide 3-kinase (PI3K). The downstream target of PI3K is Akt-1, a serine-threonine kinase. BDNF has signaling through the PLC-IP(3)/Ca(2+) pathway. Furthermore, the PLC-gamma/IP(3)/Ca(2+) pathway is regulated by the sigma-1 receptors. Here, we examined whether fluvoxamine (FLV) activated Akt-1 and increased phosphorylation of Akt-1 via sigma-1 receptor in PC12 cells. MAIN METHODS: We examined the effect of the SSRI, FLV and BDNF on the phosphorylation levels of serine-threonine kinase Akt-1 in PC12 cells using immunoblotting techniques. KEY FINDINGS: Treatment with 10 microM and 100 microM FLV of PC12 cells stimulated a 2.4- and 3.8-fold maximal increase in Ser(473)-phosphorylated Akt-1 levels at 40 min, respectively. Treatment with 50 ng/ml BDNF also stimulated Ser(473) -phosphorylated Akt-1 by 2.6-fold with a maximal increase at 5 min. In addition, the phosphorylation induced by FLV and BDNF was blocked by LY294002, a selective inhibitor of PI3K. The sigma-1 receptor agonists dehydroepiandrosterone (DHEA)-sulfate also stimulated a 2.1-fold increase in the level of Ser473-phosphorylated Akt-1. SIGNIFICANCE: This study demonstrates that fluvoxamine treatment rapidly increased phosphorylation of Akt-1. And BDNF activated Akt-1 phosphorylation by the TrkB/PI3K/Akt-1 pathway. We conclude that the phosphorylation of Akt-1, downstream of PI3K, was the key to their antidepressant effects.

Diazepam reduces both arterial blood pressure and muscle sympathetic nerve activity in human.

It is known that benzodiazepines have a hypotensive effect, but the mechanism has not been well elucidated yet. To clarify whether this effect is due to central or peripheral mechanism, we administered 5 mg of diazepam or saline intravenously to healthy volunteers and assessed the change in blood pressure, heart rate, muscle sympathetic nerve activity and heart rate variability. After diazepam administration, systolic and mean blood pressure decreased significantly. Muscle sympathetic nerve activity was also significantly reduced but heart rate did not change, whereas the variables of spectral analysis of heart rate variability did not show significant change. We concluded that the hypotensive effect of diazepam in human is mainly due to the central mechanism.

Total sleep deprivation elevates blood pressure through arterial baroreflex resetting: a study with microneurographic technique.

STUDY OBJECTIVES: Sleep deprivation has a profound effect on cardiovascular regulation through the autonomic nervous system. This study examined the effect of 24-hour total sleep deprivation on muscle sympathetic nerve activity (MSNA), which is a direct measurement of the postganglionic sympathetic efferent innervating the vascular bed in the skeletal muscle and other circulatory structures. DESIGN: The study was performed on 6 young healthy men. The factors exerting influence on MSNA, such as aging, obesity, body posture, activity, intensity of illumination, and food and beverage consumption were strictly controlled. Burst rate and burst incidence were used as parameters of MSNA. The burst rate, burst incidence, heart rate, and systolic and diastolic blood pressure were measured after total sleep deprivation and control sleep. To perform a linear regression analysis of arterial baroreflex (ABR), the incidence of MSNA bursts corresponding to a given diastolic blood pressure (%MSNA) was examined. MEASUREMENT AND RESULTS: The diastolic blood pressure was significantly higher after total sleep deprivation than after control sleep (66.5 +/- 1.7 vs 57.4 +/- 3.3 mm Hg). The burst rate (9.6 +/- 1.8 vs 13.3 +/- 2.7 bursts/min) and burst incidence (21.6 +/- 4.5 vs 30.3 +/- 8.9 bursts/100 heart beats) of MSNA were significantly lower after total sleep deprivation than after control sleep (P < .05). Analysis of the ABR disclosed a significant linear regressive relation between %MSNA and diastolic blood pressure in every subject after both total sleep deprivation and control sleep. This result implies that the ABR regulates the occurrence of MSNA bursts under different diastolic blood pressure conditions. The threshold (X-axis intercept) of the blood pressure regression line (ie, an indicator of the ABR set point) shifted by 12 +/- 4.3 mm Hg toward a higher blood pressure level after total sleep deprivation (P < .05). The ABR sensitivity, or the slope of the regression line, tended to be less steep after total sleep deprivation than after control sleep, although it was not statistically significant (P = .09). CONCLUSIONS: The diastolic blood pressure increased and both burst rate and burst incidence of MSNA decreased after total sleep deprivation. The results show that resetting of the ABR toward a higher blood pressure level occurred after total sleep deprivation. This ABR resetting probably brings about an increase in arterial blood pressure after total sleep deprivation.

Effects of Yoku-kan-san-ka-chimpi-hange on the sleep of normal healthy adult subjects.

Yoku-kan-san-ka-chimpi-hange (YKCH) is a drug used for insomnia in Japanese traditional herbal medicine. The present study evaluated the effects of YKCH on sleep by all-night polysomnography using the double-blind method. Yoku-kan-san-ka-chimpi-hange increased the total sleep time significantly, and tended to cause an increase in sleep efficiency and of stage 2 sleep, as well as a decrease of sleep latency and of stage 3 + 4 sleep. There was no apparent influence on rapid eye movement (REM) sleep. In terms of non-REM sleep, the effects of YKCH exhibit a profile similar to those of benzodiazepines.

Effects of donepezil (Aricept) on the rapid eye movement sleep of normal subjects.

Donepezil (Aricept) is a therapeutic drug for the treatment of Alzheimer's disease (AD). However, there have been only two reports describing the effects of donepezil on sleep as assessed by nocturnal polysomnography (PSG). With this in mind, the effects of donepezil on the sleep of healthy subjects was evaluated using PSG. The results indicated that the percentage of rapid eye movement sleep to total sleep time was increased significantly by a single dose of 5 mg of donepezil when given to healthy subjects immediately before retiring to bed.

Hypocretin-1 (orexin-A) concentrations in cerebrospinal fluid are low in patients with Guillain-Barré syndrome.

It is reported that cerebrospinal fluid (CSF) hypocretin-1 (orexin-A) concentrations in patients with narcolepsy are significantly low. Human narcolepsy is also known to be closely associated with a specific human histocompatibility leukocyte antigen (HLA), suggesting that autoimmunity is involved in the pathophysiology of the disease. Thus, it is important to know whether hypocretin changes are found in definite neuroimmunological diseases such as multiple sclerosis and Guillain-Barré syndrome (GBS). The results of the present study indicate that some patients with GBS have lower levels of CSF hypocretin-1.