The mitochondria-related gene risk mode revealed p66Shc as a prognostic mitochondria-related gene of glioblastoma.

Numerous studies have highlighted the pivotal role of mitochondria-related genes (MRGs) in the initiation and progression of glioblastoma (GBM). However, the specific contributions of MRGs coding proteins to GBM pathology remain incompletely elucidated. The identification of prognostic MRGs in GBM holds promise for the development of personalized targeted therapies and the enhancement of patient prognosis. We combined differential expression with univariate Cox regression analysis to screen prognosis-associated MRGs in GBM. Based on the nine MRGs, the hazard ratio model was conducted using a multivariate Cox regression algorithm. SHC-related survival, pathway, and immune analyses in GBM cohorts were obtained from the Biomarker Exploration of the Solid Tumor database. The proliferation and migration of U87 cells were measured by CCK-8 and transwell assay. Apoptosis in U87 cells was evaluated using flow cytometry. Confocal microscopy was employed to measure mitochondrial reactive oxygen species (ROS) levels and morphology. The expression levels of SHC1 and other relevant proteins were examined via western blotting. We screened 15 prognosis-associated MRGs and constructed a 9 MRGs-based model. Validation of the model's risk score confirmed its efficacy in predicting the prognosis of patients with GBM. Furthermore, analysis revealed that SHC1, a constituent MRG of the prognostic model, was upregulated and implicated in the progression, migration, and immune infiltration of GBM. In vitro experiments elucidated that p66Shc, the longest isoform of SHC1, modulates mitochondrial ROS production and morphology, consequently promoting the proliferation and migration of U87 cells. The 9 MRGs-based prognostic model could predict the prognosis of GBM. SHC1 was upregulated and correlated with the prognosis of patients by involvement in immune infiltration. Furthermore, in vitro experiments demonstrated that p66Shc promotes U87 cell proliferation and migration by mediating mitochondrial ROS production. Thus, p66Shc may serve as a promising biomarker and therapeutic target for GBM.

Levomilnacipran Improves Lipopolysaccharide-Induced Dysregulation of Synaptic Plasticity and Depression-Like Behaviors via Activating BDNF/TrkB Mediated PI3K/Akt/mTOR Signaling Pathway.

Depression is a common psychological disease with high morbidity and mortality. Recently, the involvement of synaptic plasticity in the pathogenesis of depression has shed light on the direction of developing novel antidepressants. Levomilnacipran is a newly approved medication for the treatment of adult major depressive disorder. However, the detailed mechanisms underlying its antidepressant-like effects have yet to be illuminated. In this study, we aimed to investigate the role of levomilnacipran in regulating synaptic plasticity and explore the possible molecular mechanisms of its antidepressant effects using a rat model of depression induced by lipopolysaccharide (LPS). The results demonstrated that levomilnacipran (30 mg/kg, i.p.) significantly ameliorated depression-like behaviors in rats, alleviated the dysregulation of synaptic plasticity, and suppressed neuroinflammation within hippocampus induced by LPS-treatment. Levomilnacipran increased the expression of postsynaptic dense 95 (PSD-95) and synaptophysin (Syn) and reversed the imbalance between pro- and anti-inflammatory cytokines within hippocampus of depressed rats. Additionally, levomilnacipran elevated expression level of brain-derived neurotrophic factor (BDNF), accompanied by increased tyrosine kinase B (TrkB), phosphorylated phosphatidylinositol 3-kinase (PI3K), phosphorylated protein kinase B (p-Akt), and phosphorylated mammalian target of rapamycin (p-mTOR). Taken together, these results suggest that levomilnacipran may exert antidepressant effects via upregulating BDNF/TrkB mediated PI3K/Akt/mTOR signaling pathway to improve synaptic plasticity. These findings reveal potential mechanisms for the antidepressant effects of levomilnacipran and offer new insights into the treatments for depression.

Positive regulators of T cell functions as predictors of prognosis and microenvironment characteristics of low-grade gliomas.

Background: Low-grade gliomas (LGG) are one of the most prevalent types of brain cancers. The efficacy of immunotherapy in LGG is limited compared to other cancers. Immunosuppression in the tumor microenvironment (TME) of LGG is one of the main reasons for the low efficacy of immunotherapy. Recent studies have identified 33 positive regulators of T cell functions (TPRs) that play a critical role in promoting the proliferation, activity, and functions of multiple immunocytes. However, their role in the TME of LGG has not been investigated. This study aimed to construct a risk model based on these TPRs and to detect the significance of immunotypes in predicting LGG prognosis and immunotherapy efficacy. Methods: A total of 688 LGGs and 202 normal brain tissues were extracted from The Cancer Genome Atlas (TCGA), Chinese Glioma Genome Atlas (CGGA), and Genotype-Tissue Expression (GTEx) databases. The NMF R package was used to identify TRP-related subtypes. The TPR prognostic model was established using the least absolute shrinkage and selection operator (LASSO) algorithm to predict the overall survival of LGG samples. Results: The Subtype 2 patients had worse survival outcomes, suppressed immune function, and higher immune cell infiltration. A risk regression model consisting of 14 TPRs was established, and its performance was validated in CGGA325 cohorts. The low-risk group exhibited better overall survival, immune microenvironment, and immunotherapy response, as determined via the TIDE algorithm, indicating that increasing the level of immune infiltration can effectively improve the response to immunotherapy in the low-risk group. The risk score was determined to be an independent hazard factor (p<0.001) although other clinical features (age, sex, grade, IDH status, 1p19q codel status, MGMT status, and accepted radiotherapy) were considered. Lastly, high-risk groups in both cohorts revealed optimal drug responses to rapamycin, paclitaxel, JW-7-52-1, and bortezomib. Conclusions: Our study identified two distinct TPR subtypes and built a TPR signature to elucidate the characteristics of T cell proliferation in LGG and its association with immune status and prognosis. These findings shed light on possible immunotherapeutic strategies for LGGs.

Deep-Learning Radiomics for Discrimination Conversion of Alzheimer's Disease in Patients With Mild Cognitive Impairment: A Study Based on 18F-FDG PET Imaging.

Objectives: Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder and the most common form of dementia in the older people. Some types of mild cognitive impairment (MCI) are the clinical precursors of AD, while other MCI forms tend to remain stable over time and do not progress to AD. To discriminate MCI patients at risk of AD from stable MCI, we propose a novel deep-learning radiomics (DLR) model based on 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET) images and combine DLR features with clinical parameters (DLR+C) to improve diagnostic performance. Methods: 18F-fluorodeoxyglucose positron emission tomography (PET) data from the Alzheimer's disease Neuroimaging Initiative database (ADNI) were collected, including 168 patients with MCI who converted to AD within 3 years and 187 patients with MCI without conversion within 3 years. These subjects were randomly partitioned into 90 % for the training/validation group and 10 % for the independent test group. The proposed DLR approach consists of three steps: base DL model pre-training, network features extraction, and integration of DLR+C, where a convolution network serves as a feature encoder, and a support vector machine (SVM) operated as the classifier. In comparative experiments, we compared our DLR+C method with four other methods: the standard uptake value ratio (SUVR) method, Radiomics-ROI method, Clinical method, and SUVR + Clinical method. To guarantee the robustness, 10-fold cross-validation was processed 100 times. Results: Under the DLR model, our proposed DLR+C was advantageous and yielded the best classification performance in the diagnosis of conversion with the accuracy, sensitivity, and specificity of 90.62 ± 1.16, 87.50 ± 0.00, and 93.39 ± 2.19%, respectively. In contrast, the respective accuracy of the other four methods reached 68.38 ± 1.27, 73.31 ± 6.93, 81.09 ± 1.97, and 85.35 ± 0.72 %. These results suggested the DLR approach could be used successfully in the prediction of conversion to AD, and that our proposed DLR-combined clinical information was effective. Conclusions: This study showed DLR+C could provide a novel and valuable method for the computer-assisted diagnosis of conversion to AD from MCI. This DLR+C method provided a quantitative biomarker which could predict conversion to AD in MCI patients.

Electrophysiological Evaluation in Identifying Unique Sleep Features Among Anti-LGI1 Encephalitis Patients During Active and Recovery Phase.

OBJECTIVE: The purpose of this study was to illustrate the electrophysiological features of sleep disturbances in patients with anti-leucine-rich glioma-inactivated protein 1 (anti-LGI1) encephalitis in both active and recovery stages. METHODS: Retrospectively filed video electroencephalogram (VEEG) and polysomnography (PSG) data in 24 patients with anti-LGI1 encephalitis were analyzed in comparison with that in 20 individuals without sleep disorders as control group. RESULTS: Sleep efficiency (SE) and total sleep time involving REM and NREM sleep were significantly decreased in patients with anti-LGI1 encephalitis during the active stage compared to that during the recovery stage and in the control group. Imbalanced sleep structure was found, demonstrated by elevated N1, decreased N3 and REM components, as well as abnormal N2 structure characterized with significantly lower spindle duration and density during the active stage. These findings were independent of the presence of nocturnal episodic events or sleep hyperkinetic movements (HMs). HMs were present in 11/23 patients throughout NREM and REM sleep (nonspecific in sleep stages) during the active stage. During the recovery stage, SE and sleep structures were dramatically improved, including the percentage of N3 and REM sleep, spindle duration and density. Ten of 11 patients with HMs were followed up. HMs were totally remitted in 3 patients and still persistent in 1, while evolved into REM sleep behavior disorder (RBD) in 4 with comorbid periodic limb movement syndrome (PLMS) in 3/4, and only PLMS in 2. CONCLUSION: Sleep disturbances were remarkable and intrinsic features in active anti-LGI1 encephalitis, marked by overall disruptions of both NREM and REM sleep, as well as the presence of HMs, which tend to evolve into RBD or PLMS during the recovery stage. Long-term follow-up with PSG is needed, especially for those patients with severe sleep disturbances during the active phase.

HMGB1/CXCL12-Mediated Immunity and Th17 Cells Might Underlie Highly Suspected Autoimmune Epilepsy in Elderly Individuals.

PURPOSE: Late-onset epilepsy due to autoimmune dysfunction has been reported. However, definitive diagnosis requires positive antibody results. As a result, patients with negative antibody results, but presenting with classical manifestation of autoimmune epilepsy, may be managed as suspected cases. In this study, we aim to isolate and profile the concentration of cytokines/chemokines in the cerebrospinal fluid (CSF) and the serum to ascertain if they could act as alternative diagnostic biomarkers. PATIENTS AND METHODS: Twenty patients aged ≥50 years were considered in this study. Ten patients were diagnosed with suspected autoimmune epilepsy (sAE) based on clinic manifestation, electroencephalogram, magnetic resonance imaging, and with negative antibody results of the serum and the CSF. The equivalent control group exhibited neurological disorders due to non-inflammatory pathologies. Serum and CSF were analyzed for cytokines/chemokines concentration, including interleukin (IL)-6, IL-10, IL-17, chemokine (C-X-C motif) ligand (CXCL)12 and CXCL13, as well as high-mobility group box protein 1 (HMGB1) and B cell activation factor (BAFF)). RESULTS: The CSF levels of IL-6, IL-17, HMGB1, and CXCL12 were significantly higher in the sAE group than in the control group. There was no difference in the CSF levels of IL-10, CXCL13 and BAFF. The serum levels of HMGB1 and CXCL12 were elevated in the sAE group compared with the control group, and there was no statistical difference in the serum levels of IL-6, IL-10, IL-17, CXCL13, and BAFF between the two groups. CONCLUSION: Our study shows that cytokines/chemokines may act as alternative biomarkers for diagnosis of sAE. The activation of both HMGB1/CXCL12-mediated immunity and T helper cells 17 (Th17) cells may be playing a central role in the pathogenesis of sAE. We suggest that cytokines/chemokines be treated as adjuvant biomarkers, instead of solely relying on antibody screening test. However, a larger cohort in a prospective approach is required to validate our findings.

Structured reporting of cardiovascular magnetic resonance based on expert consensuses and guidelines.

BACKGROUND: There is a gap between China and developed countries in Europe and America as to the normalization of cardiac magnetic resonance (CMR) diagnostic reports. The aim of this study was to construct a structured CMR report template suitable for China's actual conditions. METHODS: Cardiac magnetic resonance standardized image interpretation and post-processing guidelines and CMR report guidelines are the consensus and recommendations of the Society for Cardiovascular Magnetic Resonance (SCMR) experts whose goal is to ensure the consistent quality and repeatability of CMR reports. This structured CMR report template was constructed based on the guidelines for standardized image interpretation, post processing and reporting of CMR examinations, combined with the experiences learned in Germany and the practical experiences in China. It consisted of three parts: Device and Methods, Findings (Structure and function, Tissue Characterization), Summary and Conclusion. Detailed directions were provided section by section. RESULTS: This structured CMR report template underlined the comprehensive analysis of the results of morphological, functional and tissue characteristics to provide conclusive opinions and answer the corresponding important questions raised by the clinicians. CONCLUSION: The standardization of qualitative and quantitative assessments of CMR results is the core of structured reporting of CMR.

Multi-point spectroscopic gas sensing based on coherent FMCW interferometry.

We present an innovative spectroscopic method based on coherent optical frequency-modulated continuous-wave (FMCW) interferometry that can realize multi-point gas detection with high spatial resolution, high sensitivity, and high selectivity. This method takes full advantage of the intrinsic capability of spatial localization of the coherent FMCW, meanwhile efficiently decodes the spectral information from the reflected optical signals. Gas sensors are deployed by adopting bus topology, i.e., distributed along a single backbone fiber in the measurement arm of the FMCW interferometer. For validation, a multi-point acetylene gas sensing system with three sensing nodes is experimentally demonstrated. The transmission spectra of the three gas sensors are accurately extracted, and their corresponding gas concentrations are efficiently retrieved with a low crosstalk below -30 dB. The demonstrated system achieves a sensitivity of 55 ppm (noise equivalent absorbance of 0.004) over a distance of 52 m, with a sensing spatial resolution of 30 cm and a spectral resolution of 0.5 GHz. Our proposed method promotes a novel way for the development of multi-point spectroscopic gas sensing systems for challenging applications such as gas leakage detection and gas emission monitoring, where spatially resolved chemical analysis over a large area is required.

The exploration of the spectrum of motor manifestations of anti-LGI1 encephalitis beyond FBDS.

PURPOSE: The purpose of this study was to characterize the spectrum of motor events in patients with acute anti-leucine-rich glioma-inactivated protein 1 (anti-LGI1) encephalitis through video-electroencephalogram (VEEG) recordings. METHOD: We collected data retrospectively from 16 patients diagnosed with anti-LGI1 encephalitis who had completed VEEG recording during hospitalization. RESULTS: VEEG monitoring lasted a median of 11.0 h (range 4.5∼20). Fourteen types of seizures were recorded in 9 patients (56.3 %). Eight of the 14 types of seizures demonstrated typical ictal EEG evolution (including 2 subclinical seizures), 3/14 demonstrated EEG electrodecremental events (EDE) at onset but without further evolution, and 3/14 could be only judged by analyzing semiology. FBDS was recorded in 6 patients (37.5 %), and all these attacks were followed by epileptic seizures. Simple hyperkinetic movements (HMs), such as jerk-like or twisting movements, were found in 8 (50 %) patients, and 6 of them had complex HMs, such as manipulating movements or mimics of daily activities, during sleep. CONCLUSIONS: 1. Atypical seizures, for instance, seizures without EEG evolution, are not rare but likely to be overlooked. 2. FBDS is closely linked with epileptic seizures, revealing FBDS to be a part of epileptic attacks. 3. HMs could expand the spectrum of motor manifestations, overlapping with sleep disorders. 4. The high prevalence of these motor events might be due to the disrupted cortical-subcortical network, which is critical in motor control and sleep.

Use of a Sparse-Response Deep Belief Network and Extreme Learning Machine to Discriminate Alzheimer's Disease, Mild Cognitive Impairment, and Normal Controls Based on Amyloid PET/MRI Images.

In recent years, interest has grown in using computer-aided diagnosis (CAD) for Alzheimer's disease (AD) and its prodromal stage, mild cognitive impairment (MCI). However, existing CAD technologies often overfit data and have poor generalizability. In this study, we proposed a sparse-response deep belief network (SR-DBN) model based on rate distortion (RD) theory and an extreme learning machine (ELM) model to distinguish AD, MCI, and normal controls (NC). We used [18F]-AV45 positron emission computed tomography (PET) and magnetic resonance imaging (MRI) images from 340 subjects enrolled in the ADNI database, including 116 AD, 82 MCI, and 142 NC subjects. The model was evaluated using five-fold cross-validation. In the whole model, fast principal component analysis (PCA) served as a dimension reduction algorithm. An SR-DBN extracted features from the images, and an ELM obtained the classification. Furthermore, to evaluate the effectiveness of our method, we performed comparative trials. In contrast experiment 1, the ELM was replaced by a support vector machine (SVM). Contrast experiment 2 adopted DBN without sparsity. Contrast experiment 3 consisted of fast PCA and an ELM. Contrast experiment 4 used a classic convolutional neural network (CNN) to classify AD. Accuracy, sensitivity, specificity, and area under the curve (AUC) were examined to validate the results. Our model achieved 91.68% accuracy, 95.47% sensitivity, 86.68% specificity, and an AUC of 0.87 separating between AD and NC groups; 87.25% accuracy, 79.74% sensitivity, 91.58% specificity, and an AUC of 0.79 separating MCI and NC groups; and 80.35% accuracy, 85.65% sensitivity, 72.98% specificity, and an AUC of 0.71 separating AD and MCI groups, which gave better classification than other models assessed.

COX-2 inhibition rescues depression-like behaviors via suppressing glial activation, oxidative stress and neuronal apoptosis in rats.

Depression is considered a neuropsychiatric condition which is associated with neuronal injury within specific brain regions. We previously reported that cyclo-oxygenase (COX)-2, a rate-limiting enzyme for prostaglandin E2 (PGE2) synthesis, significantly enhanced depressive-like disorders induced by chronic stress in rats. However, the underlying molecular mechanisms and identification of potential therapeutic targets for preventing neuronal injury associated with depression remain largely uncharacterized. Here, we show that COX-2 inhibition by celecoxib protects against neuronal injury through suppression of oxidative stress and, in this way, mediates its antidepressant effects. COX-2 is highly expressed in the hippocampal dentate gyrus (DG) of rat depression model and its activity is responsible for depression-like behaviors as demonstrated in two independent rat models of depression. Inhibition of COX-2 exerts neuroprotective actions in DG regions, including suppressing neuroinflammatory response, against oxidative stress and neuronal apoptosis, which are the critical risk factors for neuronal injury and pathophysiology of depression. Moreover, the antioxidant, N-acetylcysteine (NAC), significantly attenuates oxidative stress levels and dendritic spine deficiencies resulting from COX-2 overexpression; and, suppression of oxidative stress by NAC also significantly ameliorates depressive behaviors in rats. These findings suggest that selective inhibition of COX-2 ameliorates depression-like behaviors in rat models of depression. This selective inhibition of COX-2 appears to be protective against oxidative stress and neuronal deterioration resulting from chronic stress. Taken together, these findings have potentially important clinical implications with regard to the development of novel therapeutic approaches in the treatment of neuropsychiatric conditions like depression.

Interleukin-6: Its role and mechanisms in rescuing depression-like behaviors in rat models of depression.

Neuronal injury within specific brain regions is considered a critical risk factor in the pathophysiology of depression. However, the underlying mechanisms of this process, and thus the potential for development of novel therapeutic strategies in the treatment of depression, remain largely unknown. Here, we report that Il-6 protects against neuronal anomalies related with depression, in part, by suppressing oxidative stress and consequent autophagic and apoptotic hyperactivity. Specifically, we show that IL-6 is downregulated within the CA1 hippocampus in two animal models of depression and upregulated by antidepressants. Increasing levels of IL-6 in the CA1 region result in pleiotropic protective actions including reductions in oxidative stress and modulation of autophagy, anti-immuno-inflammatory activation and anti-apoptotic effects in CA1 neurons, all of which are associated with the rescue of depression-like behaviors. In contrast, IL-6 downregulation exacerbates neuronal anomalies within the CA1 region and facilitates the genesis of depression phenotypes in rats. Interestingly, in addition to attenuating oxidative damage, the antioxidant, N-acetylcysteine (NAC), is also associated with significantly decreased neuronal deficits and the display of depressive behaviors in rats. These results suggest that IL-6 may exert neuroprotection within CA1 neurons via pleiotropic mechanisms and may serve as a potential therapeutic target for the treatment of depression.

Carotid-cavernous fistula(CCF) presenting as paroxysmal painful ophthalmoplegia.

BACKGROUND: Painful ophthalmoplegia can be caused by various etiologies, and broad differential diagnosis is needed. Carotid-cavernous fistula (CCF) is a rare cause of painful ophthalmoplegia, and early diagnosis is quite difficult. CASE PRESENTATION: Here, we present a case of paroxysmal painful ophthalmoplegia caused by CCF. The episodic symptoms were nonstereotypical and lasted minutes to hours. Magnetic resonance imaging (MRI) and computed tomography angiography (CTA) results were normal, which confounded efforts to determine a diagnosis. Subsequently, digital subtraction angiography (DSA) revealed a posterior-draining CCF. The CCF was treated at an early stage without residual symptoms. CONCLUSIONS: We propose that symptoms could be relapsing or remitting during an early stage of CCF and that posterior-draining CCF is prone to misdiagnosis due to atypical manifestations. Normal CTA results cannot exclude carotid-cavernous fistula, and DSA should be performed once CCF is suspected.

Simultaneous measurement of gas absorption spectra and optical path lengths in a multipass cell by FMCW interferometry.

We present a novel method based on optical frequency-modulated continuous-wave interferometry that can realize simultaneous measurement of gas absorption spectra and optical path lengths (OPLs) in the widely used multipass cells (MPCs). This method involves a Fourier transform (FT) and an inverse FT, by which the gas absorption spectrum and the OPL are retrieved in frequency and time domains, respectively. Various OPLs are achieved by retrieving gas absorption spectra associated with different reflection positions in the MPC. As a demonstration, absorption spectra of acetylene around 1520 nm are measured using a commercial White type MPC, achieving a noise equivalent absorbance of 0.01 and a spatial resolution of 290 µm over 22.5 m OPL. Our proposed method shows advantages for MPC-based gas sensing applications in the significant relaxation of OPL calibration demands and flexible extension of measurement dynamic range.

2R,4R-APDC, a Metabotropic Glutamate Receptor Agonist, Reduced Neuronal Apoptosis by Upregulating MicroRNA-128 in a Rat Model After Seizures.

This study aimed to study the protective effect of (2R,4R)-4-aminopyrrolidine-2,4-dicarboxylate (2R,4R-APDC), a selective metabotropic glutamate receptor agonist, against hippocampal neuronal apoptosis induced by seizures in a rat model of pilocarpine-induced epilepsy. The Morris water maze test was used to assess the spatial memory abilities of epileptic rats with or without 2R,4R-APDC treatment. TUNEL assay was performed to examine neuronal apoptosis in hippocampus. Western blot was conducted to evaluate changes in the levels of caspase-3 and caspase-9 in hippocampus. Real-time PCR was used to determine the levels of microRNA-128 (miR-128) in hippocampus. The results of the Morris water maze test showed that the 2R,4R-APDC treatment reduced the escape latencies and swimming lengths of rats after seizures. The TUNEL assay showed that 2R,4R-APDC significantly counteracted seizure-induced cell apoptosis. The western blot confirmed this finding, demonstrating that the levels of cleaved caspase-3 and cleaved caspase-9 were potently decreased by 2R,4R-APDC in rat hippocampus after seizures. In addition, 2R,4R-APDC upregulated miR-128 expression levels in the hippocampus. A miR-128 mimic or inhibitor decreased or increased the percentage of TUNEL-positive cells in rats after seizures and 2R,4R-APDC treatment, respectively. The levels of both cleaved caspase-3 and cleaved caspase-9 were decreased in hippocampus exposed to the miR-128 mimic, whereas they were markedly increased in miR-128 inhibitor-treated hippocampus. In conclusion, 2R,4R-APDC protected hippocampal cells from cell apoptosis after seizures, possibly by upregulating miR-128.

Pharmacokinetic study of single- and multiple-dosing with metolazone tablets in healthy Chinese population.

BACKGROUND: Metolazone is a diuretic, saluretic and antihypertensive chemical compound from the quinazoline category that possesses medicinal features similar to those of other thiazide diuretic drugs. However, the pharmacokinetics of metolazone in the Chinese population has rarely been studied. This study aimed to examine the pharmacokinetic characteristics, safety characteristic, and tolerability of metolazone in healthy Chinese subjects after single and multiple doses taken orally as well as the effects that food and gender have on oral metolazone pharmacokinetic parameters. METHODS: An open-label, randomized, and single- and multiple-dosing investigation was performed in healthy Chinese subjects. The investigation included 3 study groups: the 0.5 mg, 1 mg and 2 mg dose groups were the single-dose study groups in the first stage. Eligible volunteers were randomly and orally administered a single 0.5 mg, 1 mg, or 2 mg metolazone tablet. The 0.5 mg dose group was also part of the multiple-dose study group, and the 1 mg dose group was the food-effect study group in the second stage. Human plasma samples were gathered pre-dosing and up to 48 h after dosing. The human plasma sample concentration of metolazone was quantified using a validated liquid chromatography tandem mass spectrometry method. Pharmacokinetic data were calculated by a noncompartmental analysis method using WinNonlin version 6.4. Tolerability was evaluated based on adverse events, medical examination, 12-lead ECG, and other clinical laboratory exams. RESULTS: Thirty eligible subjects (15 men and 15 women) were registered in our investigation and completed all of the study stages. The AUC and Cmax showed dose proportionality after a single dose based on the linear-regression analysis. A comparison of the pharmacokinetic data revealed that the differences between the male and female groups were not statistically significant. The tmax of metolazone was increased by approximately 100% in the fed condition. Metolazone was well tolerated at the tested dose, and no adverse effects were observed. CONCLUSIONS: Single dosing with 0.5 mg, 1 mg, or 2 mg metolazone yielded linear plasma pharmacokinetic properties in healthy Chinese subjects. Multiple oral doses of metolazone did not display significantly different distributions or elimination characteristics from those observed for a single dose. Gender factors did not appear to influence the pharmacokinetic parameter variation of metolazone. The tmax of metolazone increased in the fed condition. Metolazone was well tolerated at the tested dose in this study. TRIAL REGISTRATION: This investigation is retrospectively registered at chictr.org.cn (ChiCTR-IIR-17012929, October 09 2017).

Clinical features and treatment status of hemifacial spasm in China.

BACKGROUND: Hemifacial spasm (HFS) is a facial nerve disorder characterized by episodic involuntary ipsilateral facial muscle contraction. Information on Chinese patients with HFS has not been well-characterized. This study aimed to evaluate the clinical feature and the treatment status of HFS across China. METHODS: A cross-sectional study including 1003 primary HFS patients had been carried out in 15 movement disorder clinics in China in 2012. The investigated information was acquired from questionnaires and medical records including demographic data, site of onset, aggravating and relieving factors, treatments prior to the investigation, etc. RESULTS: In this study, the ratio of male to female was 1.0:1.8, the mean age at onset was (46.6 ± 11.5) years. About 1.0% patients were bilaterally affected. The most often site of initial onset was the orbicularis oculi muscle. The most often affected sites were orbicularis oculi, zygomatic, and orbicularis oris muscles. Stress/anxiety and relaxation were most often aggravating and relieving factors, respectively; 2.3% patients had family history, 28.4% cases were combined with hypertension, and 1.4% patients were with trigeminal neuralgia. Botulinum toxin type A (BTX-A) injection was the most commonly used treatment, followed by acupuncture and oral medication. BTX-A maintained the highest repeat treatment ratio (68.7%), while 98.4% patients gave up acupuncture. The mean latency of BTX-A effect was (5.0 ± 4.7) days, the mean total duration of the effect was (19.5 ± 11.7) weeks, and 95.9% patients developed improvements no worse than moderate in both severity and function. The most common side effect was droopy mouth. CONCLUSIONS: The onset age of HFS in China is earlier than that in western countries. The most often used two treatments are BTX-A injection and acupuncture, while the latter kept the poor repeat treatment ratio because of dissatisfactory therapeutic effect.

Effects of the group II mGlu receptor agonist 2R,4R-APDC on dentate gyrus cell proliferation in the adult rat brain after diffuse brain injury.

OBJECTIVES: Diffuse brain injury (DBI) has been shown to increase the proliferation of granule cell precursors in the adult dentate gyrus (DG). However, the mechanism by which DBI-induced cell proliferation in the DG may enhance seizure susceptibility remains largely unknown. MATERIALS AND METHODS: Using bromodeoxyuridine (BrdU) immunohistochemistry, we examined the effects of group II metabotropic glutamate receptor (mGluR) agonist, 2R,4R-4-aminopyrrolidine-2,4-dicarboxylate (2R,4R-APDC), on cell proliferation in the DG after DBI. RESULTS: It has been found that 2R,4R-APDC significantly blocked DBI-induced increase in the number of BrdU-positive cells in the DG, especially in hilus. In addition, double-label immunofluorescence staining showed that treatment with APDC did not affect the differentiation of newborn cells into neurons or astrocytes. Taken together, our findings indicate that the activation of mGluR system may inhibit the DBI-induced cell proliferation in the DG, but not the differentiation of newborn cells. DISCUSSION: It is suggested that 2R,4R-APDC has potential neuroprotection via inhibiting the aberrant neurogenesis induced by DBI, which is an important pathological basis of seizure or other abnormalities following DBI.

2R, 4R-APDC decreases cell proliferation in the dentate gyrus of adult rats: the effect of 2R, 4R-APDC on cell proliferation.

This study investigated the effects of group II metabotropic glutamate receptor agonist, 2R, 4R-4-aminopyrrolidine-2,4-dicarboxylate (2R, 4R-APDC), on cell proliferation in the dentate gyrus of adult rats. 2R, 4R-APDC at a dose of 1 and 10 nmol/day resulted in decreased bromodeoxyuridine immunoreactive cells in the dentate gyrus. In addition, we found that APDC treatment had no effect on the number of BrdU+ and GFAP(+)-labeled cells or BrdU+ and NeuN(+)-labeled cells compared with controls. These data suggest that group II metabotropic glutamate receptor is an important site for glutamate's regulation on cell proliferation in the dentate gyrus, but 2R, 4R-APDC had no effects on newborn cell's ability to differentiate into neurons or astrocytes.