Detoxification Role of Metabolic Glutathione S-Transferase (GST) Genes in Blood Lead Concentrations of Jamaican Children with and without Autism Spectrum Disorder.

Glutathione S-transferases (GST) are involved in the detoxification of exogenous chemicals including lead (Pb). Using data from 344 pairs of autism spectrum disorder (ASD) cases and age- and sex-matched typically developing (TD) controls (2−8 years old) from Jamaica, we investigated the interaction between three GST genes and ASD status as determinants of blood Pb concentrations (BPbCs). We found that ASD cases had lower geometric mean BPbCs than TD children (1.74 vs. 2.27 µg/dL, p < 0.01). Using a co-dominant genetic model, ASD cases with the Ile/Val genotype for the GSTP1 Ile105Val polymorphism had lower GM BPbCs than TD controls, after adjusting for a known interaction between GSTP1 and GSTT1, child's parish, socioeconomic status, consumption of lettuce, fried plantains, and canned fish (Ile/Val: 1.78 vs. 2.13 µg/dL, p = 0.03). Similarly, among carriers of the I/I or I/D (I*) genotype for GSTT1 and GSTM1, ASD cases had lower adjusted GM BPbCs than TD controls (GSTT1 I*: 1.61 vs. 1.91 µg/dL, p = 0.01; GSTM1 I*: 1.71 vs. 2.04 µg/dL, p = 0.01). Our findings suggest that genetic polymorphisms in GST genes may influence detoxification of Pb by the enzymes they encode in Jamaican children with and without ASD.

Younger age of stroke in low-middle income countries is related to healthcare access and quality.

Stroke is the second leading cause of mortality globally with higher burden and younger age in low-middle income countries (LMICs) than high-income countries (HICs). However, it is unclear to what extent differences in healthcare access and quality (HAQ) and prevalence of risk factors between LMICs and HICs contribute to younger age of stroke in LMICs. In this systematic review, we conducted meta-analysis of 67 articles and compared the mean age of stroke between LMICs and HICs, before and after adjusting for HAQ index. We also compared the prevalence of main stroke risk factors between HICs and LMICs. The unadjusted mean age of stroke in LMICs was significantly lower than HICs (63.1 vs. 68.6), regardless of gender (63.9 vs. 66.6 among men, and 65.6 vs. 70.7 among women) and whether data were collected in population- (64.7 vs. 69.5) or hospital-based (62.6 vs. 65.9) studies (all p < 0.01). However, after adjusting for HAQ index, the difference in the mean age of stroke between LMICs and HICs was not significant (p ≥ 0.10), except among women (p = 0.048). In addition, while the median prevalence of hypertension in LMICs was 23.4% higher than HICs, the prevalence of all other risk factors was lower in LMICs than HICs. Our findings suggest a much larger contribution of HAQ to the younger mean age of stroke in LMICs, as compared with other potential factors. Additional studies on stroke care quality and accessibility are needed in LMICs.

Construct validity for the self-reported competency and sub-construct associated characteristics of Romanian physicians in autism spectrum disorder.

BACKGROUND: Lack of physicians' knowledge regarding mental health, including Autism Spectrum Disorder (ASD) could have adverse effects on affected individuals' health and quality of life. The purpose of this study was to provide construct validity for a modified questionnaire in order to determine the self-reported competency for underlying sub-constructs in ASD, make inferences on perceived competence in ASD based on a sample of Romanian physicians, and identify physicians' characteristics associated with these sub-domains of competency. METHODS: For this survey, we modified a questionnaire that was used in Pakistan and Turkey, and administered it to a sample of 383 practicing physicians in Romania to assess their perceived competency regarding ASD. Exploratory factor analysis on 12 knowledge questions revealed five sub-domains: stigma, potential causes, children's behavior, misconceptions, and educational needs associated with ASD knowledge. Using General Linear Models, we determined physicians' characteristics that predict the total competency score and various competency sub-scores. RESULTS: Seventy-five percent of the responding physicians were female and 30% had over 30 years practicing medicine. The majority (73-94%) of physicians have correctly responded to some basic questions regarding knowledge about ASD. We also found that younger physicians were more knowledgeable about potential causes of ASD than older physicians (Adjusted Mean Score (AMS): 2.90 vs. 2.18, P < 0.01), while older physicians knew more about the behavior of children with ASD (AMS: 0.64 vs. 0.37, P = 0.02). We found a significant interaction (P < 0.01) between television as source of ASD knowledge and city where the clinic is located in relation to knowledge of the physicians regarding stigma related to ASD. However, the total score was not associated with the variables associated with sub-domains. CONCLUSION: Using factor analysis, we demonstrated construct validity of five sub-domains related to Romanian physicians' knowledge about ASD that include stigma, potential causes, behavior in ASD children, special education needs, and misconceptions related to ASD. The lack of significant association of the knowledge of physicians on ASD neither with the Psychiatry nor the Pediatric ward rotations at medical school may support the need for improving the curriculum on ASD in Romanian medical schools.

Astaxanthin induces NADPH oxidase activation and receptor­interacting protein kinase 1­mediated necroptosis in gastric cancer AGS cells.

Astaxanthin (ASX), a red­colored xanthophyll carotenoid, functions as an antioxidant or pro­oxidant. ASX displays anticancer effects by reducing or increasing oxidative stress. Reactive oxygen species (ROS) promote cancer cell death by necroptosis mediated by receptor­interacting protein kinase 1 (RIP1) and RIP3. NADPH oxidase is a major source of ROS that may promote necroptosis in some cancer cells. The present study aimed to investigate whether ASX induces necroptosis by increasing NADPH oxidase activity and ROS levels in gastric cancer AGS cells. AGS cells were treated with ASX with or without ML171 (NADPH oxidase 1 specific inhibitor), N­acetyl cysteine (NAC; antioxidant), z­VAD (pan­caspase inhibitor) or Necrostatin­1 (Nec­1; a specific inhibitor of RIP1). As a result, ASX increased NADPH oxidase activity, ROS levels and cell death, and these effects were suppressed by ML171 and NAC. Furthermore, ASX induced RIP1 and RIP3 activation, ultimately inducing mixed lineage kinase domain­like protein (MLKL) activation, lactate dehydrogenase (LDH) release and cell death. Moreover, the ASX­induced decrease in cell viability was reversed by Nec­1 treatment and RIP1 siRNA transfection, but not by z­VAD. ASX did not increase the ratio of apoptotic Bax/anti­apoptotic Bcl­2, the number of Annexin V­positive cells, or caspase­9 activation, which are apoptosis indices. In conclusion, ASX induced necroptotic cell death by increasing NADPH oxidase activity, ROS levels, LDH release and the number of propidium iodide­positive cells, as well as activating necroptosis­regulating proteins, RIP1/RIP3/MLKL, in gastric cancer AGS cells. The results of this study demonstrated the necroptotic effect of ASX on gastric cancer AGS cells, which required NADPH oxidase activation and RIP1/RIP3/MLKL signaling in vitro.

Concentrations of Lead, Mercury, Arsenic, Cadmium, Manganese, and Aluminum in the Blood of Pakistani Children with and without Autism Spectrum Disorder and Their Associated Factors.

BACKGROUND: Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder with early onset in utero or childhood. Environmental exposure to six metals (Pb, Hg, As, Cd, Mn, Al) is believed to be associated with ASD directly or interactively with genes. Objective: To assess the association of ASD among Pakistani children with the six metals and genotype frequencies of three GST genes (GSTP1, GSTM1, GSTT1). METHODS: We enrolled 30 ASD cases, age 2-12 years old, and 30 age- and sex-matched typically developing (TD) controls in Karachi, Pakistan. We assessed associations of ASD status with various factors using Conditional Logistic Regression models. We also used General Linear Models to assess possible interaction of blood Mn and Pb concentrations with the three GST genes in relation to ASD status. RESULTS: The unadjusted difference between ASD and TD groups in terms of geometric mean blood Pb concentrations was marginally significant (p = 0.05), but for Al concentrations, the adjusted difference was marginally significant (p = 0.06). CONCLUSIONS: This is the first study reporting six blood metal concentrations of Pakistani children with ASD. Estimates provided for possible interactions of GST genes with Mn and Pb in relation to ASD status are valuable for designing future similar studies.

A meta-analysis of the global impact of the COVID-19 pandemic on stroke care & the Houston Experience.

OBJECTIVE: To review the global impact of the COVID-19 pandemic on stroke care-metrics and report data from a health system in Houston. METHODS: We performed a meta-analysis of the published literature reporting stroke admissions, intracerebral hemorrhage (ICH) cases, number of thrombolysis (tPA) and thrombectomy (MT) cases, and time metrics (door to needle, DTN; and door to groin time, DTG) during the pandemic compared to prepandemic period. Within our hospital system, between January-June 2019 and January-June 2020, we compared the proportion of stroke admissions and door to tPA and MT times. RESULTS: A total of 32,640 stroke admissions from 29 studies were assessed. Compared to prepandemic period, the mean ratio of stroke admissions during the pandemic was 70.78% [95% CI, 65.02%, 76.54%], ICH cases was 83.10% [95% CI, 71.01%, 95.17%], tPA cases was 81.74% [95% CI, 72.33%, 91.16%], and MT cases was 88.63% [95% CI, 74.12%, 103.13%], whereas DTN time was 104.48% [95% CI, 95.52%, 113.44%] and DTG was 104.30% [95% CI, 81.99%, 126.61%]. In Houston, a total of 4808 cases were assessed. There was an initial drop of ~30% in cases at the pandemic onset. Compared to 2019, there was a significant reduction in mild strokes (NIHSS 1-5) [N (%), 891 (43) vs 635 (40), P = 0.02]. There were similar mean (SD) (mins) DTN [44 (17) vs 42 (17), P = 0.14] but significantly prolonged DTG times [94 (15) vs 85 (20), P = 0.005] in 2020. INTERPRETATION: The COVID-19 pandemic led to a global reduction in stroke admissions and treatment interventions and prolonged treatment time metrics.

Coping and rumination as mediators in the development of reactive embitterment in the general population.

OBJECTIVE: Embitterment encapsulates reactive emotions such as worthlessness or helplessness after negative life events that contravene one's basic beliefs. However, no psychological model of the development of persistent embitterment has yet been investigated. We examined mediating factors for reactive embitterment, focusing on cognitive processes, including coping and rumination, among young South Korean adults. METHOD: A total of 1,000 young adults aged 18-35 answered an online survey questionnaire measuring distress caused by negative life events, coping strategies, rumination, and embitterment. To examine the mediating associations of coping and rumination with embitterment, we tested path analysis models separately. RESULTS: Distress was both directly and indirectly related to embitterment (mediated by maladaptive strategies of dysfunctional coping and intrusive rumination; total association ß = .54, p < .001). The estimated indirect association of distress via maladaptive strategy with embitterment was 0.45, accounting for 82.4% of the total association of distress on embitterment. The ratio of indirect association via maladaptive strategy to direct association was 4.64. The results of this study have implications for better clinical understanding and treatment of embitterment. CONCLUSIONS: The association between dysfunctional strategies and embitterment severity suggests that clinicians should attenuate potential aggravating factors, including dysfunctional coping and intrusive rumination. Given that a combination of dysfunctional coping approaches increased the risk of reactive embitterment fourfold, these variables can be regarded as important for the development of preventive service programs for people at risk of embitterment. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Exposure to Negative Life Events and Post-Traumatic Embitterment Symptoms in Young Adults in Korea: Cumulative and Differential Effects.

BACKGROUND: Post-traumatic embitterment disorder (PTED) has recently been introduced as a subgroup of adjustment disorders related to stressful life events. Embitterment is defined as persistent feelings of inadequacy or hoping for revenge after being insulted but feeling helpless after experiencing a life stressor. This study aims to investigate the cumulative and differential effects of negative life events on the risk of developing embitterment among young adults in South Korea. METHODS: Data for the present study were collected from a web-based survey of 1,000 young adults aged 18-35 years. All participants completed a list of negative life events, the PTED Self-Rating Scale. Logistic regression analysis was conducted to evaluate the relationships between the number of negative life events and reactive embitterment. Analyses of the relationships between each negative life event and reactive embitterment were performed using covariates, including childhood trauma, depression, and anxiety symptoms. RESULTS: The total number of participants with reactive embitterment (cut-off scores > 2.5) was 452 (45.2%). Greater exposure to negative life events increased the risk of reactive embitterment compared to no negative events. Negative life events, including financial problems, family problems, and being excluded by friends, had significant associations with the risk of reactive embitterment. CONCLUSIONS: The present study revealed a substantial number of young adults with a high level of embitterment. Furthermore, cumulative and differential effects of negative events increased the risk for reactive embitterment. Our findings underlined the crucial role of adverse life events in the development of reactive embitterment.

Effects of core and veneer thicknesses on the color of CAD-CAM lithium disilicate ceramics.

STATEMENT OF PROBLEM: The color of dental ceramics is important for achieving successful esthetic restorations. However, insufficient studies are available of the color of recently introduced computer-aided design-computer-aided manufacturing (CAD-CAM) lithium disilicate ceramics as functions of the core and veneer thicknesses. PURPOSE: The purpose of this in vitro study was to evaluate the effects of the thickness of different core and veneer thicknesses on the color of CAD-CAM lithium disilicate ceramics. MATERIAL AND METHODS: A total of 42 specimens from 2 groups of 7 ceramic cores at 3 thicknesses (0.8, 1.0, and 1.2 mm) were fabricated. The veneer was fabricated at 3 thicknesses (0.3, 0.5, and 0.7 mm). The group name was based on the name of the ceramic core (IPS e.max CAD; lithium disilicate [LD], IPS Empress CAD; leucite-reinforced glass-ceramic [LR]), and the associated number was determined by the combined thicknesses of the core and the veneer: 1=0.8+0.7; 2=1.0+0.5; and 3=1.2+0.3. The color coordinates and the color differences were calculated using a spectrophotometer. The color difference was analyzed using the CIEDE2000 chrominance and the acceptability threshold. Two-way ANOVA was used to identify the color difference based on the core/veneer thicknesses, and the Tukey honest significant differences and Games-Howell tests were conducted to verify the ΔE00 differences of the group (α=.05). In addition, regression analysis was carried out to estimate the causal relationship between the independent variables and the chrominance. RESULTS: At a certain thickness, the color differences of LD1, LR1, and LR2 were not clinically acceptable based on the thicknesses of the core and the veneer. Results of 2-way ANOVA demonstrated that the different thicknesses of core/veneer combination significantly affected the color difference (P<.05). A significant interaction was present between the thickness and the material (P<.05). The results of multiple regression analyses showed that the average color difference of LR increased by 0.019 as the thickness of the core decreased by 0.2 mm. CONCLUSIONS: The color is influenced by the thicknesses of the core and the veneer. With a certain thickness, the color differences increased as the thickness of the core decreased, and lithium disilicate ceramics were less vulnerable to standard deviation of color difference compared with the leucite-reinforced ceramics.

Evaluation of accuracy and repeatability using CBCT and a dental scanner by means of 3D software.

OBJECTIVE: The objective of the present study was to compare and evaluate the accuracy of three-dimensional (3D) image data acquired from cone beam computed tomography (CBCT) and a dental scanner using 3D software. MATERIALS AND METHODS: After selecting the full-arch forms of the maxilla and mandible as the master cast, the master cast was scanned via a high-precision optical scanner for use as master model data. The model was scanned 12 times each using CBCT and a dental scanner. Scanned data were superimposed onto the master cast data for evaluation of accuracy and repeatability. RESULTS: Although significant differences in both accuracy and repeatability were seen between CBCT and dental scanner (P < 0.05), repeatability of the maxillary arch showed little difference, with CBCT and scanner having values of 17 ± 2 µm and 22 ± 5 µm, respectively. Meanwhile, repeatability of the mandibular arch with CBCT and scanner was 15 ± 0 µm and 19 ± 3 µm, respectively. Since good repeatability was shown, this demonstrated that data can be stably acquired. CONCLUSIONS: The present study demonstrated the feasibility of using a dental scanner to create a digital model as a substitute for a plaster model for use in orthodontic diagnosis and device fabrication.

Peripheral target identification performance modulates eye movements.

We often shift our eyes to an interesting stimulus, but it is important to inhibit that eye movement in some environments (e.g., a no-look pass in basketball). Here, we investigated participants' ability to inhibit eye movements when they had to process a peripheral target with a requirement to maintain strict fixation. An array of eight letters composed of four characters was briefly presented and a directional cue was centrally presented to indicate the target location. The stimulus onset asynchrony (SOA) between the cue and the stimulus array was chosen from six values, consisting of pre-cue conditions (-400 and -200ms), a simultaneous cue condition (0ms), and post-cue conditions (200, 400, and 800ms). We found the following: 1) participants shifted their eyes toward the cued location even though the stimulus array was absent at the onset of eye movements, but the eye movement amplitude was smaller than the actual location of the target; 2) eye movements occurred approximately 150ms after the onset of stimulus array in the pre-cue conditions and 250ms after cue onset in the simultaneous and post-cue conditions; and 3) eye movement onsets were delayed and their amplitudes were smaller in correct trials than incorrect trials. These results indicate that the inhibitory process controlling eye movements also compete for cognitive resources like other cognitive processes.

Trueness of milled prostheses according to number of ball-end mill burs.

STATEMENT OF PROBLEM: Making a computer-aided design/computer-aided manufacturing (CAD/CAM) prosthesis with a milling machine often requires 2 (2- and 1-mm diameter) or 3 (2-, 1-, and 0.6-mm diameter) burs; however, using 3 burs can reduce time effectiveness and increase cost. Studies evaluating the trueness of prostheses made with 2 and 3 burs are lacking. PURPOSE: The purpose of this in vitro study was to evaluate the 3-dimensional trueness of crown prostheses made using 2 and 3 ball-end mill burs in the milling process. MATERIAL AND METHODS: The abutment die of the maxillary right first molar for ceramic crowns was designed with computer-aided design software. After the crown prosthesis design was completed, polyurethane blocks were milled using 2 and 3 burs with a 5-axis milling machine. The outer and inner surfaces of the milled crown prostheses were scanned with a dental scanner. The inner part was separated into a marginal part and an internal part using 3-dimensional evaluation software. The 3-dimensional trueness of the prostheses milled with 2 or 3 burs was compared. RESULTS: No significant differences in trueness were found for the inner or internal parts of the prosthesis (P>.05). However, the outer and marginal parts of the prosthesis did show significant differences in trueness (P<.05). CONCLUSIONS: Milling the marginal part of the inner prosthesis was better with 2 burs, whereas milling the outer part was better with 3 burs.

Digitization of dental alginate impression: Three-dimensional evaluation of point cloud.

The purpose of this study was to evaluate the digitization of alginate impressions by analyzing differences between the scan data of two types of impressions (alginate and rubber) taken from the master die and the scan data for the master die. The master die and impressions were digitized using a dental laser scanner (7 series, Dental Wings, Montreal, Canada). The crown portion of the abutment teeth in the digital data of 20 impressions was divided into three regions: cervical surface, middle surface, and occlusal surface. An independent t-test showed a significant difference (p<0.05) in the mean difference for each experimental group (alginate and rubber). One-way ANOVA and Tukey's honest significant difference test revealed a significant difference (p<0.05) among the three regions in the rubber impression. The results of this study also carefully suggest the possibility of digitization of alginate impressions in the future.

Development and validation of a highly sensitive LC-MS/MS method for quantification of IC87114 in mice plasma, bronchoalveolar lavage and lung samples: Application to pharmacokinetic study.

IC87114 is a selective PI3Kδ inhibitor. A simple, sensitive and reliable LC-MS/MS method with rapid sample preparation was developed and validated for the determination of IC87114 in mouse plasma, bronchoalveolar lavage, and lung. Chromatographic separation was achieved using an Agilent Zorbax Eclipse XDB-C18 column (150mm×2.1mm internal diameter, 3.5µm particle size). Mass spectrometric detection was conducted by electrospray ionization in positive ion multiple reaction monitoring modes. The calibration curve was linear over a concentration range of 0.01-1000ng/mL for plasma/BAL and 0.1-250ng/mL for lung tissue. Recoveries were as high as 97.29%, 102.81% and 89.70% for plasma, BAL fluid and lung sample, respectively. The lower limit of quantification was 0.01ng/mL. Intra-day and inter-day accuracy and precision were within the acceptable limits of ±15% at all concentrations. Finally, the method was successfully used in a pharmacokinetic study that measured IC87114 in mouse plasma, BAL fluid and lung tissue after administration of a single 1mg/kg intratracheal dose of IC87114. The percentage change for incurred sample reanalysis (ISR) was within ±15.0% and met the acceptance criteria for ISR.

Determination of phenylbutyric acid and its metabolite phenylacetic acid in different tissues of mouse by liquid chromatography with tandem mass spectrometry and its application in drug tissue distribution.

Endoplasmic reticulum (ER) stress is associated with various human diseases. Phenylbutyric acid (PBA) is a well-known chemical chaperone that regulates ER stress. The main objective of this study was to develop a simple, rapid, and sensitive method for the simultaneous determination of phenylbutyric acid and its metabolite, phenylacetic acid (PAA). A LC-MS/MS analysis using negative electrospray ionization was used. Samples were analyzed by multiple reaction monitoring (MRM) in 15 min of total run time, using d11-PBA and d7-PAA as internal standards. The limit of quantification was 1 µg/g for tissue and 0.8 µg/mL for plasma. Recoveries for plasma and tissues were higher than 81% for both PBA and PAA. The inter-day and intra-day accuracy and precision were within ±15%. We then further successfully validated this method by applying it to determine the tissue distribution of PBA and its metabolite PAA after i.p. injection of PBA at a dose of 500 mg/kg in mice. The maximum concentrations of PBA and PAA in plasma and tissues were seen at 15 min and 45 min, respectively. The PBA plasma concentration was 15-fold higher than the concentration in the kidney, whereas the PAA plasma concentration was 6-fold higher than the concentration in the liver. The area under the curve decreased in the order of plasma > kidney > liver > heart > muscle > lung for PBA and plasma > liver > kidney > heart > muscle > lung for PAA. The tissue to plasma ratio ranged from 0.007 to 0.063 for PBA and 0.016 to 0.109 for PAA. In summary, the LC-ESI-MS method developed in this study is simple, sensitive and reliable.

The comparative analysis of serum proteomes for the discovery of biomarkers for acute myeloid leukemia.

OBJECTIVE: Acute myeloid leukemia (AML) develops as the consequence of a series of genetic changes in a hematopoietic precursor cell. However, the definitive diagnostic protein biomarkers for AML are still unclear. In our study to identify the biomarkers for an initial diagnosis, detection of relapse, and monitoring the minimal residual disease in AML by a less invasive method, serum proteins reflecting alterations in their proteomes were analyzed. MATERIALS AND METHODS: We compared the two-dimensional electrophoresis patterns of human sera of 12 patients with AML with those of 12 normal subjects. The differentially expressed spots were identified by matrix-assisted laser desorption/ionization time-of-flight and electrospray ionization quadupole time-of-flight mass spectrometries. RESULTS: Eight proteins that expressed differentially in the AML group were found. The expression levels of alpha-2-HS-glycoprotein, complement-associated protein SP-40, 40, RBP4 gene product, lipoprotein C-III, and an unknown protein were downregulated in serum of AML patients, whereas the other three proteins, including immunoglobulin heavy-chain variant, proteosome 26S ATPase subunit 1, and haptoglobin-1 were upregulated. CONCLUSION: These results suggest that these proteins can be used as less invasive diagnostic and monitoring biomarkers of AML if further studies are done.