Objective Data on the impact of planned pregnancy on foetal outcomes in women with epilepsy (WWE) are limited. We analysed the data of a large cohort to assess the protective effects of pregnancy planning on adverse foetal outcomes and to identify associated risk factors. Methods This study involved the analysis of data from a prospectively collected database of pregnant WWE in northwest China. Participants were categorized into planned pregnancy and unplanned pregnancy groups. Clinical characteristics and foetal outcomes were evaluated, and logistic regression was used to identify risk factors for adverse foetal outcomes. Results The analysis included 806 pregnancies from 648 WWE. Planned pregnancies showed higher rates of antiseizure medications (ASMs) adjustment (44 %; P < 0.001), adherence of folic acid supplementation (88.5 %; P < 0.001), breastfeeding (48.1 %; P < 0.001). Additionally, planned pregnancies had lower generalized tonic-clonic seizure (GTCS) frequency (P < 0.001), and decreased rates of adverse foetal outcomes such as preterm birth (3 %; P < 0.001), induced abortion (4.3 %; P < 0.001), and major congenital malformations (MCMs) (1.5 %; P = 0.006). Planned pregnancy as an independent protective factor against adverse foetal outcomes (P < 0.001), while topiramate (TPM) use (P = 0.003), maternal age≥ 30 years (P = 0.023), lack of folic acid (P = 0.002), and higher GTCS frequency (P = 0.01) were independent risk factors for adverse foetal outcomes. Conclusion Planned pregnancy is associated with well folic acid adherence, proactive ASM adjustment, higher breastfeeding rates, and stable seizure control. It serves as an independent protective factor against adverse foetal outcomes. Maternal age ≥ 30 years, TPM use, and frequent GTCS increase risk, while ASM withdrawal during pregnancy is not protective.

This study was conducted as part of the China Epilepsy Prevention and Control Management Project. The research aimed to investigate the efficacy of phenobarbital (PB) and prognostic factors for convulsive seizures in rural areas of northwest China. Patients with convulsive seizures were recruited from seven rural regions in Shaanxi Province, Northwest China, between January 2011 and December 2022. Patients over 6 years old and had at least one convulsive seizure at baseline (within 12 months prior to screening) were included. They were prescribed PB monotherapy according to a standardized protocol. During follow-up, the efficacy of PB was annually estimated by the reduction in seizure frequency. At the five-year follow-up, prognosis was assessed by the proportion of patients who achieved three consecutive seizure-free years. A total of 1001 patients (mean age 40.9 years, 56.8

Objective Treatment of disorders of consciousness (DoC) remains a major clinical challenge, and noninvasive, targeted modulation of deep brain structures has emerged as a promising therapeutic strategy. We aimed to evaluate the feasibility/safety and preliminary effects of thalamic temporal interference stimulation (TIS) targeting centromedian-parafascicular (CM-PF) complex in patients with DoC.Methods We conducted a single-arm, self-controlled trial in nine patients with DoC. All patients received TIS targeting the bilateral CM-PF complex once daily for 10 consecutive days. Stimulation targets were guided by patient-specific electric field modeling to ensure precise neuromodulation. Outcome measures included adverse events, the change in Coma Recovery Scale-Revised (CRS-R) total and subscale scores from baseline to after five and 10 stimulation sessions, and alterations in EEG "ABCD" patterns and power spectral density (PSD) following the tenth session.Results No serious adverse events were reported. After 10 stimulation sessions, CRS-R total scores increased significantly, with improvements primarily observed in the auditory, visual, and motor subscales. No significant changes in CRS-R scores were detected after five stimulation sessions. EEG analyses demonstrated an increased prevalence of patterns C and D, disappearance of pattern A, and elevated global PSD in the alpha and beta frequency bands after 10 stimulation sessions.Interpretation This pilot study demonstrates that thalamic TIS is a safe and feasible noninvasive deep brain stimulation technology that may facilitate consciousness recovery in patients with DoC. Larger randomized controlled trials with longer follow-up are needed to confirm these preliminary observations.

Bacterial meningitis (BM) can lead to cognitive impairment, seriously affecting patients’ quality of life. Our previous study demonstrated a significant increase in procalcitonin (PCT) levels in cerebrospinal fluid (CSF) in BM patients, but the functional implications remain unknown. We found high expression of PCT in the hippocampus of LPS-induced neuroinflammation models. PCT had a neurotoxic effect on the primarily cultured hippocampal neurons. The high dose of PCT induced neuronal apoptosis. The low dose of PCT impaired the arborization of hippocampal neurons and reduced the expression of the growth-associated protein-43 (GAP-43) and synaptophysin (SYN). Furthermore, long-term potentiation (LTP) in hippocampal brain slices was decreased after PCT perfusion ex vivo. Our results indicated that PCT had neurotoxic effects on neuronal survival and synaptic plasticity, potentially leading to cognitive impairment after BM.

OBJECTIVES:We aimed to explore the impact of glymphatic function in patients diagnosed with autoimmune encephalitis (AE). METHODS:In this prospective longitudinal study, patients were recruited from Xijing Hospital between June 2020 and January 2024. Glymphatic function was evaluated using diffusion tensor imaging analysis along the perivascular space (DTI-ALPS). Cognitive impairment was defined as a Montreal Cognitive Assessment (MoCA) score below 26 at the 12-month follow-up. RESULTS:A total of 115 individuals were enrolled, including 85 patients with AE and 30 age- and sex-matched healthy controls (HCs). After correcting for age and sex, patients with AE had a significantly lower baseline ALPS index compared to HCs (1.173, 95 % CI [1.135, 1.210] vs. 1.456, 95 % CI [1.371, 1.541]; P < 0.001). The baseline ALPS index was correlated with cognitive performance, including a positive correlation with the Mini-Mental State Examination (MMSE) score (r = 0.568, P < 0.001) and a positive correlation with the MoCA score (r = 0.645, P < 0.001). In the longitudinal study, the ALPS index gradually increased over the follow-up period (P < 0.001), and a low level of the baseline ALPS index was associated with a higher risk of long-term cognitive impairment (HR [95 % CI] = 1.70 [1.12-2.58], P = 0.013). CONCLUSION:The glymphatic system is impaired in AE patients. A decreased DTI-ALPS index is associated with a decline in cognitive performance. Additionally, a low baseline ALPS index may predict an increased risk of long-term cognitive impairment in AE patients.

OBJECTIVE:The glymphatic system is a major waste clearance system in the central nervous system. We aim to investigate the glymphatic function and its prognostic values in patients with prolonged disorders of consciousness (pDoC). METHODS:We conducted a prospective and explorative cohort study including 40 patients with pDoC and 20 healthy controls. Glymphatic function was measured with the global and regional blood-oxygen-level-dependent and cerebrospinal fluid (BOLD-CSF) couplings, characterized by time-lags and strengths of the couplings. The clinical outcome was defined as improvement and no improvement in consciousness 6 months after enrollment, determined via a structured telephone follow-up based on the Coma Recovery Scale-Revised (CRS-R) score. RESULTS:Patients with pDoC exhibited significantly delayed time-lags in BOLD-CSF coupling (p < 0.05) and significantly reduced coupling strengths (p < 0.05) when compared to healthy controls. Follow-up studies indicated that shorter global BOLD-CSF coupling time-lags can predict an improved consciousness 6 months after enrollment, with an area under the receiver operating characteristic curve of 0.837, a sensitivity of 82.4%, and an accuracy of 85.7% using a cutoff point of 7.5. CONCLUSION:The glymphatic system was impaired in patients with pDoC, and its function, measured by BOLD-CSF coupling, can serve as a novel prognostic biomarker.

BackgroundThe cerebellum plays a crucial role in cognitive processing, making it a potential target for therapeutic intervention in Alzheimer's disease (AD).ObjectiveThis study aimed to investigate the effect of cerebellar intermittent theta-burst stimulation (iTBS) in patients with AD.MethodsWe conducted a randomized, double-blind, sham-controlled clinical trial in which patients were randomly allocated to receive either active-iTBS or sham-iTBS. The primary outcome was the change in Clinical Dementia Rating Scale Sum of Boxes (CDR-SB) scores from baseline to week 4. Secondary outcomes included evaluations of neurophysiological measures, brain network functions, and glymphatic clearance.ResultsFrom April 20 to June 25, 2024, 20 patients were analyzed. Compared with sham-iTBS, active-iTBS significantly improved cognition at week 4, indicated by reduced CDR-SB scores (mean changes: -0.60 versus 0.15; adjusted β: 0.73; 95% CI, 0.17-1.26). In the active-iTBS group compared with the sham-iTBS group, the power spectral density in electroencephalogram revealed global decreased in theta power (adjusted β, -0.014; 95% CI, -0.024-0.003) and increased beta power (adjusted β, 0.002; 95%CI, 0.000-0.005), the functional magnetic resonance imaging demonstrated enhanced the gradient values of default mode network activity along the principal gradient, and the structural magnetic resonance imaging indicated an improvement in glymphatic clearance (adjusted β, 0.097, 95% CI, 0.0381-0.1603).ConclusionsA four-week course of iTBS improved cognitive function in patients with AD, possibly via promoting the Beta frequency band power, enhancing brain network functionality, and facilitating glymphatic clearance.Trial registrationClinicalTrials.gov (NCT06379100, April 14, 2024).

OBJECTIVE:The efficacy of the community-based epilepsy management program has been validated in rural regions of China. However, a considerable proportion of patients with epilepsy in these areas continue to experience adverse outcomes. This study aims to investigate the factors influencing seizure control among patients with convulsive epilepsy in rural areas of Shaanxi Province, Northwest China. METHODS:Participants enrolled in the Rural Epilepsy Prevention and Management Project in Shaanxi Province between January 2012 and September 2020 were included in this cross-sectional study. Baseline sociodemographic, clinical characteristics, and epilepsy-related psychological concerns were collected. Patients were categorized based on seizure reduction compared to the baseline over the past year: Group with controlled seizures and group with uncontrolled seizures. Multivariate logistic regression was used to identify factors associated with seizure control. RESULTS:The study included 1242 patients (714 males, 57.5%), with a median age of 48.0 (36.0, 58.0) years. Compared to the baseline seizure frequency, 462 (37.2%) were seizure-free. Our analysis revealed that patients with higher annual income (≥24 000 RMB, OR, 0.58, 95% CI 0.40-0.84, p < 0.001), and those receiving phenobarbital monotherapy (OR, 0.66, 95% CI 0.49-0.90, p < 0.05) were more likely to achieve seizure control. In contrast, higher baseline seizure frequency (≥24 per year, OR, 2.06, 95% CI 1.59-2.66, p < 0.001), more adverse drug reactions (OR, 2.07, 95% CI 1.61-2.66, p < 0.001) and higher psychological concerns (OR, 1.89, 95% CI 1.44-2.48; p < 0.001) negatively impacted seizure control. SIGNIFICANCE:Low annual income, high baseline seizure frequency, multiple adverse drug reactions, and high psychological burden may negatively affect seizure control in epilepsy patients in rural areas. Strengthening socioeconomic support, improving access to medications, and incorporating psychological interventions may be crucial to enhancing seizure control and overall outcomes for patients in these regions. PLAIN LANGUAGE SUMMARY:The epilepsy management program in the rural areas of Northwest China has achieved some success, with about 37% of patients achieving one year of seizure freedom. However, some patients still struggle to effectively control their seizures. Nearly 90% of patients experience psychological concerns related to epilepsy, with the greatest concern being epilepsy recurrence. The heavier the psychological concern, the more difficult it is to control seizures.

Disorders of consciousness (DoC) are major clinical challenges. We aimed to evaluate the effects of cerebellar intermittent theta-burst stimulation (CRB-iTBS) in the treatment of DoC. We conducted a randomized, sham-controlled, double-blind, cross-over clinical trial. Patients with vegetative state/unresponsive wakefulness syndrome or minimally conscious state within 15 days to 1 year after brain injuries were recruited. The bilateral cerebellum was targeted by iTBS for 5 consecutive days under neuronavigation. The primary outcome was the change in Coma Recovery Scale-Revised (CRS-R) total scores after five sessions. Secondary outcomes included changes in CRS-R scores after the first session, the changes in CRS-R subscales and the alterations in “ABCD” EEG patterns after the first and fifth sessions. Follow-up outcomes included six-month functional outcomes and consciousness recovery. We included 44 patients in the intention-to-treat analysis. No significant difference was observed in the change of CRS-R total scores between active and sham groups after five sessions (difference ​= ​0.428, 95 ​% CI ​= ​−0.202 - 1.057, P ​= ​0.180). However, active stimulation induced greater CRS-R improvements after the first session (difference ​= ​1.048, 95 ​% CI ​= ​0.480–1.615, P ​< ​0.001), especially in auditory, visual, oromotor/verbal, and arousal subscales. Active stimulation increased the prevalence of EEG patterns “C” and “D” after both the first and fifth sessions. Favorable six-month functional outcomes and consciousness recovery were associated with an elevation in “ABCD” EEG patterns during active treatment periods. These findings demonstrate that CRB-iTBS exhibits potential as a neuromodulation strategy to promote consciousness recovery in DoC.

Metastatic cancer cells, originating from cancer stem cells with metastatic capacity, utilize nutrient flexibility to navigate the challenges of the metastatic cascade. However, the nutrient required to maintain the stemness potentials of metastatic cancer cells remains unclear. Here, we reveal that metastatic breast cancer cells sustain stemness and initiate metastasis upon detachment by taking up and oxidizing lactate. In detached metastasizing breast cancer cells, lactate is incorporated into the tricarboxylic acid cycle, boosting oxidative phosphorylation, and promoting the stemness potentials via α-KG-DNMT3B-mediated SOX2 hypomethylation. Moreover, lactate is taken up and oxidized in mitochondria by the CD147/MCT1/LDHB complex, which correlates with stemness potentials and tumor metastasis in patients with breast cancer. An intracellularly expressed single-chain variable fragment targeting mitochondrial CD147 (mito-CD147 scFv) effectively disrupts the mitochondrial CD147/MCT1/LDHB complex, inhibits lactate-induced stemness potential, depletes circulating breast cancer cells, and reduces metastatic burden, suggesting promising clinical applications in reducing lactate-fueled metastasis. Metastatic cancer cells rely on metabolic flexibility to survive. Here, the authors show that metastatic breast cancer cells use lactate for mitochondrial oxidation via the CD147/MCT1/LDHB complex to sustain stemness and promote metastasis.

ObjectiveSleep-related hypermotor epilepsy (SHE) is a focal epilepsy syndrome characterized by seizures that predominantly occur during sleep. The pathogenesis of these seizures remains unclear. We previously detected rare variants in GABRG2, which encodes the γ2 subunit of γ-aminobutyric acid type A receptor (GABAAR), in patients with SHE and demonstrated that these variants impaired GABAAR function in vitro. However, the mechanisms by which GABRG2 variants contribute to seizure attacks during sleep remain unclear.MethodsIn this study, we designed a knock-in (KI) mouse expressing the mouse Gabrg2 T316N variant, corresponding to human GABRG2 T317N variant, using CRISPR/Cas9. Continuous video-electroencephalogram monitoring and in vivo multichannel electrophysiological recordings were performed to explore seizure susceptibility to pentylenetetrazol (PTZ), alterations in the sleep-wake cycle, spontaneous seizure patterns, and synchronized activity in the motor thalamic nuclei (MoTN) and secondary motor cortex (M2). Circadian variations in the expression of total, membrane-bound, and synaptic GABAAR subunits were also investigated.ResultsNo obvious changes in gross morphology were detected in Gabrg2T316N/+ mice compared to their wild-type (Gabrg2+/+) littermates. Gabrg2T316N/+ mice share key phenotypes with patients, including sleep fragmentation and spontaneous seizures during sleep. Gabrg2T316N/+ mice showed increased susceptibility to PTZ-induced seizures and higher mortality after seizures. Synchronization of the local field potentials between the MoTN and M2 was abnormally enhanced in Gabrg2T316N/+ mice during light phase, when sleep dominates, accompanied by increased local activities in the MoTN and M2. Interestingly, in Gabrg2+/+ mice, GABAAR γ2 subunits showed a circadian increase on the neuronal membrane and synaptosomes in the transition from dark phase to light phase, which was absent in Gabrg2T316N/+ mice.ConclusionWe generated a new SHE mouse model and provided in vivo evidence that rare variants of GABRG2 contribute to seizure attacks during sleep in SHE.

OBJECTIVE:Epilepsy is one of the most prevalent brain diseases. Approximately one third of patients consistently experience drug-resistant epilepsy (DRE), a condition where seizures persist despite the use of antiseizure medications. Exploration of new therapies for DRE is urgently needed. In this single-center, randomized, sham-controlled, crossover clinical trial (NCT05042726), we aimed to investigate the effectiveness and safety of transcranial magnetic continuous theta burst stimulation (cTBS) targeting the cerebellum to treat DRE. METHODS:Patients with DRE for ≥2 years and a seizure frequency of ≥2 seizures per month were enrolled and randomized 1:1 to receive active stimulation followed by sham stimulation or vice versa. The bilateral cerebellum was targeted by navigated cTBS focusing on the cerebellar dentate nucleus, once daily on workdays for 2 weeks. The primary outcomes were the percentage of seizure reduction and 50% responder rate in the per-protocol population within 2 months after treatment. RESULTS:Forty-four patients were enrolled and randomized; 18 patients in the active stimulation-first group and 20 in the sham stimulation-first group were included in the final analysis. Active cTBS significantly reduced seizures compared to sham stimulation (difference in percentage of seizure reduction between treatments = 25%, 95% confidence interval [CI] = 5%-46%, p = .018). The 50% responder rate after active stimulation was significantly higher than that after sham stimulation (difference in 50% responder rate between treatments = 24%, 95% CI = 11%-40%, p = .029). Adverse events occasionally occurred during active stimulation (moderate headache in 5% of patients, tinnitus in 3% of patients, dizziness in 3% of patients) but resolved spontaneously within days after treatment completion. SIGNIFICANCE:This trial suggested that cTBS targeting the cerebellum was effective and well tolerated in the treatment of DRE. Further studies are warranted to confirm its effectiveness and mechanism.

Achieving optimal implant restoration hinges on both robust osseointegration as the structural foundation and favorable osseoperception for advanced masticatory function. The significance of nerve innervation in the peri-implant environment as the cornerstone of osseointegration and osseoperception is often underestimated. Despite the integral role of endogenous electric fields (EFs) in the human body, particularly in electrosensitive tissues like nerve tissue, the current approach involving external electrical stimulation is invasive and not clinically applicable. The present study introduces a conductive hydrogel designed to respond to endogenous EFs, aiming to foster nerve regeneration around dental implants to coordinate both osseointegration and osseoperception. The hydrogel promotes neurite outgrowth by upregulating intracellular Ca2+ concentration and activating subsequent pathways. Furthermore, the enhanced release of neuropeptides from neurocells improves the osteogenesis of osteoblasts. The impact of the conductive hydrogel on osseointegration and osseoperception is also thoroughly investigated in vivo. This conductive hydrogel represents a unique strategy for enhancing osseointegration and osseoperception within the endogenous EFs of the peri-implant environment. This advancement opens the door to achieving the physiological and psychological integration of dental implants. The decreased osseoperception results in excessive forces exerted on the implant. This brings about a high failure rate of implant fracture or aggressive bone loss. Here an injectable conductive hydrogel is developed to promote nerve regeneration in the peri-implant environment under endogenous electric field. The promotion of nerve regeneration enhances osseoperception and osseointegration simultaneously in vivo. image

AbstractObjectivesExisting data regarding the risk of COVID‐19 infection and its effects on seizure control in patients with epilepsy (PWE) are inconclusive. Our research aims to investigate the PWE who are susceptible to COVID‐19 and what factors contribute to seizure exacerbation.MethodsFrom Dec 28, 2022 to Feb 19, 2023, a cross‐sectional questionnaire survey among adult PWE was conducted. The demographics, epilepsy‐related information, COVID‐19‐related variables, and seizure outcomes after COVID‐19 infection were collected. Multivariate logistic analyses were performed to determine the risk factors associated with COVID‐19 infection and exacerbated seizures.ResultsOf 1557 PWE, 829 (53.2%) were infected with COVID‐19 and 136 (16.4%) developed seizure exacerbation after COVID‐19 infection. Overweight/obesity (OR 1.372, 95% CI 1.075–1.753, p = 0.011), immunocompromised (OR 3.301, 95% CI 1.093–9.974, p = 0.031), active epilepsy (OR 1.700, 95% CI 1.378–2.097, p < 0.001), and antiseizure medication (ASM) polytherapy (OR 1.314, 95% CI 1.065–1.621, p = 0.011) were associated with COVID‐19 infection. Active epilepsy (OR 4.696, 95% CI 2.568–8.586, p < 0.001) and fever‐associated seizures (OR 4.298, 95%CI 2.659–6.946, p < 0.001) were associated with seizure exacerbation.SignificancePWE with overweight/obesity, immunocompromised, active epilepsy, and ASM polytherapy were at higher risk of COVID‐19 infection. Once infected with COVID‐19, seizures were exacerbated in PWE with active epilepsy and fever‐associated seizures.Plain language summaryPatients with epilepsy (PWE) do not appear to be more susceptible to COVID‐19 infection than general population. Once infected with COVID‐19, 16.4% of PWE had seizure exacerbation. The PWE who have experienced seizures within the past 12 months before infection tend to contract COVID‐19 more often, and are more likely to experience seizure exacerbations following COVID‐19 infection.

Purpose: To evaluate the long-term survival and functional outcomes of patients with prolonged disorders of consciousness (pDoC) 1–8 years after brain injuries. Methods: Retrospective study to assess the long-term survival and functional outcomes of patients with pDoC was conducted. We performed Cox regression and multivariate logistic regression to calculate hazard ratios (HRs) for the outcome of survival and to identify risk factors of the functional outcome. Results: We recruited 154 patients with pDoC. The duration of follow-up from disease onset was 1–8 years. The median age was 46 years (IQR, 32–59), and 65.6% (n = 101) of them were men. During the follow-up period, one hundred and ten patients (71.4%) survived; among them, 52 patients had a good outcome. From the overall survival curve, the 1-, 3-, and 8-year survival rates of patients were about 80.5%, 72.0%, and 69.7%, respectively. Cox regression analysis revealed a significant association between the lower APACHE II score (p = 0.005) (cut-off score ≥ 18) and the presence of sleep spindles (p = 0.001) with survival. Logistic regression analysis demonstrated a higher CRS-R score (cut-off score ≥ 7), and presence of sleep spindles were related to a favorable outcome among patients with pDoC. Conclusions: Sleep spindles are correlated with both long-term survival and long-term functional outcome in pDoC patients.

Parvalbumin interneurons belong to the major types of GABAergic interneurons. Although the distribution and pathological alterations of parvalbumin interneuron somata have been widely studied, the distribution and vulnerability of the neurites and fibers extending from parvalbumin interneurons have not been detailly interrogated. Through the Cre recombinase-reporter system, we visualized parvalbumin-positive fibers and thoroughly investigated their spatial distribution in the mouse brain. We found that parvalbumin fibers are widely distributed in the brain with specific morphological characteristics in different regions, among which the cortex and thalamus exhibited the most intense parvalbumin signals. In regions such as the striatum and optic tract, even long-range thick parvalbumin projections were detected. Furthermore, in mouse models of temporal lobe epilepsy and Parkinson's disease, parvalbumin fibers suffered both massive and subtle morphological alterations. Our study provides an overview of parvalbumin fibers in the brain and emphasizes the potential pathological implications of parvalbumin fiber alterations.

Morphine is a frequently used analgesic that activates the mu-opioid receptor (MOR), which has prominent side effects of tolerance. Although the inefficiency of morphine in inducing the endocytosis of MOR underlies the development of morphine tolerance, currently, there is no effective therapy to treat morphine tolerance. In the current study, we aimed to develop a monoclonal antibody (mAb) precisely targeting MOR and to determine its therapeutic efficacy on morphine tolerance and the underlying molecular mechanisms. We successfully prepared a mAb targeting MOR, named 3A5C7, by hybridoma technique using a strategy of deoxyribonucleic acid immunization combined with cell immunization, and identified it as an immunoglobulin G mAb with high specificity and affinity for MOR and binding ability to antigens with spatial conformation. Treatment of two cell lines, HEK293T and SH-SY5Y, with 3A5C7 enhanced morphine-induced MOR endocytosis via a G protein-coupled receptor kinase 2 (GRK2)/β-arrestin2-dependent mechanism, as demonstrated by immunofluorescence staining, flow cytometry, Western blotting, coimmunoprecipitation, and small interfering ribonucleic acid (siRNA)-based knockdown. This mAb also allowed MOR recycling from cytoplasm to plasma membrane and attenuated morphine-induced phosphorylation of MOR. We established an in vitro morphine tolerance model using differentiated SH-SY5Y cells induced by retinoic acid. Western blot, enzyme-linked immunosorbent assays, and siRNA-based knockdown revealed that 3A5C7 mAb diminished hyperactivation of adenylate cyclase, the in vitro biomarker of morphine tolerance, via the GRK2/β-arrestin2 pathway. Furthermore, in vivo hotplate test demonstrated that chronic intrathecal administration of 3A5C7 significantly alleviated morphine tolerance in mice, and withdrawal jumping test revealed that both chronic and acute 3A5C7 intrathecal administration attenuated morphine dependence. Finally, intrathecal electroporation of silencing short hairpin RNA illustrated that the in vivo anti-tolerance and anti-dependence efficacy of 3A5C7 was mediated by enhanced morphine-induced MOR endocytosis via GRK2/β-arrestin2 pathway. Collectively, our study provided a therapeutic mAb, 3A5C7, targeting MOR to treat morphine tolerance, mediated by enhancing morphine-induced MOR endocytosis. The mAb 3A5C7 demonstrates promising translational value to treat clinical morphine tolerance.

Refractory status epilepticus (RSE) is a neurological emergency where sustaining seizure causes severe neuronal death. Currently, there is no available neuroprotectant effective in RSE. Aminoprocalcitonin (NPCT) is a conserved peptide cleaved from procalcitonin, but its distribution and function in the brain remain enigmatic. Survival of neurons relies on sufficient energy supply. Recently, we found that NPCT was extensively distributed in the brain and had potent modulations on neuronal oxidative phosphorylation (OXPHOS), suggesting that NPCT might be involved in neuronal death by regulating energy status. In the present study, combining biochemical and histological methods, high-throughput RNA-sequence, Seahorse XFe analyser, an array of mitochondria function assays, and behavior-electroencephalogram (EEG) monitoring, we investigated the roles and translational values of NPCT in neuronal death after RSE. We found that NPCT was extensively distributed throughout gray matters in rat brain while RSE triggered NPCT overexpression in hippocampal CA3 pyramidal neurons. High-throughput RNA-sequence demonstrated that the influences of NPCT on primary hippocampal neurons were enriched in OXPHOS. Further function assays verified that NPCT facilitated ATP production, enhanced the activities of mitochondrial respiratory chain complexes I, IV, V, and increased neuronal maximal respiration capacity. NPCT exerted multiple neurotrophic effects including facilitating synaptogenesis, neuritogenesis, spinogenesis, and suppression of caspase-3. A polyclonal NPCT immunoneutralization antibody was developed to antagonize NPCT. In the in vitro 0-Mg2+ seizure model, immunoneutralization of NPCT caused more neuronal death, while exogenous NPCT supplementation, though did not reverse death outcomes, preserved mitochondrial membrane potential. In rat RSE model, both peripheral and intracerebroventricular immunoneutralization of NPCT exacerbated hippocampal neuronal death and peripheral immunoneutralization increased mortality. Intracerebroventricular immunoneutralization of NPCT further led to more serious hippocampal ATP depletion, and significant EEG power exhaustion. We conclude that NPCT is a neuropeptide regulating neuronal OXPHOS. During RSE, NPCT was overexpressed to protect hippocampal neuronal survival via facilitating energy supply.

AIMS:The prediction of outcomes in convulsive status epilepticus (CSE) remains a constant challenge. The Encephalitis-Nonconvulsive Status Epilepticus-Diazepam Resistance-Image Abnormalities-Tracheal Intubation (END-IT) score was a useful tool for predicting the functional outcomes of CSE patients, excluding cerebral hypoxia patients. With further understanding of CSE, and in view of the deficiencies of END-IT itself, we consider it necessary to modify the prediction tool.METHODS:The prediction model was designed from a cohort of CSE patients from Xijing Hospital (China), between 2008 and 2020. The enrolled subjects were randomly divided into training cohort and validation cohort as a ratio of 2:1. The logistic regression analysis was performed to identify the predictors and construct the nomogram. The performance of the nomogram was assessed by calculating the concordance index, and creating calibration plots to check the consistency between the predicted probabilities of poor prognosis and the actual outcomes of CSE.RESULTS:The training cohort included 131 patients and validation cohort included 66 patients. Variables included in the nomogram were age, etiology of CSE, non-convulsive SE, mechanical ventilation, abnormal albumin level at CSE onset. The concordance index of the nomogram in the training and validation cohorts was 0.853 (95% CI, 0.787-0.920) and 0.806 (95% CI, 0.683-0.923), respectively. The calibration plots showed an adequate consistency between the reported and predicted unfavorable outcomes of patients with CSE at 3 months after discharge.CONCLUSIONS:A nomogram for predicting the individualized risks of poor functional outcomes in CSE was constructed and validated, which has been an important modification of END-IT score.

目的 探讨陕西省不同来源癫痫患者分别服用苯巴比妥(PB)、丙戊酸钠(VPA)、奥卡西平(OXC)、左乙拉西坦(LEV)单药治疗癫痫的疗效及经济学效应,为患者合理用药提供参考.方法 选取2012年1月至2022年1月入组陕西省农村癫痫项目及在西京医院神经内科门诊接受治疗的癫痫患者各200例,根据入组来源不同分为农村癫痫项目组(A组)及西京医院神经内科门诊组(B组).根据应用药物不同,A组再分为PB组及VPA组,B组分为OXC组及LEV组,比较患者治疗随访12个月后的总有效率及药物经济学效应.结果 本研究病例在随访终点(服药第12个月)时,在A组中,PB与VPA疗效比较差异无统计学意义(χ2=0.507,P>0.05);在B组中,OXC与LEV疗效比较差异无统计学意义(χ2=0.164,P>0.05).在服药后癫痫发作控制总有效率方面,PB组为56％、VPA组为51％、OXC组为54％及LEV组为56％.最小成本分析(CMA)表明PB组每年药物费用低于VPA组(P<0.01);OXC组每年药物费用低于LEV组(P<0.01).结论 4种药物对控制癫痫发作均有较好疗效,PB在控制癫痫发作方面有更好的经济性.临床医生可从药物经济学角度为患者选择更合适的抗癫痫药物.