Role of the autonomic nervous system in young, middle-aged, and older individuals with essential hypertension and sleep-related changes in neurocardiac regulation.

Essential hypertension involves complex cardiovascular regulation. The autonomic nervous system function fluctuates throughout the sleep-wake cycle and changes with advancing age. However, the precise role of the autonomic nervous system in the development of hypertension during aging remains unclear. In this study, we characterized autonomic function during the sleep-wake cycle in different age groups with essential hypertension. This study included 97 men (53 with and 44 without hypertension) aged 30-79 years. They were stratified by age into young (< 40 years), middle-aged (40-59 years), and older (60-79 years) groups. Polysomnography and blood pressure data were recorded for 2 min before and during an hour-long nap. Autonomic function was assessed by measuring heart rate variability and blood pressure variability. Data were analyzed using t tests, correlation analyses, and two-way analysis of variance. During nonrapid eye movement (nREM), a main effect of age was observed on cardiac parasympathetic measures and baroreflex sensitivity (BRS), with the highest and lowest levels noted in the younger and older groups, respectively. The coefficients of the correlations between these measures and age were lower in patients with hypertension than in normotensive controls. The BRS of young patients with hypertension was similar to that of their middle-aged and older counterparts. However, cardiac sympathetic activity was significantly higher (p = 0.023) and BRS was significantly lower (p = 0.022) in the hypertension group than in the control group. During wakefulness, the results were similar although some of the above findings were absent. Autonomic imbalance, particularly impaired baroreflex, plays a more significant role in younger patients with hypertension. The nREM stage may be suitable for gaining insights into the relevant mechanisms.

Effects of age and sex on vasomotor activity and baroreflex sensitivity during the sleep-wake cycle.

Cardiovascular function is related to age, sex, and state of consciousness. We hypothesized that cardiovagal baroreflex sensitivity (BRS) demonstrates different patterns in both sexes before and after 50 years of age and that these patterns are associated with patterned changes during the sleep-wake cycle. We recruited 67 healthy participants (aged 20-79 years; 41 women) and divided them into four age groups: 20-29, 30-49, 50-69, and 70-79 years. All the participants underwent polysomnography and blood pressure measurements. For each participant, we used the average of the arterial pressure variability, heart rate variability (HRV), and BRS parameters during the sleep-wake stages. BRS and HRV parameters were significantly negatively correlated with age. The BRS indexes were significantly lower in the participants aged ≥ 50 years than in those aged < 50 years, and these age-related declines were more apparent during non-rapid eye movement sleep than during wakefulness. Only BRS demonstrated a significantly negative correlation with age in participants ≥ 50 years old. Women exhibited a stronger association than men between BRS and age and an earlier decline in BRS. Changes in BRS varied with age, sex, and consciousness state, each demonstrating a specific pattern. The age of 50 years appeared to be a crucial turning point for sexual dimorphism in BRS. Baroreflex modulation of the cardiovascular system during sleep sensitively delineated the age- and sex-dependent BRS patterns, highlighting the clinical importance of our results. Our findings may aid in screening for neurocardiac abnormalities in apparently healthy individuals.

2020 Guideline for Prehospital Management, Emergency Evaluation and Treatment of Patients With Acute Ischemic Stroke: A Guideline for Healthcare Professionals from the Taiwan Society of Emergency Medicine and Taiwan Stroke Society.

To improve the clinical outcomes of patients with acute ischemic stroke, the public, pre-hospital care system, and hospitals should cooperate to achieve quick assessment and management for such patients and to start treatment as soon as possible. To reach the goal, the Consensus Group, including emergency physicians and neurologists in the Taiwan Society of Emergency Medicine and Taiwan Stroke Society, performed an updated review and discussion for the local guidelines. The guidelines consist of 12 parts, including public education program, evaluation and management in the emergency medical system, emergency medical system, assessment of stroke care capability of the hospital by independent parties, stroke team of the hospital, telemedicine, organization, and multifaceted integration, improvement of quality of care process of stroke system, initial clinical and imaging evaluations after arriving at the hospital, imaging evaluation for indications of intravenous thrombolysis, imaging evaluation for indications of endovascular thrombectomy, and other diagnostics. For detailed contents in Chinese, please refer to the Taiwan Stroke Society Guideline and Taiwan Emergency Medicine Bulletin.

Medicarpin isolated from Radix Hedysari ameliorates brain injury in a murine model of cerebral ischemia.

The development of effective post-stroke therapy is highly demanded. Medicarpin is a key active component of a famous Chinese herbal prescription used for post-stroke treatment in Taiwan; however, little is known about its biological effects and mechanisms of action. Herein, we implemented a murine model of cerebral ischemic/reperfusional injury-related stroke to elucidate medicarpin's neuroprotective effect. In male ICR mice 24 h after stroke induction, treatment with medicarpin (0.5 and 1.0 mg/kg, i.v.) markedly enhanced the survival rates, improved moving distance and walking area coverage, reduced brain infarction, and preserved the blood-brain barrier, supporting medicarpin's protective effect on stroke-induced injury. Immunohistochemistry analysis further revealed that medicarpin treatment decreased the expression/activation of p65NF-κB and caspase 3, especially near the infarct cortex, while promoting the expression of neurogenesis-associated proteins, including doublecortin (DCX), brain-derived neurotrophic factor (BDNF), and tyrosine receptor kinase B (TrkB). These changes of expression levels were accompanied by GSK-3 inactivation and ß-catenin upregulation. Notably, pretreatment with LY294002, a PI3K inhibitor, abolished the aforementioned beneficial effects of medicarpin, illustrating an essential role of PI3K/Akt activation in medicarpin's neuroprotective and reparative activities. In vitro studies revealed that medicarpin displayed strong anti-inflammatory activity by reducing nitric oxide (NO) production in lipopolysaccharide-stimulated microglial cells (BV2) with an IC50 around 5 ±1 (µM) and anti-apoptotic activity in neuronal cells (N2A) subjected to oxygen-glucose deprivation with an IC50 around 13 ± 2 (µM). Collectively, this is the first report to demonstrate that medicarpin, isolated from Radix Hedysari, ameliorates ischemic brain injury through its anti-inflammatory microglia/NO), anti-apoptotic (neuronal cells/OGD) and neuroprotective effects by activating the PI3K/Akt-dependent GSK-3 inactivation for upregulating ß-catenin, which in turn decreases the expression/activation of p65NF-κB and caspase 3 and promotes the expression of neurogenic (DCX, BDNF, TrkB) and neuroprotective (Bcl2) factors in the brain.

Suppression of Inflammatory and Fibrotic Signals by Cinnamon (Cinnamomum cassia) and Cinnamaldehyde in Cyclophosphamide-Induced Overactive Bladder in Mice.

Cinnamon (Cinnamomum cassia) is a well-known traditional Chinese medicine used to treat nocturia by tonifying and warming the kidney. Our recent clinical study found that overactive bladder (OAB) patients treated with cinnamon powder (CNP) patches exhibited significantly ameliorated OAB symptoms without significant side effects, but the mechanism of action is unclear. To explore the beneficial effects and action mechanisms of CNP and its major active component cinnamaldehyde (CNA) in an OAB-related murine model, cyclophosphamide- (CYP-) induced OAB injury was performed on male ICR mice in the presence or absence of CNP and CNA, as well as solifenacin, a clinical drug for OAB as a reference. Twenty-four-hour micturition patterns (frequency of urination and volume of urine per time), as well as histopathological examination, immunohistochemistry (IHC), and Western blotting of the bladder, were analyzed for mechanism elucidation. Administration of CYP (300 mg/kg, i.p.) induced typical OAB pathophysiological changes, including increased frequency of urination and reduced volume of urine. CYP-induced mice displayed strong edema of the bladder and hemorrhagic cystitis, accompanied by loss of normal corrugated folds and decreased muscarinic receptors (M2/M3) in the urothelium, and disordered/broken structures of the lamina propria and detrusor. These changes were correlated with increased leukocyte (CD11b) infiltration colocalized with inflammatory (pp65 NFκB, macrophage migration inhibitory factor (MIF)/Toll-like receptor 4 (TLR4)) and fibrotic (stem cell factor (SCF)/c-Kit, α-smooth muscle actin (α-SMA)/ß-catenin) signals. Treatment with CNP (600 mg/kg, p.o.) and CNA (10-50 mg/kg, p.o.), but not solifenacin (50 mg/kg), 30 min after CYP induction significantly ameliorated CYP-induced dysfunction in micturition patterns and pathophysiological changes. CNP and CNA further suppressed MIF/TLR4-associated inflammatory and SCF/c-Kit-related fibrotic signaling pathways. Our findings indicate that suppression of inflammatory and fibrotic signals contributes to the crucial mechanism in the improvement of CYP-induced OAB by CNP and CNA.

Osthole ameliorates cartilage degradation by downregulation of NF-κB and HIF-2α pathways in an osteoarthritis murine model.

Osteoarthritis (OA) is a common and disabling joint disease mainly characterized by cartilage degradation, with the knees most commonly affected. No effective treatment for the cartilage degradation of OA exists. Preliminary studies have revealed the protective and osteogenic effects of osthole, a natural coumarin first isolated from Cnidium monnieri (Fructus Cnidii); however, no evidence of osthole in an OA-related model has been published to date. This study further explored the effects of osthole in a monoiodoacetate (MIA)-induced OA-related animal model and focused on the molecular mechanism(s) behind the anti-inflammatory and cartilage protective effects of osthole. This study revealed that the cartilage protective effect of osthole in a MIA-induced osteoarthritis (OA) murine model can be explained by downregulation of COX-2 and RUNX2 by inhibition of NF-κB and HIF-2α up-regulated by OA induction, resulting in downregulation of MMP-13, Syndecan IV and ADAMTS-5. In addition, osthole might have anti-inflammatory and analgesic effects due to COX-2 inhibition. Osthole can be considered as a potential component of the treatment of OA, for it possesses a cartilage protective effect, as well as anti-inflammation, analgesic, and movement improving effects. Further preclinical and human clinical studies are needed to examine the efficacy and safety profile of long-term therapy.

Ergostatrien-7,9(11),22-trien-3ß-ol from Antrodia camphorata ameliorates ischemic stroke brain injury via downregulation of p65NF-κ-B and caspase 3, and activation of Akt/GSK3/catenin-associated neurogenesis.

Antrodia camphorata is a well-known traditional Chinese mushroom used as a functional food and nutraceutical in Taiwan and China. The aim of this study was to explore the protective effects and mechanism(s) of the ethyl acetate crude extract of A. camphorata (EtOAc-AC) and its active constituent ergostatrien-7,9(11),22-trien-3ß-ol (EK100) in an acute ischemic stroke (AIS) murine model. Treating mice with induced AIS injury by using EtOAc-AC (0.3-0.6 g kg-1, p.o.) and EK100 (60 and 120 mg kg-1, p.o.) 2 h after AIS induction significantly increased the tracking distance and reduced brain infarction. Both EtOAc-AC and EK-100 reduced the expression levels of p65NF-κB and caspase 3 near the peri-infarct cortex and promoted the expression of neurogenesis-associated protein doublecortin (DCX) near the hippocampus, accompanied by glycogen synthase kinase 3 (GSK-3) inhibition and ß-catenin upregulation. Signaling pathway analysis revealed that the advantageous effects of EtOAc-AC and EK-100 involved triggering the activation of PI3K/Akt and inhibition of GSK-3. Our findings suggest that EtOAc-AC and its active constituent EK100 display anti-inflammatory and anti-apoptotic activities. Both EtOAc-AC and EK100 reduce ischemic brain injury by decreasing p65NF-κB and caspase 3 expression, and they promote neurogenesis (DCX) and neuroprotection (Bcl2) by activating the PI3k/Akt-associated GSK3 inhibition and ß-catenin activation.

Prevalence and clinical characteristics of stroke patients with p.R544C NOTCH3 mutation in Taiwan.

Objective: Features of cerebral autosomal dominant arteriopathy with subcortical infarct and leukoencephalopathy ( CADASIL) caused by NOTCH3 mutations vary between ethnicities and regions. In Taiwan, more than 70% of CADASIL patients carry the mutation hot spot of p.R544C. We investigated the prevalence of NOTCH3 p.R544C mutation in stroke patients in Taiwan. Methods: This prospective, multicenter study recruited acute stroke patients within 10 days of symptom onset. The p.R544C mutation was identified by polymerase chain reaction with confronting two-pair primers and sequencing. Clinical parameters, vascular risk factors, stroke subtypes, and stroke outcomes were analyzed. Results: Of the 1970 stroke patients (mean age 61.1 ± 13.6 years, male 69.5%) included, 1705 (86.5%) had ischemic stroke and 265 (13.5%) had intracerebral hemorrhage. The prevalence of p.R544C in the study population was 2.8% (95% confidence interval [CI] = 2.1-3.5%). The prevalence was highest in patients with small vessel occlusion type of ischemic stroke (5.6%), followed by intracerebral hemorrhage (5.3%), and infarct of undetermined etiology (2.7%), and was low in patients with cardioembolism (0.8%) and large artery atherosclerosis (0.7%). All p.R544C patients with intracerebral hemorrhage were nonlobar hemorrhage. Sibling history of stroke (odds ratio [OR] = 4.50, 95% CI = 1.67-12.14 in ischemic stroke; OR = 6.03, 95% CI = 1.03-35.47 in intracerebral hemorrhage, respectively) and small vessel occlusion (OR, 4.03, 95% CI, 1.26-12.92) were significantly associated with p.R544C. Interpretation: p.R544C NOTCH3 mutation is underdiagnosed in stroke patients in Taiwan, especially in those with small vessel occlusion and sibling history of stroke.

Bleeding and New-Onset Cancers in Patients With Atrial Fibrillation Receiving Nonvitamin K Antagonist Oral Anticoagulants.

Whether bleeding should be considered a sufficient sign to justify thorough cancer surveillance in atrial fibrillation (AF) patients receiving nonvitamin K antagonist oral anticoagulants (NOACs) remains unclear. We investigated the relationships between bleeding events and new-onset cancers in AF patients receiving NOACs in a prospective cohort (n = 395, mean follow-up duration of 2.8 years). There were 18 patients who were diagnosed with new-onset cancers 584 ± 372 days after the initiation of NOACs. The patients with new-onset cancers had higher HAS-BLED scores (no, preexisting and new-onset cancer: 1.51 ± 0.81, 1.69 ± 0.87, and 2.11 ± 0.96, respectively; p = 0.006) and a higher incidence of bleeding events (22%, 33%, 67%, respectively; p<0.001) than did patients without new-onset cancers. Bleeding events that preceded the diagnosis of new-onset cancers were independently correlated with new-onset cancers (odds ratio: 7.89, p = 0.001) in the multivariate logistic regression. More than half of the patients (61%) with new-onset cancers had either a significant period of drug interruption for at least 2 months or discontinued NOACs. In conclusions, bleeding in AF patients receiving NOACs could be an alerting sign of new-onset cancers and should prompt the initiation of thorough surveillance to detect early cancers.

GSK-3 inhibition through GLP-1R allosteric activation mediates the neurogenesis promoting effect of P7C3 after cerebral ischemic/reperfusional injury in mice.

An aminopropyl carbazole compound, P7C3, has been shown to be a potent neurogenesis promoting agent; however, its fundamental signaling action has yet to be elucidated. A cerebral ischemic/reperfusional (CI/R) injury model in mice was implemented to elucidate the neuronal protective mechanism(s) of P7C3. Treating CI/R mice using P7C3 (50-100 µg/kg, i.v.) significantly improved tracking distance and walking behavior, and reduced brain damage. Specifically, P7C3 promoted the expression of neurogenesis-associated proteins, including doublecortin, beta tubulin III (ß-tub3), adam11 and adamts20, near the peri-infarct cortex, accompanied by glycogen synthase kinase 3 (GSK-3) inhibition and ß-catenin upregulation. The application of a specific inhibitor against glucagon-like peptide 1 receptor (GLP-1R), exendin(9-39), revealed that the beneficial effects of P7C3 involved triggering the activation of GLP-1R-associated PKA/Akt signaling. P7C3 elicited the GLP-1R-dependent intracellular cAMP increment and the insulin secretion in cellular models. Surface plasmon resonance assay of P7C3 showed a Kd value of 0.53 µM for GLP-1R binding, and the docking of P7C3 to the putative active site on GLP-1R was successfully predicted by molecular modeling. Our findings indicate that P7C3 promotes the expression of neurogenesis proteins by activation of the cAMP/PKA-dependent and Akt/GSK3-associated ß-catenin through positive allosteric stimulation of GLP-1R. Within the P7C3 class of neuroprotective molecules, this mechanism appears to be unique to the prototypical P7C3 molecule, as other active derivatives such as P7C2-A20 and P7C3-S243 they do not engage this same pathway and have been shown to work by nicotinamide phosphoribosyltransferase (NAMPT) stimulation.

Intake of potassium- and magnesium-enriched salt improves functional outcome after stroke: a randomized, multicenter, double-blind controlled trial.

Background: Stroke is one of the leading causes of mortality and neurologic deficits. Management measures to improve neurologic outcomes are in great need. Our previous intervention trial in elderly subjects successfully used salt as a carrier for potassium, demonstrating a 41% reduction in cardiovascular mortality by switching to potassium-enriched salt. Dietary magnesium has been associated with lowered diabetes and/or stroke risk in humans and with neuroprotection in animals.Objective: Because a large proportion of Taiwanese individuals are in marginal deficiency states for potassium and for magnesium and salt is a good carrier for minerals, it is justifiable to study whether further enriching salt with magnesium at an amount near the Dietary Reference Intake (DRI) amount may provide additional benefit for stroke recovery.Design: This was a double-blind, randomized controlled trial comprising 291 discharged stroke patients with modified Rankin scale (mRS) ≤4. There were 3 arms: 1) regular salt (Na salt) (n = 99), 2) potassium-enriched salt (K salt) (n = 97), and 3) potassium- and magnesium-enriched salt (K/Mg salt) (n = 95). The NIH Stroke Scale (NIHSS), Barthel Index (BI), and mRS were evaluated at discharge, at 3 mo, and at 6 mo. A good neurologic performance was defined by NIHSS = 0, BI = 100, and mRS ≤1.Results: After the 6-mo intervention, the proportion of patients with good neurologic performance increased in a greater magnitude in the K/Mg salt group than in the K salt group and the Na salt group, in that order. The K/Mg salt group had a significantly increased OR (2.25; 95% CI: 1.09, 4.67) of achieving good neurologic performance compared with the Na salt group. But the effect of K salt alone (OR: 1.58; 95% CI: 0.77, 3.22) was not significant.Conclusions: This study suggests that providing the DRI amount of magnesium and potassium together long term is beneficial for stroke patient recovery from neurologic deficits. This trial was registered at clinicaltrials.gov as NCT02910427.

Salvianolic acid A alleviates ischemic brain injury through the inhibition of inflammation and apoptosis and the promotion of neurogenesis in mice.

Salvianolic acid A (SalA), a chemical type of caffeic acid trimer, has drawn great attention for its potent bioactivities against ischemia-induced injury both in vitro and in vivo. In this study, we evaluated SalA's protective effects against acute ischemic stroke by inducing middle cerebral artery occlusion/reperfusion (MCAO) injuries in mice. Treatment of the mice with SalA (50 and 100µg/kg, i.v.) at 2h after MCAO enhanced their survival rate, improved their moving activity, and ameliorated the severity of brain infarction and apoptosis seen in the mice by diminishing pathological changes such as the extensive breakdown of the blood-brain barrier (BBB), nitrosative stress, and the activation of an inflammatory transcriptional factor p65 nuclear factor-kappa B (NF-κB) and a pro-apoptotic kinase p25/Cdk5. SalA also intensively limited cortical infarction and promoted the expression of neurogenesis protein near the peri-infarct cortex and subgranular zone of the hippocampal dentate gyrus by compromising the activation of GSK3ß and p25/Cdk5, which in turn upregulated ß-catenin, doublecortin (DCX), and Bcl-2, most possibly through the activation of PI3K/Akt signaling via the upregulation of brain-derived neurotrophic factor. We conclude that SalA blocks inflammatory responses by impairing NF-κB signaling, thereby limiting inflammation/nitrosative stress and preserving the integrity of the BBB; SalA also concomitantly promotes neurogenesis-related protein expression by compromising GSK3ß/Cdk5 activity to enhance the expression levels of ß-catenin/DCX and Bcl-2 for neuroprotection.

Quality Improvement in Acute Ischemic Stroke Care in Taiwan: The Breakthrough Collaborative in Stroke.

In the management of acute ischemic stroke, guideline adherence is often suboptimal, particularly for intravenous thrombolysis or anticoagulation for atrial fibrillation. We sought to improve stroke care quality via a collaborative model, the Breakthrough Series (BTS)-Stroke activity, in a nationwide, multi-center activity in Taiwan. A BTS Collaborative, a short-term learning system for a large number of multidisciplinary teams from hospitals, was applied to enhance acute ischemic stroke care quality. Twenty-four hospitals participated in and submitted data for this stroke quality improvement campaign in 2010-2011. Totally, 14 stroke quality measures, adopted from the Get With The Guideline (GWTG)-Stroke program, were used to evaluate the performance and outcome of the ischemic stroke patients. Data for a one-year period from 24 hospitals with 13,181 acute ischemic stroke patients were analyzed. In 14 hospitals, most stroke quality measures improved significantly during the BTS-activity compared with a pre-BTS-Stroke activity period (2006-08). The rate of intravenous thrombolysis increased from 1.2% to 4.6%, door-to-needle time ≤60 minutes improved from 7.1% to 50.8%, symptomatic hemorrhage after intravenous thrombolysis decreased from 11.0% to 5.6%, and anticoagulation therapy for atrial fibrillation increased from 32.1% to 64.1%. The yearly composite measures of five stroke quality measures revealed significant improvements from 2006 to 2011 (75% to 86.3%, p<0.001). The quarterly composite measures also improved significantly during the BTS-Stroke activity. In conclusion, a BTS collaborative model is associated with improved guideline adherence for patients with acute ischemic stroke. GWTG-Stroke recommendations can be successfully applied in countries besides the United States.

Validation of NINDS-VCI Neuropsychology Protocols for Vascular Cognitive Impairment in Taiwan.

OBJECTIVE: To validate the three time-difference neuropsychological protocols developed by the National Institute of Health/National Institute of Neurological Disorders and Stroke (NINDS) and the Canadian Stroke Network for assessment of vascular cognitive impairment (VCI) in Mandarin-speaking subjects and to investigate the clinical application of the shortest form. METHODS: Patients aged 50 years or older who had a stroke were invited to participate in the study. Clinical diagnosis of VCI was made. The NINDS-VCI Neuropsychology Protocols, 60-, 30-, and two 5-minute protocols, were administered. The criteria validities of the cognitive protocols against the diagnoses of stroke and VCI were determined via Receiver Operating Characteristic (ROC) analysis. The optimal cut-off point for the 5-minute protocols total score was estimated for clinical use in screening. RESULTS: Eighty-three patients and 53 controls were recruited during the study period. Patients with stroke performed more poorly than the control group in the three neuropsychological protocols. Forty-two patients with stroke were diagnosed with VCI. VCI was used as the standard to estimate the criteria validities. The area under the ROC curve was 0.78, 0.80, 0.75, and 0.73 for the 60-, 30-, 5-mintue protocol-A and 5-minute protocol-B, respectively. CONCLUSION: These modified neuropsychological protocols can be used as valid instruments when performing comprehensive cognitive assessment or for screening of VCI in Taiwan.

The assessment of anticoagulant activity to predict bleeding outcome in atrial fibrillation patients receiving dabigatran etexilate.

Special circumstances may require the measurement of the anticoagulant effect of dabigatran etexilate. No data currently link any given coagulation test to bleeding outcomes in patients receiving dabigatran etexilate for atrial fibrillation. Nonvalvular atrial fibrillation patients receiving dabigatran etexilate of 110 mg (DE110) or 150 mg (DE150) were consecutively enrolled. The hemoclot thrombin inhibitor (HTI) assay, prothrombin time, and activated partial thromboplastin time (APTT) measurements were correlated with bleeding events during a prospective follow-up. There were 17 bleeding events (8.2%) in 208 patients (74.7 ±â€Š10.3 years old, 67.9% male, median follow-up: 364 days), whereas 15 patients with bleeding events used DE110. Compared with DE110, the patients receiving DE150 were younger and more often male and had lower HAS-BLED and CHA2DS2VASc scores and better renal function. Patients' HTI levels were very variable (DE110, 10-90th percentile: 20.5-223.9 ng/ml). A receiver-operator characteristic curve gave a median cutoff HTI level of 117.7 ng/ml to predict bleeding events (C-statistics: 0.65; P = 0.036), but no cutoff could be determined for prothrombin time or APTT. Based on the Kaplan-Meier analysis, a dabigatran etexilate level greater than 117.7 ng/ml was associated with a higher bleeding rate (15.4% vs. 4.9%, P = 0.01). After multivariate Cox regression analysis, HTI levels, history of stroke, and male sex were independent risk factors for bleeding events. Dabigatran etexilate-HTI levels were independently associated with bleeding in patients receiving routine clinical care. Blood sampling at multiple time points might be needed to increase reliability because of high variation of dabigatran etexilate-HTI levels.

Cold Exposure Can Induce an Exaggerated Early-Morning Blood Pressure Surge in Young Prehypertensives.

Prehypertension is related to a higher risk of cardiovascular events than normotension. Our previous study reported that cold exposure elevates the amplitude of the morning blood pressure surge (MBPS) and is associated with a sympathetic increase during the final sleep transition, which might be critical for sleep-related cardiovascular events in normotensives. However, few studies have explored the effects of cold exposure on autonomic function during sleep transitions and changes of autonomic function among prehypertensives. Therefore, we conducted an experiment for testing the effects of cold exposure on changes of autonomic function during sleep and the MBPS among young prehypertensives are more exaggerate than among young normotensives. The study groups consisted of 12 normotensive and 12 prehypertensive male adults with mean ages of 23.67 ± 0.70 and 25.25 ± 0.76 years, respectively. The subjects underwent cold (16°C) and warm (23°C) conditions randomly. The room temperature was maintained at either 23°C or 16°C by central air conditioning and recorded by a heat-sensitive sensor placed on the forehead and extended into the air. BP was measured every 30 minutes by using an autonomic BP monitor. Electroencephalograms, electrooculograms, electromyograms, electrocardiograms, and near body temperature were recorded by miniature polysomnography. Under cold exposure, a significantly higher amplitude of MBPS than under the warm condition among normotensives; however, this change was more exaggerated in prehypertensives. Furthermore, there was a significant decrease in parasympathetic-related RR and HF during the final sleep transition and a higher early-morning surge in BP and in LF% among prehypertensives, but no such change was found in normotensives. Our study supports that cold exposure might increase the risk of sleep-related cardiovascular events in prehypertensives.

Differential changes and interactions of autonomic functioning and sleep architecture before and after 50 years of age.

We hypothesize that the time when age-related changes in autonomic functioning and in sleep structure occur are different and that autonomic functioning modulates sleep architecture differently before and after 50 years of age. Sixty-eight healthy subjects (aged 20 to 79 years old, 49 of them women) were enrolled. Correlation analysis revealed that wake after sleep onset, the absolute and relative value of stage 1 (S1; S1%), and relative value of stage 2 (S2) were positively correlated with age; however, sleep efficiency, stage 3 (S3), S3%, and rapid-eye-movement latency (REML) were negatively correlated with age. Significant degenerations of sleep during normal aging were occurred after 50 years of age; however, significant declines of autonomic activity were showed before 50 years of age. Before 50 years of age, vagal function during sleep was negatively correlated with arousal index; however, after 50 years of age, it was positively correlated with S1 and S1%. In addition, sympathetic activity during wake stage was positively related to S2% only after 50 years of age. Our results imply that the age-related changes in autonomic functioning decline promptly as individuals leave the younger part of their adult life span and that age-related changes in sleep slowly develop as individuals enter the older part of their adult life span. Furthermore, while various aspects of sleep architecture are modulated by both the sympathetic and vagal nervous systems during adult life span, the sleep quality is mainly correlated with the sympathetic division after 50 years of age.

Sympathetic Hyperactivity, Sleep Fragmentation, and Wake-Related Blood Pressure Surge During Late-Light Sleep in Spontaneously Hypertensive Rats.

BACKGROUND: Many cardiovascular disease events occur before morning awaking and are more severe in hypertensive patients. Sleep-related cardiovascular regulation has been suggested to play an important role in the pathogenesis. In this study, we explored whether such impairments are exaggerated during late sleep (before the active phase) in spontaneously hypertensive rats (SHRs). METHODS: Polysomnographic recording was performed through wireless transmission in freely moving SHRs and Wistar-Kyoto rats (WKYs) over 24 hours. The SHRs were injected with saline and an α1-adrenergic antagonist (prazosin: 5 mg/kg) on 2 separate days. Cardiovascular and autonomic functions were assessed by cardiovascular variability and spontaneous baroreflex analysis. RESULTS: Compared with the early-light period (Zeitgeber time (ZT) 0-6 hours), both the WKYs and SHRs during the late-light period (ZT 6-12 hours) showed sleep fragmentation, sympathovagal imbalance, and baroreflex impairment, which were exaggerated and more advanced in the SHRs. Like the morning blood pressure (BP) surge in humans, we found that there was a wake-related blood pressure surge (WBPS) during the late-light period in both groups of rats. The WBPS was also greater and occurred earlier in the SHRs, and was accompanied by a surge in vascular sympathetic index. Under α1-adrenergic antagonism, the late-light period-related sleep fragmentation and BP surge in the SHRs were partially reversed. CONCLUSIONS: Our results reveal that sleep-related sympathetic overactivity, baroreflex sensitivity impairment, WBPS, and sleep fragmentation in SHRs deteriorates during the late-light period can be partially alleviated by treatment with an α1-adrenoceptor antagonist.

Characterization of CADASIL among the Han Chinese in Taiwan: Distinct Genotypic and Phenotypic Profiles.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is originally featured with a strong clustering of mutations in NOTCH3 exons 3-6 and leukoencephalopathy with frequent anterior temporal pole involvement. The present study aims at characterizing the genotypic and phenotypic profiles of CADASIL in Taiwan. One hundred and twelve patients with CADASIL from 95 families of Chinese descents in Taiwan were identified by Sanger sequencing of exons 2 to 24 of NOTCH3. Twenty different mutations in NOTCH3 were uncovered, including 3 novel ones, and R544C in exon 11 was the most common mutation, accounting for 70.5% of the pedigrees. Haplotype analyses were conducted in 14 families harboring NOTCH3 R544C mutation and demonstrated a common haplotype linked to NOTCH3 R544C at loci D19S929 and D19S411. Comparing with CADASIL in most Caucasian populations, CADASIL in Taiwan has several distinct features, including less frequent anterior temporal involvement, older age at symptom onset, higher incidence of intracerebral hemorrhage, and rarer occurrence of migraine. Subgroup analyses revealed that the R544C mutation is associated with lower frequency of anterior temporal involvement, later age at onset and higher frequency of cognitive dysfunction. In conclusion, the present study broadens the spectrum of NOTCH3 mutations and provides additional insights for the clinical and molecular characteristics of CADASIL patients of Han-Chinese descents.

A clinical study of integrating acupuncture and Western medicine in treating patients with Parkinson's disease.

Complementary therapy with acupuncture for Parkinson's disease (PD) has been studied for quite a long time, but the effectiveness of the treatment still remains unclear. The aim of this study is to evaluate the integrated effects of acupuncture treatment in PD patients who received western medicine. In the short-term acupuncture treatment study, 20 patients received acupuncture therapy twice a week in acupoints DU 20, GB 20, LI 11, LI 10, LI 4, GB 31, ST 32, GB 34 and GB 38 along with western medicine for 18 weeks, and 20 controlled patients received western medicine only. In the long-term acupuncture treatment, 13 patients received acupuncture treatment twice a week for 36 weeks. The outcome parameters include Unified Parkinson's disease rating scale (UPDRS), Beck Anxiety Inventory (BAI), Beck Depression Inventory-Version 2 (BDI-II), and WHO quality of life (WHOQOL). In the short-term clinical trial, a higher percentage of patients in the acupuncture group had score improvement in UPDRS total scores (55% vs. 15%, p = 0.019), sub-score of mind, behavior and mood (85% vs. 25%, p < 0.001), activity of daily living (65% vs. 15%, p = 0.003), mobility (40% vs. 15%, p = 0.155) and complication of treatment (75% vs. 15%, p < 0.001), BDI-II score (85% vs. 35%, p = 0.003), and WHOQOL score (65% vs. 15%, p = 0.003) when compared to control group at the end of the 18 weeks' follow up. After 36 weeks of long-term acupuncture treatment, the mean UPDRS total scores and sub-score of mentation, behavior and mood, sub-score of complications of therapy and BDI-II score decreased significantly when compared to the pretreatment baseline. In conclusion, acupuncture treatment had integrated effects in reducing symptoms and signs of mind, behavior, mood, complications of therapy and depression in PD patients who received Western medicine.