Targeted Quantification of Glutathione/Arginine Redox Metabolism Based on a Novel Paired Mass Spectrometry Probe Approach for the Functional Assessment of Redox Status.

Glutathione (GSH) redox control and arginine metabolism are critical in regulating the physiological response to injury and oxidative stress. Quantification assessment of the GSH/arginine redox metabolism supports monitoring metabolic pathway shifts during pathological processes and their linkages to redox regulation. However, assessing the redox status of organisms with complex matrices is challenging, and single redox molecule analysis may not be accurate for interrogating the redox status in cells and in vivo. Herein, guided by a paired derivatization strategy, we present a new ultraperformance liquid chromatography tandem mass spectrometry (UPLC-MS/MS)-based approach for the functional assessment of biological redox status. Two structurally analogous probes, 6-aminoquinolyl-N-hydroxysuccinimidyl carbamate (AQC) and newly synthesized 2-methyl-6-aminoquinolyl-N-hydroxysuccinimidyl carbamate (MeAQC), were set for paired derivatization. The developed approach was successfully applied to LPS-stimulated RAW 264.7 cells and HDM-induced asthma mice to obtain quantitative information on GSH/arginine redox metabolism. The results suggest that the redox status was remarkably altered upon LPS and HDM stimulation. We expect that this approach will be of good use in a clinical biomarker assay and potential drug screening associated with redox metabolism, oxidative damage, and redox signaling.

The Global Burden of Diseases attributed to high low-density lipoprotein cholesterol from 1990 to 2019.

Background: To demonstrate the real-word situation of burdens that are attributed to the risk factor of high low-density lipoprotein cholesterol (LDL-C) at the global, regional, national levels, among different age groups and between genders. Methods: We analyzed data from the Global Burden of Disease study 2019 related to global deaths, disability-adjusted life years (DALYs), summary exposure value (SEV), average annual percentage change (AAPC), and observed to expected ratios (O/E ratios) attributable to high LDL-C from 1990 to 2019. Results: Globally, in 2019, the total numbers of deaths and DALYs attributed to high LDL cholesterol were 1.47 and 1.41 times higher than that in 1990. The age-standardized deaths and DALYs rate was 1.45 and 1.70 times in males compared to females, while the age-standardized SEVs rate was 1.10 times in females compared to males. The deaths, DALYs, and SEV rates increased with age. In 2019, the highest age-standardized rates of both deaths and DALYs occurred in Eastern Europe while the lowest occurred in high-income Asia Pacific. High-income North America experienced a dramatic reduction of risk related to high LDL-C. Correlation analysis identified that the age-standardized SEV rate was positively correlated with Socio-demographic Index (SDI; r = 0.7753, P < 0.001). The average annual percentage change (AAPC) of age-standardized SEV rate decreased in the high SDI and high-middle SDI regions but increased in the middle SDI, low-middle SDI, and low SDI regions. High LDL-C mainly contributed to ischemic heart diseases. Conclusion: High LDL-C contributed considerably to health burden worldwide. Males suffered worse health outcomes attributed to high LDL-C when compared to females. The burden attributed to high LDL-C increased with age. Lower SDI regions and countries experienced more health problem challenges attributed to high LDL-C as the result of social development and this should be reflected in policymaking.

Quantitative Assessment of the Apical and Basolateral Membrane Expression of VEGFR2 and NRP2 in VEGF-A-stimulated Cultured Human Umbilical Vein Endothelial Cells.

Endothelial cells (ECs) form a precisely regulated polarized monolayer in capillary walls. Vascular endothelial growth factor-A (VEGF-A) induces endothelial hyperpermeability, and VEGF-A applied to the basolateral side, but not the apical side, has been shown to be a strong barrier disruptor in blood-retinal barrier ECs. We show here that VEGF-A presented to the basolateral side of human umbilical vein ECs (HUVECs) induces higher permeability than apical stimulation, which is similar to results obtained with bovine retinal ECs. We investigated with immunocytochemistry and confocal imaging the distribution of VEGF receptor-2 (VEGFR2) and neuropilin-2 (NRP2) in perinuclear apical and basolateral membrane domains. Orthogonal z-sections of cultured HUVECs were obtained, and the fluorescence intensity at the apical and basolateral membrane compartments was measured. We found that VEGFR2 and NRP2 are evenly distributed throughout perinuclear apical and basolateral membrane compartments in unstimulated HUVECs grown on Transwell inserts, whereas basolateral VEGF-A stimulation induces a shift toward basolateral VEGFR2 and NRP2 localization. When HUVECs were grown on coverslips, the distribution of VEGFR2 and NRP2 across the perinuclear apical and basolateral membrane domains was different. Our findings demonstrate that HUVECs dynamically regulate VEGFR2 and NRP2 localization on membrane microdomains, depending on growth conditions and the polarity of VEGF-A stimulation.

Income Inequality Is Associated With Low Cumulative Antiretroviral Adherence in Persons With Human Immunodeficiency Virus.

BACKGROUND: The adherence biomarker tenofovir diphosphate (TFV-DP) in dried blood spots (DBS) is associated with viral suppression and predicts future viremia. However, its association with social determinants of health (SDoH) in people with human immunodeficiency virus (PWH) remains unknown. METHODS: Dried blood spots for TFV-DP were longitudinally collected from a clinical cohort of PWH receiving tenofovir disoproxil fumarate-based therapy (up to 3 visits over 48 weeks) residing in 5 Colorado counties. To assign SDoH, zip codes at enrollment were matched with SDoH data from AIDSVu (https://aidsvu.org/). The SDoH included household income, percentage living in poverty, education level, and income inequality (quantified using Gini coefficient, where 0 and 1 represent perfect income equality and inequality, respectively). Log-transformed TFV-DP concentrations were analyzed using a mixed-effects model to estimate percentage change (95% confidence interval) in TFV-DP for every significant change in the SDoH and adjusted for relevant covariates including age, gender, race, estimated glomerular filtration rate, body mass index, hematocrit, CD4+ T-cell count, antiretroviral drug class, and 3-month self-reported adherence. RESULTS: Data from 430 PWH totaling 950 person-visits were analyzed. In an adjusted analysis, income inequality was inversely associated with TFV-DP in DBS. For every 0.1 increase in the Gini coefficient, TFV-DP concentrations decreased by 9.2% (-0.5 to -17.1; P = .039). This remained significant after adjusting for human immunodeficiency virus viral suppression, where a 0.1 increase in Gini was associated with a decrease of 8.7% (-0.3 to -17.9; P = .042) in TFV-DP. CONCLUSIONS: Higher income inequality was associated with lower cumulative antiretroviral adherence. These findings support the need for further research on how SDoH impact adherence and clinical care.

General characteristics, economic burden, causative drugs and medical errors associated with medical damage litigation involving severe cutaneous adverse drug reactions in China.

WHAT IS KNOWN AND OBJECTIVE: To investigate the general characteristics, economic burden, causative drugs and medical errors associated with litigation involving severe cutaneous adverse drug reactions (SCADRs) in China, with the aims of improving rational medication use and reducing the extent of damage from SCADRs. METHODS: This study analysed 150 lawsuit judgements involving SCADRs from 2005 to 2019, collected from China Judgments Online. RESULTS AND DISCUSSION: In total, 50% of lawsuits stemmed from SCADRs occurring in general hospitals. The average time elapsed from the date of occurrence of the SCADRs to the end of litigation procedures was 1055 days. Of the patients involved, 51% were female and more than two thirds (69%) were under 60 years old. The most common outcome of SCADRs was death (39%), followed by disabilities (30%). The average responsibility of the medical provider was 48 ± 29%. The average amount of compensation was $43 424. Of the cases studied, 51% of SCADRs were Stevens-Johnson syndrome or toxic epidermal necrolysis, which together accounted for 75% of cases with known clinical subtype. The overall average economic burden of SCADRs was $99 178, of which indirect costs made up the largest proportion (more than 60%). The most common causative drug groups were antimicrobial drugs (49%), Chinese patent medicine and Chinese herbal medicine (17%), and antipyretic analgesics (16%). Finally, 61% of medical errors were found to stem from violation of duty of care, 20% from violation of informed consent and 18% from violations related to the medical record writing and management system. WHAT IS NEW AND CONCLUSION: Severe cutaneous adverse drug reactions not only severely affect patient survival and quality of life, but also impose a heavy economic burden in terms of health care and societal costs. Medical providers should be better educated on strategies to reduce risk to patients and establish mechanisms of risk sharing and management.

Associations between ideal blood pressure based on different BMI categories and stroke incidence.

OBJECTIVES: The 2017 American College of Cardiology/American Heart Association (ACC/AHA) Guideline for high blood pressure (BP) in adults redefined hypertension as SBP at least 130 mmHg or DBP at least 80 mmHg. However, the optimal BP for different BMI population to reduce stroke incidence is uncertain. METHODS: A prospective cohort study was designed by four examinations: baseline (2004-2006), 2008, 2010 and 2017 follow-up. The study group composed of 36 352 individuals, to determine the ideal BP range to reduce stroke incidence of two BMI level, adjusted Cox proportional hazards models were utilized to establish the associations between SBP/DBP and the risk of stroke incident. Then, the restricted cubic spline regression was applied to find the ideal range of SBP/DBP values for two kinds of BMI categories definitions. RESULTS: During a median follow-up period of 12.5 years, 2548 (7.0%) nonstroke individuals at baseline developed incident stroke. After fully adjusting confounding factors, SBP (per 20 mmHg increase) and DBP (per 10 mmHg increase) are independently associated with the risk of stroke incidence [SBP, hazard ratio = 1.277, 95% confidence interval (95% CI), 1.217-1.340, P < 0.001; DBP, hazard ratio = 1.138, 95% CI, 1.090-1.189, P < 0.001]. CONCLUSION: Our study revealed that the ideal BP for a population with BMI less than 24 kg/m was less than 130/80 mmHg, whereas the ideal BP for BMI at least 24 kg/m was less than 120/80 mmHg. The sensitivity analyses between BMI less than 25 kg/m and BMI at least 25 kg/m showed similar findings. This finding provides more accurate primary prevention strategies based on various BMI populations.

Temporal relationship between body mass index and triglyceride-glucose index and its impact on the incident of hypertension.

BACKGROUND AND AIMS: Obesity and insulin levels can influence each other by metabolism. However, their temporal sequences and influence on hypertension are generally unknown, especially in Chinese adults. Recently, some scholars have proposed that triglycerides-glucose index (TyG) is an important indicator of insulin resistance. The study aims to describe the relationship between body mass index (BMI) and TyG index and its impact on hypertension. METHODS AND RESULTS: A total of 4081 adults (56.33% women) without antihypertensive, hypoglycemic or lipid-lowering medications were selected for the present study. Measurements of BMI and TyG index were obtained twice from 2012 to 2017. Cross-lagged panel analysis was used to describe the temporal sequences between BMI and TyG index, and the effect of their temporal relationship patterns on hypertension was explored through mediation analysis. After adjusting for confounding factors (age, sex, ethnicity et al.), the cross-lagged path coefficient from baseline BMI to follow-up TyG (ρ2 = 0.135, P < 0.001) was significantly greater than the path coefficient from baseline TyG to follow-up BMI (ρ1 = 0.043, P < 0.001), and P < 0.001 for the difference between ρ1 and ρ2. Furthermore, the sensitivity analyses between women and men revealed identical findings. In addition, TyG index mediation effect on BMI-hypertension was estimated to be 38.45% (P < 0.001) in total population, 25.24% in women and 57.35% in men. CONCLUSION: These results provided evidence that the temporal relationship between BMI and insulin resistance is reciprocal and a higher BMI precedes hyperinsulinemia in Chinese adults. This relationship plays an essential role in the development of hypertension, while there is a difference between women and men.

Presence of pink-color sign within 1 min after iodine staining has high diagnostic accordance rate for esophageal high-grade intraepithelial neoplasia/invasive cancer.

BACKGROUND/AIM: The dramatic color change after iodine staining (from white-yellow to pink after 2-3 min), designated as the "pink-color sign" (PCS), is indicative of esophageal high-grade intraepithelial neoplasia (HGIN) or an invasive lesion. However, no study has yet examined the association between the time of PCS appearance and histopathology. We investigated the association between the time of PCS appearance and esophageal histopathology in 456 lesions of 438 patients who were examined for suspected esophageal cancer. MATERIALS AND METHODS:: The records of 495 consecutive patients who had suspected esophageal cancer based on gastroscopy and who underwent Lugol's chromoendoscopy from January 2015 to March 2018 were retrospectively reviewed. The time of PCS appearance was recorded in all patients, and tissue specimens were examined. RESULTS: We examined 456 lesions in 438 patients. Use of PCS positivity at 2 min for the diagnosis of HGIN/invasive cancer had a sensitivity of 84.1%, a specificity of 72.7%, and an accuracy of 80.4%. We classified the PCS-positive patients in whom the time of PCS appearance was recorded (168 lesions) into 4 groups: 0-30, 31-60, 61-90, and 91-120 s. Based on a 60-s time for appearance of the PCS, the area under the receiver operating characteristic curve was 0.897, indicating good validity. At the optimal cutoff value of 60 s, the sensitivity was 90.2% and the specificity was 82.3%. The appearance of the PCS within 60 s had a diagnostic accordance rate of 88.6%, significantly higher than appearance of the PCS within 2 min (79.7%, P < 0.05). CONCLUSION: Appearance of the PCS within 1 min after iodine staining has a higher diagnostic accordance rate for esophageal HGIN/invasive cancer than appearance of the PCS at 2 min.

Estimate of Health Burden on Smoking-associated Oral Cancer in Shanghai and its Surrounding Areas.

OBJECTIVE: To evaluate the temporal trend of inpatients with smoking-associated oral cancer in Shanghai and its surrounding areas and to forecast the public health burden in the next decade. METHODS: Data of inpatients with oral cancer were retrieved from Shanghai Ninth People's Hospital during a 15-year period. The annual numbers of inpatients were compared by Chi-test. The hospitalization expenditures were compared by Student's t test. The trend analysis and inpatient forecasting were performed by exponential smoothing, regression models, and the forecasting function in Excel software. The financial burden of smoking-associated oral cancer was calculated by polynomial equation. RESULTS: The annual number of inpatients with oral cancer increased during the study period. Most male patients were reported to have a smoking habit. Among the three estimation methods, polynomial regression model was most fitted to the existing data. By a conservative estimation, the public health burden of smoking-associated oral cancer patients will be 120 million RMB by the year 2026, not including the cost by prevalent patients and the patients' family members. CONCLUSION: Smoking-associated oral cancer will cost a lot of public resource in the next decade. Efforts should be made to lower the amount of tobacco consumption.

Validity Assessment of 5 Day Repeated Forced-Swim Stress to Model Human Depression in Young-Adult C57BL/6J and BALB/cJ Mice.

The development of animal models with construct, face, and predictive validity to accurately model human depression has been a major challenge. One proposed rodent model is the 5 d repeated forced swim stress (5d-RFSS) paradigm, which progressively increases floating during individual swim sessions. The onset and persistence of this floating behavior has been anthropomorphically characterized as a measure of depression. This interpretation has been under debate because a progressive increase in floating over time may reflect an adaptive learned behavioral response promoting survival, and not depression (Molendijk and de Kloet, 2015). To assess construct and face validity, we applied 5d-RFSS to C57BL/6J and BALB/cJ mice, two mouse strains commonly used in neuropsychiatric research, and measured a combination of emotional, homeostatic, and psychomotor symptoms indicative of a depressive-like state. We also compared the efficacy of 5d-RFSS and chronic social defeat stress (CSDS), a validated depression model, to induce a depressive-like state in C57BL/6J mice. In both strains, 5d-RFSS progressively increased floating behavior that persisted for at least 4 weeks. 5d-RFSS did not alter sucrose preference, body weight, appetite, locomotor activity, anxiety-like behavior, or immobility behavior during a tail-suspension test compared with nonstressed controls. In contrast, CSDS altered several of these parameters, suggesting a depressive-like state. Finally, predictive validity was assessed using voluntary wheel running (VWR), a known antidepressant intervention. Four weeks of VWR after 5d-RFSS normalized floating behavior toward nonstressed levels. These observations suggest that 5d-RFSS has no construct or face validity but might have predictive validity to model human depression.

Opto-physiological modeling applied to photoplethysmographic cardiovascular assessment.

This paper presents opto-physiological (OP) modeling and its application in cardiovascular assessment techniques based on photoplethysmography (PPG). Existing contact point measurement techniques, i.e., pulse oximetry probes, are compared with the next generation non-contact and imaging implementations, i.e., non-contact reflection and camera-based PPG. The further development of effective physiological monitoring techniques relies on novel approaches to OP modeling that can better inform the design and development of sensing hardware and applicable signal processing procedures. With the help of finite-element optical simulation, fundamental research into OP modeling of photoplethysmography is being exploited towards the development of engineering solutions for practical biomedical systems. This paper reviews a body of research comprising two OP models that have led to significant progress in the design of transmission mode pulse oximetry probes, and approaches to 3D blood perfusion mapping for the interpretation of cardiovascular performance.

Development of an industrial medium and a novel fed-batch strategy for high-level expression of recombinant ß-mananase by Pichia pastoris.

An industrial medium, Corn Steep Liquor Powder Dextrose (CSD medium) was developed for constitutive expression of recombinant ß-mananase by Pichia pastoris. The ß-mananase activity (513 U/mL) with CSD medium was 1.64- and 2.5-fold higher than with YPD and BSM in shaken flasks. The ß-mananase productivity with CSD medium was 61.0 U/mL h, which was 1.7- and 2.5-fold higher than with YPD and BSM in a 5-L fermenter based on a novel fed-batch strategy combining the real-time exponential feed mode with the DO-stat feed mode. The ß-mananase activity, dry cell weight and the recombinant enzyme reached up to 5132 U/mL, 110.0 g/L and 4.50 g/L after 50 h cultivation in a 50-L fermenter. The high efficient expression of recombinant ß-mananase by P. pastoris indicated that CSD medium and the novel fed-batch strategy have great potential for the production of recombinant ß-mananase in industrial fermentation.

[Vulnerability assessment of eco-environment in Yimeng mountainous area of Shandong Province based on SRP conceptual model].

Based on the ecological sensitivity-resilience-pressure (SRP) conceptual model, and selecting 13 indices including landscape diversity index, soil erosion, and elevation, etc. , the vulnerability of the eco-environment in Yimeng mountainous area of Shandong Province was assessed under the support of GIS and by using principal component analysis and hierarchy analytical method. According to the eco-environmental vulnerability index (EVI) values, the eco-environment vulnerability of study area was classified into 5 levels, i.e., slight (<1.8), light (1.8-2.8), moderate (2.8-3.5), heavy (3.5-4.0), and extreme vulnerability (>4.0). In the study area, moderately vulnerable area occupied 43.3% of the total, while the slightly, lightly, heavily, and extremely vulnerable areas occupied 6.1%, 33.8%, 15.9%, and 0.9%, respectively. The heavily and extremely vulnerable areas mainly located in the topographically complicated hilly area or the hill-plain ecotone with frequent human activities.

A study of opto-physiological modeling to quantify tissue absorbance in imaging photoplethysmography.

This paper presents an opto-physiological model (OPM) to quantify the absorbance of multi-layered tissue in imaging photoplethysmography (IPPG). The approach used to generate such a model is to revise the path length of the Beer Lambert law through the Monte Carlo (MC) simulation of multi-layered tissue. The OPM can mathematically quantify the effect of optical properties on the absorbance of multilayered tissue. Subsequently, the absorbance measured from homogeneous, multi-layered tissue phantoms compares with model predictions. To this end, the model is validated to predict the widest range of experimental outcomes while maintaining the highest possible level of accuracy. This study brings a new approach to understand the principle of IPPG.

Development of effective photoplethysmographic measurement techniques: from contact to non-contact and from point to imaging.

This paper provides an overview of the most recent developments in photoplethysmography (PPG). Existing contact point measurement techniques, i.e. pulse oximetry probes, are contrasted with the next generation non-contact and imaging implementations, i.e. non-contact reflection and camera-based PPG. The development of effective PPG monitoring techniques relies on novel approaches to opto-physiological modeling.

[Application of the Children's Impact of Event Scale (Chinese Version) on a rapid assessment of posttraumatic stress disorder among children from the Wenchuan earthquake area].

OBJECTIVE: To explore the reliability and validity of the Children's Impact of Event Scale (Chinese version, CRIES-13) and to determine the value and the optimal cutoff point of the score of CRIES-13 in screening posttraumatic stress disorder (PTSD), so as to provide evidence for PTSD prevention and identify children at risk in Wenchuan earthquake areas. METHODS: A total of 253 children experienced the Wenchuan earthquake were tested through Stratified random cluster sampling. The authors examined CRIES-13's internal consistency, discriminative validity and predictive value of the cut-off. PTSD was assessed with the DSM-IV criteria. Area under the curve while sensitivity, specificity and Youden index were computed based on the receiver operating characteristic curve analysis. Optimal cutoff point was determined by the maximum of Youden index. RESULTS: 20.9% of the subjects were found to have met the DSM-IV criteria for PTSD 7 months after the Wenchuan earthquake accident. The Cronbach's coefficient of CRIES-13 was 0.903 and the mean inter-item correlation coefficients ranged from 0.283 to 0.689, the correlation coefficient of the three factors with the total scale scores ranged from 0.836 to 0.868 while the correlation coefficient among the three factors ranged from 0.568 to 0.718, PTSD cases indicated much higher scores than non-PTSD cases, the Youden index reached maximum value when the total score approached 18 in CRIES-13 with sensitivity and specificity as 81.1% and 76.5% respectively. Consistency check showed that there were no significant differences between the results of CRIES-13 score >/= 32 and clinical diagnosis (Kappa = 0.529) from the screening program. CONCLUSION: CRIES-13 appeared to be a reliable and valid measure for assessing the posttraumatic stress symptoms among children after the earthquake accident in the Wenchuan area. The CRIES-13 seemed to be a useful self-rating diagnostic instrument for survivors with PTSD symptoms as a clinical concern by using a 18 cut-off in total score. Consistency check showed that there was no significant difference between the screening result of CRIES-13 score >/= 32 and clinical diagnosis.