Tongxinluo and Functional Outcomes Among Patients With Acute Ischemic Stroke: A Randomized Clinical Trial.

Importance: Previous studies revealed limited effectiveness of neuroprotective agents in treating acute ischemic stroke (AIS). Tongxinluo, developed from traditional Chinese medicines, has been recognized as a novel neuroprotective agent with anti-inflammatory properties that stabilize vulnerable plaques in animal models and patients with myocardial infarction. Objective: To assess the efficacy and safety of Tongxinluo in patients with acute ischemic stroke (AIS). Design, Setting, and Participants: This multicenter, open-label, double-blind, randomized clinical trial included 2007 patients with AIS and a National Institutes of Health Stroke Scale score between 4 and 22 at admission. The trial was conducted at 50 hospitals in China from March 1, 2014, to October 31, 2016. Data were analyzed from November 14, 2016, to November 16, 2017. Interventions: Eligible patients were randomized within 72 hours of symptom onset to the Tongxinluo group or the control group. Participants received 4 oral capsules of Tongxinluo or placebo, 3 times a day for 90 days. Other treatment was administrated according to guidelines. Main Outcomes and Measure: The primary outcome was a favorable functional outcome at day 90 after randomization, defined as a modified Rankin Scale (mRS) score of 0 to 1 (on a scale of 0 [no neurologic deficit, no symptoms, or completely recovered] to 6 [death]). All statistical analyses were performed in a modified intention-to-treat population, defined as all patients who underwent randomization, were given any treatment, and underwent any posttreatment assessment. Results: Among 2007 patients with AIS who were randomized, 1946 (96.5%) were included in the modified intention-to-treat analysis (973 in the Tongxinluo group and 973 in the control group, with mean [SD] age of 60.5 [9.2] years and 1342 [69.0%] male). Patients in the Tongxinluo group had a significantly higher proportion of favorable functional outcomes at day 90 compared with those in the control group (mRS score of 0-1, 640 [65.8%] vs 575 [59.1%]; odds ratio, 1.33 [95% CI, 1.11-1.60]; P = .002). The prespecified subgroup analyses indicated that, among all subgroups, additional Tongxinluo treatment had similar outcomes. Conclusions and Relevance: Among patients with ischemic stroke within 72 hours after symptom onset, those additionally receiving Tongxinluo were more likely to have a favorable functional outcome, compared with a placebo group. Further research in patients with thrombolysis and endovascular treatment are needed to explore these outcomes. Trial registration: ClinicalTrials.gov Identifier: NCT01919671.

Machine learning-based predictive model for the development of thrombolysis resistance in patients with acute ischemic stroke.

BACKGROUND: The objective of this study was to establish a predictive model utilizing machine learning techniques to anticipate the likelihood of thrombolysis resistance (TR) in acute ischaemic stroke (AIS) patients undergoing recombinant tissue plasminogen activator (rt-PA) intravenous thrombolysis, given that nearly half of such patients exhibit poor clinical outcomes. METHODS: Retrospective clinical data were collected from AIS patients who underwent intravenous thrombolysis with rt-PA at the First Affiliated Hospital of Bengbu Medical University. Thrombolysis resistance was defined as ([National Institutes of Health Stroke Scale (NIHSS) at admission - 24-hour NIHSS] × 100％/ NIHSS at admission) ≤ 30%. In this study, we developed five machine learning models: logistic regression (LR), extreme gradient boosting (XGBoost), support vector machine (SVM), the least absolute shrinkage and selection operator (LASSO), and random forest (RF). We assessed the model's performance by using receiver operating characteristic (ROC) curve, calibration curve, and decision curve analysis (DCA), and presented the results through a nomogram. RESULTS: This study included a total of 218 patients with AIS who were treated with intravenous thrombolysis, 88 patients experienced TR. Among the five machine learning models, the LASSO model performed the best. The area under the curve (AUC) on the testing group was 0.765 (sensitivity: 0.767, specificity: 0.694, accuracy: 0.727). The apparent curve in the calibration curve was similar to the ideal curve, and DCA showed a positive net benefit. Key features associated with TR included NIHSS at admission, blood glucose, white blood cell count, neutrophil count, and blood urea nitrogen. CONCLUSION: Machine learning methods with multiple clinical variables can help in early screening of patients at high risk of thrombolysis resistance, particularly in contexts where healthcare resources are limited.

Explore the pharmacological basis of ShengJiYiSui decoction in the treatment of amyotrophic lateral sclerosis based on network pharmacology and molecular docking technology.

Neurodegenerative illnesses have long been handled clinically by traditional Chinese medicine. This study is the first time to explore the pharmacological basis of application in amyotrophic lateral sclerosis (ALS) through network pharmacology and molecular docking techniques. In the present investigation, the TCMSP database and HIT2 database were examined for 9 TCM constituents of Sheng Ji Yu Sui Decoction (SJYSD), and the desired sites for the components were searched in the Drugbank database. and the Sjysd-target network was constructed. Associated targets for Amyotrophic lateral sclerosis (ALS) were then retrieved and collected in the OMIM, TTD, Genecards and DisGeNET databases. Protein-protein interaction and enrichment analysis were performed for the common targets of drugs and diseases, and molecular anchoring for the chosen core targets and related molecules was carried out. The results showed that SJYSD had 100 active compounds corresponding to 598 targets. ALS has a total of 5,325 genes. SJYSD and ALS share 163 genes, and these targets involve PI3K-AKT signaling, p53 signaling and IL-17 signaling, etc. The core components of luteolin and quercetin were discovered and may be used to treat ALS by regulating PI3K-AKT signaling pathway by HSP90AB1 protein.

Effect of high-frequency repetitive transcranial magnetic stimulation under different intensities upon rehabilitation of chronic pelvic pain syndrome: protocol for a randomized controlled trial.

INTRODUCTION: Nearly one in seven women worldwide suffers from chronic pelvic pain syndrome (CPPS) each year. Often, CPPS necessitates a combination of treatments. Studies have shown the good therapeutic effects of repetitive transcranial magnetic stimulation (rTMS) upon CPPS. We wish to undertake a randomized controlled trial (RCT) to observe the effect of high-frequency rTMS at different intensities upon CPPS. METHODS AND ANALYSES: In this prospective, double-blinded RCT, 63 female CPPS participants will be recruited and randomized (1:1:1) to high-intensity rTMS, low-intensity rTMS, or sham rTMS. The control group will receive a 10-day course of conventional pelvic floor (PF) rehabilitation (neuromuscular stimulation, magnetic therapy, or light therapy of the PF). On the basis of conventional treatment, participants in the high-intensity rTMS group will receive pulses of 10 Hz with a resting motor threshold (RMT) of 110% for a total of 15,000 pulses. Participants in the low-intensity rTMS group will receive pulses of 10 Hz with an RMT of 80% with 15,000 pulses. The sham rTMS group will be subjected to sham stimulation with the same sound as produced by the real magnetic stimulation coil. The primary outcome will be determined using a visual analog scale, the Genitourinary Pain Index, Zung Self-Rating Anxiety Scale, and Zung Self-Rating Depression Scale. The secondary outcome will be determined by electromyography of the surface of PF muscles at baseline and after treatment completion. ETHICS AND DISSEMINATION: This study is approved by the Ethics Committee of Bao'an People's Hospital, Shenzhen, Guangdong Province (approval number: BYL20211203). The results will be submitted for publication in peer-reviewed journals and disseminated at scientific conferences (Protocol version 1.0-20220709). TRIAL REGISTRATION: Chictr.org.cn, ID: ChiCTR2200055615. Registered on 14 January 2022, http://www.chictr.org.cn/showproj.aspx?proj=146720 . Protocol version 1.0-20220709.

B.infantis enhances immunotherapy for Guillain-Barre syndrome through regulating PD-1.

BACKGROUND: Guillain-Barré syndrome (GBS) is a rare, autoimmune disease. B.infantis is reported to be effective in alleviating GBS by regulating abnormal function of T helper (Th) cells. OBJECTIVES: In this study, T cells were isolated from healthy and GBS patients. The therapeutic effect of Bifidobacterium infantis (B.infantis) and whether it is achieved by PD-1 was examined at cellular and animal models. METHODS: We used CCK-8, flow cytometry and real-time PCR to determine the differentiation of T cell subsets at cellular level. Then, an experimental autoimmune neuritis (EAN) animal model using six-week SD rats (n = 30, male) weighing 180-200 g was established to support the role of B. infantis in GBS through PD-1. RESULTS: B. infantis inhibited the proliferation and promoted apoptosis of T cells from GBS. At the same time, the expression levels of PD-1 increased, which was correlated with decreased T-bet (Th1) and ROR-γt (Th17) and increased Foxp3 (Treg) expression. Moreover, B. infantis alleviated the symptoms of GBS. Th1 and Th17 cells decreased while Treg cells increased after B. infantis treatment, which could be partly abrogated by PD-1 inhibitor. CONCLUSIONS: We concluded from this study that B.infantis alleviated GBS partly through PD-1.

Clinical analysis of 4 cases of Wernekink commissure syndrome. / Wernekink连合综合征4例临床分析.

Wernekink commissure syndrome (WCS) is very rare. Four patients with WCS, admitted to our hospital from April to May 2018, were chosen for this study, and their clinical manifestations, imaging features, and etiology were retrospectively analyzed based on the literatures. All patients with WCS manifested as bilateral cerebellar ataxia such as symmetrical limb and trunk ataxia, but the degree of ataxia was asymmetrical distribution based on the anatomy. Dysarthria was the main and constant clinical manifestation of the syndrome. Ophthalmoplegia had great variability, and WCS with oculomotor nerve palsy may be considered as atypical WCS. The incidence of olivary degeneration and palatine myoclonus is relatively low, which may be related to the difference in the reported time intervals of cases. Changes in consciousness and emotion may be the characteristic of neglected WCS, which should be paid more attention. Cerebral infarction is the main etiology of WCS. We reported that cerebral infarction and WCS was the first symptom in a patient with systemic lupus erythematosus (SLE). We should pay more attention to special etiology in diagnosis and treatment of WCS.

Early administration of tirofiban after urokinase-mediated intravenous thrombolysis reduces early neurological deterioration in patients with branch atheromatous disease.

OBJECTIVES: To investigate the effects of early administration of tirofiban after intravenous thrombolysis on early neurological deterioration in patients with branch atheromatous disease. METHODS: We analyzed clinical data from patients with branch atheromatous disease. We enrolled seven cases into the urokinase-only (UO) control group and 10 cases into the urokinase + tirofiban (UT) treatment group. National Institutes of Health Stroke Scale (NIHSS) scores were obtained at admission and on days 3 and 5 after admission. Modified Rankin Scale (mRS) scores were obtained 3 months after admission. RESULTS: Significant differences between the UO and UT groups were evident on days 3 and 5 after admission. In the UT group, there was a significant difference between NIHSS scores at admission and on day 5, while there were no significant differences in scores in the UO group. The early neurological deterioration rates were not significantly different between the two groups. However, there were significant differences in these rates at 72 and 120 hours. Both the mRS scores and the prognoses at 3 months differed between the two groups. CONCLUSION: Early administration of tirofiban after urokinase-mediated intravenous thrombolysis reduces early neurological deterioration and improves the long-term prognosis of patients with branch atheromatous disease.

Treatment of Guillain-Barré syndrome with Bifidobacterium infantis through regulation of T helper cells subsets.

BACKGROUND: Guillain-Barré syndrome (GBS) is a rare, autoimmune-mediated disease. The use of Bifidobacterium is reportedly effective in alleviating GBS since they act by regulating T helper (Th) cells. OBJECTIVES: In this study, we explored the differentiation of T helper cell subsets in patients with GBS. We also evaluated the effect of GBS on Bifidobacterium levels in patients and the likely protective influence of this bacterium in alleviating the disease in an animal model. MATERIALS AND METHODS: We used flow cytometry, and real-time polymerase chain reaction (PCR) to determine the T cell subsets differentiation among 30 GBS patients and 20 healthy controls (HC). The concentration of Bifidobacterium was assayed by real-time PCR. Experimental autoimmune neuritis (EAN) animal model was established to support the protective role of Bifidobacterium in GBS. RESULTS: The expression of Th cells, Th2 and Th17 in the patients was significantly higher than that in the HC, while Treg cells decreased substantially. Moreover, the levels of Bifidobacterium in the GBS patients were considerably lower than those in the HC, the concentration of Bifidobacterium correlating with Th2 and Th17 subsets negatively. Treatment with Bifidobacterium significantly reduced the levels of Th2 and Th17 and promoted the levels of Treg cells. CONCLUSIONS: We concluded from this study that Bifidobacterium alleviated GBS by regulating Th cells, although in-depth studies might be required to fully understand the mechanism of action.

Metabolic syndrome contributes to cognitive impairment in patients with Parkinson's disease.

INTRODUCTION: Metabolic syndrome (MetS) increases the risk of cognitive impairment in normal aging but this has not been studied in Parkinson's Disease (PD). The purpose of this study was to investigate the impact of MetS on cognitive impairment in PD. METHODS: This study investigated subjects older than 60 years who were diagnosed with PD. They were enrolled into this study between January 2010 and December 2011, and followed for 5 years. The assessment of cognitive function in subjects with PD was based on the cognitive and neuropsychiatric tests, and MetS was diagnosed according to the National Cholesterol Education Program's Adult Treatment Panel III. The subjects were divided into three groups according to the cognitive function at the end of follow-up: PD with normal cognitive function (PD-NC), mild cognitive impairment in PD (PD-MCI) and PD dementia (PDD). RESULTS: Of the 787 subjects with PD included in our study, 255 (32.4%) were diagnosed with PD-MCI, and 105 (13.3%) were diagnosed with PDD. MetS was significantly associated with PD-MCI (odds radio [OR]: 1.45, 95% confidence interval [CI]: 1.17-1.72) and PDD (OR: 2.12, 95% CI: 1.57-2.83). The associations between MetS and the main cognition domains of PDD were statistically significant. The treatment of MetS was helpful in reducing the risk of PDD. CONCLUSIONS: We found that MetS increase the risk of cognitive impairment in patients with PD, and is significantly associated with the severity of cognitive impairment. The results suggest that the intervention against MetS is helpful in managing cognitive impairment in PD.

Protective effects of DL­3­n­butylphthalide in the lipopolysaccharide­induced mouse model of Parkinson's disease.

DL­3­n­butylphthalide (NBP) is extracted from rapeseed and exhibits multiple neuroprotective effects, exerted by inhibiting the inflammatory process, including reducing oxidative stress, improving mitochondrial function and reducing neuronal apoptosis. The present study aimed to investigate the neuroprotective effects of NBP in a lipopolysaccharide (LPS)­induced mouse model of Parkinson's disease (PD). The behavior of mice was assessed using the rotarod test and open­field test, the amount of tyrosine hydroxylase in the substantia nigra pars compacta was evaluated by immunohistochemistry, and the levels of phosphorylated c­Jun N­terminal kinase (JNK), mitogen­activated protein kinase 14 (p38) and extracellular signal­regulated kinase 1 were determined by western blotting. It was demonstrated that the LPS­induced behavioral deficits were significantly improved. LPS­induced dopaminergic neurodegeneration was relieved following treatment with NBP, as determined from tyrosine hydroxylase­positive cells. Phosphorylation of JNK and p38 was significantly inhibited following treatment with NBP. Therefore in the present study, a role for NBP has been established in the treatment of a PD murine model, laying the experimental basis for the treatment of PD with this agent.

Therapeutic effects of paeonol on methyl-4-phenyl-1,2,3,6-tetrahydropyridine/probenecid-induced Parkinson's disease in mice.

Paeonol is a major phenolic compound of the Chinese herb, Cortex Moutan, and is known for its antioxidant, anti-inflammatory and antitumor properties. The present study was designed to investigate the therapeutic potential and underlying mechanisms of paeonol on a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/probenecid (MPTP/p)-induced mouse model of Parkinson's disease (PD). MPTP (25 mg/kg), followed by probenecid (250 mg/kg), was administered via i.p. injection for five consecutive days to induce the mouse model of PD. Paeonol (20 mg/kg) was administrated orally for 21 days. Behavior was assessed using the rotarod performance and open­field tests. Additionally, the levels of tyrosine hydroxylase (TH), microglia, interleukin­1ß (IL­1ß), and brain­derived neurotrophic factor (BDNF) in the substantia nigra pars compacta (SNpc) were evaluated by immunohistochemical staining. MPTP/p­induced motor deficits were observed to be significantly improved following long­term treatment with paeonol. Paeonol treatment decreased MPTP/p­induced oxidative stress, as determined by evaluating the activity levels of superoxide dismutase, catalase and glutathione. Additionally, MPTP/p­induced neuroinflammation was assessed by examining the levels of microglia and IL­1ß, which were significantly decreased following paeonol treatment. Paeonol treatment improved the MPTP/p­induced dopaminergic neurodegeneration, as measured by observing the increased TH level in the SNpc. Furthermore, the BDNF level was significantly elevated in the paeonol treatment group compared with mice treated with MPTP/p only. In conclusion, paeonol exerted therapeutic effects in the MPTP/p­induced mouse model of PD, possibly by decreasing the damage from oxidative stress and neuroinflammation, and by enhancing the neurotrophic effect on dopaminergic neurons. The results demonstrate paeonol as a potential novel treatment for PD.

Neuroprotective effects of piperine on the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced Parkinson's disease mouse model.

Parkinson's disease (PD) is second only to Alzheimer's disease as the most common and debilitating age-associated neurodegenerative disorder. Currently, no therapy has been shown to unequivocally retard or arrest the progression of the disease. The aim of the present study was to investigate the protective effect of piperine on the 1-methyl-4-phenyl-1,2,3,6­tetrahydropyridine (MPTP)-induced Parkinson's mouse model. For MPTP treatment, the animals received repeated intraperitoneal injections (i.p.) of MPTP (30 mg/kg) solution for 7 days. Piperine (10 mg/kg) was administered orally for 15 days including 8 days of pretreatment. Motor behavior analysis was conducted with the rotarod test. The Morris water maze (MWM) was used to assess the cognitive learning ability of the mice. A histological examination was subsequently conducted. The results ddemonstrate that piperine treatment attenuated MPTP-induced deficits in motor coordination and cognitive functioning. Piperine also prevented MPTP-induced decreases in the number of tyrosine hydroxylase-positive cells in the substantia nigra. Additionally, piperine reduced the number of activated microglia, expression of cytokine IL-1ß, and oxidative stress following MPTP treatment. An anti-apoptotic property of piperine was identified by maintaining the balance of Bcl-2/Bax. In conclusion, the results show that piperine exerts a protective effect on dopaminergic neurons via antioxidant, anti-apoptotic, and anti-inflammatory mechanisms in an MPTP-induced mouse model of PD. Thus, piperine is a potential therapeutic treatment for PD.

Clinical correlation of peripheral CD4+­cell sub­sets, their imbalance and Parkinson's disease.

Emerging evidence suggests that the peripheral immune system has an active role in the progression of Parkinson's disease (PD). The finding of T­helper (Th; CD4+) cells infiltrating into the substantia nigra in PD patients demonstrated that Th cells are involved in PD. However, the association between peripheral T­helper cell sub­sets (Th1, Th2, Treg and Th17) and the sub­set balance (Th1/Th2 and Th17/Treg) and PD has remained elusive. In the present study, sixty PD patients of the First Affiliated Hospital of Bengbu Medical College as well as 40 age­ and environment­matched healthy individuals were enrolled. The fraction of CD4+ T cells in the peripheral blood was assessed by automated hematology analysis and its sub­sets (Thl, Th2, Thl7, Treg) were quantified by flow cytometry. The results showed that in the PD group, the proportion of Th1 and Th17 cells was increased, while that of Th2 and Treg cells was decreased. Compared with the control group, the Th1/Th2 and Th17/Treg ratios were significantly enhanced, and shifted towards Th1 and Th17, respectively. Furthermore, this Th1­type response (Th1/Th2 balance shifting towards Th1) were associated with motor function scores determined by Unified Parkinson's Disease Rating Scale III (UPDRS­III) scores. However, no correlation was found between the change in the Th17/Treg cell balance (Th17/Treg balance shifting towards Th1) and UPDRS­III scores. These data supported that chronic immune stimulation, specifically CD4+­cell sub­set imbalance, is linked to PD pathobiology and disease severity. CD4+­cell sub­sets and their imbalance may therefore represent novel biomarkers or therapeutic targets for PD.

Clinical characteristics and peripheral T cell subsets in Parkinson's disease patients with constipation.

Constipation is frequently reported in Parkinson's disease (PD). We evaluated the characteristics of patients with PD and constipation and explored the role of T cell subsets in PD-associated constipation. One hundred and two patients with PD treated at the First Affiliated Hospital of Bengbu Medical College were enrolled in this study between January 2012 and October 2013. All patients completed KESS questionnaires and constipation was rated. The proportions of peripheral blood Thl7 and Treg cells were assessed by flow cytometry in 45 patients. Colonoscopies were performed in six patients. Thirty-one patients with PD reported slow-transit constipation (STC), 15 rectal evacuation disorder (RED) and 33 mixed constipation (Mixed). STC most frequently occurred before onset of PD motor symptoms, while Mixed occurred before or after motor symptoms, and RED occurred most frequently after motor symptoms. CD4+ T cell infiltration in the colonic mucosa was observed in patients with PD and constipation. The frequency of Th17 and Treg cells in patients with PD and constipation was significantly higher than in those without constipation (P<0.001). Among patients with PD and constipation, the frequency of Th17 and Treg cells in STC was the highest. However, there was no difference in the ratio of Th17/Tregs between the patients with PD with and without constipation, or patients with PD and different types of constipations (P>0.05). Constipation reported before the onset of PD motor symptoms was most often STC or Mixed, and PD constipation may be associated with immune activation in the colonic mucosa.

Proliferative response of peripheral blood mononuclear cells in anti-Hu antibody-associated patients with paraneoplastic neurological syndrome and their depressant effect on small cell lung cancer cells.

Previous studies have suggested that common antigens that exist in neurons and tumor cells trigger cross immunoreaction, which attacks the neurons and tumor cells simultaneously. This action leads to paraneoplastic symptoms and slowed tumor growth. The present study co­cultured peripheral blood mononuclear cells (PBMCs) from anti­Hu antibody­associated patients with paraneoplastic neurological syndrome (PNS) and the small cell lung cancer cell line NCI­H446 (H446) in vitro. In the PNS group, no significant difference was observed in the proliferation index of PBMCs and H446 cells between the mixed or separate cultures. The proportion of CD4+ T cells in patients with PNS (76.54±3.96%) was significantly higher (P<0.05) compared with the healthy control individuals (51.75±17.3%). In conclusion, the sensitized specific T cells in the PBMCs of PNS patients predominantly comprised of CD4+ T cells, which had no inhibitory effect on small cell lung cancer cells in vitro.

Berberine enhances chemosensitivity to irinotecan in colon cancer via inhibition of NF­κB.

Previous studies have shown that irinotecan (CPT­11) impairs chemotherapy­induced apoptosis by activating nuclear factor­κB (NF­κB) and a number of strategies have been employed to augment chemosensitivity through the suppression of NF­κB activation. Berberine, a botanical alkaloid, was reported to enhance chemosensitivity to 5­fluorouracil and doxorubicin by suppressing NF­κB activation. In the present study, the effect of berberine on CPT­11­induced apoptosis was investigated through the inhibition of NF­κB. Inhibition of NF­κB activation by p65 small interfering RNA was shown to potentiate apoptosis induced by CPT­11. Berberine suppressed CPT­11­induced NF­κB activation in a dose­dependent manner and enhanced chemosensitivity to CPT­11 by downregulating NF­κB activation of antiapoptotic genes, c­IAP1, c­IAP2, survivin and Bcl­xL. The current observations indicate that berberine inhibits NF­κB activation and may be used to enhance CPT­11­induced apoptosis in colon cancer.

Fc receptor like 3 in Chinese patients of Han nationality with Guillain-Barré syndrome.

Fc receptor like 3 gene (FcRL3) has been associated with some autoimmune diseases. Here, its role in Guillain-Barré syndrome (GBS) was evaluated by studying nine FcRL3 gene SNPs in a Chinese cohort of GBS patients. The frequencies of FcRL3-3-169C, FcRL3-6 intron3A, and FcRL3-8 exon15G alleles were significantly increased in GBS patients compared with healthy controls. The frequency of FcRL3-1→9 CCTGGAGAA haplotype was significantly increased, and the frequencies of FcRL3-1→9 CCTACAAAA,CCCACGAAA, and CCTGCGGAA haplotypes were significantly decreased compared with healthy controls. These results suggest that FcRL3 is associated with GBS incidence.