Effect of Argatroban Plus Intravenous Alteplase vs Intravenous Alteplase Alone on Neurologic Function in Patients With Acute Ischemic Stroke: The ARAIS Randomized Clinical Trial.

Importance: Previous studies suggested a benefit of argatroban plus alteplase (recombinant tissue-type plasminogen activator) in patients with acute ischemic stroke (AIS). However, robust evidence in trials with large sample sizes is lacking. Objective: To assess the efficacy of argatroban plus alteplase for AIS. Design, Setting, and Participants: This multicenter, open-label, blinded end point randomized clinical trial including 808 patients with AIS was conducted at 50 hospitals in China with enrollment from January 18, 2019, through October 30, 2021, and final follow-up on January 24, 2022. Interventions: Eligible patients were randomly assigned within 4.5 hours of symptom onset to the argatroban plus alteplase group (n = 402), which received intravenous argatroban (100 µg/kg bolus over 3-5 minutes followed by an infusion of 1.0 µg/kg per minute for 48 hours) within 1 hour after alteplase (0.9 mg/kg; maximum dose, 90 mg; 10% administered as 1-minute bolus, remaining infused over 1 hour), or alteplase alone group (n = 415), which received intravenous alteplase alone. Both groups received guideline-based treatments. Main Outcomes and Measures: The primary end point was excellent functional outcome, defined as a modified Rankin Scale score (range, 0 [no symptoms] to 6 [death]) of 0 to 1 at 90 days. All end points had blinded assessment and were analyzed on a full analysis set. Results: Among 817 eligible patients with AIS who were randomized (median [IQR] age, 65 [57-71] years; 238 [29.1%] women; median [IQR] National Institutes of Health Stroke Scale score, 9 [7-12]), 760 (93.0%) completed the trial. At 90 days, 210 of 329 participants (63.8%) in the argatroban plus alteplase group vs 238 of 367 (64.9%) in the alteplase alone group had an excellent functional outcome (risk difference, -1.0% [95% CI, -8.1% to 6.1%]; risk ratio, 0.98 [95% CI, 0.88-1.10]; P = .78). The percentages of participants with symptomatic intracranial hemorrhage, parenchymal hematoma type 2, and major systemic bleeding were 2.1% (8/383), 2.3% (9/383), and 0.3% (1/383), respectively, in the argatroban plus alteplase group and 1.8% (7/397), 2.5% (10/397), and 0.5% (2/397), respectively, in the alteplase alone group. Conclusions and Relevance: Among patients with acute ischemic stroke, treatment with argatroban plus intravenous alteplase compared with alteplase alone did not result in a significantly greater likelihood of excellent functional outcome at 90 days. Trial Registration: ClinicalTrials.gov Identifier: NCT03740958.

Dual Antiplatelet Therapy vs Alteplase for Patients With Minor Nondisabling Acute Ischemic Stroke: The ARAMIS Randomized Clinical Trial.

Importance: Intravenous thrombolysis is increasingly used in patients with minor stroke, but its benefit in patients with minor nondisabling stroke is unknown. Objective: To investigate whether dual antiplatelet therapy (DAPT) is noninferior to intravenous thrombolysis among patients with minor nondisabling acute ischemic stroke. Design, Setting, and Participants: This multicenter, open-label, blinded end point, noninferiority randomized clinical trial included 760 patients with acute minor nondisabling stroke (National Institutes of Health Stroke Scale [NIHSS] score ≤5, with ≤1 point on the NIHSS in several key single-item scores; scale range, 0-42). The trial was conducted at 38 hospitals in China from October 2018 through April 2022. The final follow-up was on July 18, 2022. Interventions: Eligible patients were randomized within 4.5 hours of symptom onset to the DAPT group (n = 393), who received 300 mg of clopidogrel on the first day followed by 75 mg daily for 12 (±2) days, 100 mg of aspirin on the first day followed by 100 mg daily for 12 (±2) days, and guideline-based antiplatelet treatment until 90 days, or the alteplase group (n = 367), who received intravenous alteplase (0.9 mg/kg; maximum dose, 90 mg) followed by guideline-based antiplatelet treatment beginning 24 hours after receipt of alteplase. Main Outcomes and Measures: The primary end point was excellent functional outcome, defined as a modified Rankin Scale score of 0 or 1 (range, 0-6), at 90 days. The noninferiority of DAPT to alteplase was defined on the basis of a lower boundary of the 1-sided 97.5% CI of the risk difference greater than or equal to -4.5% (noninferiority margin) based on a full analysis set, which included all randomized participants with at least 1 efficacy evaluation, regardless of treatment group. The 90-day end points were assessed in a blinded manner. A safety end point was symptomatic intracerebral hemorrhage up to 90 days. Results: Among 760 eligible randomized patients (median [IQR] age, 64 [57-71] years; 223 [31.0%] women; median [IQR] NIHSS score, 2 [1-3]), 719 (94.6%) completed the trial. At 90 days, 93.8% of patients (346/369) in the DAPT group and 91.4% (320/350) in the alteplase group had an excellent functional outcome (risk difference, 2.3% [95% CI, -1.5% to 6.2%]; crude relative risk, 1.38 [95% CI, 0.81-2.32]). The unadjusted lower limit of the 1-sided 97.5% CI was -1.5%, which is larger than the -4.5% noninferiority margin (P for noninferiority <.001). Symptomatic intracerebral hemorrhage at 90 days occurred in 1 of 371 participants (0.3%) in the DAPT group and 3 of 351 (0.9%) in the alteplase group. Conclusions and Relevance: Among patients with minor nondisabling acute ischemic stroke presenting within 4.5 hours of symptom onset, DAPT was noninferior to intravenous alteplase with regard to excellent functional outcome at 90 days. Trial Registration: ClinicalTrials.gov Identifier: NCT03661411.

Identification of cytokines for early prediction of malignant middle cerebral artery infarction.

PURPOSE: We aimed to profile cytokines in patients with malignant middle cerebral artery infarction (MMI) and non-acute cerebral infarction (NACI), and identify potential cytokines for early prediction of MMI. MATERIALS AND METHODS: A total of 16 subjects were recruited, including 8 patients with MMI and 8 patients with NACI. Cytokine profiles and levels in serums were analyzed by Quantibody® Human Cytokine Antibody Array700. The two-tailed Student t-test and Fisher's Exact Test were respectively conducted for continuous variables and categorical variables to evaluate their differences between patients with MMI and those with NACI. Binary logistic regression was further conducted to verify the association of differentially expressed cytokines with MMI. RESULTS: The concentrations of 320 unique inflammatory cytokines in serums were measured. Ten cytokines were discovered to be differentially expressed between patients with MMI and patients with NACI, including transforming growth factor beta-1 (TGFB1), matrix metallopeptidase 10 (MMP10), neural cell adhesion molecule 1 (NCAM1), interleukin-27 (IL27), epidermal growth factor (EGF), insulin-like growth factor-binding protein 6 (IGFBP6), platelet-derived growth factor subunit A (PDGFA), C-C motif chemokine 2 (C-C CCL2), neutrophil gelatinase-associated lipocalin (Lipocalin 2) and lymphatic vessel endothelial hyaluronic acid receptor 1 (LYVE1). Among these cytokines, the concentrations of NCAM1, IGFBP6, Lipocalin2 and LYVE1 were significantly higher while the concentrations of the other six cytokines were significantly lower in patients with MMI compared with those in patients with NACI. Multivariate logistic regression analysis verified the association of these 10 cytokines with MMI except for IL-27 (p = 0.5422). CONCLUSIONS: Nine cytokines, including NCAM1, IGFBP6, Lipocalin2, LYVE1, TGFB1, MMP10, EGF, PDGFA and CCL2, might act as potential markers for early prediction of MMI and involve in the progression from NACI to MMI. Further studies with a better control group are still needed.

Baseline neurological deficit and argatroban plus alteplase in acute ischemic stroke: A post hoc analysis of ARAIS trial.

BACKGROUND: The ARAIS trial didn't demonstrate argatroban significantly improve functional outcome at 90 days in acute ischemic stroke. We conducted post hoc analysis of ARAIS to investigate whether baseline neurological deficit was associated with outcomes. METHODS: Patients without endovascular therapy who met screening criteria as protocol and completed argatroban treatment were enrolled and classified into two subgroups according to NIHSS score at admission. Primary outcome was excellent functional outcome at 90 days, defined as mRS score of 0 to 1. Early neurological deterioration (END), defined as an increase of ≥4 in the NIHSS score from baseline within 48 hours, was investigated as secondary outcome. Compared with alteplase alone, we investigated treatment effect of argatroban plus alteplase on outcomes in subgroups and interaction with subgroups. RESULTS: A total of 675 patients from full analysis set were included: 390 were assigned into NIHSS score <10 subgroup and 285 into NIHSS score ≥10 subgroup. For primary outcome, there was similar treatment effect between argatroban plus alteplase and alteplase alone in NIHSS score ≥10 subgroup (adjusted RD, 5.8%; 95% CI, -6.0% to 17.5%; P = 0.33) and in NIHSS score <10 subgroup (adjusted RD, -1.4%; 95% CI, -9.9% to 7.1%; P = 0.75), and no significant interaction (P = 0.43). Occurrence of early neurological deterioration within 48 hours were significantly lower in NIHSS score ≥10 subgroup, compared with NIHSS score <10 subgroup (P = 0.006). CONCLUSION: Among patients with NIHSS score ≥10, argatroban plus alteplase could safely reduce END within 48 hours.

The association of admission ionized calcium with outcomes of thrombolysed patients with anterior circulation ischemic stroke.

BACKGROUND AND PURPOSE: The relationship between ionized calcium and prognosis of ischemic stroke is controversial. We aim to determine the relationship of admission ionized calcium levels with acute ischemic stroke (AIS) after intravenous thrombolysis (IVT). METHODS: Consecutive anterior circulation AIS patients treated with recombinant tissue plasminogen activator (rt-PA) were retrospectively enrolled. According to ionized calcium quartiles, the patients were divided into four groups and clinical data were analyzed between groups. Ionized calcium was entered into logistic regression analysis in two models, separately: model 1, calcium as a continuous variable (per 1-mmol/L increase), and model 2, calcium as the four-categorized variable (being collapsed into quartiles: Q1-Q4). Early neurologic improvement (ENI) was defined as improvement of four or more points at 24 h after intravenous rt-PA, while long-term good outcome as the modified Rankin Scale (mRS) 0-1 at 90 days. RESULTS: A total of 546 patients met the study criteria (mean age was 63.51 ± 11.26 years and 365 [66.8%] were men). The median admission National Institute of Health Stroke Scale was 9 (range 4 to 15). When not adjusted, in model 1: ionized calcium was related to good outcome (odds ratio [OR] 69.061, 95%CI: 1.638-2911.111, p=0.027), but not ENI (OR 14.097, 95%CI: 0.133-1492.596, p=0.266); in model 2: compared with Q4, while good outcome was less common in Q1 (OR 0.623, 95%CI: 0.388-0.999, p=0.049). After adjusting for confounding factors, calcium in Q2 (OR 0.502, 95%CI: 0.253-0.997, p=0.049) was independently associated with ENI, but no matter as a continuous variable or categorized variable, ionized calcium displayed no association with a good outcome. CONCLUSION: The current results found that ionized calcium might be associated with early neurological improvement, but had no association with 3 months' outcome in anterior circulation AIS patients after IVT.

Cretaceous basin evolution in northeast Asia: tectonic responses to the paleo-Pacific plate subduction.

Cretaceous rift basin evolution was an important part of the tectonic history of northeast Asia in the late Mesozoic. Three types of rift basins are identified-active, passive and wide rift basins-and they developed in different regions. Passive rift basins in the eastern North China craton are thought to be the consequence of crustal stretching and passive asthenospheric upwelling. Wide rift basins in the eastern Central Asian orogen are assumed to originate from gravitational collapse of the thickened and heated orogenic crust. Active rift basins in the northern North China craton are attributed to uprising of asthenospheric materials along a lithospheric-scale tear fault. Slab tearing of the subducting paleo-Pacific plate is postulated and well explains the spatial distribution of different types of rift basins and the eastward shifting of magmatism in the northern North China craton. The Late Cretaceous witnessed a period of mild deformation and weak magmatism, which was possibly due to kinematic variation of the paleo-Pacific plate.

Safety and preliminary efficacy of argatroban plus dual antiplatelet therapy for acute mild to moderate ischemic stroke with large artery atherosclerosis.

OBJECTIVE: Previous studies suggest the benefit of dual antiplatelet therapy (DAPT) for acute ischemic stroke with large artery atherosclerosis (LAA) etiology, but there is no study about the effect of DAPT plus anticoagulant in this population. METHODS: A prospective single arm trial was performed to determine the effect of DAPT combined with argatroban on acute mild to moderate ischemic stroke patients with LAA, which was compared with historical populations. The main outcome was the proportion of early neurological deterioration (END). The secondary outcomes included scores of 0 to 1 and 0 to 2 on the modified Rankin Scale (mRS) at 90 days, and changes in National Institutes of Health Stroke Scale (NIHSS) from baseline to day 7 after admission. The safety outcomes included intracranial hemorrhage at 7 days, organ hemorrhage, and all-cause mortality at 90 days. RESULTS: A total of 120 patients with argatroban plus DAPT were prospectively enrolled and 529 patients with only DAPT were retrospectively collected. There was no significant difference in baseline characteristics between groups. Compared with control group, combined treatment group had lower proportion of END (4.2% vs. 10.0%, adjusted p = .046), more reduction in NIHSS score from the baseline to day 7 after admission (1.06 ± 2.03 vs. 0.39 ± 1.97, adjusted p = .003), and higher proportion of mRS (0-2) at 90 days (87.5% vs. 79.2%, adjusted p = .048). No intracranial hemorrhage was found between groups. CONCLUSIONS: This is the first report that short-term argatroban combined with DAPT seems to be safe and may effectively prevent END and improve neurological prognosis for acute mild to moderate ischemic stroke patients with LAA; however, interpretation of the conclusion required caution due to nonrandomized controlled trial with medium sample size.

Treatment with Delipid Extracorporeal Lipoprotein Filter from Plasma after Intravenous Thrombolysis for Acute Ischemic Stroke: A Single-Center Experience.

INTRODUCTION: The delipid extracorporeal lipoprotein filter from plasma (DELP) has been approved for the treatment of acute ischemic stroke (AIS) by the China Food and Drug Administration, but its effectiveness and mechanism are not yet fully determined. The purpose of this study was to evaluate the effect of DELP treatment on AIS patients after intravenous thrombolysis. METHODS: A retrospective study was performed on AIS patients with no improvement within 24 h after intravenous thrombolysis who were subsequently treated with or without DELP. Primary outcome was the proportion with a modified Rankin scale (mRS) of 0-1 at 90 days. Secondary outcomes were changes in National Institute of Health Stroke Scale (NIHSS) score from 24 h to 14 days after thrombolysis, and the rate of improvement in stroke-associated pneumonia (SAP). The main safety outcomes were the rates of symptomatic intracranial hemorrhage and mortality. To investigate its mechanisms, serum biomarkers were measured before and after DELP. RESULTS: A total of 252 patients were recruited, 63 in the DELP group and 189 matched patients in the NO DELP group. Compared with the NO DELP group, the DELP group showed an increase in the proportion of mRS 0-1 at 90 days (p = 0.042). More decrease in NIHSS from 24 h to 14 days (p = 0.024), a higher rate of improvement in SAP (p = 0.022), and lower mortality (p = 0.040) were shown in DELP group. Furthermore, DELP decreased levels of interleukin (IL)-1ß, E-selectin, malondialdehyde, matrix metalloprotein 9, total cholesterol, low-density lipoprotein, and fibrinogen, and increased superoxide dismutase (p< 0.05). CONCLUSIONS: DELP following intravenous thrombolysis should be safe, and is associated with neurological function improvement, possibly through multiple neuroprotective mechanisms. Prospective trials are needed.

Remote ischemic conditioning for acute moderate ischemic stroke (RICAMIS): Rationale and design.

RATIONALE: A large number of basic and clinical studies have proved that remote ischemic conditioning has neuroprotective effect. For example, remote ischemic conditioning showed a neuroprotective role in cerebral ischemia-reperfusion injury model. Recent clinical studies suggested that remote ischemic conditioning may improve neurological function and reduce the risk of recurrence in ischemic stroke patients. However, there is a lack of convincing evidence for the neuroprotective effect of remote ischemic conditioning on ischemic stroke, which deserves further study. AIM: To explore the efficacy and safety of remote ischemic conditioning for acute moderate ischemic stroke. SAMPLE SIZE ESTIMATES: A maximum of 1800 subjects are required to test the superiority hypothesis with 80% power according to a one-sided 0.025 level of significance, stratified by gender, age, time from onset to treatment, National Institutes of Health Stroke Scale (6-10 vs. 11-16), degree of responsible vessel stenosis, location of stenosis, and stroke etiology. METHODS AND DESIGN: Remote Ischemic Conditioning for Acute Moderate Ischemic Stroke is a prospective, random, open label, blinded endpoint and multi-center study. The subjects are divided into experimental group and control group randomly. The experimental group was treated with remote ischemic conditioning twice daily with 200 mmHg pressure for 10-14 days besides guideline-based therapy. The control group was treated according to the guidelines. STUDY OUTCOME: The primary efficacy endpoint is favorable functional outcome, defined as modified Rankin Scale 0-1 at 90 days post-randomization.

Effect of Argatroban Combined With Dual Antiplatelet Therapy on Early Neurological Deterioration in Acute Minor Posterior Circulation Ischemic Stroke.

There is a lack of studies on anticoagulant plus antiplatelet therapy for acute ischemic stroke. The present study made a pilot effort to investigate the efficacy and safety of argatroban plus dual antiplatelet therapy (DAPT) in patients with acute posterior circulation ischemic stroke (PCIS). We retrospectively collected patients diagnosed with acute PCIS according to inclusion/exclusion criteria. According to treatment drugs, patients were divided into an argatroban plus DAPT group and a DAPT group. The primary efficacy end point was the proportion of early neurological deterioration (END). The primary safety outcome was symptomatic intracranial hemorrhage. All outcomes were compared between the 2 groups before and after propensity score matching (PSM). A total of 502 patients were enrolled in the study, including 35 patients with argatroban plus DAPT and 467 patients with DAPT. There was a higher National Institutes of Health Stroke Scale (NIHSS) score in the argatroban plus DAPT group than the DAPT group before PSM (3 vs 2, P = .017). Compared with the DAPT group, the argatroban plus DAPT group had no END (before PSM: 0% vs 6.2%, P = .250; after PSM: 0% vs 5.9%, P = .298). Argatroban plus DAPT yielded a significant decrease in the NIHSS score from baseline to 7 days after hospitalization, compared with that of the DAPT group before PSM (P = .032), but not after PSM (P = .369). No symptomatic intracranial hemorrhage was found in any patient. A short-term combination of argatroban with DAPT appears safe in acute minor PCIS.

Antiplatelet vs. R-tPA for acute mild ischemic stroke: A prospective, random, and open label multi-center study.

RATIONALE: The evidence of intravenous thrombolysis in patients with not clearly disabling minor stroke (low National Institutes of Health Stroke Scale of 0-5) is still insufficient. Recent early terminated PRISMS trial could not provide definitive conclusion, although suggesting the similar functional outcome between alteplase and aspirin groups. Recent two clinical trials provide a definitive evidence for the superiority of dual antiplatelet to mono-antiplatelet in minor stroke. However, the efficacy and safety of dual antiplatelet vs. alteplase in the treatment of acute minor stroke are not known. AIM: To explore the efficacy and safety of dual antiplatelet with aspirin and clopidogrel vs. alteplase in the treatment of acute minor stroke. SAMPLE SIZE ESTIMATES: A maximum of 760 subjects are required to test the non-inferiority hypothesis with 80% power according to a one-sided 0.025 level of significance, stratified by age, diabetes, time from onset to treatment, stroke etiology, degree of vascular stenosis, location of index vessel. METHODS AND DESIGN: ARAMIS is a prospective, randomized, open label, blinded assessment of endpoints (PROBE) and multicenter clinical trial in China. The subjects are randomized to the control arm (intravenous alteplase with standard dose of 0.9 mg/kg, followed by guideline-based treatment 24 h after thrombolysis) or the experiment arm (clopidogrel: loading dose of 300 mg on the first day, followed by 75 mg daily for 10-14 days; aspirin: 100 mg on the first day, followed by 100 mg daily for 10-14 days; after the combination, antiplatelet will be given based on guideline till 90 days). STUDY OUTCOME: The primary efficacy endpoint is favorable functional outcome, defined as a mRS 0-1 assessed at 90-day post-randomization.

Dehydration is a strong predictor of long-term prognosis of thrombolysed patients with acute ischemic stroke.

Background and Purpose: Dehydration was found to be involved in the poor prognosis of patients with acute ischemic stroke. It is unclear whether dehydration status before onset is related with prognosis of thrombolysed patients with acute ischemic stroke. If it is the case, quickly hydrating may improve the prognosis. The present study was designed to explore the issue. Methods: Eligible 294 patients with acute ischemic stroke after thrombolysis were enrolled in the present study according to inclusion/exclusion criteria. According to the modified Rankin scale (mRS) 90 days post stroke, the patients were divided into two groups: mRS 0-2 (n = 191) and mRS 3-6 (n = 103). In the present study, BUN/Cr ≥ 15 combined with USG > 1.010 or either of them were chosen as dehydration marker. Clinical data were analyzed between two groups. Univariate and multivariate statistical analyses were carried out. Results: Age, fibrinogen, blood glucose, BUN/Cr, NIHSS score at admission, the systolic blood pressure (SBP) before thrombolysis, dehydration status (BUN/Cr ≥ 15 plus USG > 1.010), hyperlipidemia, USG and D-dimer on admission day, and TOAST classification showed significant difference between two groups (p < .05). Further stratification analysis showed that BUN/Cr ≥ 15, NIHSS ≥ 6, blood glucose ≥8, and SBP > 150 were markedly associated with poor outcome (mRS 3-6, p < .05). After adjusting for age, fibrinogen, USG, D-dimer, dehydration status, NIHSS, blood glucose, SBP, hyperlipidemia, and BUN/Cr at admission, multivariate logistic regression showed that dehydration status, higher NIHSS, higher blood glucose, and higher SBP at admission were independent risk factors for predicting the long-term poor prognosis of thrombolysed patients. Conclusions: The present findings suggest that BUN/Cr ≥ 15 combined with USG > 1.010 as a marker of dehydration status was an independent risk factor for long-term poor prognosis of thrombolysed patients with acute ischemic stroke.

Comorbidity burden of patients with Parkinson's disease and Parkinsonism between 2003 and 2012: A multicentre, nationwide, retrospective study in China.

Parkinson's disease (PD) and Parkinsonism are common neurodegenerative disorders with continuously increasing prevalence, causing high global burdens. However, data concerning the comorbidity burden of patients with PD or Parkinsonism in China are lacking. To investigate the health condition and comorbidity burden, a total of 3367 PD and 823 Parkinsonism patients were included from seven tertiary hospitals in seven cities across China from 2003 to 2012. Their comorbidity burden was collected and quantified by the Elixhauser Comorbidity Index (ECI) and Charlson Comorbidity Index (CCI). The comorbidity spectra differed between PD and Parkinsonism patients. Compared with PD patients, Parkinsonism patients were older (69.8 ± 11.5 vs. 67.9 ± 11.4, P < 0.001); had a higher comorbidity burden, including ECI (1.1 ± 1.2 vs. 1.0 ± 1.2, P < 0.001) and CCI (1.3 ± 1.6 vs. 1.1 ± 1.5, P < 0.001); and had higher hospitalization expenses. The ECI (1.1 ± 1.3 vs. 0.9 ± 1.1, P < 0.001) and CCI (1.3 ± 1.6 vs. 0.9 ± 1.2, P < 0.001) were higher in males than in females. The average length of stay and daily hospitalization expenses increased with age, as did ECI and CCI. This is the first study to report the disease burden of Chinese PD and Parkinsonism patients. It provides useful information to better understand their health status, and to raise the awareness of clinicians for providing better health care.

Comorbidity Burden of Dementia: A Hospital-Based Retrospective Study from 2003 to 2012 in Seven Cities in China.

Dementia is increasing dramatically and imposes a huge burden on society. To date, there is a lack of data on the health status of patients with dementia in China. In an attempt to investigate the comorbidity burden of dementia patients in China at the national level, we enrolled 2,938 patients with Alzheimer's disease (AD), vascular dementia (VaD), or other types of dementia, who were admitted to tertiary hospitals in seven regions of China from January 2003 to December 2012. The Charlson Comorbidity Index (CCI) was used to evaluate the comorbidity burden of the patients with dementia. Among these patients, 53.4% had AD, 26.3% had VaD, and 20.3% had other types of dementia. The CCI was 3.0 ± 1.9 for all patients, 3.4 ± 1.8 for those with VaD, and 3.0 ± 2.1 for those with AD. The CCI increased with age in all patients, and the length of hospital stay and daily expenses rose with age and CCI. Males had a higher CCI and a longer stay than females. Moreover, patients admitted in the last 5 years of the study had a higher CCI than those admitted in the first 5 years. We found that the comorbidity burden of patients with dementia is heavy. These findings provide a better understanding of the overall health status of dementia patients, and help to increase the awareness of clinicians and policy-makers to improve medical care for patients.

Chronic restraint stress exacerbates nociception and inflammatory response induced by bee venom in rats: the role of the P2X7 receptors.

OBJECTIVE: Chronic restraint stress exacerbates pain and inflammation. The present study was designed to evaluate the effect of chronic restraint stress on inflammatory pain induced by subcutaneous injection of bee venom (BV). METHODS: First, we investigated: (1) the effect of two-week restraint stress with daily 2 or 8 h on the baseline paw withdrawal mechanical threshold (PWMT), paw withdrawal thermal latency (PWTL) and paw circumference (PC); (2) the effect of chronic stress on the spontaneous paw-flinching reflex (SPFR), decrease in PWM, PWTL and increase in PC of the injected paw induced by BV. RESULTS: The results showed that (1) chronic restraint decreased significantly the PWMT and inhibited significantly the increase in PC, but had no effect on PWTL, compared with control group; (2) chronic restraint enhanced significantly BV-induced SPFR and inflammatory swelling of the injected paw. In a second series of experiments, the role of P2X7 receptor (P2X7R) in the enhancement of BV-induced inflammatory pain produced by chronic restraint stress was determined. Systemic pretreatment with P2X7R antagonist completely reversed the decrease in PWMT produced by chronic restraint, inhibited significantly the enhancement of BV-induced inflammatory pain produced by chronic restraint stress. CONCLUSION: Taken together, our data indicate that chronic restraint stress-enhanced nociception and inflammation in the BV pain model, possibly involving the P2X7R.

Contribution of capsaicin-sensitive primary afferents to mechanical hyperalgesia induced by ventral root transection in rats: the possible role of BDNF.

OBJECTIVE: A recent study showed that brain-derived neurotrophic factor (BDNF) may play a role in the development of the neuropathic pain resulting from injury to motor efferent fibres, such as that in the ventral root transection (VRT) model. Capsaicin stimulation of afferent fibres was also shown to result in the release of BDNF into the spinal cord. Here, the effects of ablation of capsaicin-sensitive primary afferents (CSPAs) by local application of capsaicin on the sciatic nerve on VRT-induced mechanical hyperalgesia were observed. METHODS: The paw withdrawal mechanical threshold (PWMT) was measured before and then 1 and 3 days and 1, 2, 3, 4 and 6 weeks after VRT. RESULTS: The results showed that local application of capsaicin significantly inhibited the decrease in the PWMT induced by VRT, suggesting the inhibitory effect of locally delivered capsaicin. Furthermore, intrathecal administration of exogenous BDNF not only produced mechanical hyperalgesia but also significantly blocked the inhibitory effect of capsaicin. CONCLUSION: Taken together, the results of this study suggest that CSPA fibres may contribute to mechanical hyperalgesia in the VRT model.

Clopidogrel plus aspirin versus aspirin alone for preventing early neurological deterioration in patients with acute ischemic stroke.

Recent studies have suggested that combination antiplatelet therapy may be superior to monotherapy in the treatment of acute stroke. However, additional prospective studies are needed to confirm this finding. The present trial compared the efficacy and safety of clopidogrel plus aspirin versus aspirin alone in the treatment of non-cardioembolic ischemic stroke within 72 hours of onset. Six hundred and ninety patients aged ⩾ 40 years with minor stroke or transient ischemic attack (TIA) were identified for enrollment. Experienced physicians determined baseline National Institutes of Health Stroke Scale scores at the time of admission. All patients were randomly allocated (1:1) to receive aspirin alone (300 mg/day) or clopidogrel (300 mg for the first day, 75 mg/day thereafter) plus aspirin (100mg/day). The main endpoints were neurological deterioration, recurrent stroke, and development of stroke in patients with TIA within 14 days of admission. After 43 patients were excluded, 321 patients in the dual therapy group and 326 patients in the monotherapy group completed the treatment. Baseline characteristics were similar between groups. During the 2 week period, stroke deterioration occurred in nine patients in the dual therapy group and 19 patients in the monotherapy group. Stroke occurred after TIA in one patient in the dual therapy group and three patients in the monotherapy group. Similar numbers of adverse events occurred in both groups. This study showed that early dual antiplatelet treatment reduced early neurological deterioration in patients with acute ischemic stroke, compared with antiplatelet monotherapy. These results imply that dual antiplatelet therapy is superior to monotherapy in the early treatment of acute ischemic stroke.

Contribution of brain-derived neurotrophic factor to mechanical hyperalgesia induced by ventral root transection in rats.

It is generally believed that the development of neuropathic pain primarily results from injuries to sensory afferent fibers. Recent studies found that injuries to the motor efferent fibers (e.g. ventral root transection) also contribute to the development of neuropathic pain. Furthermore, an increase in brain-derived neurotrophic factor (BDNF) synthesis has been found in the ventral root transection model, suggesting a possible role of BDNF in this model. To determine the role of BDNF, we observed the effects of intrathecal antibody against BDNF treatment on ventral root transection-induced mechanical hyperalgesia. Paw withdrawal thresholds to mechanical stimuli were measured before and after surgery. The results showed that ventral root transection in rats produced a significant, lasting decrease of mechanical withdrawal thresholds, presenting the development of mechanical hyperalgesia. Intrathecal antibody against BDNF treatment markedly inhibited ventral root transection-induced mechanical hyperalgesia in a dose-related manner. The findings suggest that BDNF-mediated signaling pathway within spinal cord may be involved in the development of neuropathic pain involving injuries to motor efferent fibers.

Contribution of the spinal P2X7 receptors to bee venom-induced nociception and inflammation in conscious rats.

Recently, P2X7 receptor (P2X7R) has been found to contribute to the development of inflammatory pain, however, the role of spinal P2X7R is not clear. The present study was designed to determine the roles of spinal P2X7R in the bee venom (BV) model, characterized by multiple pain-related behaviors and obvious inflammatory edema. We determined the effects of P2X7R antagonist A438790 on BV-induced PSN, mechanical allodynia and inflammatory swelling. Pre-treatment with intrathecal administration of A438079 significantly inhibited BV-induced PSN and mechanical allodynia in a dose-dependent manner, but had no effect on BV-induced inflammatory swelling. These data suggest that the activation of spinal P2X7Rs may play a key role in BV-induced nociception, but not inflammation.

Systemic administration of argatroban inhibits protease-activated receptor-1 expression in perihematomal tissue in rats with intracerebral hemorrhage.

The present study investigated the role of thrombin in the expression of protease-activated receptor-1 (PAR-1), and the effect of argatroban (Arg) a direct thrombin inhibitor, on PAR-1 expression in perihematomal tissue with intracerebral hemorrhage (ICH). For these experiments 90 rats were divided into 5 groups: sham, ICH, argatroban-treated ICH (ICH+Arg), thrombin (TM) and argatroban-treated thrombin (TM+Arg). The ICH model or thrombin injection models were established by injecting autologous blood or thrombin, respectively. Rats in TM+Arg and ICH+Arg groups were administered argatroban (0.9mg/kg) after models were established for 3h and 12h, intraperitoneally. All rats were killed to harvest brains after models were established for 24h. The levels of PAR-1 protein and PAR-1 mRNA expression were detected by Western blot and RT-PCR, respectively. Brain water content was also measured. Our results showed that the levels of PAR-1 protein or PAR-1 mRNA in ICH and TM groups were up-regulated compared to that observed for the sham group; while the levels observed in ICH+Arg group and TM+Arg group were significantly lower than that observed for the ICH group and TM group (P<0.01 or P<0.05). The intraperitoneal administration argatroban also significantly reduced edema in ICH or TM group (P<0.05). Our observations suggested that the production of thrombin following ICH play a key role in the up-regulation of PAR-1 and anti-PAR-1 by systemic administration of argatroban, and may be a potential strategy for ICH therapy.