Local and Remote Chemogenetic Suppression of Hippocampal Seizures in Rats.

BACKGROUND: Innovative treatments of refractory epilepsy are widely desired, for which chemogenetic technology can provide region- and cell-type-specific modulation with relative noninvasiveness. OBJECTIVES: We aimed to explore the specific applications of chemogenetics for locally and remotely networks controlling hippocampal seizures. METHODS: A virus coding for a modified human Gi-coupled M4 muscarinic receptor (hM4Di) on pyramidal cells was injected into either the right hippocampal CA3 or the bilateral anterior nucleus of the thalamus (ANT) in rats. After one month, seizures were induced by 4-aminopyridine (4-AP) injection into the right CA3. Simultaneously, clozapine-N-oxide (CNO) (2.5 mg/kg) or clozapine (0.1 mg/kg), the specific ligands acting on hM4Di, were injected intraperitoneally. We also set up hM4Di control and clozapine control groups to eliminate the influence of viral transfection and the ligand alone on the experimental results. RESULTS: For both local and remote controls, the mean seizure duration was significantly reduced upon ligand application in the experimental groups. Seizure frequency, on the other hand, only showed a significant decrease in local control, with a lower frequency in the clozapine group than in the CNO group. Both the effects of CNO and clozapine were time-dependent, and clozapine was faster than CNO in local seizure control. CONCLUSION: This study shows the potency of chemogenetics to attenuate hippocampal seizures locally or remotely by activating the transfected hM4Di receptor with CNO or clozapine. ANT is suggested as a potentially safe chemogenetic application target in the epileptic network for focal hippocampal seizures.

Elevated ApoB/ApoA-I ratio is associated with acute anti-N-Methyl-D-aspartate receptor encephalitis, but not disease outcomes.

Objective: The purpose of the present study is to clarify the relationship between the apolipoprotein B100/apolipoprotein A-I (ApoB/ApoA-I) ratio and anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis. Methods: A total of 71 patients with anti-NMDAR encephalitis were included in this study, and their ApoB/ApoA-I ratios in baseline and follow-up were retrospectively analyzed. Results: The ApoB/ApoA-I ratio was closely correlated with the baseline-modified Rankin scale (mRS) score of >3 in patients with anti-NMDAR encephalitis. A subgroup analysis showed obvious differences between the high and low ApoB/ApoA-I ratio groups. The ApoB/ApoA-I ratio was positively correlated with intensive care unit (ICU) treatment, length of hospital stay, baseline mRS score, C-reactive protein (CRP), and erythrocyte sedimentation rate (ESR). The ratios of the high and low ApoB/ApoA-I groups both improved in the follow-up. Conclusion: The increased ApoB/ApoA-I ratio is associated with acute anti-NMDAR encephalitis, but not disease outcomes. Serum ApoB/ApoA-I ratio was related to inflammation and immunity in peripheral blood. The findings might provide a new idea for further exploration of the pathogenesis and treatment of anti-NMDAR encephalitis.

Simple and effective serum biomarkers potential for predicting status epilepticus in anti-N-methyl-D-aspartate receptor encephalitis.

BACKGROUND: Patients with anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis who also present with status epilepticus (SE) often have a poor prognosis. The aim of this study is to explore simple and effective predictors for anti-NMDAR encephalitis accompanied with SE. METHODS: We retrospectively analyzed 65 anti-NMDAR encephalitis patients from January 2015 to December 2018 who admitted to the Third Affiliated Hospital of Sun Yat-sen University. Patients were divided into SE group and non-SE groups. Their pre-treatment data and 3-month follow-up data were retrospectively analyzed. RESULTS: The results showed that compared with the non-SE group, the levels of serum uric acid (UA) and high-density lipoprotein cholesterol (HDL-C) in anti-NMDAR encephalitis patients with SE decreased significantly before treatment. Additionally, the levels of serum UA and HDL-C increased while the level of C-reactive protein (CRP) decreased 3 months after treatment in the SE group. Compared with the non-SE group, the SE patients had higher modified Rankin scale (mRS) scores before (mRS1) and after treatment (mRS2). Serum UA concentrations before treatment showed significantly negative correlations with mRS1 (r = - 0.407, p < 0.01) and mRS2 (r = - 0.458, p < 0.001), while the level of serum CRP before treatment had strong positive correlations with mRS1 (r = 0.304, p < 0.05) and mRS2 (r = 0.301, p < 0.05) in anti-NMDAR encephalitis patients. The receiver operating characteristic curve demonstrated that the combined detection of UA, HDL-C and CRP before treatment had a significantly higher value (the area under the curve = 0.848; 95% confidence interval [CI], 0.74-0.957; p < 0.001) to predict anti-NMDAR encephalitis accompanied with SE than that of single detection. CONCLUSIONS: Hence, the combined detection of serum UA, HDL-C and CRP before treatment may be simple and effective indicators for predicting SE in anti-NMDAR encephalitis, which may be helpful in early stages to remind clinicians to be alert to the emergence of SE.

Constipation induced gut microbiota dysbiosis exacerbates experimental autoimmune encephalomyelitis in C57BL/6 mice.

BACKGROUND: Constipation is a common gastrointestinal dysfunction which has a potential impact on people's immune state and their quality of life. Here we investigated the effects of constipation on experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). METHODS: Constipation was induced by loperamide in female C57BL/6 mice. The alternations of gut microbiota, permeability of intestinal barrier and blood-brain barrier, and histopathology of colon were assessed after constipation induction. EAE was induced in the constipation mice. Fecal microbiota transplantation (FMT) was performed from constipation mice into microbiota-depleted mice. Clinical scores, histopathology of inflammation and demyelination, Treg/Th17 and Treg17/Teff17 imbalance both in the peripheral lymphatic organs and central nervous system, cytokines include TGF-ß, GM-CSF, IL-10, IL-17A, IL-17F, IL-21, IL-22, and IL-23 in serum were assessed in different groups. RESULTS: Compared with the vehicle group, the constipation mice showed gut microbiota dysbiosis, colon inflammation and injury, and increased permeability of intestinal barrier and blood-brain barrier. We found that the clinical and pathological scores of the constipation EAE mice were severer than that of the EAE mice. Compared with the EAE mice, the constipation EAE mice showed reduced percentage of Treg and Treg17 cells, increased percentage of Th17 and Teff17 cells, and decreased ratio of Treg/Th17 and Treg17/Teff17 in the spleen, inguinal lymph nodes, brain, and spinal cord. Moreover, the serum levels of TGF-ß, IL-10, and IL-21 were decreased while the GM-CSF, IL-17A, IL-17F, IL-22, and IL-23 were increased in the constipation EAE mice. In addition, these pathological processes could be transferred via their gut microbiota. CONCLUSIONS: Our results verified that constipation induced gut microbiota dysbiosis exacerbated EAE via aggravating Treg/Th17 and Treg17/Teff17 imbalance and cytokines disturbance in C57BL/6 mice.

Do early HER2-overexpression breast cancer patients benefit from undergoing neoadjuvant trastuzumab and mastectomy? A meta-analysis.

PURPOSE: To assess the overall survival (OS) of early human epidermal growth factor receptor 2 (HER2)-enriched breast cancer patients after receiving neoadjuvant trastuzumab (NAT) compared to adjuvant trastuzumab (AT) treatment and the difference in local-regional relapse (LRR) rate with this tumor and treatment between women after mastectomy and women after breast-conserving therapy (BCT). METHODS: Articles were retrieved from PubMed, Embase, Web of Science, and Cochrane Library. A pooled odds ratio (OR) with a 95% confidential interval (CI) was calculated. The StataSE version 12.0 software was employed for meta-analysis. RESULTS: Twelve available clinical studies containing 2366 subjects were included. The OS of NAT compared with that of AT was not significantly different (pooled OR=1.04; 95% CI, 0.47-2.33). There was a significantly lower LRR rate for patients with mastectomy compared to those with BCT (pooled OR=0.58; 95% CI, 0.38-0.89); however, subgroup analysis revealed that the significant advantage of LRR for mastectomy compared to BCT was only represented in women without trastuzumab treatment (pooled OR=0.52; 95% CI, 0.31-0.88) compared to those who received trastuzumab treatment (pooled OR=0.71; 95% CI, 0.34-1.49). CONCLUSION: Early stage HER2-overexpression breast cancer patients benefit with an equivalent OS from NAT treatment compared to AT. Patients who underwent mastectomy and BCT experienced a similar LRR rate if they received anti-HER2 targeted therapy of trastuzumab, but the LRR rate was discernibly reduced in patients who received mastectomy compared to BCT if they did not also receive trastuzumab treatment.

The reciprocal influences of prognosis between two types of surgical interventions and early breast cancer patients with diverse luminal subtypes: A meta-analysis.

BACKGROUND: To investigate and compare the effects of breast-conserving therapy (BCT) and mastectomy on the disease recurrence and long-term survival in early-stage luminal breast cancer and the difference in prognosis across diverse luminal subtypes receiving single surgical modality. METHODS: The databases of PubMed and Embase were retrieved to select eligible trials that were published from inception to 13 November 2018. The clinical trials that offered the details about recurrent disease and/or survival in luminal tumors underwent BCT or mastectomy met the inclusion criteria (n=24). With the random- or fixed-effect model basing on heterogeneity Chi test with its significant level of P < .1, pooled odds ratio (OR) with its 95% CI, and P value were identified for endpoints. RESULTS: The analyzed data were constituted of 25 qualified trials with 13,032 unique women suffered from luminal cancers. The fixed-effect models were utilized. On the LRR regarding BCT versus mastectomy, the pooled data indicated no significant difference in luminal carcinomas (OR, 0.84; 95%CI, 0.43-1.64; P = .61; n = 867). In BCT cohort, the pooled data showed that there were some significant benefits favoring luminal A over luminal B in LR (OR, 0.61; 95%CI, 0.46-0.81; P = .0007; n = 5406), DM (OR, 0.53; 95%CI, 0.41-0.69; P < .00001; n = 4662), DFS (OR, 0.59; 95%CI, 0.36-0.96; P = .03; n = 776) and OS (OR, 0.65; 95%CI, 0.42-0.99; P = .05; n = 1149), but not in LRR (OR, 0.74; 95%CI, 0.48-1.13; P = .16; n = 3732), coupled with luminal A/B over luminal-HER2 in LRR (OR, 0.43; 95%CI, 0.25-0.76; P = .004; n = 890), DM (OR, 0.56; 95%CI, 0.35-0.90; P = .02; n = 1396), DFS (OR, 0.47; 95%CI, 0.27-0.83; P = .009; n = 532); in mastectomy cohort, there were apparent advantages of LRR (OR, 0.58; 95%CI, 0.36-0.92; P = .02; n = 1768), LR (OR,0.56; 95%CI, 0.38-0.83; P = .004; n = 1209), DM (OR, 0.58; 95%CI, 0.40-0.84; P = .004; n = 652) and OS (OR, 0.62; 95%CI, 0.43-0.89; P = .009; n = 652) in luminal A vs luminal B. CONCLUSION: For early luminal breast cancer, the equality of LRR was achieved in BCT and mastectomy. In comparison, luminal A cancers benefit the most improved tumor re-appearence and survival in luminal diseases regardless of the option of surgical modality, whereas luminal-HER2 is affected by the worst clinical outcomes in them who follows BCT.