A dorsal CA2 to ventral CA1 circuit contributes to oxytocinergic modulation of long-term social recognition memory.

BACKGROUND: Social recognition memory (SRM) is the ability to distinguish familiar from novel conspecifics and is crucial for survival and reproductive success across social species. We previously reported that oxytocin (OXT) receptor (OXTR) signaling in the CA2/CA3a of dorsal hippocampus is essential to promote the persistence of long-term SRM, yet how the endogenous OXT system influences CA2 outputs to regulate long-term SRM formation remains unclear. METHODS: To achieve a selective deletion of CA2 OXTRs, we crossed Amigo2-Cre mice with Oxtr-floxed mice to generate CA2-specific Oxtr conditional knockout (Oxtr-/-) mice. A three-chamber paradigm test was used for studying SRM in mice. Chemogenetic and optogenetic targeting strategies were employed to manipulate neuronal activity. RESULTS: We show that selective ablation of Oxtr in the CA2 suffices to impair the persistence of long-term SRM but has no effect on sociability and social novelty preference in the three-chamber paradigm test. We find that cell-type specific activation of OXT neurons within the hypothalamic paraventricular nucleus enhances long-term SRM and this enhancement is blocked by local application of OXTR antagonist L-368,899 into dorsal hippocampal CA2 (dCA2) region. In addition, chemogenetic neuronal silencing in dCA2 demonstrated that neuronal activity is essential for forming long-term SRM. Moreover, chemogenetic terminal-specific inactivation reveals a crucial role for dCA2 outputs to ventral CA1 (vCA1), but not dorsal lateral septum, in long-term SRM. Finally, targeted activation of the dCA2-to-vCA1 circuit effectively ameliorates long-term SRM deficit observed in Oxtr-/- mice. CONCLUSIONS: These findings highlight the importance of hippocampal CA2 OXTR signaling in governing the persistence of long-term SRM and identify a hippocampal circuit linking dCA2 to vCA1 necessary for controlling long-term SRM formation.

Tellimagrandin II, A Type of Plant Polyphenol Extracted from Trapa bispinosa Inhibits Antibiotic Resistance of Drug-Resistant Staphylococcus aureus.

The emergence of methicillin-resistant Staphylococcus aureus (MRSA) has become a critical global concern. Identifying new candidates of anti-S. aureus agents is urgently required because the therapeutic strategies for infected patients are limited currently. Therefore, the present study investigated whether Tellimagrandin II (TGII), a pure compound extracted from the shells of Trapa bispinosa, exhibits antibacterial effects against MRSA. We first showed that TGII exerted potent inhibitory activity against MRSA with a minimum inhibitory concentration of 128 µg/mL. The obtained fractional inhibitory concentration suggested that TGII could alone exert antistaphylococcal activity, and TGII combined with low doses of antibiotics displayed synergistic effects against MRSA. Moreover, we found that TGII exerted bactericidal activity by reducing the expression of mecA followed by the negative regulation of the penicillin-binding protein 2a (PBP2a) of MRSA. Transmission electron microscopy (TEM) images further confirmed that TGII destroyed the integrity of the cell wall of MRSA and caused the loss of cytoplasm content. In conclusion, we evidenced the antibacterial effects of TGII against MRSA, which enables the effective dose of current antibiotics to be reduced and the predicament of drug-resistant S. aureus isolates to be overcome.

Validation of a novel claims-based stroke severity index in patients with intracerebral hemorrhage.

BACKGROUND: Stroke severity is an important outcome predictor for intracerebral hemorrhage (ICH) but is typically unavailable in administrative claims data. We validated a claims-based stroke severity index (SSI) in patients with ICH in Taiwan. METHODS: Consecutive ICH patients from hospital-based stroke registries were linked with a nationwide claims database. Stroke severity, assessed using the National Institutes of Health Stroke Scale (NIHSS), and functional outcomes, assessed using the modified Rankin Scale (mRS), were obtained from the registries. The SSI was calculated based on billing codes in each patient's claims. We assessed two types of criterion-related validity (concurrent validity and predictive validity) by correlating the SSI with the NIHSS and the mRS. Logistic regression models with or without stroke severity as a continuous covariate were fitted to predict mortality at 3, 6, and 12 months. RESULTS: The concurrent validity of the SSI was established by its significant correlation with the admission NIHSS (r = 0.731; 95% confidence interval [CI], 0.705-0.755), and the predictive validity was verified by its significant correlations with the 3-month (r = 0.696; 95% CI, 0.665-0.724), 6-month (r = 0.685; 95% CI, 0.653-0.715) and 1-year (r = 0.664; 95% CI, 0.622-0.702) mRS. Mortality models with NIHSS had the highest area under the receiver operating characteristic curve, followed by models with SSI and models without any marker of stroke severity. CONCLUSIONS: The SSI appears to be a valid proxy for the NIHSS and an effective adjustment for stroke severity in studies of ICH outcome with administrative claims data.

Lipopolysaccharide-Induced Nitric Oxide, Prostaglandin E2, and Cytokine Production of Mouse and Human Macrophages Are Suppressed by Pheophytin-b.

Sepsis is an overwhelming systemic response to infection that frequently results in tissue damage, organ failure, and even death. Nitric oxide (NO), prostaglandin E2 (PGE2), and cytokine overproduction are thought to be associated with the immunostimulatory cascade in sepsis. In the present study, we analyzed the anti-inflammatory efficacy of the pheophytin-b on both RAW 264.7 murine macrophage and purified human CD14⁺ monocytes stimulated with lipopolysaccharide (LPS) and elucidated the mechanisms by analyzing the cell signaling pathways known to be activated in sepsis. Pheophytin-b suppressed the overexpression of NO, PGE2, and cytokines in LPS-stimulated macrophages without inducing cytotoxicity. It also reduced NOS2 and COX-2 mRNA and protein levels. The inhibitory effects on NO, PGE2, and cytokine overproduction arose from the suppression of STAT-1 and PI3K/Akt pathways; no changes in NF-κB, MAPK, and AP-1 signaling were detected. Thus, pheophytin-b may represent a potential candidate to beneficially modulate the inflammatory response in sepsis.

Clinical Profile and Outcome of Myasthenic Crisis In Central Taiwan.

BACKGROUND: Myasthenia gravis (MG) is an autoimmune disease caused by antibodies to acetylcholine receptors of the skeletal muscle. Myasthenic crisis (MC) is a complication observed during both early and late stage MG cases. In this study, we examined current treatments and three years outcomes in patients with MG and MC. We also investigated the impact of thymectomy and systemic lupus erythematosus (SLE) in patients with MG and MC. METHODS: In this retrospective study, we reviewed the medical records of all patients admitted to one teaching hospital between January 2006 and December 2014 and identified those for whom discharge diagnosis included the International Classification of Diseases, ninth revision (ICD-9) codes corresponding to MG (358.X, all extensions and all positions). RESULTS: We identified 29 patients and 49 hospitalizations. Among these patients, the cause for initial hospitalization was MG in 16 cases and MC in 13 cases. Six out of the 16 MG patients were readmitted within 3 years; with 2 of the cases due to MC. Eight of the initial 13 MC patients were readmitted within 3 years, and 6 of the cases due to MC. Among these 15 MC patients, 14 were admitted to the intensive care unit (ICU), and 8 were intubation and put on mechanical ventilators. The median ICU stay was 7 days (3-45). Both MG patients who were also diagnosed with SLE experienced MC. One patient died during the first-time hospitalization, and one patient died during re-hospitalization within 2 years. CONCLUSION: Plasma exchange (PE) is the main treatment modality of MC, and most patients in our cohort had a good response. Infection is the most common trigger of MC and a significant cause of death. Despite significant morbidity and mortality in patients with MC, a favorable long-term outcome is possible with intensive treatment. Key Words: myathenia gravis, myasthenic crisis, systemic lupus erythematosus, outcome.

Exploring the impact of intravenous thrombolysis on length of stay for acute ischemic stroke: a retrospective cohort study.

BACKGROUND: Understanding the factors that influence the hospital length of stay (LOS) for patients with stroke will help in discharge planning and stroke unit management. We explored how intravenous thrombolysis (IVT) affects LOS in an acute-care hospital setting. METHODS: We analyzed adult patients with ischemic stroke who presented within 48 h of onset from a hospital-based stroke registry. The relationship between IVT and prolonged LOS (LOS ≥ 7 days) was studied by both multivariate logistic regression and the classification and regression tree (CART) analyses. RESULTS: Among the study population of 3054 patients, 1110 presented within 4.5 h. The median LOS (interquartile range) was 7 (4 to 11) days, and 1619 patients had prolonged LOS. Multivariate logistic regression revealed that IVT (odds ratio, 0.53; 95 % confidence interval 0.38-0.74) was an independent factor that reduced the risk of prolonged LOS, whereas age, National Institutes of Health Stroke Scale (NIHSS) score, diabetes mellitus, and leukocytosis at admission predicted prolonged LOS. CART analysis identified 4 variables (NIHSS score, IVT, leukocytosis at admission, and age) as important factors to partition the patients into six subgroups. The patient subgroup that had an NIHSS score of 5 to 7 and received IVT had the lowest probability (19 %) of prolonged LOS. CONCLUSIONS: IVT reduced the risk of prolonged LOS in patients with acute ischemic stroke. Measures to increase the rate of IVT are encouraged.

Underestimated Rate of Status Epilepticus according to the Traditional Definition of Status Epilepticus.

PURPOSE: Status epilepticus (SE) is an important neurological emergency. Early diagnosis could improve outcomes. Traditionally, SE is defined as seizures lasting at least 30 min or repeated seizures over 30 min without recovery of consciousness. Some specialists argued that the duration of seizures qualifying as SE should be shorter and the operational definition of SE was suggested. It is unclear whether physicians follow the operational definition. The objective of this study was to investigate whether the incidence of SE was underestimated and to investigate the underestimate rate. METHODS: This retrospective study evaluates the difference in diagnosis of SE between operational definition and traditional definition of status epilepticus. Between July 1, 2012, and June 30, 2014, patients discharged with ICD-9 codes for epilepsy (345.X) in Chia-Yi Christian Hospital were included in the study. A seizure lasting at least 30 min or repeated seizures over 30 min without recovery of consciousness were considered SE according to the traditional definition of SE (TDSE). A seizure lasting between 5 and 30 min was considered SE according to the operational definition of SE (ODSE); it was defined as underestimated status epilepticus (UESE). RESULTS: During a 2-year period, there were 256 episodes of seizures requiring hospital admission. Among the 256 episodes, 99 episodes lasted longer than 5 min, out of which 61 (61.6%) episodes persisted over 30 min (TDSE) and 38 (38.4%) episodes continued between 5 and 30 min (UESE). In the 38 episodes of seizure lasting 5 to 30 minutes, only one episode was previously discharged as SE (ICD-9-CM 345.3). Conclusion. We underestimated 37.4% of SE. Continuing education regarding the diagnosis and treatment of epilepsy is important for physicians.

Oxfordshire Community Stroke Project classification improves prediction of post-thrombolysis symptomatic intracerebral hemorrhage.

BACKGROUND: The Oxfordshire Community Stroke Project (OCSP) classification is a simple stroke classification system with value in predicting clinical outcomes. We investigated whether and how the addition of OCSP classification to the Safe Implementation of Thrombolysis in Stroke (SITS) symptomatic intracerebral hemorrhage (SICH) risk score improved the predictive performance. METHODS: We constructed an extended risk score by adding an OCSP component, which assigns 3 points for total anterior circulation infarcts, 0 point for partial anterior circulation infarcts or lacunar infarcts. Patients with posterior circulation infarcts were assigned an extended risk score of zero. We analyzed prospectively collected data from 4 hospitals to compare the predictive performance between the original and the extended scores, using area under the receiver operating characteristic curve (AUC) and net reclassification improvement (NRI). RESULTS: In a total of 548 patients, the rates of SICH were 7.3% per the National Institute of Neurological Diseases and Stroke (NINDS) definition, 5.3% per the European-Australasian Cooperative Acute Stroke Study (ECASS) II, and 3.5% per the SITS-Monitoring Study (SITS-MOST). Both scores effectively predicted SICH across all three definitions. The extended score had a higher AUC for SICH per NINDS (0.704 versus 0.624, P = 0.015) and per ECASS II (0.703 versus 0.612, P = 0.016) compared with the SITS SICH risk score. NRI for the extended risk score was 22.3% (P = 0.011) for SICH per NINDS, 21.2% (P = 0.018) per ECASS II, and 24.5% (P = 0.024) per SITS-MOST. CONCLUSIONS: Incorporation of the OCSP classification into the SITS SICH risk score improves risk prediction for post-thrombolysis SICH.

Revised iScore to predict outcomes after acute ischemic stroke.

The iScore is a validated tool to predict mortality and functional outcome after acute ischemic stroke. It incorporates stroke subtype according to the Trial of Org 10172 in Acute Stroke Treatment (TOAST) classification as one of its factors. However, the TOAST stroke subtype may not be easily determined without extensive investigations. We aimed to test if the stroke subtype can be substituted by the Oxfordshire Community Stroke Project (OCSP) classification. We applied the iScore and the revised iScore, in which the TOAST subtype was replaced by the OCSP classification, to patients admitted to a single hospital for acute ischemic stroke. Outcome measures included poor functional status (modified Rankin scale score, 3-6) at discharge and 3 months. The performance between the iScore and the revised iScore was assessed by determining the discrimination and calibration of the scores. We studied 3196 patients at the acute stage, and among them 2349 patients were available for the 3-month assessment. The discrimination of the revised iScore was comparable with the iScore for poor outcome at discharge (area under the receiver operating characteristic curve, .767 versus .775; P=.06) and at 3-month (.801 versus .810; P=.06). The correlation between the observed and the expected outcomes was high for both the iScore (Pearson correlation coefficient, .993 at discharge and .995 at 3 months; both P<.0001) and the revised iScore (.985 and .993, respectively; both P<.0001). The revised iScore reliably predicts clinical outcomes at discharge and 3 months for patients with acute ischemic stroke.

Association Between Abnormal Course of Carotid Artery and Cerebrovascular Disease.

PURPOSE: Abnormal course of the carotid artery (ABCA) is commonly identified during carotid sonography studies. Whether ABCA is related to the risk of stroke and stroke risk factors remains unclear. The purpose of the study is to investigate the prevalence of ABCA and the relationship with stroke and the risk factors of stroke. METHODS: Color duplex ultrasound scanning of carotid arteries was performed on 615 subjects (between January 1, 2012 and March 31, 2012). ABCA and intimal thickness were recorded. Risk factors of stroke such as hypertension, diabetes mellitus, dyslipidemia, atherosclerosis, stroke history, and heart disease were recorded. The prevalence of ABCA was analyzed and its relationship with stroke and stroke risk factors was evaluated. RESULTS: ABCA was found in 4.1% (25/615) patients, 6.29% (19/302) in women, and 1.91% (6/313) in men. ABCA in 1 vessel was noted in 18 patients, 2 vessels in 3 patients, 3 vessels in 3 patients, and 4 vessels in 1 patient. The frequency of ABCA was significantly higher in women than in men (6.3% vs 1.9%, p = 0.01). There was no difference in the prevalence of ABCA between stroke patients and nonstroke subjects ( p = 0.60). ABCA was more frequent in patients older than 65 years. (5.91% (22/372) vs. 1.23% (3/243) p = 0.01). Logistic regression analysis did not reveal associations between ABCA and stroke risk factors (hypertension, diabetes mellitus, dyslipidemia, stroke history, heart disease and atherosclerosis). During 1 year follow-up, 2.88% (17/590) of non-ABCA patients and 4.0% (1/25) of ABCA patients had event of stroke or transient ischemic attack (TIA) ( p =0.08). CONCLUSION: The prevalence of ABCA in the present study is significantly lower than that in previous studies (Togay-Isikay et al., 24.6%, Del Corso et al., 58%). ABCA is more frequent in women and older patients. ABCA is not related to stroke and stroke risk factors. From our results, we suggest that patients with ABCA be placed under observation unless they exhibit neurological symptoms.

Brain biopsy-proven intravascular lymphomatosis presenting as rapidly recurrent strokes-two case reports.

PURPOSE: Intravascular lymphomatosis (IVL) is rare and usually goes undiagnosed until the time of autopsy because of its protean neurological manifestations. CASE REPORT: In this report, we describe two women who developed rapidly recurrent strokes within one to two months. In both cases, brain magnetic resonance imaging showed progression of bilateral cerebral infarcts, and histopathology from brain biopsy confirmed the diagnosis of IVL. The first case did not receive chemotherapy and died of septic shock one month after diagnosis. The second case received whole brain radiotherapy followed by rituximab-containing chemotherapy, and experienced partial improvement of neurological deficits. However, she began to deteriorate in consciousness at 8 months and became stuporous at 10 months after the onset of symptoms. CONCLUSION: IVL should be considered as a possible etiology if multiple strokes occur in a short period of time.

Epidermoid cyst presenting as isolated trigeminal neuralgia - two case reports.

PURPOSE: Symptomatic TN accounts for up to 15% of all TN. Though there are many established "red flag" signs, it is still sometimes difficult to sift symptomatic from classic TN. We herein report two cases of isolated TN with normal neurologic examinations and then tissue proved as epidermoid cyst. CASE 1: A 17-year-old girl presented with paroxysmal intense pain mixed dull background pain at right mandibular region for one month. The blink reflex demonstrated brainstem lesion and brain magnetic resonance imaging (MRI) revealed a huge lobulated tumor in right cerebellopontine angle (CPA) with obvious brainstem compression. Her right facial pain was nearly completely disappeared postoperatively. CASE 2: The 48-year-old woman had chronic paroxysmal electric-like and burning pain in left V3 region for more than 5 years. Because of refractory pain, brain MRI was arranged and showed a non-enhancing cystic lesion at left CPA. Post operative complications occurred as left multiple lower cranial nerve palsies and Horner syndrome, and truncal ataxia. Her facial pain was completely free after 1 month follow up. CONCLUSION: In the first patient, teenage onset, abnormal trigeminal reflex, and early developing background pain struck us directly to symptomatic TN. In the second case, we suspected symptomatic TN with uncertainty before image study. TN could be the isolated initial symptom of CPA epidermoid cysts. In consideration about pretty high prevalence of symptomatic TN, physicians should be more alert and straightforward arrange neuroimage when facing TN patients with atypical presentation.

Clinical narratives as a predictor for prognosticating functional outcomes after intracerebral hemorrhage.

BACKGROUND: Intracerebral hemorrhage (ICH) is a devastating stroke type that causes high mortality rates and severe disability among survivors. Many prognostic models are available for prognosticating patients with ICH. This study aimed to investigate whether clinical narratives can improve the performance for predicting functional outcomes after ICH. METHODS: This study used data from the hospital stroke registry and electronic health records. The study population (n = 1363) was randomly divided into a training set (75%, n = 1023) and a holdout test set (25%, n = 340). Five risk scores for ICH were used as baseline prognostic models. Using natural language processing (NLP), text-based markers were generated from the clinical narratives of the training set through machine learning (ML) and deep learning (DL) approaches. The primary outcome was a poor functional outcome (modified Rankin Scale score of 3 to 6) at hospital discharge. The predictive performance was compared between the baseline models and models enhanced by incorporating the text-based markers using the holdout test set. RESULTS: The enhanced prognostic models outperformed the baseline models, regardless of whether ML or DL approaches were used. The areas under the receiver operating characteristic curve (AUCs) of the baseline models were between 0.760 and 0.892. Adding the text-based marker to the baseline models significantly increased the model discrimination, with AUCs ranging from 0.861 to 0.914. The net reclassification improvement and integrated discrimination improvement indices also showed significant improvements. CONCLUSIONS: Using NLP to extract textual information from clinical narratives could improve the predictive performance of all baseline prognostic models for ICH.

Topiramate related reversible erectile dysfunction in temporal lobe epilepsy.

Topiramate (TPM) is a newer antiepileptic drug with high efficacy in treating various neurological disorders, especially epilepsy and migraine. The adverse effects of TPM therapy are mainly central nervous system-related somnolence and dizziness. There are rare reports about the role of TPM on sexual effects, but with inconsistent results. In this report, we describe a 31-year-old man who developed erectile dysfunction after several months of TPM use. Complete urological and sexual psychiatric evaluations were done. There was lack of an identifiable organic basis and psychiatric pathology in this patient. The erectile dysfunction improved only after the termination of TPM, documenting the temporal relationship. We reviewed and discussed the clinical aspect of TPM use in erectile dysfunction. This case and the rare cases of erectile dysfunction in TPM use reported in the literature show that TPM is worth to be paid attention to whenever it is prescribed in a wide range of neurological disorders.

Developing a stroke alert trigger for clinical decision support at emergency triage using machine learning.

BACKGROUND: Acute stroke is an urgent medical condition that requires immediate assessment and treatment. Prompt identification of patients with suspected stroke at emergency department (ED) triage followed by timely activation of code stroke systems is the key to successful management of stroke. While false negative detection of stroke may prevent patients from receiving optimal treatment, excessive false positive alarms will substantially burden stroke neurologists. This study aimed to develop a stroke-alert trigger to identify patients with suspected stroke at ED triage. METHODS: Patients who arrived at the ED within 12 h of symptom onset and were suspected of a stroke or transient ischemic attack or triaged with a stroke-related symptom were included. Clinical features at ED triage were collected, including the presenting complaint, triage level, self-reported medical history (hypertension, diabetes, hyperlipidemia, heart disease, and prior stroke), vital signs, and presence of atrial fibrillation. Three rule-based algorithms, ie, Face Arm Speech Test (FAST) and two flavors of Balance, Eyes, FAST (BE-FAST), and six machine learning (ML) techniques with various resampling methods were used to build classifiers for identification of patients with suspected stroke. Logistic regression (LR) was used to find important features. RESULTS: The study population consisted of 1361 patients. The values of area under the precision-recall curve (AUPRC) were 0.737, 0.710, and 0.562 for the FAST, BE-FAST-1, and BE-FAST-2 models, respectively. The values of AUPRC for the top three ML models were 0.787 for classification and regression tree with undersampling, 0.783 for LR with synthetic minority oversampling technique (SMOTE), and 0.782 for LR with class weighting. Among the ML models, logistic regression and random forest models in general achieved higher values of AUPRC, in particular in those with class weighting or SMOTE to handle class imbalance problem. In addition to the presenting complaint and triage level, age, diastolic blood pressure, body temperature, and pulse rate, were also important features for developing a stroke-alert trigger. CONCLUSIONS: ML techniques significantly improved the performance of prediction models for identification of patients with suspected stroke. Such ML models can be embedded in the electronic triage system for clinical decision support at ED triage.

Lipopolysaccharide-Induced Nitric Oxide and Prostaglandin E2 Production Is Inhibited by Tellimagrandin II in Mouse and Human Macrophages.

Sepsis develops from a serious microbial infection that causes the immune system to go into overdrive. The major microorganisms that induce sepsis are Gram-negative bacteria with lipopolysaccharide (LPS) in their cell walls. Nitric oxide (NO) and cyclooxygenase-2 (COX-2) are the key factors involved in the LPS-induced pro-inflammatory process. This study aimed to evaluate the effects of polyphenol Tellimagrandin II (TGII) on anti-inflammatory activity and its underlying basic mechanism in murine macrophage cell line RAW 264.7 and human monocyte-derived macrophages. Macrophages with more than 90% cell viability were found in the cytotoxicity assay under 50 µM TGII. Pre- or post-treatment with TGII significantly reduced LPS-induced inducible nitric oxide synthase (NOS2) protein and mRNA expression, reducing LPS-induced COX-2 protein. Downstream of NOS2 and COX-2, NO and prostaglandin E2 (PGE2) were significantly inhibited by TGII. Upstream of NOS2 and COX-2, phospho-p65, c-fos and phospho-c-jun were also reduced after pre-treatment with TGII. Mitogen-activated protein kinases (MAPKs) are also critical to nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) stimulation, and phospho-p38 expression was found to have been blocked by TGII. TGII efficiently reduces LPS-induced NO production and its upstream regulatory factors, suggesting that TGII may be a potential therapeutic agent for sepsis and other inflammatory diseases.

Mono-(2-ethylhexyl) phthalate Promotes Dengue Virus Infection by Decreasing IL-23-Mediated Antiviral Responses.

Exposure to environmental hormones such as di(2-ethylhexyl) phthalate (DEHP) has become a critical human health issue globally. This study aimed to investigate the correlations between DEHP/mono-(2-ethylhexyl) phthalate (MEHP) levels and macrophage-associated immune responses and clinical manifestations in dengue virus (DV)-infected patients. Among 89 DV-infected patients, those with DV infection-related gastrointestinal (GI) bleeding (n = 13, 15% of patients) had significantly higher DEHP exposure than those without GI bleeding (n = 76, 85% of patients), which were 114.2 ng/ml versus 52.5 ng/ml ΣDEHP in urine; p = 0.023). In an in vitro study using cultured human monocyte-derived macrophages (MDMs) to investigate the effects of MEHP, treatment increased IL-1ß and TNF-α release but decreased IL-23 release, with negative correlations observed between urine ΣDEHP and serum IL-23 levels in patients. MEHP-treated MDMs had lower antiviral Th17 response induction activity in mixed T-cell response tests. The in vitro data showed that MEHP increased DV viral load and decreased IL-23 release dose-dependently, and adding IL-23 to MEHP-exposed MDMs significantly reduced the DV viral load. MEHP also suppressed IL-23 expression via the peroxisome proliferator-activated receptor-gamma (PPAR-γ) pathway. Further, the PPAR-γ antagonist GW9662 significantly reversed MEHP-induced IL-23 suppression and reduced the DV viral load. These study findings help to explain the associations between high MEHP levels and the high global burden of dengue disease.

The Impact of Loading Dose on Outcome in Stroke Patients Receiving Low-Dose Tissue Plasminogen Activator Thrombolytic Therapy.

BACKGROUND: Intravenous tissue plasminogen activator (tPA) (0.9 mg/kg, maximum 90 mg) with a bolus of 10% of the total dose given within 1-2 mins is the standard therapy for patients receiving thrombolytic therapy. Low-dose (0.6 mg/kg) tPA is also approved for thrombolytic therapy for ischemic stroke patients. Low-dose tPA is associated with a low bolus dose. It is unknown whether increasing the bolus dose in patients receiving low-dose tPA thrombolysis may improve outcomes or increase the risk of hemorrhagic transformation (HT). AIM: This study investigated the impact of the bolus dose on the outcome in ischemic stroke patients receiving low-dose tPA thrombolytic therapy. METHODS: In this retrospective, observational study, we enrolled 214 ischemic stroke patients receiving low-dose tPA thrombolytic therapy. Of these 214 patients, 107 patients received 10% of the total dose as a bolus dose, and 107 patients received 15% of the total dose as a bolus dose. The National Institutes of Health Stroke Score (NIHSS) were evaluated before tPA infusion, 24 h after thrombolytic therapy, and at discharge. Stroke severity was categorized as mild (0-5), moderate (6-14), severe (15-24), or very severe (≥25). Neurological improvement (NI) was defined as an improvement of 6 or more points in the NIHSS, and no response (NR) was defined as an increase in the NIHSS of ≤4 points or a decrease ≤6 points. Neurological deterioration (ND) was defined as an increase in the NIHSS >4 points. A good outcome was defined as a modified Ranking Score (mRS) of 0 or 1. We compared the NI, NR, and ND rates at 24 hrs after thrombolytic therapy and discharge between the 15% and 10% bolus dose groups. RESULTS: In patients with mild and moderate stroke, there was no significant difference in the NI, NR, ND, and HT rates and 6-month outcomes between the 15% and 10% bolus groups. In patients with severe and very severe stroke, outcomes at 6 months were significantly better in the 15% bolus group than in the 10% bolus group. The factors affecting the outcomes of severe and very severe stroke patients are hypertension and bolus dose. CONCLUSION: In severe and very severe stroke patients receiving low-dose tPA thrombolytic therapy, a bolus dose of 15% of the total dose can improve outcomes.

Insulin Reduces Inflammation by Regulating the Activation of the NLRP3 Inflammasome.

The NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome is the platform for IL-1ß maturation, aimed at mediating a rapid immune response against danger signals which must be tightly regulated. Insulin is well known as the critical hormone in the maintenance of glucose in physiologic response. Previous studies have proved insulin has the anti-inflammatory effect but the molecular mechanism of immunomodulation provided by insulin is not clear so far. Here we investigated whether insulin reduces inflammation by regulating the NLRP3 inflammasome. In the present study, we used LPS and ATP to induce the intracellular formation of the NLRP3 inflammasome. Insulin inhibited the secretion of IL-1ß by preventing the assembly of the ASC in THP-1 cells and human CD14+ monocyte-derived macrophages. The phosphorylation status of Syk, p38 mitogen-activated protein kinase (MAPK) and ASC were altered by insulin. These effects were attenuated in THP-1 cells transfected with small interfering RNA targeting insulin receptors. In vivo, administration of glucose-insulin-potassium reduced serum IL-1ß level, intestinal ASC speck formation, local macrophage infiltration and alleviated intestinal injury in mice exposed to LPS. Insulin may play an immunomodulatory role in anti-inflammation by regulating the NLRP3 inflammasome.