The Effects and Mechanisms of Action of TC-G 1008, GPR39 Agonist, in Animal Models of Seizures and Epilepsy

Background and purpose: The G-protein coupled receptor 39 (GPR39) may be activated by zinc ions. Activation of GPR39 was suggested as a novel pharmacological strategy for treating seizures. Experimental approach: We utilized a specific agonist of GPR39, TC-G 1008, and the nonspecific agonist, zinc chloride and a variety of models of acute seizures or a chronic model of epilepsy which were induced in non-genetically modified mice, GPR39 knockout mice or in zebrafish larvae. We examined total serum zinc (by Inductively Coupled Plasma Optical Emission Spectrometry) as well as intracellular zinc ([Zn2+]I) (by Zinpyr-1 staining) concentrations and the expression of selected proteins (by Western blot) which are associated with GPR39 signaling in the hippocampus. Key results: Liquid chromatography tandem mass spectrometry analysis showed that TC-G 1008 is brain penetrant. TC-G 1008 decreased the seizure threshold in the maximal electroshock seizure (MES) threshold test, but it increased the seizure threshold in the 6-Hz induced seizure threshold test. The behavioral effects of TC-G 1008 and MES or 6-Hz seizure were accompanied by alterations in hippocampal [Zn2+]I. TC-G 1008 increased the mean duration of EEG discharges in response to pentylenetetrazole (PTZ) in zebrafish larvae and facilitated the development of PTZ kindling in mice. Using GPR39 knockout mouse line, generated by the CRISPR-Cas-9 method, we showed that GPR39 is a target for TC-G 1008 regarding PTZ-induced epileptogenesis. Conclusion and implications: Our in vivo data obtained using TC-G 1008 generally argue against GPR39 activation as a therapeutic strategy for alleviating seizures/epilepsy.

Deficits in color detection in patients with Alzheimer disease

Deficits in color vision and related retinal changes hold promise as early screening biomarkers in patients with Alzheimer’s disease. This study aimed to determine a cut-off score that can screen for Alzheimer’s dementia using a novel color vision threshold test named the red, green, and blue (RGB) modified color vision plate test (RGB-vision plate). We developed the RGB-vision plate consisting of 30 plates in which the red and green hues of Ishihara Plate No.22 were sequentially adjusted. A total of 108 older people participated in the mini-mental state examination (MMSE), Ishihara plate, and RGB-vision plate. For the analyses, the participants were divided into two groups: Alzheimer’s dementia (n = 42) and healthy controls (n = 38). K-means cluster analysis and ROC curve analysis were performed to identify the most appropriate cut-off score. As a result, the cut-off screening score for Alzheimer’s dementia on the RGB-vision plate was set at 25, with an area under the curve of 0.773 (p<0.001). Moreover, there was a negative correlation between the RGB-vision plate thresholds and MMSE scores (r = -0.36, p = 0.02). In conclusion, patients with Alzheimer’s dementia had a deficit in color vision. The RGB-vision plate is a potential early biomarker that may adequately detect Alzheimer’s dementia.

Adapting Audiology Procedures During the Pandemic: Validity and Efficacy of Testing Outside a Sound Booth

Purpose: This investigation aims to provide outcomes from a clinical perspective on the validity and efficacy of a wireless automated audiometer system that could be used in multiple settings when a sound booth is not accessible. Testing was conducted in a clinical setting under modified protocols meeting safety precautions during the COVID-19 pandemic. Method: Four doctoral students in audiology served as examiners. Participants were 69 adults between the ages of 20 and 69 years, with normal hearing (≤ 25 dB HL; n = 110 ears) or hearing loss (> 25 dB HL; n = 25 ears). Two versions of a pure-tone air-conduction threshold test following a modified Hughson-Westlake approach were performed and compared at 500, 1000, 2000, 3000, 4000, 6000, and 8000 Hz (a) in a sound-treated test booth using standard manual audiometry and (b) in a quiet, nonsound-treated clinical room (sound booth free) using automated KUDUwave audiometry. Participants were asked to complete a five-item feedback questionnaire, and examiners were interviewed to report on their experience. Results: Clinical validity to within ±10 dB of standard audiometry was demonstrated for 94.5% of the total thresholds ( n = 937) measured with the sound booth–free approach. Less accuracy (73.3%) was observed using a ±5 dB comparison. When comparing the mean thresholds, there were significant differences ( p < .01) between the mean thresholds at most frequencies, with mean sound booth thresholds being higher than the sound booth–free mean thresholds. A strong threshold correlation (.91–.98) was found between the methods across frequencies. Participant and examiner feedback supported the efficacy of the sound booth–free technology. Conclusions: Findings support sound booth–free, automated software-controlled audiometry with active noise monitoring as a valid and efficient procedure for pure-tone hearing threshold assessment. This method offers an effective alternative when circumstances require more transportable hearing assessment technology or do not allow for standard manual audiometry in a sound booth.

Unbalanced-Tests to the Improvement of Yield and Quality

An integrated-circuit testing model (DITM) is used to describe various factors that affect test yield during a test process. We used a probability distribution model to evaluate test yield and quality and introduced a threshold test and a guardband test. As a result of the development speed of the semiconductor manufacturing industry in the future being unpredictable, we use electrical properties of existing products and the current manufacturing technology to estimate future product-distribution trends. In the development of very-large-scale integration (VLSI) testing, the progress of testing technology is very slow. To improve product testing yield and quality, we change the test method and propose an unbalanced-test method, leading to improvements in test results. The calculation using our proposed model and data estimated by the product published by the IEEE International Roadmap for Devices and Systems (IRDS, 2017) proves that the proposed unbalanced-test method can greatly improve test yield and quality and achieve the goal of high-quality, near-zero-defect products.

Do Environmental Regulations Improve Industrial Efficiency?

This study was based on research on the impact of environmental regulation on industrial efficiency in 30 provinces from 2005 to 2017 in China. For the explained variables, the industrial efficiency of the DEA-Malmquist method was utilized for the decomposition and measurement of overall factor productivity, and government environmental governance variables were added as instrumental variables for two-stage least-squares regression. In addition, environmental regulatory intensity and year were utilized as threshold variables for the threshold test. In the benchmark regression, environmental regulation harms regional industrial efficiency. However, according to the IV estimation of government environmental governance variables, environmental regulation has a positive effect on the transformation of regional industrial efficiency. The influence of environmental regulation on industrial efficiency will be first suppressed and then promoted with the gradual increase of regulatory intensity. Furthermore, there is significant spatial heterogeneity in the impact of environmental regulations.

The Stepping Threshold Test for Reactive Balance: Validation of Two Observer-Based Evaluation Strategies to Assess Stepping Behavior in Fall-Prone Older Adults

Introduction: Measurement of reactive balance is critical for fall prevention but is severely underrepresented in the clinical setting due to the lack of valid assessments. The Stepping Threshold Test (STT) is a newly developed instrumented test for reactive balance on a movable platform, however, it has not yet been validated for fall-prone older adults. Furthermore, different schemes of observer-based evaluation seem possible. The aim of this study was to investigate validity with respect to fall risk, interpretability, and feasibility of the STT using two different evaluation strategies.Methods: This study involved 71 fall-prone older adults (aged ≥ 65) who underwent progressively increasing perturbations in four directions for the STT. Single and multiple-step thresholds for each perturbation direction were determined via two observer-based evaluation schemes, which are the 1) consideration of all steps (all-step-count evaluation, ACE) and 2) consideration of those steps that extend the base of support in the direction of perturbation (direction-sensitive evaluation, DSE). Established balance measures including global (Brief Balance Evaluations Systems Test, BriefBEST), proactive (Timed Up and Go, TUG), and static balance (8-level balance scale, 8LBS), as well as fear of falling (Short Falls Efficacy Scale—International, FES-I) and fall occurrence in the past year, served as reference measurements.Results: The sum scores of STT correlated moderately with the BriefBEST (ACE: r = 0.413; DSE: r = 0.388) and TUG (ACE: r = −0.379; DSE: r = −0.435) and low with the 8LBS (ACE: r = 0.173; DSE: r = 0.246) and Short FES-I (ACE: r = −0.108; DSE: r = −0.104). The sum scores did not distinguish between fallers and non-fallers. No floor/ceiling effects occurred for the STT sum score, but these effects occurred for specific STT thresholds for both ACE (mean floor effect = 13.04%, SD = 19.35%; mean ceiling effect = 4.29%, SD = 7.75%) and DSE (mean floor effect = 7.86%, SD = 15.23%; mean ceiling effect = 21.07%, SD = 26.08). No severe adverse events occurred.Discussion: Correlations between the STT and other balance tests were in the expected magnitude, indicating convergent validity. However, the STT could not distinguish between fallers and non-fallers, referring to a need for further studies and prospective surveys of falls to validate the STT. Current results did not allow a definitive judgment on the advantage of using ACE or DSE. Study results represented a step toward a reactive balance assessment application in a clinical setting.

152 Comparison of an Antioxidant Source and Antioxidant Plus BCAA on Athletic Performance and Post Exercise Recovery of Horses

Antioxidant supplementation has been shown to decrease post exercise oxidative stress but can lead to decreased post-exercise muscle protein synthesis. The objective of this study was to compare the effects of the supplementation with a control feed with low antioxidant content (CONT) to a high antioxidant feed (AO), versus a high antioxidant and branched chain amino acid feed (BCAO) on post-exercise protein synthesis and oxidative stress. Our hypothesis is that supplementing AO with BCAO will reduce oxidative stress without hindering muscle protein synthesis. Eighteen mixed breed conditioned polo horses were assigned to one of the three treatments. All horses consumed CONT for 30 days and were then submitted to a lactate threshold test (LT). One hour after this and all LT, each group was assigned and given their treatments. LT were done at 15 and 30 days of supplementation. Blood was collected before, two and four hours after LT, and analyzed for oxidative stress based on glutathione peroxidase, superoxide dismutase and malondialdehyde concentrations by ELISA. Muscle biopsies were taken before and 4 hours after LT and analyzed for the expression of protein synthesis by RT-PCR. Results were analyzed in a mixed model by ANOVA and compared by LSM. A reduction of oxidative stress was found over time (P &lt; 0.050) with no treatment effect (P &gt;0.50). An upregulation of protein synthesis after exercise was found for muscle primers CD36, CPT1, DK4, MyF5, and Myogenin (P &lt; 0.050). There was a treatment by time effect for MyoD (P = 0.027), where AO was upregulated the most after exercise compared to BCAO and CONT. DK4 had a treatment by time effect trend (P = 0.073), where AO and BCAO were upregulated and CONT was unchanged after exercise. This study demonstrated post exercise muscle synthesis with no advantage of AO plus BCAO compared to AO.

A New Method for a Shorter and Valid Assessment of Olfactory Threshold in Repeated Measurement Designs Based on the Sniffin’ Sticks Test

Introduction The Sniffin’ Sticks threshold test is widely used to assess olfactory threshold due to its high reliability and validity. Nevertheless, this test procedure is quite long with an average duration of 10 to 20 min. In study designs that require multiple olfactory threshold tests on short intervals, this could exhaust participants. To counteract this limitation, we developed the informed-four-reversal (INFOUR) short version of the Sniffin’ Sticks threshold test for repeated measurement designs and piloted it in a sample of normosmic participants. Methods Forty-two participants performed the original Sniffin’ Sticks version before being assigned either to the control group that repeated the original version or to the test group that conducted the INFOUR short version. Results The correlation between the original version at T1 and INFOUR at T2 was r = .75 and did not differ significantly from the retest reliability of the original version. Compared to the original version, the INFOUR took 42% less time to perform. Conclusion The INFOUR leads to a significant time saving, while maintaining good validity. Implications Therefore, this approach has the potential to be a useful tool for study protocols with repeated olfactory threshold measurements. In particular, when research protocols are time intensive or testing needs to the shortened, because the interventional effects are short or subtle.