Anticonvulsant effect of equilibrative nucleoside transporters 1 inhibitor in a mouse model of Dravet syndrome.

There are limited therapeutic options for patients with Dravet syndrome (DS). The equilibrative nucleoside transporters 1 (ENT1) mediate both the influx and efflux of adenosine across the cell membrane exerted beneficial effects in the treatment of epilepsy. This study aimed to evaluate the anticonvulsant effect of the ENT1 inhibitor in an animal model of DS (Scn1aE1099X/+ mice). J7 (5 mg/kg) treatment was efficacious in elevating seizure threshold in Scn1aE1099X/+ mice after hyperthermia exposure. Moreover, the J7 treatment significantly reduced the frequency of spontaneous excitatory post-synaptic currents (sEPSCs, ~35% reduction) without affecting the amplitude in dentate gyrus (DG) granule cells. Pretreatment with the adenosine A1 receptor (A1R) antagonist, DPCPX, abolished the J7 effects on sEPSCs. These observations suggest that the J7 shows an anticonvulsant effect in hyperthermia-induced seizures in Scn1aE1099X/+ mice. This effect possibly acts on presynaptic A1R-mediated signaling modulation in granule cells.

Ten existing osteoporosis prediction tools for the successful application of National Health Insurance-reimbursed anti-osteoporosis medications in long-term care residents in Taiwan.

BACKGROUND/PURPOSE: Osteoporotic fracture introduce enormous societal and economic burden, especially for long-term care residents (LTCRs). Although osteoporosis prevention for LTCRs is urgently needed, obstacles such as frail status and inconvenient hospital visits hurdled them from necessary examinations and diagnoses. We aimed to test 10 existing osteoporosis screening tools (OSTs), which can be easily used in institutions and serve as a prediction, for accurately determining the outcome of a Taiwan's National Health Insurance (NHI)-reimbursed anti-osteoporosis medications (AOMs) application for LTCRs. METHODS: This prospective analysis recruited 444 patients from LTC institutions between October 2018 and November 2019. Predictions of whether the NHI-reimbursed AOMs criteria was met were tested for 10 OSTs. The results of OSTs categorized into self-reported or validated based on previous fracture history were self-reported by LTCRs or validated by imaging data and medical records, respectively. The receiver operating characteristic curve and the optimal cut-off points for LTCRs based on Youden's index were explored. RESULTS: Overall, the validated OSTs had a higher positive predictive value (PPV) and negative predictive value (NPV) summation than the corresponding reported OSTs. The validated FRAX-Major was the best OST (PPV = 63.6%, NPV = 82.4% for the male group and, PPV = 78.8%, NPV = 90.0% for the female group). After applying the optimum cut-off derived from Youden's index, the validated FRAX-Major (PPV = 75.4%, NPV = 92.0%)) remained performed best for men. In female population, validated FRAX-Major (PPV = 87.2%, NPV = 84.1%) and validated osteoporosis prescreening risk assessment (OPERA; PPV = 96.1%, NPV = 79.7%)) both provided good prediction results. CONCLUSION: FRAX-Major and OPERA have better prediction ability for LTCRs to acquire NHI-reimbursed AOMs. The validated fracture history and adjusted cut-off points could prominently increase the PPV during prediction.

Cost-effectiveness of the add-on exenatide to conventional treatment in patients with Parkinson's disease when considering the coexisting effects of diabetes mellitus.

OBJECTIVE: This study aims to investigate the cost-effectiveness of the add-on exenatide to conventional pharmacotherapy in patients with Parkinson's disease (PD) when considering the coexistence of diabetes mellitus (DM). METHODS: We used the Keelung and Community-based Integrated Screening databases to understand the medical utilisation in the Hoehn and Yahr stages of patients with PD. A Markov model with 1-year cycle length and 50-year time horizon was used to assess the cost-effectiveness of add-on exenatide to conventional pharmacotherapy compared to conventional pharmacotherapy alone. All costs were adjusted to the value of the new Taiwanese dollar (NT$) as of the year 2020. One-way sensitivity and probability analyses were performed to test the robustness of the results. RESULTS: From a societal perspective, the add-on exenatide brought an average of 0.39 quality-adjusted life years (QALYs) gained, and a cost increment of NT$104,744 per person in a 50-year horizon compared to conventional pharmacotherapy. The incremental cost-effectiveness ratio (ICER) was NT$268,333 per QALY gained. As the ICER was less than the gross domestic product per capita (NT$839,558), the add-on exenatide was considered to be very cost-effective in the two models, according to the World Health Organization recommendation. Add-on exenatide had a 96.9% probability of being cost-effective in patients with PD, and a 100% probability of being cost-effective in patients with PD and DM. CONCLUSION: Add-on exenatide is cost-effective in PD combined with DM. Considering that DM may be a risk factor for neurodegenerative diseases, exenatide provides both clinical benefits and cost-effectiveness when considering both PD and DM.

The psychopathology and happiness of the older adults in Yunlin, Taiwan: What do we need for long-term care service?

BACKGROUND: The purpose of this study was to investigate the psychopathology and level of happiness and their association with the demographic data of the older population in long-term care situations in Taiwan. METHODS: The study enrolled 500 participants who were the elderly in long-term care situations and used the Brief Symptom Rating Scale (BSRS-5) and Chinese Happiness Inventory (CHI) to determine the psychopathology and level of happiness. Multiple linear regression analysis (using a stepwise method) and a two-step cluster analysis were performed to examine the data. RESULTS: The results revealed mean scores for total CHI and total BSRS-5 of 16.08 and 2.34, respectively. Regular exercise habits, higher living expense and having a job were positively associated with happiness. Being older and living in an apartment/condominium were factors negatively associated with happiness. Living in an apartment/condominium was positively associated with a higher BSRS-5 score. Four clusters were grouped according to the variables that contributed the most: housing, exercise habits, living expense and working status. The cluster with no work, no exercise habits and lower living expense had the highest BSRS-5 score and the lowest CHI score. CONCLUSION: We concluded that the association between demographic data and happiness is stronger than the association between demographic data and psychopathology in a community sample in Taiwan. Those who have steady work, higher living expense and regular exercise habits have better happiness and less psychopathology.

The impact of active community-based survey on dementia detection ratio in Taiwan: A cohort study with historical control.

Background: Although early dementia detection is crucial to optimize the treatment outcomes and the management of associated symptoms, the published literature is scarce regarding the effectiveness of active screening protocols in enhancing dementia awareness and increasing the rate of early detection. The present study compared the detection ratio of an active community-based survey for dementia detection with the detection ratio of passive screening during routine clinical practice. Data for passive screening were obtained from the National Health Insurance (NHI) system, which was prospectively collected during the period from 2000 to 2003. Design: A population-based cohort study with historical control. Setting: Taiwan. Participants: A total of 183 participants aged 65 years or older were involved in a community-based survey. Data from 1,921,308 subjects aged 65 years or older were retrieved from the NHI system. Measurements: An adjusted detection ratio, defined as a ratio of dementia prevalence to incidence was used. Results: The results showed that the dementia prevalence during the 2000-2003 period was 2.91% in the elderly population, compared with a prevalence of 6.59% when the active survey was conducted. The incidence of dementia in the active survey cohort was 1.83%. Overall, the dementia detection ratio was higher using active surveys [4.23, 95% confidence interval (CI): 2.68-6.69] than using passive detection (1.45, 95% CI: 1.43-1.47) for those aged 65-79 years. Similar findings were observed for those aged 80 years and older. Conclusion: The implementation of an active community-based survey led to a 3-fold increase in the detection rate of early dementia detection compared to passive screening during routine practice.

Perampanel Reduces Hyperthermia-Induced Seizures in Dravet Syndrome Mouse Model.

Treatment options for Dravet syndrome are limited. The aim of this study was to evaluate the antiepileptic effect of the AMPA receptor antagonist perampanel (PER) on a mouse model of Dravet syndrome (Scn1a E1099X/+ ). We report here that the PER (2 mg/kg) treatment inhibited the spontaneous recurrent seizures and attenuated epileptic activity in Scn1a E1099X/+ mice. In the hyperthermia-induced seizure experiment, PER clearly increased temperature tolerance and significantly ameliorated seizure frequency and discharge duration. PER also demonstrated antiepileptic effects in a cross-over study and a synergistic effect for attenuating heat-induced seizure when given in combination with stiripentol or valproic acid. The results showed that PER effectively decreased the occurrence of spontaneous recurrent seizures and showed significant therapeutic potential for hyperthermia-induced seizures with regard to both susceptibility and severity in a Dravet syndrome mouse model. Potential therapeutic effects of PER for treatment of Dravet syndrome were demonstrated.

A proactive remote pharmaceutical care for rural elderly population: The Houston-Apollo polypharmacy project.

AIMS: To evaluate polypharmacy-related problems in the elderly people who live in rural through a proactive pharmaceutical care project under a novel remote medical service infrastructure (the Houston-Apollo polypharmacy project). METHODS: It is a prospectively cross-sectional study. The elderly aged 65 years old lived in communities executed the congregate meal service and joined the Houston-Apollo project were included. During March and July on 2020, the pharmaceutical care team of Houston-Apollo polypharmacy project interviewed old people and collected their medications by remote video. Polypharmacy situation and drug-related problems, including potentially inappropriate medications (PIMs), anticholinergic burden (ACB) and risk of sarcopaenia, were evaluated by clinical pharmacists. In addition, we analysed the categories of the prescription types between polypharmacy and non-polypharmacy users, polypharmacy users with and without PIMs or ACB. A patient-specific integrated pharmacist's note for medication education and a dear doctor letter (as needed) were generated and delivered within 2-weeks postinterviewed. Age- and sex-adjusted logistic regression model was used to evaluate the association between polypharmacy and these potential medication problems. RESULTS: There were 87 older people (mean age = 75.9) and 536 long-term medications were collected. Among them, 52% were defined as polypharmacy users. Polypharmacy was significantly associated with higher risk of PIMs and ACB. The adjusted odd ratio was 5.31 (95% CI: 2.02-13.9) and 10.1 (95% CI: 3.4-29.7), respectively. Among polypharmacy users, there were nearly double the prescriptions for the nervous system and musculoskeletal system among patients with PIMs compared with those without PIMs. Besides, polypharmacy users with ACB showed higher rate of prescriptions for the nervous system and the alimentary tract and metabolism system compared with those without ACB. CONCLUSION: Polypharmacy was significantly associated with negative impact of medication safety among the elderly people in rural area. A persistent remote pharmaceutical care intervention was crucial for improving this problem.

Development of the Houston-Apollo model for older people living in remote areas in Taiwan.

AIM: Senior healthcare is challenging in remote areas, particularly in an economically disadvantaged population. This study examined the benefits of a combined healthcare system (Houston-Apollo model) in improvements of physical performance and medical care utilization of local older people. METHODS: People aged ≥65 years who participated in congregate meal services were recruited. Using concepts of telemedicine and community health records, participants received consultation from local general physicians, who provided advice or arranged referrals to the National Taiwan University Hospital Yunlin Branch. Physical parameters including blood pressure, body mass index, grip strength, walking speed, and five times sit-to-stand test (FTSST) were transferred to the National Taiwan University Hospital Yunlin Branch and local doctors in a timely manner. Changes in physical parameters and utilization of healthcare facilities were measured at the beginning of recruitment and 1 year later. RESULTS: In the 470 registered participants, 66% had hypertension, 50% had weakness in grip strength, 58% were slow at FTSST and 78% had disability in 6-meter walking speed. In total, 97 participants were followed up at 1 year. The systolic and diastolic blood pressure (mmHg) decreased from 137.4 to 133.3 (P = 0.019) and from 76.9 to 74.4 (P = 0.008), respectively. The time of FTSST (s) decreased from 11.3 to 10.4 (P = 0.011). The walking speed (m/s) increased from 0.71 to 0.74 (P = 0.039). Medical and dental outpatient usage increased by 2 and 1.14 times, respectively. CONCLUSIONS: The Houston-Apollo model could provide benefits for the physical status of older adults, promote proactive and preventive healthcare utilization, and contribute to medical equality. Geriatr Gerontol Int 2021; ••: ••-••.

Seizure Frequency Is Associated with Effective Connectivity of the Hippocampal-Diencephalic-Cingulate in Epilepsy with Unilateral Mesial Temporal Sclerosis.

Background: Temporal lobe epilepsy (TLE) with mesial temporal sclerosis (MTS) is a common intractable epilepsy. To seek neural correlates of seizure recurrence, this study investigated aberrant intrinsic effective connectivity (iEC) in TLE with unilateral MTS and their associations with seizure frequency. Methods: Thirty patients with unilateral MTS (left/right MTS = 14/16) and 37 age-matched healthy controls underwent resting-state functional magnetic resonance imaging (rsfMRI) on a 3-Tesla magnetic resonance imaging (MRI) system. The structural equation modeling was employed to estimate the iEC of the three candidate epilepsy models, including the Papez circuit, hippocampal-diencephalic-cingulate (HDC) model, and simplified HDC model. After comparing the performance of model fitting, the best model was selected to compare iEC among the study groups. The linear regression analysis was performed to associate abnormal iEC with seizure frequency. Results: The simplified HDC model was the best model to estimate iEC across the three study groups (p < 0.05), and it composed of the 26 interconnected pathway between the mesial temporal lobe, thalamus, and cingulate cortices. The linear regression analysis revealed a significant relationship between the shared iEC alterations in both patient groups and seizure frequency (adjusted-R2 = 0.350; p = 0.037), including the three paths of mammillary body (MB) → bilateral anterior thalamic nuclei (left: standardized ß-value = 0.580, p = 0.013; right: standardized ß-value = -0.711, p = 0.006) and right hippocampus → MB (standardized ß-value = 0.541, p = 0.045). Conclusions: Our findings provide new insights into neurophysiological significance relevant to seizure recurrence. Aberrant iEC on the neural paths connected to the MB can be a potential imaging marker, aiding the therapeutic management in TLE with unilateral MTS. Impact statement Within the simplified hippocampal-diencephalic-cingulate model, we identified that altered intrinsic effective connectivity (iEC) on the three paths connecting to the mammillary body was common in temporal lobe epilepsy (TLE) with left and right mesial temporal sclerosis (MTS) and was associated with seizure frequency. Therefore, these common iEC alterations could be a potential imaging marker, aiding the therapeutic management in patients with TLE with unilateral MTS.

Cost-Effectiveness Analysis of Deep Brain Stimulation for Parkinson Disease in Taiwan.

BACKGROUND: Deep brain stimulation of the subthalamic nucleus (STN-DBS) is an effective therapy for Parkinson disease (PD). However, cost-effectiveness analysis is required because most patients are older adults and decision makers must therefore consider whether the long-term effectiveness outweighs the initial cost. METHODS: A Markov decision model was constructed on the basis of a societal perspective. The Hoehn and Yahr scale and Unified PD Rating Scale motor score were used in the polytomous logistic regression model. Markov Chain Monte Carlo simulation was used to initiate the probabilistic cost-effectiveness analysis. RESULTS: The life-year gained (LYG) in the STN-DBS group and medication group was, respectively, 2.937 and 2.632 years at the 3-year follow-up and 7.417 and 5.971 years at the 10-year follow-up. The quality-adjusted life-year (QALY) gained in the STN-DBS and medication groups was, respectively, 1.739 and 1.220 at the 3-year follow-up and 4.189 and 2.88 at the 10-year follow-up. The incremental cost-effectiveness ratio of STN-DBS compared with medication was $147,065 per LYG and $123,436 per QALY gained at the 3-year follow-up and $36,833 and $69,033 at the 10-year follow-up, respectively. STN-DBS is an optimal strategy when the willingness to pay is $150,000 per LYG and over $90,000 per QALY gained in 3 years and when the willingness to pay is over $38,000 per LYG and over $41,000 per QALY gained in 10 years. CONCLUSIONS: This study provided data comparing STN-DBS and medical treatment for PD with respect to LYG and QALY gained. STN-DBS was more cost-effective in terms of LYG and QALY gained according to the current gross domestic product of Taiwan.

Application of heart rate variability during blood pressure measurement in patients with somatic symptom disorder.

OBJECTIVE: This study wants to test whether the heart rate variability (HRV) analysis using sphygmomanometers can effectively reflect the physical and emotional distress of somatic symptom disorder (SSD) cases and assist in further health management. METHODS: This study includes 66 female SSD cases and 32 male SSD cases. All cases received a 200-second blood pressure (BP) measurement, after which the numerical figure for the heart rate was obtained from the BP signal for HRV analysis. All cases also filled out Patient Health Questionnaire-15 (PHQ-15), Beck Depression Inventory-II (BDI-II), Beck Anxiety Inventory (BAI) to understand the extent of their somatic distress, depression, and anxiety. The relationship between psychological conditions and HRV indicators are examined statistically. Receiver operating characteristic (ROC) curve analysis was used to understand whether HRV indicators can assist in the determination of psychosomatic problems. RESULTS: Considering all and female SSD cases, low-frequency power (LF) and PHQ-15 in the HRV index have the most significant correlations. In male SSD cases, root mean square of successive NN interval differences (RMSSD) and BDI-II have the highest correlations. The results of ROC curve analysis indicate that LF is useful to judge the severity of female SSD cases, while RMSSD has reference value in determining whether male patients of SSD cases have depression or not. In addition, physical stress index (PSI) can also help determine the degree of depression in male SSD cases. CONCLUSION: The use of BP in HRV analysis can help in the monitoring of somatic distress and depression issues in SSD cases. LF, RMSSD, PSI are potential physiological indicators.

Equilibrative Nucleoside Transporters-1 Inhibitors Act as Anti-epileptic Agents by Inhibiting Glutamatergic Transmission.

Background and Purpose: Adenosine dysregulation is associated with the occurrence of the epilepsy and equilibrative nucleoside transporters-1 (ENT-1) functions as an important regulator of extracellular adenosine in the brain. This study was aimed to prove the anti-epileptic effect of BBB permeable ENT-1 inhibitors, JMF1907 and J4, on animal models of various epilepsy, and the mechanisms that are involved. Experimental Approach: Maximal electroshock seizure (MES), pentylenetetrazol (PTZ)-induced seizure and kindling models were used as mouse models of generalized tonic-clonic epilepsy, generalized myoclonic epilepsy, and partial epilepsy, respectively. The epilepsy frequency, duration, and Racine score were evaluated. Whole-cell recordings were made from the hippocampal dentate granule cells by using a patch-clamp technique in the brain slice of the mice. Key Results: In MES, JMF1907 at a dose of 5 mg kg-1 was efficacious in decreasing hindlimb extension, while J4 did not decrease hindlimb extension until a higher dose (10 mg kg-1). Both JMF1907 and J4 were more potent in lengthening onset latency than ethosuximide (ETH) in PTZ-induced myoclonic epilepsy model, whereas ETH had better effects on the Racine score. In kindling model, JMF1907 and J4 at a dose of 1 mg kg-1 had effects on seizure frequency and duration, and the effects of JMF1907 were comparable with those of carbamazepine. Both JMF1907 and J4 can reduce the glutamatergic spontaneous excitatory post-synaptic currents (sEPSCs) frequency. The maximal inhibition was about 50% for JMF1907 at a concentration of 1 µg L-1, whereas J4 only inhibited 40% of sEPSCs frequency at a dose of 10 µg L-1. Conclusion and Implications: ENT-1 inhibitors, JMF1907 and J4, showed anti-epileptic effects in different epilepsy models and the effects involved pre-synaptic neuronal modulation.

Premature white matter aging in patients with right mesial temporal lobe epilepsy: A machine learning approach based on diffusion MRI data.

Brain age prediction based on machine learning has been applied to various neurological diseases to discover its clinical values. By this innovative approach, it has been reported that the patients with refractory epilepsy had premature brain aging. Of refractory epilepsy, right and left subtypes of mesial temporal lobe epilepsy (MTLE) are the most common forms and exhibit distinct patterns in white matter alterations. So far, it is unclear whether these two subtypes of MTLE would have difference in white matter aging due to distinct white matter alterations. To address this issue, a machine learning based brain age model using diffusion MRI data was established to investigate biological age of white matter tracts. All diffusion MRI datasets were obtained from the same 3-Tesla MRI scanner. To build the brain age prediction model, diffusion MRI datasets of 300 healthy participants were processed to extract age-relevant diffusion indices from 76 major white matter tracts. The extracted diffusion indices underwent Gaussian process regression to build the prediction model for white matter brain age. The model was validated in an independent testing set (N = 40) to ensure no overfitting of the model. The model was then applied to patients with right and left MTLE and matched controls (right MTLE: N = 17, left MTLE: N = 18, controls: N = 37), and predicted age difference (PAD) was obtained by calculating the difference between each individual's predicted brain age and chronological age. The higher PAD score indicated older brain age. The results showed that right MTLE exhibited older predicted brain age than the other two groups (PAD of right MTLE = 10.9 years [p < 0.05 against left MTLE; p < 0.001 against control]; PAD of left MTLE = 2.2 years [p > 0.1 against control]; PAD of controls = 0.82 years). Patients with right and left MTLE showed strong correlations of the PAD scores with age of onset and duration of illness, but both groups showed opposite directions of correlations. In right MTLE, positive correlation of PAD with seizure frequency was found, and the right uncinate fasciculus was the most attributable tract to the increase in PAD. In conclusion, the present study found that patients with right MTLE exhibited premature white matter brain aging and their PAD scores were correlated with seizure frequency. Therefore, PAD is a potentially useful indicator of white matter impairment and disease severity in patients with right MTLE.

Static Magnetic Field Induced Neural Stem/Progenitor Cell Early Differentiation and Promotes Maturation.

The potential impacts of magnetic field exposures on brain development have raised public concern. In the present study, we aimed to investigate the biophysical effects of moderate-intensity (0.5 T, Tesla) static magnetic field (SMF) on mice neural progenitor cells (mNPCs). Our results showed that the SMF exposure increased the number of neurosphere formation and enhanced proliferative activity in mNPCs. In addition, our flow cytometry data demonstrated that the proportions of S phase and G2/M phase mNPCs were remarkably increased following 5 days of SMF exposure. Moreover, the level of a mitotic regulatory protein, cyclin B, was upregulated after SMF exposure. Furthermore, the mNPCs exposed to SMF exhibited a significant increase in Sox2 expression. When mNPCs were induced to differentiation, our immunofluorescence assay revealed that the percentage of neurons (Tuj-1-positive cells) but not astrocyte (s100ß-positive cells) was significantly higher and displayed morphological complexity in the SMF group. Finally, our electrophysiological results demonstrated the mNPC-derived neurons from the SMF group showing a significantly increased in input resistance, which indicated more functional maturation. Based on these findings, it appears reasonable to suggest that SMF exposure could affect normal neurogenesis and promote neural lineage differentiation as well as neuronal maturation.

Low ambient temperature as the only meteorological risk factor of seizure occurrence: A multivariate study.

BACKGROUND: The onset of epileptic seizures is influenced by weather, which is multifactorial. It is unknown which specific weather factors affect the occurrence of seizures. OBJECTIVES: We studied the correlation between the onset of epileptic seizures and multiple weather parameters based on a population-based registry profile. METHODS: We determined the number of patients who visited emergency services in Taiwan diagnosed as having epilepsy. Then we used a linear regression model to analyze the monthly average number of patients who received emergency treatment for epilepsy in relation to temperature, barometric pressure, accumulated precipitation, relative humidity, and hours of sunshine. The Poisson regression model was used to analyze multiple meteorological factors in relation to the number of daily emergency visits because of epilepsy. A receiver operating characteristic curve was used to determine the cutoff temperature for the occurrence of seizures. RESULTS: Temperature appeared to be the robust factor for the onset of epilepsy. For every 1 °C decrease in temperature, there was a relative risk increase of 1.016 in the number of emergency visits as a result of epilepsy. Temperature lower than 18 °C had the best predictive value for seizure. Barometric pressure, accumulated precipitation, relative humidity, and the number of hours of sunshine were not related to the occurrence of seizures. SIGNIFICANCE: Our results suggest that temperature is the only influential meteorological factor that affects seizure occurrence.

Electrical Abnormalities in Dopaminergic Neurons of the Substantia Nigra in Mice With an Aromatic L-Amino Acid Decarboxylase Deficiency.

Aromatic L-acid decarboxylase (AADC) deficiency causes severe motor disturbances in affected children. A putamen-targeted gene therapy improves the motor function of patients. The present study investigated the electrical properties of dopaminergic (DA) neurons in the substantia nigra compacta (SNc) of mice with an AADC deficiency (DdcKI). The basal firing of DA neurons, which determines DA release in the putamen, was abnormal in the DdcKI mice, including a low frequency and irregular firing pattern, because of a decrease in the after-hyperpolarization (AHP) amplitude of action potentials (APs). The frequency of spontaneous excitatory postsynaptic currents (sEPSCs) increased and that of spontaneous inhibitory PSCs (sIPSCs) decreased in the SNc DA neurons from the DdcKI mice, suggesting an elevation in glutamatergic excitatory stimuli and a reduction in GABAergic inhibitory stimuli, respectively. Altered expression patterns of genes encoding receptors and channels were also observed in the DdcKI mice. Administration of a widespread neuron-specific gene therapy to the brains of the DdcKI mice partially corrected these electric abnormalities. The overexcitability of SNc DA neurons in the presence of generalized dopamine deficiency likely underlies the occurrence of motor disturbances.

The Mycobacterial Adjuvant Analogue TDB Attenuates Neuroinflammation via Mincle-Independent PLC-γ1/PKC/ERK Signaling and Microglial Polarization.

Microglial activation has long been recognized as a hallmark of neuroinflammation. Recently, the bacillus Calmette-Guerin (BCG) vaccine has been reported to exert neuroprotective effects against several neurodegenerative disorders. Trehalose-6,6'-dibehenate (TDB) is a synthetic analogue of trehalose-6,6'-dimycolate (TDM, also known as the mycobacterial cord factor) and is a new adjuvant of tuberculosis subunit vaccine currently in clinical trials. Both TDM and TDB can activate macrophages and dendritic cells through binding to C-type lectin receptor Mincle; however, its action mechanism in microglia and their relationship with neuroinflammation are still unknown. In this article, we found that TDB inhibited LPS-induced M1 microglial polarization in primary microglia and BV-2 cells. However, TDB itself had no effects on IKK, p38, and JNK activities or cytokine expression. In contrast, TDB activated ERK1/2 through PLC-γ1/PKC signaling and in turn decreased LPS-induced NF-κB nuclear translocation. Furthermore, TDB-induced AMPK activation via PLC-γ1/calcium/CaMKKß-dependent pathway and thereby enhanced M2 gene expressions. Interestingly, knocking out Mincle did not alter the anti-inflammatory and M2 polarization effects of TDB in microglia. Conditional media from LPS-stimulated microglial cells can induce in vitro neurotoxicity, and this action was attenuated by TDB. Using a mouse neuroinflammation model, we found that TDB suppressed LPS-induced M1 microglial activation and sickness behavior, but promoted M2 microglial polarization in both WT and Mincle-/- mice. Taken together, our results suggest that TDB can act independently of Mincle to inhibit LPS-induced inflammatory response through PLC-γ1/PKC/ERK signaling and promote microglial polarization towards M2 phenotype via PLC-γ1/calcium/CaMKKß/AMPK pathway. Thus, TDB may be a promising therapeutic agent for the treatment of neuroinflammatory diseases.

Gradient Relationship between Increased Mean Corpuscular Volume and Mortality Associated with Cerebral Ischemic Stroke and Ischemic Heart Disease: A Longitudinal Study on 66,294 Taiwanese.

The gradient relationship between mean corpuscular volume (MCV) and mortality due to ischemic vascular disease has not been researched using a large-scale population-based study. This study evaluated the association between MCV and death attributable to cerebrovascular disease (CVD) and cardiovascular disease (CAD) in a large population- and community-based Taiwanese cohort. A longitudinal study with a 9-year follow-up was conducted to evaluate individuals aged 20 years or older who had participated in the Keelung (the northernmost city in Taiwan) community-based integrated screening (abbreviated as KCIS) program since September 1999. The mortality rates associated with CVD and CAD were classified across a range of different MCV levels. Increased MCV levels were associated with an increased risk of CVD/CAD-related death (adjusted hazard ratio [aHR] = 1.42, trend test P = 0.0119). Marginally statistically significant associations were noted for specific deaths from ischemic heart disease (aHR = 1.44, trend test P = 0.0992) and cerebral ischemic stroke (aHR = 1.66, trend test P = 0.0667), respectively, but no significant gradient relationship was noted for death from cerebral hemorrhage stroke (aHR = 1.23, trend test, P = 0.6278). A gradient relationship between baseline MCV level and CVD/CAD-related death was noted, but whether such gradient relationships existed for two specific deaths and how these relationships may be confounded by extraneous factors that were not considered here should be investigated in the future.

The Penetration Depth for Hanatoxin Partitioning into the Membrane Hydrocarbon Core Measured with Neutron Reflectivity.

Hanatoxin (HaTx) from spider venom works as an inhibitor of Kv2.1 channels, most likely by interacting with the voltage sensor (VS). However, the way in which this water-soluble peptide modifies the gating remains poorly understood as the VS is deeply embedded within the bilayer, although it would change its position depending on the membrane potential. To determine whether HaTx can indeed bind to the VS, the depth at which HaTx penetrates into the POPC membranes was measured with neutron reflectivity. Our results successfully demonstrate that HaTx penetrates into the membrane hydrocarbon core (∼9 Šfrom the membrane surface), not lying on the membrane-water interface as reported for another voltage sensor toxin (VSTx). This difference in penetration depth suggests that the two toxins fix the voltage sensors at different positions with respect to the membrane normal, thereby explaining their different inhibitory effects on the channels. In particular, results from MD simulations constrained by our penetration data clearly demonstrate an appropriate orientation for HaTx to interact with the membranes, which is in line with the biochemical information derived from stopped-flow analysis through delineation of the toxin-VS binding interface.