Cul3-KLHL20 Ubiquitin Ligase Governs the Turnover of ULK1 and VPS34 Complexes to Control Autophagy Termination.

Autophagy, a cellular self-eating mechanism, is important for maintaining cell survival and tissue homeostasis in various stressed conditions. Although the molecular mechanism of autophagy induction has been well studied, how cells terminate autophagy process remains elusive. Here, we show that ULK1, a serine/threonine kinase critical for autophagy initiation, is a substrate of the Cul3-KLHL20 ubiquitin ligase. Upon autophagy induction, ULK1 autophosphorylation facilitates its recruitment to KLHL20 for ubiquitination and proteolysis. This autophagy-stimulated, KLHL20-dependent ULK1 degradation restrains the amplitude and duration of autophagy. Additionally, KLHL20 governs the degradation of ATG13, VPS34, Beclin-1, and ATG14 in prolonged starvation through a direct or indirect mechanism. Impairment of KLHL20-mediated regulation of autophagy dynamics potentiates starvation-induced cell death and aggravates diabetes-associated muscle atrophy. Our study identifies a key role of KLHL20 in autophagy termination by controlling autophagy-dependent turnover of ULK1 and VPS34 complex subunits and reveals the pathophysiological functions of this autophagy termination mechanism.

Relationship Between Serum 25-Hydroxyvitamin D and Bone Mineral Density, Fracture Risk, and Bone Metabolism in Adults With Osteoporosis/Fractures.

OBJECTIVE: To evaluate the association of serum 25-hydroxyvitamin D (25(OH) D) levels with bone mineral density (BMD), fracture risk, and bone metabolism. METHODS: This multicenter cross-sectional study recruited menopausal females and males greater than or equal to 50 year old with osteoporosis/fractures between September 2016 and September 2021. Assessment included clinical data, 25(OH)D, intact parathyroid hormone (iPTH), procollagen type 1 amino-terminal propeptide (P1NP), carboxy-terminal collagen crosslinks (CTX), lateral thoracolumbar spine x-rays, and BMD. RESULTS: A total of 3003 individuals were stratified by 25(OH) D levels: 720 individuals (24%) <20 ng/mL, 1338 individuals (44.5%) 20 to 29 ng/mL, and 945 individuals (31.5%) ≥30 ng/mL. In unadjusted and multivariable models, BMD T-score, except spine, was significantly and positively associated with 25(OH)D levels. 25(OH) D levels were inversely associated with Fracture Risk Assessment Tool scores. Patients with 25(OH)D <20 ng/mL had significantly higher iPTH and bone turnover markers (P1NP and CTX) than patients with 25(OH)D â‰§20 ng/mL in all models. When analyzing bone-related markers and BMD, total hip and femoral neck BMD T-scores were positively correlated with 25(OH)D concentrations and BMI but negatively correlated with iPTH, P1NP, CTX, and age. In multivariate models with all bone-related markers, only 25(OH)D levels were significantly associated with total hip and femoral neck BMD. CONCLUSION: Vitamin D deficiency is significantly associated with decreased total hip and femoral neck BMD and increased fracture risk as assessed by Fracture Risk Assessment Tool. In those with osteoporosis/fractures, vitamin D is implicated in the causal relationship between bone remodeling and BMD. Assessing vitamin D status is imperative for those at risk for osteoporosis/fractures.

Effects of an assist-as-needed equipped Tenodesis-Induced-Grip Exoskeleton Robot (TIGER) on upper limb function in patients with chronic stroke.

BACKGROUND: The original version of the Tenodesis-Induced-Grip Exoskeleton Robot (TIGER) significantly improved the motor and functional performance of the affected upper extremity of chronic stroke patients. The assist-as-needed (AAN) technique in robot-involved therapy is widely favored for promoting patient active involvement, thereby fostering motor recovery. However, the TIGER lacked an AAN control strategy, which limited its use in different clinical applications. The present study aimed to develop and analyze the training effects of an AAN control mode to be integrated into the TIGER, to analyze the impact of baseline patient characteristics and training paradigms on outcomes for individuals with chronic stroke and to compare training effects on the upper limb function between using the AAN-equipped TIGER and using the original prototype. METHODS: This was a single-arm prospective interventional study which was conducted at a university hospital. In addition to 20 min of regular task-specific motor training, each participant completed a 20-min robotic training program consisting of 10 min in the AAN control mode and 10 min in the functional mode. The training sessions took place twice a week for 9 weeks. The primary outcome was the change score of the Fugl-Meyer Assessment of the Upper Extremity (FMA-UE), and the secondary outcomes were the change score of the Box and Blocks Test (BBT), the amount of use (AOU) and quality of movement (QOM) scales of the Motor Activity Log (MAL), the Semmes-Weinstein Monofilament (SWM) test, and the Modified Ashworth Scale (MAS) for fingers and wrist joints. The Generalized Estimating Equations (GEE) and stepwise regression model were used as the statistical analysis methods. RESULTS: Sixteen chronic stroke patients completed all steps of the study. The time from stroke onset to entry into the trial was 21.7 ± 18.9 months. After completing the training with the AAN-equipped TIGER, they exhibited significant improvements in movement reflected in their total score (pre/post values were 34.6 ± 11.5/38.5 ± 13.4) and all their sub-scores (pre/post values were 21.5 ± 6.0/23.3 ± 6.5, 9.5 ± 6.2/11.3 ± 7.2, and 3.6 ± 1.0/3.9 ± 1.0 for the shoulder, elbow, and forearm sub-category, the wrist and hand sub-category, and the coordination sub-category, respectively) on the FMA-UE (GEE, p < 0.05), as well as their scores on the BBT (pre/post values were 5.9 ± 6.5/9.5 ± 10.1; GEE, p = 0.004) and the AOU (pre/post values were 0.35 ± 0.50/0.48 ± 0.65; GEE, p = 0.02). However, the original TIGER exhibited greater improvements in their performance on the FMA-UE than the participants training with the AAN-equipped TIGER (GEE, p = 0.008). The baseline score for the wrist and hand sub-category of the FMA-UE was clearly the best predictor of TIGER-mediated improvements in hand function during the post-treatment assessment (adjusted R2 = 0.282, p = 0.001). CONCLUSIONS: This study developed an AAN-equipped TIGER system and demonstrated its potential effects on improving both the function and activity level of the affected upper extremity of patients with stroke. Nevertheless, its training effects were not found to be advantageous to the original prototype. The baseline score for the FMA-UE sub-category of wrist and hand was the best predictor of improvements in hand function after TIGER rehabilitation. Clinical trial registration ClinicalTrials.gov, identifier NCT03713476; date of registration: October19, 2018. https://clinicaltrials.gov/ct2/show/NCT03713476.

Trends in suicide attempts and suicide deaths before and during the COVID-19 pandemic in New Taipei City, Taiwan: an interrupted time-series analysis.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic is an unprecedented global health crisis that may cause mental health problems and heighten suicide risk. We investigated the impact of the COVID-19 pandemic on trends in suicide attempts and suicide deaths in New Taipei City, Taiwan. METHODS: The current study used the official daily data on suicide attempts and deaths in New Taipei City, Taiwan (4 million inhabitants) between 2015 and 2020 from the Taiwan National Suicide Prevention Reporting System. Interrupted time-series (ITS) analyses with parameters corrected by the estimated autocorrelations were applied on weekly aggregated data to examine whether the suicide trends during the early COVID-19 pandemic (late January to July 2020) deviated from previous trends (January 2015 to late January 2020). The impact due to the suicide prevention policy change was also examined (since August 2020). RESULTS: ITS analyses revealed no significant increases in both mean and trend on weekly suicide deaths during the COVID-19 pandemic and after the policy change. In contrast, there was a significant increasing trend in weekly suicide attempts since the COVID-19 outbreak at the rate of 1.54 attempts per week (95% confidence interval 0.49-2.60; p = 0.004). Sex difference analysis revealed that, however, this increasing trend was observed only in females not in males. CONCLUSIONS: The COVID-19 pandemic has different impacts on suicides attempts and deaths during the early pandemic in New Taipei City, Taiwan. The COVID-19 outbreak drastically increased the trend of suicide attempts. In contrast, the number of suicide deaths had remained constant in the investigated periods.

Using T1 mapping indices to evaluate muscle function and predict conservative treatment outcomes in diabetic patients with peripheral arterial disease.

OBJECTIVES: To investigate interstitial muscle fibrosis via T1 mapping indices and its relationships with muscle function and conservative treatment outcomes. METHODS: A total of 49 DM patients with PAD were prospectively recruited from 2016 to 2017. All PAD patients underwent pre-treatment MRI with conservative treatment via a rehabilitation program and antiplatelet therapy. The need to require percutaneous transluminal angioplasty intervention was recorded as intolerance to conservative treatment outcomes. We quantified calf interstitial muscle fibrosis using T1 mapping indices (native T1, post-contrast T1, and the extracellular volume fraction [ECV]). Muscle function was evaluated using a 6-min walking test (6MWT) and a 3-min stepping test (3MST). PAD patients were divided into two groups according to their tolerance or intolerance of the conservative treatment. Pearson's correlation, reproducibility, and multivariable Cox hazard analyses were performed with p < 0.05 indicating statistical significance. RESULTS: Among the T1 mapping indices in the posterior compartment of the calf in PAD patients, the native T1 value was significantly correlated with 6MWT (r = -0.422, p = 0.010) and 3MST (r = -0.427, p = 0.009). All T1 mapping indices showed excellent intra-observer and inter-observer correlations. ECV was an independent predictor of conservative treatment intolerance (average ECV, hazard ratio: 1.045, 95% confidence interval: 1.011-1.079, p = 0.009). CONCLUSIONS: T1 mapping measurements are reproducible with excellent intra-observer and inter-observer correlations. T1 mapping indices may be predictive of treatment and functional outcomes and carry promise in patient evaluation. TRIAL REGISTRATION: Clinical Trials Identifier: NCT02850432 . KEY POINTS: • T1 mapping measurements of the calf muscles are reproducible with excellent intra-observer and inter-observer correlations (0.98 and 0.95 for anterior and posterior compartment muscle extracellular volume matrix [ECV] measurements, respectively). • ECV is shown to independently predict conservative treatment intolerance. • T1 mapping indices may be predictive of treatment and functional outcomes and carry promise in patient evaluation.

AuAg nanocomposites suppress biofilm-induced inflammation in human osteoblasts.

Staphylococcus aureus (S. aureus)forms biofilm that causes periprosthetic joint infections and osteomyelitis (OM) which are the intractable health problems in clinics. The silver-containing nanoparticles (AgNPs) are antibacterial nanomaterials with less cytotoxicity than the classic Ag compounds. Likewise, gold nanoparticles (AuNPs) have also been demonstrated as excellent nanomaterials for medical applications. Previous studies have showed that both AgNPs and AuNPs have anti-microbial or anti-inflammatory properties. We have developed a novel green chemistry that could generate the AuAg nanocomposites, through the reduction of tannic acid (TNA). The bioactivity of the nanocomposites was investigated inS. aureusbiofilm-exposed human osteoblast cells (hFOB1.19). The current synthesis method is a simple, low-cost, eco-friendly, and green chemistry approach. Our results showed that the AuAg nanocomposites were biocompatible with low cell toxicity, and did not induce cell apoptosis nor necrosis in hFOB1.19 cells. Moreover, AuAg nanocomposites could effectively inhibited the accumulation of reactive oxygen species (ROS) in mitochondria and in rest of cellular compartments after exposing to bacterial biofilm (by reducing 0.78, 0.77-fold in the cell and mitochondria, respectively). AuAg nanocomposites also suppressed ROS-triggered inflammatory protein expression via MAPKs and Akt pathways. The current data suggest that AuAg nanocomposites have the potential to be a good therapeutic agent in treating inflammation in bacteria-infected bone diseases.

Internet of Things (IoT) Enables Robot-Assisted Therapy as a Home Program for Training Upper Limb Functions in Chronic Stroke: A Randomized Control Crossover Study.

OBJECTIVE: To compare the effects of using an Internet of things (IoT)-assisted tenodesis-induced-grip exoskeleton robot (TIGER) and task-specific motor training (TSMT) as home programs for the upper-limb (UL) functions of patients with chronic stroke to overturn conventional treatment modes for stroke rehabilitation. DESIGN: A randomized 2-period crossover study. SETTING: A university hospital. PARTICIPANTS: Eighteen chronic stroke patients were recruited and randomized to receive either the IoT-assisted TIGER first or TSMT first at the beginning of the experiment (N=18). INTERVENTION: In addition to the standard hospital-based therapy, participants were allocated to receive a 30-minute home-based, self-administered program of either IoT-assisted TIGER first or TSMT first twice daily for 4 weeks, with the order of both treatments reversed after a 12-week washout period. The exercise mode of the TIGER training included continuous passive motion and the functional mode of gripping pegs. The TSMT involved various movement components of the wrist and hand. MAIN OUTCOME MEASURES: The outcome measures included the box and block test (BBT), the Fugl-Meyer assessment for upper extremity (FMA-UE), the motor activity log, the Semmes-Weinstein Monofilament test, the range of motion (ROM) of the wrist joint, and the modified Ashworth scale. RESULTS: Significant treatment-by-time interaction effects emerged in the results for the BBT (F(1.31)=5.212 and P=.022), the FMA-UE (F(1.31)=6.807 and P=.042), and the ROM of the wrist extension (F(1.31)=8.618 and P=.009). The participants who trained at home with the IoT-assisted TIGER showed more improvement of their UL functions. CONCLUSIONS: The IoT-assisted TIGER training has the potential for restoring the UL functions of stroke patients.

Recurrent spinal meningeal melanocytoma at lumbar spine level: a case report.

INTRODUCTION: Spinal meningeal melanocytoma is an extremely rare tumour with an estimated annual incidence of 1 per 10 million people. It usually arises from the intradural extramedullary compartment at the cervical levels. Although these tumours are histologically benign, they may behave aggressively. Local recurrence could occur even after total tumour excision. CASE REPORT: We report a case of a 33-year-old Asian male who developed progressive weakness and numbness of the bilateral lower extremities as well as urinary retention five years after complete tumour resection of lumbar spinal meningeal melanocytoma. Magnetic resonance imaging of the lumbar spine revealed a mass with thecal sac compression which was hypointense on T2-weighted images and hyperintense on T1-weighted images. The patient underwent total tumour removal. Histologic examination was compatible with recurrent meningeal melanocytoma. After a 4-week inpatient rehabilitation programme, he was able to ambulate without assistance and to do clean intermittent catheterisation for micturition on a regular basis. DISCUSSION: This is the first reported case of intradural extramedullary meningeal melanocytoma located at the lumbar region. Clinicians should consider the possibility of these rare tumours at any level of the spine, and be aware of sphincter dysfunction in addition to motor and sensory deficits of extremities.

Sleep disturbances, glycaemic control, stress, and coping among diabetic patients: A structural equation modelling approach.

BACKGROUND: Sleep disturbances are more prevalent in diabetic patients than in the general population and may consequently be comorbid with hyperglycaemia. OBJECTIVE: The two study aims were to (1) verify the factors associated with sleep disturbances and glycaemic control and (2) further understand the mediation effects of coping and social support in the relationship among stress, sleep disturbances, and glycaemic control. METHODS: A cross-sectional study design was used. Data were collected at two metabolic clinics in southern Taiwan. The study recruited 210 patients with type II diabetes mellitus who were aged 20 years or above. Demographic information and data on stress, coping, social support, sleep disturbances, and glycaemic control were collected. The Pittsburgh Sleep Quality Index (PSQI) was used to assess sleep quality, and PSQI scores >5 were considered to indicate sleep disturbances. Structural equation modelling (SEM) approaches were employed to analyse the path association for sleep disturbances in diabetic patients. RESULTS: The mean age of the 210 participants was 61.43 (standard deviation, SD 11.41) years old, and 71.9 % reported sleep disturbances. The final path model had acceptable model fit indices. Stress perception was divided into stress perceived positively and negatively. Stress perceived positively was associated with coping (ß = 0.46, p < .01) and social support (ß = 0.31, p < .01), whereas stress perceived negatively was significantly associated with sleep disturbances (ß = 0.40, p < .001). CONCLUSIONS: The study shows that sleep quality is essential to glycaemic control, and stress perceived negatively might play a critical role to sleep quality.

Double Fascicular Transfer Using Partially Injured Donor Nerves: Is It Powerful Enough to Restore Elbow Flexion in Acute Brachial Plexus Injuries?

BACKGROUND: Loss of elbow flexion is a common sequela of acute brachial plexus injuries (BPIs). The Mackinnon/Oberlin-II double fascicular transfer (DFT) is a widely used method to restore this function in acute C5-6 or C5-7 injuries. This study attempted to evaluate if this technique can be applied reliably for cases involving C8 and/or T1 injuries. METHODS: Adult patients with acute BPIs who underwent the Mackinnon/Oberlin-II DFT in our center between 2008 and 2018 were retrospectively identified. Group I (n = 37) included patients with only C5-6 or C5-7 injury, while group II (n = 32) patients presented C5-8 ± T1 injuries. The demographic data, pre- and postoperative neurologic evaluations, electrodiagnostic studies, and grip strength assessment were collected. RESULTS: A total of 69 patients met the inclusion criteria. Preoperatively, the patients in group II presented poorer nerve conduction and electromyography in both the median and the ulnar nerves and the supply muscles. The percentage of M3 achievement in both groups was 91.9 versus 87.5% and M4 was 73.0 and 71.9%, respectively, which both were not statically significant but the achievement of group II was slower than the group I, 1 to 2 months slower, respectively. Both groups had 57.57 and 46.0% of the postoperative grip power compared with the healthy side, the result of shoulder abduction was not different (p = 0.480). CONCLUSION: With careful preoperative evaluation, early intervention, appropriate intraoperative functional fascicle selection, and aggressive postoperative rehabilitation, indications for the Mackinnon/Oberlin-II DFT technique can safely include acute C5-8 injuries and even partial T1 acute BPIs.

Clinical Significance of Frailty on Treatment Outcome in Nongeriatric Patients With Head and Neck Cancer and Esophageal Cancer Undergoing Curative-Intent Concurrent Chemoradiotherapy.

BACKGROUND: Whether the prevalence of frailty and its clinical significance are relevant to treatment outcomes in younger (aged < 65 years) cancer patients remains uncertain. This study aimed to evaluate the impact of frailty on treatment outcomes in younger cancer patients with head and neck and esophageal malignancy. MATERIAL AND METHODS: This multicenter prospective study recruited 502 patients with locally advanced head and neck and esophageal cancer during 2016-2017 in Taiwan, aged 20-64 years who received curative-intent concurrent chemoradiotherapy (CCRT) as first-line antitumor treatment. Baseline frailty assessment using geriatric assessment (GA) was performed for each patient within 7 days before CCRT initiation. RESULTS: Frailty was observed in 169 (33.7%) of 502 middle-aged patients. Frail patients had significantly higher incidences of chemotherapy incompletion (16.6% versus 3.3%, P < .001) and radiotherapy incompletion (16.6% versus 3.6%, P < .001) than fit patients. During CCRT, frail patients had a significantly higher percentage of hospitalizations (42.0% versus 24.6%, P < .001) and a trend toward a higher percentage of emergency room visits (37.9% versus 30.0%, P = .08) than fit patients. Frail patients more likely had a significantly higher incidence of grade ≥ 3 adverse events than fit patients during CCRT. The 1-year survival rate was 68.7% and 85.2% (hazard ratio 2.56, 95% confidence interval 1.80-3.63, P < .001) for frail and fit patients, respectively. CONCLUSIONS: This study demonstrated the significance of pretreatment frailty on treatment tolerance, treatment-related toxicity, and survival outcome in younger patients with head and neck and esophageal cancer undergoing CCRT. While GA is commonly targeted toward the older population, frailty assessment by GA may also be utilized in younger patients for decision-making guidance and prognosis prediction.

Bioactivity Study of Tricyclic and Tetracyclic Genipin Derivatives as Anti-inflammatory Agents.

A series of genipin derivatives included tricyclic cyclopentaimidazopyridine, cyclopentapyridopyrimidine, octahydrocyclopentapyridodiazepine, and tetracyclic decahydrobenzoimidazocyclopentapyridine were synthesized and developed as anti-inflammatory agents. All of them were tested against NO production in LPS-induced RAW264.7 cells. Based on IC50 data and the SAR study, we found that tricyclic cyclopentaimidazopyridines 3d-f and 7-9 presented the better inhibitory activities (≦ 28.1 µM) in comparison with the reference standard Indomethacin (166 µM). On the other hand, all of them showed inactivity for in vitro cyclooxygenase COX-2 inhibition assays and compounds 8 and 9 possessed the cell toxity. To explore the further anti-inflammatory mechanism, Western blot analysis was carried out. Furthermore, compound 3d shown better bioactivity than Indomethacin. The suppression of NF-κB signal pathway by compound 3d was also determined. To sum-up, compound 3d would be the potential anti-inflammatory lead compound.

Brain CT can predict low lean mass in the elderly with cognitive impairment: a community-dwelling study.

BACKGROUND: The coexistence of sarcopenia and dementia in aging populations is not uncommon, and they may share common risk factors and pathophysiological pathways. This study aimed to evaluate the relationship between brain atrophy and low lean mass in the elderly with impaired cognitive function. METHODS: This cross-sectional study included 168 elderly patients who visited the multi-disciplinary dementia outpatient clinic at Kaohsiung Chang Gung Memorial Hospital for memory issues, between 2017 and 2019. The body composition was assessed by dual energy X-ray absorptiometry (DEXA) and CT based skeletal muscle index including L3 skeletal muscle index (L3SMI) and masseter muscle mass index (MSMI). The brain atrophy assessment was measured by CT based visual rating scale. Possible predictors of low lean mass in the elderly with cognitive impairement were identified by binary logistic regression. ROC curves were generated from binary logistic regression. RESULTS: Among the 81 participants, 43 (53%) remained at a normal appendicular skeletal muscle index (ASMI), whereas 38 (47%) showed low ASMI. Compared with the normal ASMI group, subjects with low ASMI exhibited significantly lower BMI, L3SMI, and MSMI (all p < 0.05), and showed significant brain atrophy as assessed by visual rating scale (p < 0.001). The accuracy of predictive models for low ASMI in the elderly with cognitive impairment were 0.875, (Area under curve (AUC) = 0.926, 95% confidence interval [CI] 0.844-0.972) in model 1 (combination of BMI, GCA and L3SMI) and 0.885, (Area under curve (AUC) = 0.931, [CI] 0.857-0.979) in model 2 (combination of BMI, GCA and MSMI). CONCLUSIONS: Global cortical atrophy and body mass index combined with either L3 skeletal muscle index or masseter skeletal muscle index can predict low lean mass in the elderly with cognitive impairment.

Efficacy and safety of botulinum toxin type A in distraction osteogenesis of the lower extremities: a meta-analysis of randomized controlled trials.

BACKGROUND: To explore the efficacy and safety of botulinum toxin in patients who received distraction osteogenesis of the lower extremities. METHODS: We searched the PubMed, Medline, Cochrane Library, and Web of Science databases for randomized controlled trials that administered botulinum toxin to individuals who underwent distraction osteogenesis of the lower limbs. The final search was conducted on July 6, 2021. Quality assessments were conducted using the Cochrane risk of bias tool and the Jadad scale. We performed random-effects meta-analysis to calculate the standardized mean differences (SMDs) and confidence intervals (CIs) of the pooled effect sizes, and subgroup analysis and meta-regression were performed for potential moderators. RESULTS: Our analysis of four randomized controlled trials, which enrolled a total of 257 participants, revealed that the difference in pain during the distraction phase was not statistically significant between groups (SMD, - 0.165; 95% CI, - 0.379 to 0.050, p = 0.133, I2 = 0.0%). The meta-regression analyses did not find any influence on the effect size, considering age (ß = - 0.0092; p = 0.61) and the amount of lengthening (ß = 0.0023; p = 0.99). Subgroup analysis did not reveal difference between different doses of botulinum toxin and single or multi-site study design. An analysis of two randomized controlled trials enrolling a total of 177 individuals demonstrated a limited effect of botulinum toxin in reducing postoperative pain (SMD, - 0.239; 95% CI, - 0.641 to 0.162, p = 0.24, I2 = 37.6%), total adverse events (SMD, - 0.207; 95% CI, - 0.505 to 0.090, p = 0.17, I2 = 0.0%), and infection of pin site (SMD, - 0.131; 95% CI, - 0.428 to 0.165, p = 0.39, I2 = 0.0%). No botulinum toxin-related adverse events were reported. CONCLUSIONS: The current evidence does not support the administration of botulinum toxin in patients who receive distraction osteogenesis of the lower limbs. However, we were unable to draw decisive conclusions because of the limitations of our meta-analysis. Future well-designed, large-scale randomized controlled trials are necessary to confirm our conclusions.

Effective Modulation by Lacosamide on Cumulative Inhibition of INa during High-Frequency Stimulation and Recovery of INa Block during Conditioning Pulse Train.

The effects of lacosamide (LCS, Vimpat®), an anti-convulsant and analgesic, on voltage-gated Na+ current (INa) were investigated. LCS suppressed both the peak (transient, INa(T)) and sustained (late, INa(L)) components of INa with the IC50 values of 78 and 34 µM found in GH3 cells and of 112 and 26 µM in Neuro-2a cells, respectively. In GH3 cells, the voltage-dependent hysteresis of persistent INa (INa(P)) during the triangular ramp pulse was strikingly attenuated, and the decaying time constant (τ) of INa(T) or INa(L) during a train of depolarizing pulses was further shortened by LCS. The recovery time course from the INa block elicited by the preceding conditioning train can be fitted by two exponential processes, while the single exponential increase in current recovery without a conditioning train was adequately fitted. The fast and slow τ's of recovery from the INa block by the same conditioning protocol arose in the presence of LCS. In Neuro-2a cells, the strength of the instantaneous window INa (INa(W)) during the rapid ramp pulse was reduced by LCS. This reduction could be reversed by tefluthrin. Moreover, LCS accelerated the inactivation time course of INa activated by pulse train stimulation, and veratridine reversed its decrease in the decaying τ value in current inactivation. The docking results predicted the capability of LCS binding to some amino-acid residues in sodium channels owing to the occurrence of hydrophobic contact. Overall, our findings unveiled that LCS can interact with the sodium channels to alter the magnitude, gating, voltage-dependent hysteresis behavior, and use dependence of INa in excitable cells.

Lipid Droplets in Lung Cancers Are Crucial for the Cell Growth and Starvation Survival.

For rapid and unlimited cell growth and proliferation, cancer cells require large quantities of nutrients. Many metabolic pathways and nutrient uptake systems are frequently reprogrammed and upregulated to meet the demand from cancer cells, including the demand for lipids. The lipids for most adult normal cells are mainly acquired from the circulatory system. Whether different cancer cells adopt identical mechanisms to ensure sufficient lipid supply, and whether the lipid demand and supply meet each other, remains unclear, and was investigated in lung cancer cells. Results showed that, despite frequent upregulation in de novo lipogenesis and the lipid transporter system, different lung cancer cells adopt different proteins to acquire sufficient lipids, and the lipid supply frequently exceeds the demand, as significant amounts of lipids stored in the lipid droplets could be found within lung cancer cells. Lipid droplet surface protein, PLIN3, was found frequently overexpressed since the early stage in lung cancer tissues. Although the expression is not significantly associated with a specific gender, age, histology type, disease stage, and smoking habit, the frequently elevated expression of PLIN3 protein indicates the importance of lipid droplets for lung cancer. These lipid droplets are not only for nutrient storage, but are also crucial for tumor growth and proliferation, as well as survival in starvation. These results suggest that manipulation of lipid droplet formation or TG storage in lung cancer cells could potentially decrease the progression of lung cancer. Further exploration of lipid biology in lung cancer could help design novel treatment strategies.

Cognitive Predictors of Social Interaction in Daily Contexts Among Children With Autism Spectrum Disorder.

IMPORTANCE: Theory of mind (ToM) and executive function (EF) are often used to explain social interaction deficits in children with autism spectrum disorder (ASD), but no behavioral studies have specifically examined their relationship. OBJECTIVE: To investigate the cognitive correlates of social interaction in daily contexts by ToM as well as cool and hot EFs among children with ASD. DESIGN: Cross-sectional study. SETTING: Teaching hospitals, clinics, and developmental centers. PARTICIPANTS: One hundred thirty-two children with ASD and their caregivers. OUTCOMES AND MEASURES: Measurements included the Vineland Adaptive Behavior Scales, Theory of Mind Task Battery, Dimensional Change Card Sort, and Children's Gambling Task, respectively, for children's daily social interaction, ToM, cool EF, and hot EF. Pearson's correlation analyses and three hierarchical regression models were conducted to identify the significant predictors of daily social interaction while controlling for verbal comprehension, measured using the Verbal Comprehension Index (VCI) of two Wechsler scales. RESULTS: ToM and cool EF were significant cognitive predictors of social interaction in daily contexts in children with ASD whose verbal comprehension was average or above average. CONCLUSIONS AND RELEVANCE: Our results suggest that ToM and cool EF are predictors of social interaction in daily contexts when considering children's verbal comprehension. Hot EF was not a significant predictor, contrary to our hypothesis. This behavioral study fills a research gap by enhancing the understanding of important cognitive correlates of social interaction in daily contexts for children with ASD to improve evaluation and intervention planning with this population. What This Article Adds: This study identified two cognitive predictors, ToM and cool EF, of social interaction in daily contexts for children with ASD. In addition to verbal comprehension, occupational therapy practitioners should assess ToM and cool EF to inform more comprehensive evaluation and intervention planning to improve social interaction in daily contexts for children with ASD.

The association of aspirin use with overall survival of patients with inoperable non-small cell lung cancer: a retrospective study.

BACKGROUND: Studies have indicated that individuals taking aspirin have a reduced risk of cancers and have also established chemo-preventive benefit of aspirin in colorectal cancer. However, research on the association between aspirin use and the survival in patients with lung cancer has revealed inconsistent results. In this study, we investigated the effect of aspirin use on the survival of inoperable non-small cell lung cancer (NSCLC) patients. METHODS: We identified a cohort of 38,842 patients diagnosed with NSCLC between 2000 and 2012 using the Taiwan's National Health Insurance Research Database and used propensity score matching to reduce possible confounding factors. In total, 9864 patients (4932 matched pairs) were included in the matched cohort. Aspirin exposure was analyzed to identify a possible association with mortality in patients with inoperable NSCLC. Time-dependent Cox regression models were used to calculate the hazard ratios (HRs) and the 95% confidence intervals (95% CIs) that corresponded with aspirin exposure. RESULTS: A total of 4979 patients used aspirin at the time of diagnosis of NSCLC. The median overall survival (OS) of the aspirin users was 1.73 (interquartile range, 0.94-3.53) years compared with the 1.30 (interquartile range, 0.69-2.62) years of the non-aspirin users. The Cox proportional hazard model with the time-dependent covariate revealed that aspirin use was associated with a significantly longer OS (HR: 0.83, 95.0% CI: 0.80-0.86). After controlling the sociodemographic characteristics (age, sex, income, and level of urbanization) and lung cancer treatments by propensity score matching, the aspirin users still had a significantly longer OS than the non-aspirin users (HR: 0.79, 95.0% CI: 0.75-0.83). CONCLUSION: Aspirin use is associated with a longer OS in patients with inoperable NSCLC, suggesting that aspirin has a potential anticancer effect. These results warrant further randomized clinical trials to evaluate the actual role of aspirin in the treatment of NSCLC patients.

A comparison of the MNA-SF, MUST, and NRS-2002 nutritional tools in predicting treatment incompletion of concurrent chemoradiotherapy in patients with head and neck cancer.

BACKGROUND: Concurrent chemoradiotherapy (CCRT) treatment incompletion is a known negative prognosticator for patients with head and neck cancer (HNC). Malnutrition is a common phenomenon which leads to treatment interruption in patients with HNC. We aimed to compare the performance of three nutritional tools in predicting treatment incompletion in patients with HNC undergoing definitive CCRT. MATERIAL AND METHODS: Three nutritional assessment tools, Mini Nutritional Assessment-Short Form (MNA-SF), Malnutritional Universal Screening Tool (MUST), and Nutritional Risk Screening 2002 (NRS-2002), were prospectively assessed prior to CCRT for HNC patients. Patients were stratified into either normal nutrition or malnourished groups using different nutrition tools. Treatment incompletion and treatment-related toxicities associated with CCRT were recorded. RESULTS: A total of 461 patients were included in the study; malnourished rates ranged from 31.0 to 51.0%. The CCRT incompletion rates were 4.9-6.3% and 14.5-18.2% for normal nutrition patients and malnourished patients, respectively. The tools had significant correlations with each other (Pearson correlation 0.801-0.837, p<0.001 for all) and accurately predicted the incompletion of CCRT. MNA-SF had the highest performance in predicting treatment-related toxicity, including emergency room visits, need for hospitalization, any grade III or higher hematological adverse events, and critical body weight loss, compared to the other tools. CONCLUSIONS: MNA-SF, MUST, and NRS2002 were all shown to be competent tools for prediction of treatment incompletion and treatment-related toxicity in HNC patients undergoing CCRT. We suggest implementing nutritional assessment prior to treatment to improve the rate of treatment completion and to reduce treatment-related toxicity in HNC patients.

Effects of vibrotactile-enhanced music-based intervention on sensorimotor control capacity in the hand of an aging brain: a pilot feasibility randomized crossover trial.

BACKGROUND: Music-based interventions (MBI), using music as a therapeutic medium, has been utilized as a promising strategy for motor relearning and shaping. However, currently, MBI with active performance training is restricted to being extensively applied for patients with various levels of defects in fine motor skills and cognitive functions. Therefore, the integration of vibrotactile stimulation with MBI has been adopted as a motor training strategy intended to enhance motor learning through use of vibration stimuli. The current study was designed to investigate differences in the sensorimotor performance of older adults' hands under baseline, a single session of active MBI, and vibrotactile-enriched MBI conditions. METHODS: Thirty healthy older adults were recruited and randomized to receive either the single session of 30-min of vibrotactile-enriched MBI or 30-min of active MBI at the beginning of the experiment. After a one-week washout period, they switched their treatment programs and then were assessed to study the training effects of both approaches through measuring precision pinch performance, hand function, and sensory status. RESULTS: The results of the Pinch-Holding-Up Activity test revealed a statistically significant difference in the FRpeak parameter (F = 14.37, p < 0.001, η2p = 0.507) under the vibrotactile-enriched MBI condition compared to the baseline and active MBI conditions. In addition, significant beneficial effects were found on the results of the barognosis (F = 19.126, p < 0.001, η2p = 0. 577) and roughness differentiation subtests (F = 15.036, p < 0.001, η2p = 0.518) in the Manual Tactile Test for the participants in the vibrotactile-enriched MBI group. In addition, the participants under both the active MBI and vibrotactile-enriched MBI conditions exhibited better performance in the three subtests of the Purdue Pegboard Test as compared to under the baseline condition (p < 0.016). CONCLUSIONS: The findings indicated that vibrotactile-enriched MBI potentially improves the precision pinch performance of hands in healthy older adults. In addition, the add-on effect of vibrotactile stimulation to the MBI condition provides beneficial effects on the sensory functions of the upper extremities. TRIAL REGISTRATION: NCT04802564 . Date of registration: 15/03/2021. The first posted date: 17/03/2021.