The Influence of Prenatal Exposure to Methamphetamine on the Development of Dopaminergic Neurons in the Ventral Midbrain.

Methamphetamine, a highly addictive central nervous system (CNS) stimulant, is used worldwide as an anorexiant and attention enhancer. Methamphetamine use during pregnancy, even at therapeutic doses, may harm fetal development. Here, we examined whether exposure to methamphetamine affects the morphogenesis and diversity of ventral midbrain dopaminergic neurons (VMDNs). The effects of methamphetamine on morphogenesis, viability, the release of mediator chemicals (such as ATP), and the expression of genes involved in neurogenesis were evaluated using VMDNs isolated from the embryos of timed-mated mice on embryonic day 12.5. We demonstrated that methamphetamine (10 µM; equivalent to its therapeutic dose) did not affect the viability and morphogenesis of VMDNs, but it reduced the ATP release negligibly. It significantly downregulated Lmx1a, En1, Pitx3, Th, Chl1, Dat, and Drd1 but did not affect Nurr1 or Bdnf expression. Our results illustrate that methamphetamine could impair VMDN differentiation by altering the expression of important neurogenesis-related genes. Overall, this study suggests that methamphetamine use may impair VMDNs in the fetus if taken during pregnancy. Therefore, it is essential to exercise strict caution for its use in expectant mothers.

Evaluation of efficacy of non-resorbable membranes compared to resorbable membranes in patients undergoing guided bone regeneration.

Background: Replacement of missing teeth in patients with prolonged edentulism poses a challenge for clinicians. An extended period of edentulism results in severe atrophy of alveolar ridges rendering them unsatisfactory for rehabilitation using an implant-supported prosthesis. To overcome this difficulty, Guided Bone Regeneration (GBR) was introduced and constructed upon the principles of Guided Tissue Regeneration (GTR) procedures. Evidence suggests that GBR has proven to be a predictable treatment modality for treating vertical and horizontal ridge deficiencies. Objective: The present systematic review aimed to evaluate the efficacy of non-resorbable (N-RES) membranes compared to resorbable (RES) membranes in patients undergoing GBR. Methods: An electronic search of three databases, including PubMed, Web of Science, and Scopus, was conducted for articles published until March 2022. A supplementary manual search of references from these articles was performed to include any articles that may have been overlooked in the electronic search. Articles that evaluated the efficacy of RES membranes and N-RES membranes in GBR were included. Case reports, case series, commentaries, letters to the editor, narrative or systematic reviews were excluded. Articles in languages other than English were also excluded. The articles were assessed against risk of bias 2 tool for Randomized Control Trials (RCTs) and ROBINS-I tool for Non-Randomized Clinical Trials (N-RCTs). The Grading of Recommendations Assessment, Development and Evaluation (GRADE) assessment was followed based on the Cochrane Handbook for quality assessment. A summary of findings table was used to present the results. Results: One hundred and fifty one articles were identified in an electronic search. Eight articles met the inclusion criteria and were included in the present systematic review. The studies were conducted on partially or completely edentulous patients with alveolar ridge deficiencies undergoing vertical or horizontal bone for subsequent implant placement. The majority of the studies reported similar results for bone gain in both RES and N-RES membrane groups. Conclusion: The available evidence suggests that RES and N-RES membranes are equally effective in GBR. However, the evidence must be interpreted with caution due to its 'low quality' GRADE assessment. Clinical implications: Further research focusing on human clinical trials with well-matched subjects with homogeneity in the type and method of GBR and method of assessment of new bone formation will derive conclusive results on the efficacy of RES and N-RES membranes in achieving new bone formation.

Apigenin protects from hepatorenal damage caused by lead acetate in rats.

Exposure to lead (Pb) is associated with serious health problems including hepatorenal toxicity. Apigenin is a natural-sourced flavonoid with promising antioxidant and anti-inflammatory effects. In this research, we investigated the potential protective role of apigenin against lead acetate (PbAc)-induced hepatorenal damage. Thus, this experiment studied the exposure of male Wistar Albino rats to apigenin and/or PbAc and their effects in comparison to the control rats. Apigenin administration decreased the levels of Pb and prevented the histopathological deformations in liver and kidney tissues following PbAc exposure. This was confirmed by the normalized levels of liver and kidney function markers. Additionally, apigenin inhibited significantly oxidative reactions through upregulating Nrf2 and HO-1, and activating their downstreamed antioxidants accompanied by a marked depletion of pro-oxidants. Moreover, apigenin decreased the elevated pro-inflammatory cytokines and inhibited cell loss in liver and kidney tissues in response to PbAc intoxication in both tissues. The obtained results demonstrated that apigenin could be used to attenuate the molecular, biochemical, and histological alterations associated with Pb exposure due to its potent antioxidant, anti-inflammatory, and antiapoptotic effects.

Survival, mortality, and related comorbidities among COVID-19 patients in Saudi Arabia: A hospital-based retrospective cohort study.

OBJECTIVES: To assess the survival of COVID-19 patients in Saudi Arabia and to investigate possible mortality predictors. METHODS: This is a retrospective cohort study involving 248 patients with severe acute respiratory syndrome coronavirus-2 who were admitted to the primary COVID-19 referral hospital in Jeddah between March and June of 2020. Socio-demographic characteristics, comorbidities, laboratory investigations, management protocols, complications, treatment options, and mortality data were extracted from electronic medical records. The time analysis began at the first signs of illness thorough discharge or death. RESULTS: Our study showed that in-hospital complications including heart failure followed by acute renal failure had the largest effect size on mortality (p<0.001). Elderly patients and those with comorbid asthma had a higher risk of death. Non-survivors presented more commonly with shortness of breath and fever than survivors. High D-Dimer level was a marginally significant indicator of mortality in the studied population (p=0.05). We did not find a significant benefit in relation to any treatment option. CONCLUSION: Age, asthma, some in-hospital complications are important survival indicators in hospitalized COVID-19 patients. The controllable co-factors should be monitored and managed by healthcare workers to reduce mortality rates in those hospitalized with COVID-19.

Role of Toothbrushes as Gene Expression Profiling Tool for Oral Cancer Screening in Tobacco and Alcohol Users.

AIM: The use of toothbrushes was investigated as a potential RNA source and gene expression profiling tool for oral cancer screening in tobacco and alcohol users. METHODOLOGY: A total of 20 subjects were selected on the basis of inclusion and exclusion criteria. They were divided into two groups: group I-healthy controls (n = 6); group II-individuals who consume tobacco and alcohol (n = 14). After the volunteers brushed their teeth using a soft-bristle toothbrush with ~0.5 gm of toothpaste, the toothbrushes were collected, and the gene expression of BAX, BCL2, CDK4, CKDN2A, GNB3, and TCF7L2 was assessed. RESULTS: The gene expression of BAX decreased significantly in alcoholics and smokers (0.13867 ± 0.12014), while the gene expression of BCL2 increased in alcoholics and smokers (1.91001 ± 0.90425) in comparison with healthy controls (p = 0.0054 and p = 0.0055). Although there was increased expression of CDK4, CKDN2A, and TCF7L2 and decreased expression of GNB3 in smokers and alcoholics, the results were not significant. CONCLUSIONS: A toothbrush is a good source of RNA, and gene expression analysis can be performed using the genetic material retrieved from toothbrushes, which can aid in the early diagnosis of oral squamous cell carcinoma among tobacco and alcohol users. Further studies with a larger sample size and different durations of toothbrush use should be conducted to explore the role of toothbrushes as a noninvasive tool for disease diagnosis.

Myocarditis in Children: Impact of Early Presentation on Disease Outcomes at a Single Tertiary Center in Saudi Arabia.

Purpose: Myocarditis is the inflammation of the heart muscle and can be caused by a variety of infections, incendiary diseases, and pollutants. It is challenging for an emergency pediatrician to have a sufficiently high degree of suspicion for myocarditis to avoid diagnostic delay given the broad overlap of myocarditis symptoms with other disease processes. The study aimed to evaluate the impact of early presentation and diagnosis on the outcomes of acute myocarditis in children. Patients and Methods: We performed a retrospective analysis of the complete records of 80 pediatric patients diagnosed with acute myocarditis between 2015 and 2019 at a single tertiary center in Saudi Arabia. Patients were two weeks to 14 years of age and were admitted to the pediatric intensive care unit (PICU) for various sequelae of myocarditis. Data from routine clinical and laboratory investigations were collected. Results: The incidence of delayed presentation at the hospital after the onset of symptoms of myocarditis was 42.5%. A total of 22 (27.5%) patients expired during their hospital stay. There was marginally significant association of earlier presentation with in-hospital survival (80.4% vs 61.8%) and delayed presentation with higher proportion of in-hospital mortality (38.2% vs 19.6%, p=0.064). The rate of mechanical ventilator was also marginally significant in delayed presentation (p=0.068). Shock and multisystem organ failure were the significantly associated manifestations of delayed acute myocarditis presentations. Length of stay in PICU was also significant in delayed presentation group. The impact of presenting symptoms, ECG findings, and use of mechanical ventilator was not significantly associated with delayed presentation. Conclusion: An earlier presentation may have a substantial impact on overall prognosis and length of PICU stay and may lead to comparatively lesser frequency of mechanical ventilation use.

Assessing the therapeutic potential of agomelatine, ramelteon, and melatonin against SARS-CoV-2.

BACKGROUND: The SARS-Cov-2(severe acute respiratory syndrome coronavirus 2) infection affecting human populations worldwide is now a very concerning issue considering the morbidity and mortality rates. Despite several measures followed by the medical fraternity and general public, there is no resolution. Therapeutic measures to tackle the infection have been based on researching new designer drug molecules that could prevent viral entry into the human host. Melatonin has been tried as an adjuvant in the management of COVID 19(coronavirus disease) illness but its specific antiviral role has not been investigated. Objectives: The objectives of the present study were to conduct an in-silico analysis to investigate if melatonin and related drugs namely ramelteon and agomelatine could be used as antiviral agents in SARS-CoV-2 infection based on their binding to the SARS-CoV-2 receptor binding site (RBD) and Angiotensin-converting enzyme 2 (ACE 2). METHODS: For docking studies (Pdb Id 1M0J), the SARS-CoV-2 spike protein receptor-binding domain (RBD) crystal structure which was ACE2 cell receptor bounded was employed. From the PubChem database, the three-dimensional configuration of the ligands melatonin, ramelteon, and agomelatine was retrieved, and conceptual density functional theory (CDFT) was performed to determine molecular descriptors. Charges were added and optimized with the universal force field to prepare the ligands for the process of docking. For facilitation of readability by the AutoDock software conversion to PDBQT(Protein Data Bank, Partial Charge (Q), & Atom Type (T)) format was performed. AutoDock version 4.2.6 docking program and AutoDock Tools (ADT) version 1.5.6 were used for molecular docking. Desmond, a Package of Schrödinger LLC was used to simulate molecular dynamics for hundred nanoseconds using. RESULTS: Data from the present study reveal that melatonin, ramelteon, and agomelatine demonstrate significant binding with SARS-CoV-2 RBD and ACE 2 demonstrating the fact that they can strongly prevent viral entry into the host cells through dual binding effects. However, Ramelteon was found to be the most superior amongst the 3 drugs analyzed in its antiviral properties against SARS-CoV-2. CONCLUSION: Results advocate further research in exploring the potential therapeutic applications of melatonin, ramelteon, and agomelatine for the management of SARS-CoV-2 infection.

Use of a Mortality Prediction Model in Children on Mechanical Ventilation: A 5-Year Experience in a Tertiary University Hospital.

PURPOSE: Currently, several scoring systems for predicting mortality in severely ill children who require treatment in a pediatric intensive care unit (PICU) have been established. However, despite providing high-quality care, children might develop complications that can cause rapid deterioration in health status and can lead to death. Hence, this study aimed to establish a simple early predictive mortality (SEPM) model with high specificity in identifying severely ill children who would possibly benefit from extensive mechanical ventilation during PICU admission. PATIENTS AND METHODS: This is a retrospective longitudinal study that included pediatric patients aged older than two weeks who were on mechanical ventilation and were admitted to the PICU of King Fahd Hospital of the University from January 2015 to December 2019. RESULTS: In total, 400 pediatric patients were included in this study. The mortality rate of children on mechanical ventilation was 28.90%, and most deaths were associated with respiratory (n = 124 [31%]), cardiovascular (n = 76 [19%]), and neurological (n = 68 [17%]) causes. The SEPM model was reported to be effective in predicting mortality, with an accuracy, specificity, and sensitivity of 92.5%, 97.31%, and 66.15%, respectively. Moreover, the accuracy, specificity, and sensitivity of the Pediatric Risk of Mortality (PRISM) III score in predicting mortality was 95.25%, 98.51%, and 78.46%, respectively. CONCLUSION: The SEPM model had a high specificity for mortality prediction. In this model, only six clinical predictors were used, which might be easily obtained in the early period of PICU admission. The ability of the SEPM model and the PRISM III score in predicting mortality in severely ill children was comparable. However, the accuracy of the newly established model in other settings should be validated, and a prospective longitudinal study that considers the effect of the treatment on the model's predictive ability must be conducted.

Comparative study of visual dysfunctions in 6-10-year-old very preterm- and full-term-born children.

PURPOSE: To compare visual dysfunction between very preterm-born (VPB) children with no retinopathy of prematurity (no-ROP) at 6-10 years of age and age- and sex-matched full-term-born controls. METHODS: This is an observational, prospective study that included 30 children, 6-10 years of age, born ≤ 32 weeks of gestation, with no-ROP, and 30 age- and sex-matched full-term-born controls, conducted from January 2015 until August 2015. All children underwent complete ophthalmic evaluation. Main outcome measures include visual functions (best corrected visual acuity (BCVA), color vision, and stereoacuity), ocular alignment, refractive errors, and the presence of amblyopia and nystagmus. RESULTS: Mean BCVA of the right eyes was 0.04 ± 0.08 logMAR for VPB children and 0.02 ± 0.05 logMAR for the full-term children (P = 0.075). Mean BCVA for the left eyes was 0.07 ± 0.09 logMAR for VPB children and 0.02 ± 0.05 logMAR for the full-term children (P = 0.014). Refractive errors were slightly higher though not statistically significant in VPB children compared to full-term children (P = 0.125). The incidence of myopia and hypermetropia was 16.7 and 40%, respectively, in VPB children and 10 and 23.3%, respectively, in full-term children. Anisometropia found only in VPB children with an incidence of 16.7%. Amblyopia found in 10% of VPB children compared to 3.3% in full-term children. Strabismus was found equally in 10% of each group. CONCLUSION: VPB children with no-ROP are at an increased risk of developing decreased BCVA at least in one eye and anisometropia compared to age-matched full-term controls.

Prognostic significance of vascular endothelial growth factor in squamous cell carcinomas of the tonsil in relation to human papillomavirus status and epidermal growth factor receptor.

BACKGROUND: Angiogenesis markers, vascular endothelial growth factor (VEGF) and microvessel density (MVD) have been associated with prognosis in squamous cell carcinomas (SCCs) of the head and neck. Other prognostic variables such as human papillomavirus (HPV) and epidermal growth factor (EGFR) may also be involved in tumour angiogenesis. This study determined relationships between VEGF, MVD, EGFR, HPV, response to radiotherapy and clinical outcome in 85 tonsillar SCCs. METHODS: HPV status was determined by an HPV multiplex real-time polymerase chain reaction (PCR) assay/p16 immunohistochemistry. Expression of VEGF, CD31 (as marker of MVD) and EGFR was assessed by semiquantitative immunohistochemistry. RESULTS: Strong VEGF expressers were significantly more likely to have higher MVD than were weak expressers. There were no associations between VEGF or MVD and gender, patient age, TNM stage, EGFR expression or HPV status. Tumours with MVD of >15 per high-power field were significantly more likely to be poorly differentiated. There was a significant inverse relationship between EGFR and HPV status. HPV was a strong independent marker of loco-regional recurrence and death. VEGF and EGFR were risk factors for local recurrence and disease-specific death on univariate analysis but the associations weakened after adjustment for HPV. Among patients treated with radiotherapy, VEGF was associated with disease-specific death after adjusting for HPV and TMN stage. High-VEGF-expressing tumours positive for EGFR had a worse prognosis than all other groups combined after adjusting for HPV and TNM stage. CONCLUSIONS: HPV is a stronger prognostic marker than VEGF or EGFR in tonsillar SCCs. VEGF correlates with MVD in these tumours.

Can Doppler sonography be used to diagnose neonatal cerebral infarction caused by portal vein thrombosis.

Neonatal cerebral infarction is a serious and disabling condition. It is extremely rare if it occurs in association with portal vein thrombosis. We are reporting 2 cases of neonatal cerebral infarction with this etiology. The unique mechanism of cerebral infarction will be discussed. We propose that in the absence of any identifiable cause for the cerebral infarction, portal vein thrombosis should be considered and a Doppler sonography for the portal system is worth carrying out to confirm the diagnosis.