Acetylsalicylic Acid Suppresses Alcoholism-Induced Cognitive Impairment Associated with Atorvastatin Intake by Targeting Cerebral miRNA155 and NLRP3: In Vivo, and In Silico Study

Alcoholism is one of the most common diseases that can lead to the development of several chronic diseases including steatosis, and cognitive dysfunction. Statins are lipid-lowering drugs that are commonly prescribed for patients with fatty liver diseases; however, the exact effect of statins on cognitive function is still not fully understood. In the present study, we have investigated the molecular and microscopic basis of cognitive impairment induced by alcohol and/or Atorvastatin (ATOR) administration to male Wistar albino rats and explored the possible protective effect of acetylsalicylic acid (ASA). The biochemical analysis indicated that either alcohol or ATOR or together in combination produced a significant increase in the nucleotide-binding domain–like receptor 3 (NLRP3), interleukin-1β (IL-1β) miRNA155 expression levels in the frontal cortex of the brain tissue. The histological and morphometric analysis showed signs of degeneration in the neurons and the glial cells with aggregations of inflammatory cells and a decrease in the mean thickness of the frontal cortex. Immunohistochemical analysis showed a significant increase in the caspase-8 immunoreaction in the neurons and glial cells of the frontal cortex. Interestingly, administration of ASA reversed the deleterious effect of the alcohol and ATOR intake and improved the cognitive function as indicated by biochemical and histological analysis. ASA significantly decreased the expression levels of miRNA155, NLRP3, and IL1B, and produced a significant decrease in caspase-8 immunoreaction in the neurons and glial cells of the frontal cortex with a reduction in the process of neuroinflammation and neuronal damage. To further investigate these findings, we have performed an extensive molecular docking study to investigate the binding affinity of ASA to the binding pockets of the NLRP3 protein. Our results indicated that ASA has high binding scores toward the active sites of the NLRP3 NACHT domain with the ability to bind to the NLRP3 pockets by a set of hydrophilic and hydrophobic interactions. Taken together, the present study highlights the protective pharmacological effect of ASA to attenuate the deleterious effect of alcohol intake and long term ATOR therapy on the cognitive function via targeting miRNA155 and NLRP3 proteins

Mortality from gastrointestinal congenital anomalies at 264 hospitals in 74 low-income, middle-income, and high-income countries: a multicentre, international, prospective cohort study

Summary Background Congenital anomalies are the fifth leading cause of mortality in children younger than 5 years globally. Many gastrointestinal congenital anomalies are fatal without timely access to neonatal surgical care, but few studies have been done on these conditions in low-income and middle-income countries (LMICs). We compared outcomes of the seven most common gastrointestinal congenital anomalies in low-income, middle-income, and high-income countries globally, and identified factors associated with mortality. Methods We did a multicentre, international prospective cohort study of patients younger than 16 years, presenting to hospital for the first time with oesophageal atresia, congenital diaphragmatic hernia, intestinal atresia, gastroschisis, exomphalos, anorectal malformation, and Hirschsprung’s disease. Recruitment was of consecutive patients for a minimum of 1 month between October, 2018, and April, 2019. We collected data on patient demographics, clinical status, interventions, and outcomes using the REDCap platform. Patients were followed up for 30 days after primary intervention, or 30 days after admission if they did not receive an intervention. The primary outcome was all-cause, in-hospital mortality for all conditions combined and each condition individually, stratified by country income status. We did a complete case analysis. Findings We included 3849 patients with 3975 study conditions (560 with oesophageal atresia, 448 with congenital diaphragmatic hernia, 681 with intestinal atresia, 453 with gastroschisis, 325 with exomphalos, 991 with anorectal malformation, and 517 with Hirschsprung’s disease) from 264 hospitals (89 in high-income countries, 166 in middleincome countries, and nine in low-income countries) in 74 countries. Of the 3849 patients, 2231 (58·0%) were male. Median gestational age at birth was 38 weeks (IQR 36–39) and median bodyweight at presentation was 2·8 kg (2·3–3·3). Mortality among all patients was 37 (39·8%) of 93 in low-income countries, 583 (20·4%) of 2860 in middle-income countries, and 50 (5·6%) of 896 in high-income countries (p<0·0001 between all country income groups). Gastroschisis had the greatest difference in mortality between country income strata (nine [90·0%] of ten in lowincome countries, 97 [31·9%] of 304 in middle-income countries, and two [1·4%] of 139 in high-income countries; p≤0·0001 between all country income groups). Factors significantly associated with higher mortality for all patients combined included country income status (low-income vs high-income countries, risk ratio 2·78 [95% CI 1·88–4·11], p<0·0001; middle-income vs high-income countries, 2·11 [1·59–2·79], p<0·0001), sepsis at presentation (1·20 [1·04–1·40], p=0·016), higher American Society of Anesthesiologists (ASA) score at primary intervention (ASA 4–5 vs ASA 1–2, 1·82 [1·40–2·35], p<0·0001; ASA 3 vs ASA 1–2, 1·58, [1·30–1·92], p<0·0001]), surgical safety checklist not used (1·39 [1·02–1·90], p=0·035), and ventilation or parenteral nutrition unavailable when needed (ventilation 1·96, [1·41–2·71], p=0·0001; parenteral nutrition 1·35, [1·05–1·74], p=0·018). Administration of parenteral nutrition (0·61, [0·47–0·79], p=0·0002) and use of a peripherally inserted central catheter (0·65 [0·50–0·86], p=0·0024) or percutaneous central line (0·69 [0·48–1·00], p=0·049) were associated with lower mortality. Interpretation Unacceptable differences in mortality exist for gastrointestinal congenital anomalies between lowincome, middle-income, and high-income countries. Improving access to quality neonatal surgical care in LMICs will be vital to achieve Sustainable Development Goal 3.2 of ending preventable deaths in neonates and children younger than 5 years by 2030

The Effect of Using Two Teaching Models of Constructivism on the Motivation Towards Learning Science

This study aimed at investigating the effect of using two teaching models of constructivism on the motivation towards learning science. The sample of the study consisted of 211 male and female students from grade 8. They were distributed into three groups: The first experimental group which was taught by using a Bybee Model and consisted of 71 students, the second group consisted of 70 students and it was taught by adopting Zahorik model, while the third group (the control group) consisted of 71 students and it was taught by adopting the traditional method of teaching. The researchers used a 35- item questionnaire to measure student motivation toward learning science. Findings of the study indicated that there were statistically significant differences on all dimensions of the overall measure of motivation due to the impact of the teaching model, and came to favor the two experimental groups compared to the traditional group. And to favor first group which was taught by Bybee model compared to the group which was taught by Zahorik model. There were also statistically significant differences on the overall measure of motivation, due to the effect of gender; the differences were in favor of females.

GSTM1, GSTT1 and EPHX1 gene polymorphisms and susceptibility to COPD in a sample of Egyptian population

Background: Gene polymorphisms and COPD susceptibility have been paid special attention and were explored in a large number of studies. The results varied between studies and populations. We aimed to analyze the relation between susceptibility to COPD and polymorphisms of Glutathione S-transferases (GST); GSTM1, GSTT1 and Microsomal epoxide hydrolase-1 (EPHX1) genes in a sample of Egyptian population. Methods: Genetic polymorphisms of GSTM1, GSTT1 and EPHX1 genes in 146 COPD patients and 130 controls were investigated using multiplex PCR for GSTM1 and GSTT1 genes and PCR-RFLP for EPHX1 genes. Results: The frequency of GSTM1-null genotype was higher in patients than in controls (72.6% versus 43.8%, P < 0.001). Carriers with both null GSTT1 and GSTM1 genes were at a higher risk of COPD (OR 3.45, 95% CI = 1.07–11.14). The frequency of EPHX1 exon 3 His allele was higher in patients than controls (19.2% versus 12.7%, P = 0.04). Carriers with exon 3 His allele were at a higher risk of COPD (OR 1.63, 95% CI = 1.02–2.6, P = 0.04). Carriers with both GSTM1-null and EPHX1 113Tyr/Tyr or EPHX1 113Tyr/His genotypes were at a higher risk of COPD (OR 3.33, 95% CI = 1.32–8.35 and OR 14.24, 95% CI = 3.02–67.17 respectively). Carriers with both GSTM1-null and EPHX1 139His/His genotypes were at a higher risk of COPD (OR 5.58, 95% CI = 2.14–14.52). Conclusions: EPHX1 exon 3 His allele in addition to the coexistence of other genetic variants, were significant risk factors in susceptibility to COPD in the Egyptian population