Detecting prokaryote-specific gene and other bacterial signatures in thrombi from patients with acute ischemic stroke.

BACKGROUND AND PURPOSE: Microbial infection has been associated with thrombogenesis. This study aimed to detect bacterium-specific genes and other signatures in thrombi from patients with acute ischemic stroke and to relate these signatures to clinical characteristics. METHODS: Blood samples were collected before thrombectomy procedures, and thrombus samples were obtained during the procedure. Identification and classification of bacteria in the samples were accomplished using 16 S rRNA gene sequencing. Bacterium-specific structures were observed with transmission electron microscopy. Bacterium-specific biomarkers were detected through immunohistochemical staining. RESULTS: 16 S rRNA gene was detected in 32.1% of the thrombus samples from 81 patients. Bacillus (0.04% vs. 0.00046%, p = 0.003), Parabacteroides (0.20% vs. 0.09%, p = 0.029), Prevotella (1.57% vs. 0.38%, p = 0.010), Streptococcus (1.53% vs. 0.29%, p = 0.001), Romboutsia (0.18% vs. 0.0070%, p = 0.029), Corynebacterium (1.61% vs. 1.26%, p = 0.026) and Roseburia (0.53% vs. 0.05%, p = 0.005) exhibited significantly higher abundance in thrombi compared to arterial blood. Bacteria-like structures were observed in 22 (27.1%), while whole bacteria-like structures were observed in 7 (8.6%) thrombi under transmission electron microscopy. Immunohistochemical staining detected bacterium-specific monocyte/macrophage markers in 51 (63.0%) out of 81 thrombi. Logistic regression analysis indicated that alcohol consumption was associated with a higher bacteria burden in thrombi (odds ratio = 3.19; 95% CI, 1.10-9.27; p = 0.033). CONCLUSION: Bacterial signatures usually found in the oral cavity and digestive tract were detected in thrombi from patients with ischemic stroke. This suggests a potential involvement of bacterial infection in the development of thrombosis. Long-term alcohol consumption may potentially enhance this possibility.

The impact of COVID-19 pandemic on treatment delay and short-term neurological functional prognosis for acute ischemic stroke during the lockdown period.

Background: Preventive strategies implemented during the COVID-19 pandemic may negatively influence the management of patients with acute ischemic stroke (AIS). Nowadays, studies have demonstrated that the pandemic has led to a delay in treatment among patients with AIS. Whether this delay contributes to meaningful short-term outcome differences warranted further exploration. Objective: The objective of this study was to evaluate the impacts of the COVID-19 pandemic on treatment delay and short-term outcomes of patients with AIS treated with IVT and MT. Methods: Patients admitted before (from 11/1/2019 to 1/31/2020) and during the COVID-19 pandemic (from 2/1/2020 to 3/31/2020) were screened for collecting sociodemographic data, medical history information, and symptom onset status, and comparing the effect of treatment delay. The patients treated with IVT or MT were compared for delay time and neurological outcomes. Multivariable logistic regression was used to estimate the effect of treatment delay on short-term neurological prognosis. Results: In this study, 358 patients receiving IVT were included. DTN time increased from 50 min (IQR 40-75) before to 65 min (IQR 48-84), p = 0.048. 266 patients receiving MT were included. The DTP was 120 (112-148) min vs. 160 (125-199) min before and during the pandemic, p = 0.002. Patients with stroke during the pandemic had delays in treatment due to the need for additional PPE (p < 0.001), COVID-19 screening processes (p < 0.001), multidisciplinary consultation (p < 0.001), and chest CT scans (p < 0.001). Compared with pre-COVID-19, during the pandemic, patients had a higher likelihood of spontaneous intracranial hemorrhage after IVT (OR: 1.10; 95% CI, 1.03-1.30) and a lower likelihood of mRS scores 0-2 at discharge (OR: 0.90; 95% CI, 0.78-0.99). In logistic regression analysis, high NIHSS score at admission, increasing age, worse pre-admission mRS, large vessel occlusion, admission during the lockdown period, and low mTICI grade after MT were associated with an mRS ≥ 3. Conclusion: The COVID-19 pandemic has had remarkable impacts on the management of AIS. The pandemic might exacerbate certain time delays and play a significant role in early adverse outcomes in patients with AIS.

Delayed Stroke Treatment during COVID-19 Pandemic in China.

BACKGROUND: Social distance, quarantine, pathogen testing, and other preventive strategies implemented during CO-VID-19 pandemic may negatively influence the management of acute ischemic stroke (AIS). OBJECTIVE: The current study aimed to evaluate the impacts of COVID-19 pandemic on treatment delay of AIS in China. METHODS: This study included patients with AIS admitted in 2 hospitals in Jiangsu, China. Patients admitted before and after the COVID-19 pandemic outbreak (January 31, 2020, as officially announced by the Chinese government) were screened to collect sociodemographic data, medical history information, and symptom onset status from clinical medical records and compared for pre- (measured as onset-to-door time [ODT]) and posthospital delay (measured as door-to-needle time [DNT]). The influencing factors for delayed treatment (indicated as onset-to-needle time >4.5 h) were analyzed with multivariate logistic regression analysis. RESULTS: A total of 252 patients were included, of which 153 (60.7%) were enrolled before and 99 (39.3%) after the COVID-19 pandemic. ODT increased from 202 min (interquartile range [IQR] 65-492) before to 317 min (IQR 75-790) after the COVID-19 pandemic (p = 0.001). DNT increased from 50 min (IQR 40-75) before to 65 min (IQR 48-84) after the COVID-19 pandemic (p = 0.048). The proportion of patients with intravenous thrombolysis in those with AIS was decreased significantly after the pandemic (15.4% vs. 20.1%; p = 0.030). Multivariate logistic regression analysis indicated that patients after COVID-19 pandemic, lower educational level, rural residency, mild symptoms, small artery occlusion, and transported by other means than ambulance were associated with delayed treatment. CONCLUSIONS: COVID-19 pandemic has remarkable impacts on the management of AIS. Both pre- and posthospital delays were prolonged significantly, and proportion of patients arrived within the 4.5-h time window for intravenous thrombolysis treatment was decreased. Given that anti-COVID-19 measures are becoming medical routines, efforts are warranted to shorten the delay so that the outcomes of stroke could be improved.

TNFRSF11B polymorphisms predict poor outcome after large artery atherosclerosis stroke.

Osteoprotegerin is involved in the progression of atherosclerosis. This study aimed to determine whether TNFRSF11B polymorphisms are associated with prognosis of large artery atherosclerosis (LAA) stroke. Three TNFRSF11B polymorphisms (rs2073617, rs2073618 and rs3134069) were genotyped in 1010 patients with LAA stroke. Short-term outcome was evaluated using the modified Rankin Scale score at 3-month after stroke onset. Long-term outcome was assessed using the stroke recurrence. We found that rs2073617G was associated with an increased risk of poor outcome of LAA stroke (additive model: odds ratio (OR) = 1.35, 95% confidence interval (CI) = 1.06-1.73). This association was also observed in rs3134069C (additive model: OR = 1.53, 95% CI = 1.10-2.12). Furthermore, when we combined these two polymorphisms according to the numbers of risk alleles (rs2073617G and rs3134069C), we found that the patients with 3-4 risk alleles were statistically significantly associated with an increased risk of poor outcome of LAA stroke (OR = 1.90, 95% CI = 1.10-3.28) compared with 0-2 risk alleles, and this increased risk was more evident among those with hypertension (OR = 2.02, 95% CI = 1.04-3.91), those without diabetes (OR = 2.02, 95% CI = 1.02-4.01) and those with smoking (OR = 2.43, 95% CI = 1.09-5.42). In silico analysis showed that rs2073617 and rs3134069 are located in various histone modification marked regions, DNase I hypersensitive sites and can change the binding of regulatory motifs. Moreover, rs2073617 is also located in the binding site of transcription factors. Our findings suggested that TNFRSF11B polymorphisms may be associated with an increased risk of short-term poor outcome of LAA stroke.

Recurrent risk of ischemic stroke due to Vertebrobasilar Dolichoectasia.

BACKGROUND: Patients with vertebrobasilar dolichoectasia usually have persistent hemodynamic abnormalities, and therefore, may bear an increased risk of stroke. This study aimed to identify risk factors for stroke recurrence in patients with vertebrobasilar dolichoectasia. METHODS: Patients with acute ischemic stroke were screened and evaluated for eligibility. Enrolled patients were followed via scheduled clinical visits or telephone interviews. Ischemic stroke recurrence was proposed with clinical symptoms and confirmed with cranial Magnetic Resonance Imaging or Computerized Tomography scans. Baseline characteristics and vascular geometry were compared between patients with and without stroke recurrence. Significant parameters were introduced into COX proportional hazard model to detect possible predictors of stroke recurrence. RESULTS: A total of 115 stroke patients with vertebrobasilar dolichoectasia were enrolled, of which 22 (19.1%) had recurrence during 22 ± 6 months follow-up. Basilar artery diameter ≥ 5.3 mm (HR = 4.744; 95% CI, 1.718-13.097; P = 0.003), diffuse intracranial dolichoectasia (HR = 3.603; 95% CI, 1.367-9.496; P = 0.010) and ischemic heart disease history (HR = 4.095; 95% CI, 1.221-13.740; P = 0.022) had increased risk of recurrence. CONCLUSIONS: Stroke patients with vertebrobasilar dolichoectasia may have a high risk of recurrence. Larger basilar artery diameter or diffuse intracranial dolichoectasia may increase the risk of recurrence.

Preprocedural Neutrophil to Albumin Ratio Predicts In-Stent Restenosis Following Carotid Angioplasty and Stenting.

BACKGROUND AND PURPOSE: In-stent restenosis (ISR) is unfavorable to the long-term efficacy of carotid angioplasty and stenting (CAS). Inflammation plays a critical role in the development of ISR. The aim of the study was to investigate whether neutrophil to albumin ratio (NAR) is a predictor of ISR in patients undergoing CAS. METHODS: We retrospectively recruited patients who underwent CAS. These patients were divided into restenosis group and nonrestenosis group. NAR was examined prior to the CAS procedure. Clinical and radiographic assessments were performed at 6 months and annually after the procedure. ISR was defined as greater than or equal to 50% stenosis in the treated lesion. Cox regression was used to identify predictors of ISR following CAS. RESULTS: During a mean follow-up period of 14.6 months, a total of 459 treated arteries (in 427 participants) were enrolled, among which 72 (15.7%) developed ISR. On multivariate analysis, baseline NAR greater than or equal to13.4, residual stenosis, lesion length, and baseline glucose level were associated with ISR (hazard ratio 1.94[95% confidence interval (CI), 1.08-3.49], 1.09[95% CI, 1.07-1.12], 1.04[95% CI, 1.01-1.06], and 1.01[95% CI, 1.00-1.02], respectively). CONCLUSION: Elevated preprocedural NAR may be a predictor of ISR in patients undergoing CAS.

Enhancing the effects of transcranial magnetic stimulation with intravenously injected magnetic nanoparticles.

Transcranial magnetic stimulation (TMS) is a non-invasive and clinically approved method for treating neurological disorders. However, the relatively weak intracranial electric current induced by TMS is an obvious inferiority which can only produce limited treatment effects in clinical application. The present study aimed to investigate the possibility of enhancing the effects of TMS with intravenously administrated magnetic nanoparticles. To facilitate crossing of the blood-brain barrier (BBB), the superparamagnetic iron oxide nanoparticles (SPIONs) were coated with carboxylated chitosan and poly(ethylene glycol). To aid the nanoparticles in crossing the BBB and targeting the predesigned brain regions, an external permanent magnet was attached to the foreheads of the rats before the intravenous administration of SPIONs. The electrophysiological tests showed that the maximum MEP amplitude recorded in an individual rat was significantly higher in the SPIONs + magnet group than in the saline group (5.78 ± 2.54 vs. 1.80 ± 1.55 mV, P = 0.015). In the M1 region, biochemical tests detected that the number density of c-fos positive cells in the SPIONs + magnet group was 3.44 fold that of the saline group. These results suggest that intravenously injected SPIONs can enhance the effects of TMS in treating neurological disorders.

Carotid Geometry as a Predictor of In-Stent Neointimal Hyperplasia　- A Computational Fluid Dynamics Study.

BACKGROUND: Carotid angioplasty and stenting (CAS) is emerging as an alternative treatment for carotid stenosis, but neointimal hyperplasia (NIH) remains a drawback of this treatment strategy. This study aimed to evaluate the effect of variations of carotid bifurcation geometry on local hemodynamics and NIH.Methods and Results:Hemodynamic and geometric effects on NIH were compared between 2 groups, by performing computational fluid dynamics (CFD) simulations both on synthetic models and patient-specific models. In the idealized models, multiple regression analysis revealed a significant negative relationship between internal carotid artery (ICA) angle and the local hemodynamics. In the patient-derived models, which were reconstructed from digital subtraction angiography (DSA) of 25 patients with bilateral CAS, a low time-average wall shear stress (TAWSS) and a high oscillatory shear index (OSI) were often found at the location of NIH. Larger difference values of the OSI percentage area (10.56±20.798% vs. -5.87±18.259%, P=0.048) and ECA/CCA diameter ratio (5.64±12.751% vs. -3.59±8.697%, P=0.047) were detected in the NIH-asymmetric group than in the NIH-symmetric group. CONCLUSIONS: Changes in carotid bifurcation geometry can make apparent differences in hemodynamic distribution and lead to bilateral NIH asymmetry. It may therefore be reasonable to consider certain geometric variations as potential local risk factors for NIH.

Impact of Smoking Status on Stroke Recurrence.

Background Smoking is a well-established risk factor of stroke and smoking cessation has been recommended for stroke prevention; however, the impact of smoking status on stroke recurrence has not been well studied to date. Methods and Results Patients with first-ever stroke were enrolled and followed in the NSRP (Nanjing Stroke Registry Program). Smoking status was assessed at baseline and reassessed at the first follow-up. The primary end point was defined as fatal or nonfatal recurrent stroke after 3 months of the index stroke. The association between smoking and the risk of stroke recurrence was analyzed with multivariate Cox regression model. At baseline, among 3069 patients included, 1331 (43.4%) were nonsmokers, 263 (8.6%) were former smokers, and 1475 (48.0%) were current smokers. At the first follow-up, 908 (61.6%) patients quit smoking. After a mean follow-up of 2.4±1.2 years, 293 (9.5%) patients had stroke recurrence. With nonsmokers as the reference, the adjusted hazard ratios for stroke recurrence were 1.16 (95% CI , 0.75-1.79) in former smokers, 1.31 (95% CI , 0.99-1.75) in quitters, and 1.93 (95% CI , 1.43-2.61) in persistent smokers. Among persistent smokers, hazard ratios for stroke recurrence ranged from 1.68 (95% CI , 1.14-2.48) in those who smoked 1 to 20 cigarettes daily to 2.72 (95% CI , 1.36-5.43) in those who smoked more than 40 cigarettes daily ( P for trend <0.001). Conclusions After an initial stroke, persistent smoking increases the risk of stroke recurrence. There exists a dose-response relationship between smoking quantity and the risk of stroke recurrence.

Magnetic stimulation of carotid sinus as a treatment for hypertension.

Previously, we reported that magnetic stimulation of carotid sinus (MSCS) could lower arterial pressure in rabbits. In this randomized, sham-controlled pilot study, we evaluated the effects of MSCS on blood pressure in pre-hypertensive and hypertensive subjects. A total of 15 subjects with blood pressure higher than 130/80 mm Hg were randomized to receive sham or 1Hz MSCS. The changes of systolic blood pressure (SBP), diastolic blood pressure (DBP), mean blood pressure (MAP) during treatment were compared between groups. The heart rate variability (HRV) and baroreflex sensitivity (BRS) before, during, and after treatments were analyzed. Reduction of SBP was significantly greater in subjects with MSCS than those with sham stimulation (6.6 ± 0.4 vs -2.5 ± 0.4 mm Hg, P < 0.001). Reduction of DBP was significantly greater in subjects with MSCS than those with sham stimulation (1.2 ± 0.2 vs -2.8 ± 0.2 mm Hg, P < 0.001). Reduction of MAP was significantly greater in subjects with MSCS than those with sham stimulation (1.4 ± 0.3 mm Hg vs -4.0 ± 0.3 mm Hg, P < 0.001). Reduction of HR was significantly greater in subjects with MSCS than those with sham stimulation (0.5 ± 0.5 vs -1.9 ± 0.3 beats/min, P = 0.002). BRS increased from 6.85 ± 0.77 to 8.79 ± 0.95 ms/mm Hg after MSCS compared with that at baseline (P = 0.027). Thus, MSCS can lower blood pressure and heart rate in pre-hypertensive and hypertensive subject, warranting further study for establishing MSCS as a treatment for hypertension.

A GWAS-supported variant interacting with diabetes predicts risk of atherothrombotic stroke in Han Chinese population.

BACKGROUND: A recent genome-wide association study has identified that rs4376531 variant conferred risk of atherothrombotic stroke (AS) in a Japanese population. This study was to explore the association in Han Chinese population. METHODS: A total of 1036 cases and 643 healthy controls were enrolled. We genotyped rs4376531 variant with SNPscan. Multivariate logistic regression analysis was used to determine the association of genetic variation with risk of AS. Interaction analysis was examined by SNPStats web tool. RESULTS: After adjusting for gender, age, body mass index (BMI), hypertension, diabetes and smoking, compared with CC genotype, we observed that GC and GG/GC genotypes were associated with a significantly decreased risk of AS (OR = 0.76, 95% CI = 0.58-0.99 and OR = 0.76, 95% CI = 0.58-0.98, respectively). The decreased risk was more obvious among subgroups with high BMI (OR = 0.63, 95% CI = 0.45-0.88), no hypertension (OR = 0.66, 95% CI = 0.46-0.94), diabetes (OR = 0.33, 95% CI = 0.17-0.64), and smoking (OR = 0.65, 95% CI = 0.44-0.95) in the dominant model (GG/GC vs CC). Interaction analysis also revealed that compared with non-diabetic patients with CC genotype, diabetic patients with CC genotype had a 4.48-fold (OR = 4.48; 95% CI = 2.98-6.72) increased risk of AS. CONCLUSION: Our data suggested that GC and GG/GC of rs4376531 contributed to a decreased risk of AS while CC genotype, interacting with diabetes, increased the stroke risk in Han Chinese population.

Neutrophil to Lymphocyte Ratio as a Predictor of Restenosis After Angioplasty and Stenting for Asymptomatic Carotid Stenosis.

The inflammatory response plays a vital role in the development of in-stent restenosis (ISR) after carotid angioplasty and stenting (CAS). The neutrophil to lymphocyte ratio (NLR) has been suggested as a sensitive inflammatory marker. We explored the association between NLR and ISR in CAS patients. A total of 427 patients who underwent CAS were enrolled. Neutrophil to lymphocyte ratio was measured before the procedure. Clinical examination and radiographic evaluation were performed at 6 months and annually after the procedure. In-stent restenosis was defined as ≥50% stenosis in the treated lesion. Cox regression was used to identify predictors of ISR after CAS. Of the 459 arteries (in 427 patients) with CAS, 72 (15.7%) were identified with ISR during a mean follow-up of 14.6 (19.1) months (range, 0.7-120.7 months). Increased NLR (≥2.13) was significantly related to ISR in patients with asymptomatic stenosis ( P = .001). However, significance was not observed in symptomatic stenosis. On multivariate analysis, baseline NLR ≥ 2.13 (hazard ratio [HR], 2.74; 95% confidence interval [CI], 1.46-5.14), smoking (HR, 1.99; 95% CI, 1.11-3.58), residual stenosis (HR, 1.12; 95% CI, 1.09-1.15), and baseline glucose level (HR, 1.01; 95% CI, 1.01-1.02) were associated with ISR. Elevated NLR may be a predictor of ISR after CAS for asymptomatic stenosis.

HDAC9 Polymorphisms Predict Susceptibility, Severity, and Short-Term Outcome of Large Artery Atherosclerotic Stroke in Chinese Population.

Recently, a genome-wide association study (GWAS) detected two histone deacetylase 9 (HDAC9) polymorphisms (rs2074633 and rs28688791) which may be associated with risk of large artery atherosclerotic (LAA) stroke. This study aimed to investigate whether these two polymorphisms were associated with susceptibility, severity, and short-term outcome of LAA stroke in a southern Chinese Han population. rs2074633 and rs28688791 were genotyped using SNPscan technology in 1011 LAA stroke patients and 1121 healthy controls. Stroke severity on admission and short-term outcome were, respectively, assessed by the National Institute of Health Stroke Scale (NIHSS) score on admission and modified Rankin Scale score at 3 months after stroke onset. rs2074633 (P = 0.039) and rs28688791 (P = 0.025) were associated with risk of LAA stroke. In subgroup analysis according to sex and age, this increased risk was only found in males (P = 0.029 for rs2074633; P = 0.013 for rs28688791) and adults aged < 60 years (P = 0.009 for rs2074633; P = 0.003 for rs28688791). Moreover, we detected significant interactions between these two polymorphisms and age (Pinteraction = 0.027 for rs2074633; Pinteraction = 0.044 for rs28688791). The CC genotype of rs28688791 (P = 0.037) was also associated with moderate and severe stroke (NIHSS ≥ 6). Additionally, the CC genotype of rs2074633 and rs28688791 (rs2074633, P = 0.019; rs28688791, P = 0.023) showed significant association with unfavorable short-term outcome of LAA stroke. Our results indicated that HDAC9 polymorphisms may be used as biomarkers for susceptibility, severity, and short-term outcome of LAA stroke.

New vessels formation in young strokes with isolated steno-occlusive MCA.

OBJECTIVE: New vessels formation (NVF) along the steno-occlusive middle cerebral artery (MCA) is often observed in digital subtraction angiography (DSA) imaging. In the study, we aim to explore the clinical relevance of NVF in young ischemic stroke patients with isolated middle cerebral artery (MCA) stenosis. METHODS: We retrospectively reviewed the digital subtraction angiography (DSA) images of 93 young ischemic stroke patients (age ≤ 45 years old) in our center from January 2006 to June 2016. All the patients were diagnosed with isolated steno-occlusive middle cerebral artery (MCA) disease.NVF was defined as new vessels formation along the stenotic MCA on anteroposterior DSA projection. The association between NVF and functional outcome was analyzed. RESULTS: The prevalence of NVF was 0 in moderate stenosis, 15.8% in severe stenosis, and 53.7% in MCA occlusions. The presence of NVF had a strong correlation with the severity of MCA stenosis (r = 0.467, p < 0.001). Compared to patients without NVF, patients with NVF were more likely to suffer an unfavorable functional outcome (6.2% vs. 21.4%, p = 0.061) at 3 months. Univariate logistic regression analysis showed that NVF was associated with unfavorable outcome [Odds Ratio (OR) = 4.159, 95% confidence intervals (CI) = (1.072, 16.137), p = 0.039]. CONCLUSIONS: This study demonstrated that NVF were associated with poor clinical outcome in young ischemic stroke patients who were diagnosed with isolated steno-occlusive MCA.

Mean Platelet Volume as a Predictor for Restenosis After Carotid Angioplasty and Stenting.

BACKGROUND AND PURPOSE: Platelet aggregation plays a vital role in the development of in-stent restenosis (ISR) after carotid angioplasty and stenting (CAS). Mean platelet volume (MPV) has been suggested as an index of platelet reactivity. This study aimed to investigate the association between MPV and ISR in CAS patients. METHODS: A total of 261 patients with CAS were enrolled. MPV was measured before CAS procedure. Digital subtraction angiography, computed tomographic angiography, or duplex ultrasonography was performed at 6 months and annually after the procedure. ISR was defined as ≥50% stenosis in the treated lesion. Cox regression was used to identify predictors of ISR after CAS. RESULTS: Of the 261 patients with CAS, 46 (17.6%) were determined with ISR during a mean follow-up of 12.1±16.1 months (range, 2.1-120.7). On multivariate analysis, baseline MPV >10.1 fL (hazard ratio, 3.20; 95% confidence interval, 1.28-8.03), lesion length (hazard ratio, 1.05; 95% confidence interval, 1.02-1.08), residual stenosis (hazard ratio, 1.07; 95% confidence interval, 1.05-1.10), and baseline glucose (hazard ratio, 1.01; 95% confidence interval, 1.00-1.02) were associated with ISR. CONCLUSIONS: Elevated MPV may be associated with ISR after CAS. Patients with high preprocedural MPV may benefit from an intensified antiplatelet therapy after CAS.

Restenosis after carotid artery stenting.

As a common etiology for ischemic stroke, atherosclerotic carotid stenosis has been targeted by vascular surgery since 1950s. Compared with carotid endarterectomy, carotid angioplasty and stenting (CAS) is almost similarly efficacious and less invasive. These advantages make CAS an alternative in treating carotid stenosis. However, accumulative evidences suggested that the long-term benefit-risk ratio of CAS may be decreased or even neutralized by the complications related to in-stent restenosis (ISR). Therefore, investigating the mechanisms and identifying the influential factors of ISR are of vital importance for improving the long-term outcomes of CAS. As responses to intrinsic and extrinsic injuries, intimal hyperplasia and vascular smooth muscle cell proliferation have been regarded as the principle mechanisms for ISR development. Due to the lack of consensus-based definition and consistent follow-up protocol, the reported incidences of ISR after CAS varied widely among studies. These variations made the inter-study comparisons of ISR largely illogical. To eliminate restenosis after CAS, both surgery and endovascular procedures have been attempted with promising results. For preventing ISR, drug-eluting stents and antiplatelets have been proposed as potential solutions.

The effect of L-stepholidine, a novel extract of Chinese herb, on the acquisition, expression, maintenance, and re-acquisition of morphine conditioned place preference in rats.

The effect of L-stepholidine (SPD), a novel alkaloid extract of the Chinese herb Stephania with partial dopamine D1 receptor agonistic and D2 receptor antagonistic dual actions, on morphine conditioned place preference (CPP) was studied. Daily injection of morphine (10 mg/kg, i.p.) for 6 days induced CPP in rats, and daily treatment with SPD at 10 or 20 mg/kg before morphine injection dose-dependently attenuated morphine-induced CPP. On the day following acquisition of morphine CPP, a single administration of SPD at 10 or 20 mg/kg failed to block the expression of CPP. However, daily administration of SPD at 20 mg/kg for 7 days attenuated the maintenance of CPP. Morphine-induced CPP extinguished after a 21-day saline training and then a single injection of morphine (3 mg/kg, i.p.) induced re-acquisition of morphine CPP; however, pretreatment with SPD at 10 or 20 mg/kg 30 min before morphine injection dose-dependently blocked morphine (3 mg/kg, i.p.)-induced re-acquisition of morphine CPP. Furthermore, our data indicate that SPD had no effect on food-induced CPP or state-dependent learning, suggesting that the observed effect of SPD does not result from an inhibition of general learning ability. These results demonstrate that SPD can inhibit acquisition, maintenance, and re-acquisition of morphine conditioned place preference and suggest its potential for treatment of opioid addiction.

Different roles of dopamine receptor subtypes in footshock stress-induced enhancement of morphine conditioned place preference.

The present study investigated the involvement of dopamine mechanism in the effect of intermittent footshock stress on the morphine-induced place preference. A single intermittent footshock session significantly enhanced the place preference induced by 3.0mg/kg morphine. This enhancing effect was inhibited by selective D(1) receptor antagonist SCH23390 and selective D(2) receptor antagonist sulpiride pretreatment 20min before footshock session, suggesting dopamine D(1) and D(2) receptors are required for the development of intermittent footshock stress-induced enhancement of morphine-associated place preference. However, different from D(1) and D(2) receptors this enhancing effect was blocked by stimulation of dopamine D(3) receptor with selective D(3) receptor agonist 7-OH-DPAT pretreatment 20min before footshock session which suggest dopamine D(3) receptor play a negative mediation effect on the intermittent footshock stress-induced this enhancement. These results indicate that dopamine D(1), D(2), and D(3) receptor subtypes play different roles in footshock stress-induced enhancement of morphine conditioned place preference.

Environmental cues associated with morphine modulate release of glutamate and gamma-aminobutyric acid in ventral subiculum.

Objective To investigate whether environmental cues associated with different properties of morphine could regulate the extracellular levels of glutamate and gamma-aminobutyric acid (GABA) in the hippocampal ventral subiculum, which play a critical role in the reinstatement of drug-seeking behavior induced by environmental cues. Methods Conditioning place preference (CPP) and conditioning place aversion (CPA) models were used to establish environment associated with rewarding and aversive properties of morphine respectively. Microdialysis and high performance liquid chromatography were used to measure the extracelluar level of glutamate and GABA in the ventral subiculum under these environmental cues. Results Exposure to the environmental cues associated with rewarding properties of morphine resulted in a decrease (approximately 11%) of extracellular level of GABA in ventral subiculum, and exposure to the environmental cues associated with aversive properties of morphine resulted in an increase (approximately 230%) of extracellular level of glutamate in ventral subiculum. Conclusion Environmental cues associated with different properties of morphine modulate the release of distinct neurotransmitters in the hippocampal ventral subiculum possibly through different neural circuit.