Neutrophil Extracellular Traps in Cardiovascular and Aortic Disease: A Narrative Review on Molecular Mechanisms and Therapeutic Targeting.

Neutrophil extracellular traps (NETs), composed of DNA, histones, and antimicrobial proteins, are released by neutrophils in response to pathogens but are also recognized for their involvement in a range of pathological processes, including autoimmune diseases, cancer, and cardiovascular diseases. This review explores the intricate roles of NETs in different cardiovascular conditions such as thrombosis, atherosclerosis, myocardial infarction, COVID-19, and particularly in the pathogenesis of abdominal aortic aneurysms. We elucidate the mechanisms underlying NET formation and function, provide a foundational understanding of their biological significance, and highlight the contribution of NETs to inflammation, thrombosis, and tissue remodeling in vascular disease. Therapeutic strategies for preventing NET release are compared with approaches targeting components of formed NETs in cardiovascular disease. Current limitations and potential avenues for clinical translation of anti-NET treatments are discussed.

Synthesis of novel pyrimido[4,5-b]quinoline derivatives as dual EGFR/HER2 inhibitors as anticancer agents.

A series of novel N-aryl-5-aryl-6,7,8,9-tetrahydropyrimido[4,5-b]quinolin-4-amines 4a-4l was synthesized as potential anticancer agents through Dimroth rearrangement reaction of intermediates 3a-3c. Pyrimido[4,5-b]quinolines 4a-4l showed promising activity against the Michigan Cancer Foundation-7 (MCF-7) cell line, compared with lapatinib as the reference drug. Compounds 4d, 4h, 4i, and 4l demonstrated higher cytotoxic activity than lapatinib, with IC50 values of 2.67, 6.82, 4.31, and 1.62 µM, respectively. Compounds 4d, 4i, and 4l showed promising epidermal growth factor receptor (EGFR) inhibition with IC50 values of 0.065, 0.116, and 0.052 µM, respectively. These compounds were subjected to human epidermal growth factor receptor 2 (HER2) inhibition and showed IC50 values of 0.09, 0.164, and 0.055 µM, respectively. Compounds 4d, 4i, and 4l are good candidates as dual EGFR/HER2 inhibitors. The most active compound, 4l, was subjected to cell-cycle analysis and induced cell-cycle arrest at the S phase. Compound 4l induced apoptosis 60-fold compared with control untreated MCF-7 cells. 4l can inhibit cancer metastasis. It reduced MCF-7 cell infiltration and metastasis by 45% compared with control untreated cells.

Synthesis of novel pyrimido[4,5-b]quinolines as potential anticancer agents and HER2 inhibitors.

A series of N-arylpyrimido[4,5-b]quinolines 3a-e and 2-aryl-2,3-dihydropyrimido[4,5-b]quinoline-4(1H)-ones 5a-e was designed and synthesized as potential anticancer agents against breast cancer. Compounds 3e, 5a, 5b, 5d, and 5e showed promising activity against the MCF-7 cell line. Among them, compound 5b was the most active with IC50 of 1.67 µM. Compound 5b promoted apoptosis and induced cell cycle arrest at S phase. 5b increased the level of pro-apoptotic proteins p53, Bax, and caspase-7 and inhibited the anti-apoptotic protein Bcl-2. Furthermore, all the synthesized compounds were docked into the crystal structure of HER2 (PBD: 3 pp0). Compounds 3e, 5a, 5b, 5d, and 5e showed good energy scores and binding modes. Finally, Compound 5b was evaluated on the HER2 assay and revealed good inhibition with IC50 of 0.073 µM.

False-positive magnetic resonance imaging prostate cancer correlates and clinical implications.

Background: False-positive (FP) multiparametric magnetic resonance imaging (MPMRI) obscures and swift needless biopsies in men with a high prostate-specific antigen. Materials and Methods: This was a retrospective study, in which all patients who had been exposed to consecutive MP-MRI of the prostate combined with transrectal ultrasound-guided-magnetic resonance imaging fusion-guided prostate biopsy between 2017 and 2020 were involved in the study. The FP was measured as the number of biopsies that did not encompass prostate cancer divided by the whole number of biopsies. Results: The percentage of FP cases was 51.1%, the highest percentage was found in Prostate Imaging-Reporting and Data System (PI-RADs) 3 (37.7%) and the lowest was detected in PI-RAD 5 (14.5%). Those with FP biopsies are younger, and their total prostate antigen (PSA) and PSA density (PSAD) are significantly lesser. The area under the curve PSAD, age, and total PSA are 0.76, 0.74, and 0.69, respectively. An optimum PSAD value of 0.135 was chosen as a cutoff because it showed the highest sum of sensitivity and specificity, 68% and 69%, respectively. Conclusion: FP results of mpMRI were detected in more than half of our sample, more than one-third were presented in Pi-RAD3, improved imaging techniques to decrease FP rates are highly needed.

Translating mouse models of abdominal aortic aneurysm to the translational needs of vascular surgery.

INTRODUCTION: Abdominal aortic aneurysm (AAA) is a condition that has considerable socioeconomic impact and an eventual rupture is associated with high mortality and morbidity. Despite decades of research, surgical repair remains the treatment of choice and no medical therapy is currently available. Animal models and, in particular, murine models, of AAA are a vital tool for experimental in vivo research. However, each of the different models has individual limitations and provide only partial mimicry of human disease. This narrative review addresses the translational potential of the available mouse models, highlighting unanswered questions from a clinical perspective. It is based on a thorough presentation of the available literature and more than a decade of personal experience, with most of the available models in experimental and translational AAA research. RESULTS: From all the models published, only the four inducible models, namely the angiotensin II model (AngII), the porcine pancreatic elastase perfusion model (PPE), the external periadventitial elastase application (ePPE), and the CaCl2 model have been widely used by different independent research groups. Although the angiotensin II model provides features of dissection and aneurysm formation, the PPE model shows reliable features of human AAA, especially beyond day 7 after induction, but remains technically challenging. The translational value of ePPE as a model and the combination with ß-aminopropionitrile to induce rupture and intraluminal thrombus formation is promising, but warrants further mechanistic insights. Finally, the external CaCl2 application is known to produce inflammatory vascular wall thickening. Unmet translational research questions include the origin of AAA development, monitoring aneurysm growth, gender issues, and novel surgical therapies as well as novel nonsurgical therapies. CONCLUSION: New imaging techniques, experimental therapeutic alternatives, and endovascular treatment options provide a plethora of research topics to strengthen the individual features of currently available mouse models, creating the possibility of shedding new light on translational research questions.

Are proton pump inhibitors among the risk factors for acute coronary syndrome? A multi-centric case-control study between patients attending governmental hospitals in western Saudi Arabia.

OBJECTIVES: To identify the predictors of acute coronary syndrome (ACS) and to determine the relationship between usage of proton pump inhibitors (PPIs) and the occurrence of a first non-fatal ACS event among patients that attended governmental hospitals in Jeddah, Saudi Arabia. METHODS: A matched, multi-centric case-control study was performed between January and June of 2015 in Jeddah involving 2 governmental hospitals and the main university hospital. A total of 118 cases aged ≥18 years who were recently diagnosed with ACS were selected. For each case, one control matched by age and gender was selected. Information from an interview questionnaire and from reviewing patients' medical records was recorded on a standardized data collection sheet. RESULTS: Risk factors for ACS and the relationship between usage of PPIs and the occurrence of a first non-fatal ACS event were measured in 236 cases and matched controls. Current smoking (OR: 4.5; 95% CI: 1.92-10.98), excessive body weight (OR: 2.99; 95% CI: 1.38-6.45), and dyslipidemia (OR: 2.51; 95% CI: 1.07-5.84) were the predictors of ACS. Hypertension, diabetes, and moderate-to-high physical activity were associated with ACS. However, there was no statistical association between use of PPIs and occurrence of the first non-fatal ACS event (p greater than 0.05). CONCLUSIONS: There was no association between PPIs and the occurrence of a first non-fatal ACS event. Smoking, increased weight, and dyslipidemia are considered predictors of ACS. Furthermore, ACS is associated with self-reported diabetes, hypertension, and physical activity.

Neutrophil-Mediated Proteolysis of Thrombospondin-1 Promotes Platelet Adhesion and String Formation.

Thrombospondin-1 (TSP-1) is primarily expressed by platelets and endothelial cells (ECs) and rapidly released upon their activation. It functions in haemostasis as a bridging molecule in platelet aggregation, by promoting platelet adhesion to collagen and by protecting von Willebrand factor strings from degradation. In blood of patients undergoing surgery and in co-cultures of neutrophils with platelets or ECs, we observed proteolysis of the 185 kDa full-length TSP-1 to a 160-kDa isoform. We hypothesized that TSP-1 processing may alter its haemostatic properties. Selective enzyme inhibitors in co-cultures revealed that neutrophil proteases elastase and cathepsin G mediate TSP-1 processing. The cut site of cathepsin G was mapped to TSP-1 amino acids R237/T238 by Edman sequencing. Formation of neutrophil extracellular traps protected TSP-1 from complete degradation and promoted controlled processing to the 160-kDa isoform. Haemostatic properties were tested by platelet aggregation, adhesion, coagulation and string formation under flow. Platelets from TSP-1 deficient mice did not differ from wild-type in platelet aggregation but showed severe impairment of platelet adhesion to collagen and string formation under flow. Reconstitution experiments revealed that the 160-kDa TSP-1 isoform was markedly more potent than the 185-kDa full-length molecule in restoring function. Thus, TSP-1 processing by neutrophil proteases yields a 160-kDa isoform which shows enhanced potency to promote platelet adhesion and string formation. This finding reveals a novel mechanism of neutrophil-mediated thrombus formation and provides first evidence for the impact of TSP-1 proteolysis on its haemostatic properties.

Predictors and correlations of emotional intelligence among medical students at King Abdulaziz University, Jeddah.

OBJECTIVES: To determine the predictors of Emotional Intelligence (EI), and its relationship with academic performance, leadership capacity, self-efficacy and the perceived stress between medical students at King Abdulaziz University, Jeddah, Saudi Arabia. METHODS: A cross-sectional study was done among 540 students selected through a multi-stage stratified random sampling method during 2015/2016. A standardized, confidential data collection sheet was used. It included Schutte Self-Report Emotional Intelligence (SSREI) scale, Authentic Leadership questionnaire, General Self-Efficacy Scale and the short version of Perceived Stress Scale (PSS-4). Both descriptive and inferential statistics were done, and a multiple linear regression model was constructed. RESULTS: The predictors of high EI were gender (female), increasing age, and being non-smoker. EI was positively associated with better academic performance, leadership capacity and self-efficacy. It was negatively correlated to perceived-stress. CONCLUSION: Female gender, age, non-smoking were the predictors of high EI. Conduction of holistic training programs on EI, leadership and self-efficacy are recommended. More smoking control programs and stress management courses are required.

Dysmenorrhea among female medical students in King Abdulaziz University: Prevalence, Predictors and outcome.

OBJECTIVE: To determine the prevalence, predictors and outcome of dysmenorrhea among female medical students in King Abdulaziz University (KAU), Jeddah, Saudi Arabia. METHODS: A cross-sectional study was conducted among 435 medical students at KAU, Jeddah selected through stratified random sample method. A pre-constructed, validated, self-administered questionnaire was used to collect personal and socio-demographic information. Data about menstrual history, stress, smoking were also collected. The severity of dysmenorrhea was scored by the "Visual Analogue Scale (VAS)". Descriptive and analytical statistics were conducted. RESULTS: The prevalence of dysmenorrhea was 60.9%. Logistic regression showed that heavy period was the first predictor of dysmenorrhea (aOR=1.94; 95% CI: 1.29- 2.91), followed by stress (aOR=1.90; 95% C.I.: 1.19-3.07). The prevalence of severe dysmenorrhea among the sufferers was 38.6%. Depressed mood was the commonest (80.8%) symptom accompanying dysmenorrhea. Regarding the outcome of dysmenorrhea, 67.5% of the sufferes reported emotional instability, while 28.3% reported absenteeism from the university. CONCLUSIONS: A high prevalence of dysmenorrhea was prevalent among medical students in King Abdulaziz University (KAU), Health promotion, screening programs, and stress management courses are recommended.

Risk factors of coronary heart disease among medical students in King Abdulaziz University, Jeddah, Saudi Arabia.

BACKGROUND: Nowadays, Cardiovascular Diseases (CVDs) represents an escalating worldwide public health problem. Providing consistent data on the magnitude and risk factors of CVDs among young population will help in controlling the risks and avoiding their consequences. OBJECTIVE: The objective was to estimate the prevalence of risk factors of Coronary Heart Disease (CHD) among medical students during their clinical clerkship (4th - 6th years). METHODS: A cross-sectional study was done during the educational year 2012-2013 at King Abdulaziz University (KAU), Jeddah. Ethical standards were followed and a multistage stratified random sample method was used for selection of 214 medical students. Data was collected through an interviewing questionnaire, measurements and laboratory investigations. Both descriptive and analytical statistics were done by SPSS version 21. CHD risk percent in thirty years was calculated using Framingham algorithm for each student, then the risk among all students was determined. RESULTS: The commonest risk factors of CHDs were daily intake of high fat diet (73.4%), physical inactivity (57.9%), overweight/or obesity (31.2%) and daily consumption of fast food (13.1%). Hyper-cholesterolemia (17.2%) and hypertension (9.3%) were also prevalent risk factors. Smoking prevalence was low (2.8%). Males had significantly higher mean scores for most of CHD risk factors compared to females (p < 0.05). Systolic Blood pressure was higher among males (119.47 ± 11.17) compared to females (112.26 ± 9.06). A highly statistical significant difference was present (Students't test = 4.74, p < 0.001). Framingham Risk Score revealed that CHD risk percent in thirty-years among all students was 10.7%, 2.3% and 0.5% for mild, moderate and severe risk, respectively. CONCLUSION: An alarmingly high prevalence of CHD risk factors was prevailed among medical students, especially among males. However, a low prevalence of smoking may indicate the success of "Smoke-free Campus" program. Screening risk factors of CHD among medical students and implementation of intervention programs are recommended. Programs to raise awareness about CHD risk factors, encourage young adult students to adopt a healthy dietary behavior and promote physical exercise should be initiated.

An educational program about premarital screening for unmarried female students in King Abdul-Aziz University, Jeddah.

UNLABELLED: The present study was conducted to assess knowledge and attitude of unmarried female students in King Abdul-Aziz University (KAU) towards premarital screening (PMS) program, to determine predictors of high students' knowledge scores and to improve their knowledge about PMS through conduction of an educational campaign. Multi-stage stratified random sample method was used with recruitment of 1563 students from all faculties of KAU, during the educational year 2008-2009. The Pre-test included 30 knowledge items and 14 attitude statements with student's response through a 5-point Likert scale. Health education was conducted using audiovisual aids through pre-designed educational materials. Statistical analysis was done by SPSS version 16. RESULTS: Students' knowledge about the program was generally low before the educational campaign. The predictors of high knowledge scores were being a health science student (aOR=4.15; 95% CI: 2.97-5.81), age ≥20 years (aOR=2.78; 95% CI: 2.01-3.85), family history of hereditary diseases and income ≥10,000 SR/month. Regarding attitude, almost all students (99.0%) agreed on the importance of PMS. After the educational program, students' knowledge about PMS was markedly improved. The mean students' knowledge score was 9.85 ± 5.36 in Pre-test and improved to 18.45 ± 4.96 in Post-test, with a highly statistical significant difference (paired t=25.40, p<0.000). CONCLUSION AND RECOMMENDATIONS: The educational program was successful in improving students' knowledge about the PMS. Conduction of similar educational programs and adding PMS in the curriculum of secondary and university education are recommended.

Slow-release fluoride devices: a literature review

Although the prevalence of caries has decreased dramatically over the past decades, it has become a polarised disease, with most of subjects presenting low caries levels and few individuals accounting for most of the caries affected surfaces. Thus it become evident for the need of clinical approaches directed at these high-risk patients, in order to overcome problems related to compliance and low attendance at dental care centres. Slow-release fluoride devices were developed based on the inverse relationship existing between intra-oral fluoride levels and dental caries experience. The two main types of slow-release devices - copolymer membrane type and glass bead - are addressed in the present review. A substantial number of studies have demonstrated that these devices are effective in raising intra-oral F concentrations at levels able to reduce enamel solubility, resulting in a caries-protective effect. Studies in animals and humans demonstrated that the use of these devices was able to also protect the occlusal surfaces, not normally protected by conventional fluoride regimens. However, retention rates have been shown to be the main problem related to these devices and still requires further improvements. Although the results of these studies are very promising, further randomised clinical trials are needed in order to validate the use of these devices in clinical practice. The concept of continuously providing low levels of intra-oral fluoride has great potential for caries prevention in high caries-risk groups.