The impact of purine nucleosides on neuroplasticity in the adult brain.

Neuroplasticity refers to the nervous system's ability to adapt and reorganize its cell structures and neuronal networks in response to internal and external stimuli. In adults, this process involves neurogenesis, synaptogenesis, and synaptic and neurochemical plasticity. Several studies have reported the significant impact of the purinergic system on neuroplasticity modulation. And, there is considerable evidence supporting the role of purine nucleosides, such as adenosine, inosine, and guanosine, in this process. This review presents extensive research on how these nucleosides enhance the neuroplasticity of the adult central nervous system, particularly in response to damage. The mechanisms through which these nucleosides exert their effects involve complex interactions with various receptors and signaling pathways. Adenosine's influence on neurogenesis involves interactions with adenosine receptors, specifically A1R and A2AR. A1R activation appears to inhibit neuronal differentiation and promote astrogliogenesis, while A2AR activation supports neurogenesis, neuritogenesis, and synaptic plasticity. Inosine and guanosine positively impact cell proliferation, neurogenesis, and neuritogenesis. Inosine seems to modulate extracellular adenosine levels, and guanosine might act through interactions between purinergic and glutamatergic systems. Additionally, the review discusses the potential therapeutic implications of purinergic signaling in neurodegenerative and neuropsychiatric diseases, emphasizing the importance of these nucleosides in the neuroplasticity of brain function and recovery.

Effect of Prenatal Care on Perinatal Outcomes of Pregnant Women with Diabetes Mellitus: A Systematic Review.

Objective: to evaluate the effect of prenatal care (PC) on perinatal outcomes of pregnant women with diabetes mellitus (DM). Methods: systematic review developed according to Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) 2020 guidelines and conducted through the population, intervention, control, and outcomes (PICO) strategy. Clinical trials and observational studies were selected, with adult pregnant women, single-fetus pregnancy, diagnosis of DM, or gestational DM and who had received PC and/or nutritional therapy (NT). The search was carried out in PubMed, Scopus, and BIREME databases. The quality of the studies was evaluated using the tools of the National Heart, Lung and Blood Institute-National Institutes of Health (NHLBI-NIH). Results: We identified 5972 records, of which 15 (n=47 420 pregnant women) met the eligibility criteria. The most recurrent outcomes were glycemic control (14 studies; n=9096 participants), hypertensive disorders of pregnancy (2; n=39 282), prematurity (6; n=40 163), large for gestational age newborns (4; n=1556), fetal macrosomia (birth weight >4kg) (6; n=2980) and intensive care unit admission (4; n=2022). Conclusions: The findings suggest that PC interferes with the perinatal outcome, being able to reduce the risks of complications associated with this comorbidity through early intervention, especially when the NT is an integral part of this assistance.

Pattern of Dental Emergencies at a Pediatric Tertiary Care Hospital during the COVID-19 Pandemic: A Retrospective Study.

BACKGROUND: The onset of the COVID-19 pandemic and government restrictions affecting dental health care professionals had an impact on pediatric dental emergency trends. The purpose of this study was to describe the effect of the COVID-19 pandemic on the characteristics, outcomes and management of pediatric dental emergencies in a single tertiary care hospital. METHODS: A retrospective review of children presenting to Montreal Children's Hospital for dental emergencies before and during the pandemic was conducted. Data collected included children's demographic characteristics, type of emergency visit, clinical signs and symptoms, as well as emergency management. For the pandemic period, data regarding patient symptoms of COVID-19 infection were also noted. RESULTS: Of the 2745 pediatric dental emergencies included, 1336 (48.7%) occurred in 2019 and 1409 (51.3%) in 2020. During the first wave of COVID-19, the number of pediatric dental emergencies increased by 21% over pre-pandemic levels. A significant increase in the number of emergencies associated with dental infection was noted during the pandemic period (p = 0.04). A significant increase in the number of visits not receiving effective immediate treatment (p < 0.01) occurred during the early pandemic period. CONCLUSION: Our study shows a significant increase in the rates of dental emergencies and acuity of dental conditions during the first wave of the pandemic. Increased public health measures and adaptation to this ongoing public health crisis are important to ensure continued high-quality dental care for pediatric patients.

Does the Transversus Abdominis Plane Block Reduce Morbidity Following Iliac Crest Bone Harvest in Pediatric Patients With Alveolar Clefts?

OBJECTIVE: The purpose of this study is to determine whether a Transversus Abdominis Plane (TAP) block can reduce donor site morbidity among pediatric patients undergoing iliac crest bone grafting for repair of their alveolar cleft. DESIGN: This retrospective cohort study was carried out at the Division of Dentistry at the Montreal Children's Hospital. Medical charts of patients who underwent alveolar cleft bone grafting between January 2011 and January 2021 were reviewed and they were divided into two groups, intraoperative TAP block and intraoperative local anesthesia infiltration (control group). The outcomes measured were patients' post-operative pain at the donor site, in-hospital narcotics requirements and length of stay. RESULTS: A total of 66 patients were included. There were no significant differences in pain scale among the TAP group and control group [1.9 (SD 2.5) and 1.3 (SD 2.1), respectively (p = 0.23)]. The mean length of stay for both groups was 1 day. Interestingly, there was a significant higher proportion of patients who required in-hospital opioids (morphine) in the TAP block group when compared to the control group (p = 0.03). CONCLUSIONS: The results of our study suggest there may be no role for a TAP block in reducing pain and improving opioid stewardship.

Aetiologies of low alkaline phosphatase in a Canadian Paediatric Tertiary Care Centre.

Objectives: Increasingly, laboratories flag low serum alkaline phosphatase (sALP) that are age-and sex-specific in paediatrics. The aim of this study was to report clinical manifestations of paediatric patients with age-and sex-specific low sALP, thereby increasing awareness of its potential aetiologies. Methods: This retrospective Canadian tertiary care paediatric hospital study assessed all sALP of ambulatory patients aged less than 18 years from 2015 to 2017. The hospital used a Beckman Coulter AU assay to measure sALP and compared values to the Canadian age-and sex-specific reference intervals from CALIPER. All children who had at least one subnormal age-and sex-specific sALP were evaluated. A review of medical charts of included patients was performed and demographic characteristics, medical history and diagnosis were collected, and categorized under groups of medical disorders. Results: Of 11,874 included patients, 1,001 patients (9.2%) had low sALP. Of those, 48% (485/1,001) had transient low sALP activity and 9.6% (96/1,001) had persistently low sALP. Prolonged immobilization and inflammatory bowel disease represented the main aetiologies for persistently low sALP. Interestingly, 13.5% (13/96) of patients with persistently low sALP had no apparent aetiology. Conclusions: Our results report aetiologies of low sALP in a Canadian paediatric population using age-and sex-specific Canadian reference ranges. This study highlights that healthcare providers should be aware that a low sALP may have clinical significance and should be repeated if warranted based on further clinical assessment.

Hepatitis C screening, diagnosis, and cascade of care among people aged > 40 years in Brasilia, Brazil.

BACKGROUND: Identifying patients with hepatitis C virus (HCV) infection and enhancing the cascade of care are essential for eliminating HCV infection. This study aimed to estimate the prevalence of positive anti-HCV serology in Brasilia, Brazil, and evaluate the efficiency of the cascade of care for HCV-positive individuals. METHODS: This cross-sectional study analyzed 57,697 rapid screening tests for hepatitis C in individuals aged > 40 years between June 2018 and June 2019. HCV-positive patients were contacted and scheduled to undergo the HCV RNA viral test, genotyping, and transient elastography. RESULTS: The prevalence of positive serology was 0.27%. Among 161 patients with positive anti-HCV serology, 124 (77%) were contacted, 109 (67.7%) were tested for HCV RNA viral load, and 69 (42.8%) had positive results. Genotype 1 (75%) was the most prevalent genotype. Among 65 patients (94.2%) who underwent transient elastography, 30 (46.2%) presented with advanced fibrosis. Additionally, of the 161 patients, 55 (34.1%) were referred for treatment, but only 39 (24.2%) complied, with 36 (22.4%) showing sustained virological response. By the end of the study, 16 patients were still awaiting to receive medication. CONCLUSIONS: The prevalence of HCV-positive patients was low in Brasilia, and the gaps in the cascade of care for these patients were significantly below the targets of HCV infection elimination. This study opens new avenues for eliminating HCV infection and suggests that partnerships with clinical laboratories to conduct anti-HCV tests are a useful strategy to improve HCV diagnosis. TRIAL REGISTRATION: Research Ethics Committee of the Faculty of Health Sciences of the University of Brasília - UNB (CAAE number 77818317.2.0000.0030) and by the Ethics Committee of the Health Science Teaching and Research Foundation - FEPECS/SES/DF (CAAE number 77818317.2.3001.5553).

A 10-year retrospective study of paediatric emergency department visits for dental conditions in Montreal, Canada.

BACKGROUND: Trends of paediatric emergency visits (ED) for dental conditions have been broadly discussed; however, little has been published in the Canadian context. AIM: To describe the utilization of ED for dental conditions among children and to investigate demographic characteristics influencing its use. DESIGN: A comprehensive review of records of all children aged 1-17 years who attended the ED service of a paediatric hospital in Montreal, Canada, for dental conditions over a 10-year period (2004-2013) was completed. Information on the child's principal dental diagnosis, sociodemographic data, and source of referral was obtained. RESULTS: A total of 10 905 paediatric ED visits were seen during the study period. Among the children, 54.7% were male and the majority was younger than 6 years old. Dental caries constituted the most common reason for ED presentation comprising close to 43% of total visits for a dental complaint. Females, teenagers, and self-referred children were more likely to experience ED visits due to non-traumatic dental conditions. CONCLUSIONS: The utilization of ED for dental conditions has increased among pre-school children in the last decade and was mostly due to caries-related dental problems. Effective preventive strategies are needed to improve the oral health condition of children.

Dental malocclusion among children with attention deficit hyperactivity disorder.

INTRODUCTION: Children with attention deficit hyperactivity disorder (ADHD) have more sleep breathing problems and parafunctional oral habits than individuals without ADHD. However, there is scarce information on the correlation between their dental malocclusion and these functional disorders. The objective of this study was to assess the severity of malocclusion in patients with and without ADHD and to evaluate the correlation between their functional disorders and dental malocclusion. METHODS: Eighty-eight patients aged 6-17 years were divided into 2 groups: ADHD (n = 44) and control (n = 44). A medical questionnaire to assess functional disorders and an orthodontic examination to evaluate malocclusion were completed for each patient. Distribution of the data was evaluated using Shapiro-Wilk test, whereas the 2 groups were compared with a t test, Mann-Whitney U test, Fisher exact test, and Spearman correlation. The association between parafunctional oral habits, ADHD drug intake, and malocclusion severity were assessed with a t test and Mann-Whitney U test. RESULTS: Patients with ADHD had significantly higher severity of malocclusion (P = 0.042), more dental rotation (P = 0.021) and more parafunctional oral habits (P = 0.001), specifically bruxism (P = 0.005), and a history of pacifier use (P = 0.009), than the control group. CONCLUSIONS: It is important to be aware of the increased risk of parafunctional oral habits and dental malocclusion among ADHD patients to develop preventive programs, as well as therapeutic strategies for them.

Cerium catalyst promoted C-S cross-coupling: synthesis of thioethers, dapsone and RN-18 precursors.

In this work, we present a novel, efficient and green methodology for the synthesis of thioethers by the C-S cross-coupling reaction with the assistance of [Ce(l-Pro)2]2Ox as a heterogeneous catalyst in good to excellent yields. A scale-up of the protocol was explored using an unpublished methodology for the synthesis of a dapsone-precursor, which proved to be very effective over a short time. The catalyst [Ce(l-Pro)2]2Ox was recovered and it was shown to be effective for five more reaction cycles.

Prevalence of malocclusion in Canadian children with autism spectrum disorder.

INTRODUCTION: The purposes of this study were to determine the prevalence of malocclusion among children with autism spectrum disorder (ASD) and to describe the most common malocclusion traits in this population. METHODS: This cross-sectional study included patients diagnosed with ASD aged between 5 and 18 years. Randomly selected healthy children with the same demographic characteristics comprised the control group. Dental charts were reviewed to obtain the children's sociodemographic characteristics and type of occlusion. Information on each child's molar occlusion classification (Angle classification), midline deviation, crossbite, open bite, overbite, overjet, and crowding were recorded. The statistical analysis used descriptive analysis, the Pearson chi-square test, and multivariate logistic regression. RESULTS: Ninety-nine children comprised the ASD group, and 101 children were in the control group. Our results demonstrated a significantly higher prevalence of malocclusion in children with ASD compared with the control group (P <0.001). Patients with ASD were significantly more likely to have posterior crossbite (P = 0.03), increased overjet (P <0.0001), and severe maxillary crowding (P <0.01). Furthermore, children with ASD were more likely to have malocclusion than non-ASD children, independently of their demographic characteristics (odds ratio, 2.6; 95% confidence interval, 1.46, -4.65). CONCLUSIONS: The prevalence of malocclusion was higher among children with ASD. Posterior crossbite, increased overjet, and severe maxillary crowding were the most common malocclusion traits in these children.

Burden of asthma among inner-city children from Southern Brazil.

OBJECTIVE: To assess the impact of asthma in a population of inner-city Brazilian children. METHODS: In a cross-sectional study, we selected children with asthma and healthy controls from public schools (8-16 years) from a capital city of Southern Brazil. Divided into three phases, questionnaires were administered, assessing lung function, body mass index and allergic sensitization. RESULTS: From 2500 children initially included in the study (48.4% males; mean age of 11.42 ± 2.32 years), asthma prevalence was detected in 28.6% (715/2500). The disease was not controlled in 42.7% (305/715) of the children, with 7.6% of hospitalization rate. School absenteeism (at least one day of missing school because of asthma) and sedentary behavior were high (57.1 and 67.2%, respectively), with 47.9% of subjects requiring oral steroids in the previous year, and physical well-being significantly lower than controls, directly interfering with quality of life, and therefore in the daily activities of these students. Moreover, 38% of the parents admitted to being non-adherent to treatment with their children and 31.1 and 53.6%, respectively, believed that rescue medication and exercise might be harmful. CONCLUSIONS: The burden of asthma in Brazilian children seems to be substantial. New international guidelines with a special focus in developing countries settings, with more pragmatic approaches, should be a priority for discussion and implementation actions.

Association of onabotulinum toxin A treatment with salivary pH and dental caries of neurologically impaired children with sialorrhea.

BACKGROUND: Sialorrhea is a common manifestation of several neurological disorders. The use of intraglandular onabotulinum toxin A (OBTXA) injection has been recognized to effectively treat sialorrhea. As OBTXA injection reduces salivary flow rate and alters salivary quality, its use may have a detrimental effect on oral health. AIM: To examine the effect of OBTXA injection on caries experience and salivary pH of neurologically impaired children with sialorrhea. DESIGN: Twenty-five children receiving OBTXA treatment and 25 control children were enrolled in the study. Whole saliva was collected to determine salivary pH. All participants underwent an interview on their dietary habits. Dental clinical examinations were carried out to evaluate caries experience and oral hygiene level. RESULTS: Overall, mean salivary pH value was significantly lower in the OBTXA group (6.92 ± 0.77) compared with the control group (7.36 ± 0.70). Caries activity was significantly higher in the OBTXA group (P = 0.01). The regression analyses showed a significant association between OBTXA treatment and salivary pH value (P = 0.03). Results from the logistic regression show that dental caries was significantly associated with OBTXA treatment (OR = 1.73, CI = 1.14-27.3). CONCLUSIONS: The study showed an intricate relationship between OBTXA treatment and oral findings. Hence, special dental care should be given to children receiving OBTXA treatment.

Intracerebral hemorrhage after deep brain stimulation surgery guided with microelectrode recording: analysis of 297 procedures.

OBJECTIVES: Report the incidence of symptomatic and asymptomatic intracerebral hemorrhage (ICH) in patients submitted to deep brain stimulation (DBS) guided with microelectrode recording (MER) with further analysis of potential risk factors, both inherent to the patient and related to the pathology and surgical technique. METHODS: We performed a retrospective observational study. 297 DBS procedures were concluded in 277 patients in a single hospital centre between January 2010 and December 2020. All surgeries were guided with MER. We analysed the incidence of symptomatic and asymptomatic ICH and its correlation to age, sex, diagnosis, hypertension and perioperative hypertension, diabetes, dyslipidaemia, antiplatelet drugs, anatomic target, and number of MER trajectories. RESULTS: There were a total of 585 electrodes implanted in 277 patients. 16 ICH were observed, of which 6 were symptomatic and 10 asymptomatic, none of which incurred in permanent neurological deficit. The location of the hemorrhage varied between cortical and subcortical plans, always in relation with the trajectory or the final position of the electrode. The incidence of symptomatic ICH per lead-implantation was 1%, and the CT-scan demonstrated asymptomatic ICH in 1.7% more patients. Male patients or with hypertension are 2.7 and 2.2 times more likely to develop ICH, respectively. However, none of these characteristics has been shown to have a statistically significant association with the occurrence of ICH, as well as age, diagnosis, diabetes, dyslipidaemia, antiplatelet drugs, anatomic target, number of MER trajectories and perioperative hypertension. CONCLUSIONS: MER-guided DBS is a safe technique, with low incidence of ICH and no permanent deficits in our study. Hypertension and male sex seem to be risk factors for the development of ICH in this surgery. Nevertheless, no statistically significant factors were found for the occurrence of this complication.

Unveiling the hidden reserves: allocation strategies associated with underground organs of Cerrado legumes in fire-prone savannas.

The synthesis and differential allocation of reserve compounds is an important adaptive mechanism that enables species to resprout in fire-prone ecosystems. The analysis of compound allocation dynamics (differential accumulation of compounds between plant organs) provides insights into plant responses to disturbances. The aim was to quantify reserves in eight legume species from Cerrado open savannas with high fire frequency in order to investigate the patterns of allocation and distribution of compounds between leaves and underground organs, drawing ecophysiological inferences. The species were collected in 'campo sujo' areas of the Cerrado. Leaves and underground organs (xylopodium, taproot tubers) were subjected to physiological analyses. Overall, underground organs were characterised by greater deposits of carbohydrates, mainly soluble sugars, and also with the accumulation of proteins and amino acids. This suggests that nitrogen reserves, as well as carbohydrates, may have an ecophysiological function in response to fire, being allocated to the underground organs. Phenols were mainly evident in leaves, but a morphophysiological pattern was identified, where the two species with taproot tubers tended to concentrate more phenols in the underground portion compared to species with xylopodium, possibly due to functional differences between these organs. Such data allow inferring relevant ecophysiological dynamics in legumes from open savannas.

Mechanisms involved in the antidepressant-like action of orally administered 5-((4-methoxyphenyl)thio)benzo[c][1,2,5]thiadiazole (MTDZ) in male and female mice.

RATIONALE: The compound 5-((4-methoxyphenyl)thio)benzo[c][1,2,5]thiadiazole (MTDZ) has recently been shown to inhibit in vitro acetylcholinesterase activity, reduce cognitive damage, and improve neuropsychic behavior in mice, making it a promising molecule to treat depression. OBJECTIVES: This study investigated the antidepressant-like action of MTDZ in mice and its potential mechanisms of action. RESULTS: Molecular docking assays were performed and suggested a potential inhibition of monoamine oxidase A (MAO-A) by MTDZ. The toxicity study revealed that MTDZ displayed no signs of toxicity, changes in oxidative parameters, or alterations to biochemistry markers, even at a high dose of 300 mg/kg. In behavioral tests, MTDZ administration reduced immobility behavior during the forced swim test (FST) without adjusting the climbing parameter, suggesting it has an antidepressant effect. The antidepressant-like action of MTDZ was negated with the administration of 5-HT1A, 5-HT1A/1B, and 5-HT3 receptor antagonists, implying the involvement of serotonergic pathways. Moreover, the antidepressant-like action of MTDZ was linked to the NO system, as L-arginine pretreatment inhibited its activity. The ex vivo assays indicated that MTDZ normalized ATPase activity, potentially linking this behavior to its antidepressant-like action. MTDZ treatment restricted MAO-A activity in the cerebral cortices and hippocampi of mice, proposing a selective inhibition of MAO-A associated with the antidepressant-like effect of the compound. CONCLUSIONS: These findings suggest that MTDZ may serve as a promising antidepressant agent due to its selective inhibition of MAO-A and the involvement of serotonergic and NO pathways.

Mammography and breast ultrasound analysis in male and female transgender persons using long-term gender affirming hormone therapy: a cross-sectional study in Brazil.

AIM: There is not much information about breast health in transgender (transexual) persons given the historical stigma that this population suffers. This research aimed to describe breast imaging patterns in transgender (trans) women and men that had been using gender affirmation hormone treatment for at least 3 years. MATERIAL AND METHODS: In this observational, cross-sectional study, 67 transgender individuals (34 trans women and 33 trans men) had mammography and breast ultrasound performed. We also classified the findings by the American College of Radiology - Breast Imaging Reporting and Data System (ACR BI-RADS®). RESULTS: We found that there was a higher frequency of dense breasts in trans women (75.8%) and in trans men (66,6%) than expected for cisgender (cis) women. CONCLUSIONS: This study highlights the importance of a deeper understanding of the image patterns of transgender breasts because of hormonal effects that the gender transition entails so we can offer better health care and preventive services in the transgender (transexual) population.

The Antinociceptive Responses of MTDZ to Paclitaxel-Induced Peripheral Neuropathy and Acute Nociception in Mice: Behavioral, Pharmacological, and Biochemical Approaches.

The efficacy of 5-((4-methoxyphenyl)thio)benzo[c][1,2,5] thiodiazole (MTDZ) in mitigating paclitaxel (PTX)-induced peripheral neuropathy was investigated in male and female Swiss mice. The study examined the effects of MTDZ on various pathways, including transient receptor potential cation channel subfamily V member 1 (TRPV1), glutamatergic, nitrergic, guanylate cyclase (cGMP), serotonergic, and opioidergic. Mice received intraperitoneal PTX (2 mg/kg) or vehicle on days 1, 2, and 3, followed by oral MTDZ (1 mg/kg) or vehicle from days 3 to 14. Mechanical and thermal sensitivities were assessed using Von Frey and hot plate tests on days 8, 11, and 14. The open field test evaluated locomotion and exploration on day 12. On day 15, nitrite and nitrate (NOx) levels and Ca2+-ATPase activity in the cerebral cortex and spinal cord were measured after euthanizing the animals. MTDZ administration reversed the heightened mechanical and thermal sensitivities induced by PTX in male and female mice without affecting locomotion or exploration. MTDZ also modulated multiple pathways, including glutamatergic, NO/L-arginine/cGMP, serotonergic (5-HT1A/1B), opioid, and TRPV1 pathways. Additionally, MTDZ reduced NOx levels and modulated Ca2+-ATPase activity. In conclusion, MTDZ effectively alleviated PTX-induced peripheral neuropathy and demonstrated multi-targeted modulation of pain-related pathways. Its ability to modulate multiple pathways, reduce NOx levels, and modulate Ca2+-ATPase activity makes it a potential pharmacological candidate for peripheral neuropathy, acute nociceptive, and inflammatory conditions. Further research is needed to explore its therapeutic potential in these areas.

Mortality among over 6 million internal and international migrants in Brazil: a study using the 100 Million Brazilian Cohort.

Background: To understand if migrants living in poverty in low and middle-income countries (LMICs) have mortality advantages over the non-migrant population, we investigated mortality risk patterns among internal and international migrants in Brazil over their life course. Methods: We linked socio-economic and mortality data from 1st January 2011 to 31st December 2018 in the 100 Million Brazilian Cohort and calculated all-cause and cause-specific age-standardised mortality rates according to individuals' migration status for men and women. Using Cox regression models, we estimated the age- and sex-adjusted mortality hazard ratios (HR) for internal migrants (i.e., Brazilian-born individuals living in a different Brazilian state than their birth) compared to Brazilian-born non-migrants; and for international migrants (i.e., people born in another country) compared to Brazilian-born individuals. Findings: The study followed up 45,051,476 individuals, of whom 6,057,814 were internal migrants, and 277,230 were international migrants. Internal migrants had similar all-cause mortality compared to Brazilian non-migrants (aHR = 0.99, 95% CI = 0.98-0.99), marginally higher mortality for ischaemic heart diseases (aHR = 1.04, 95% CI = 1.03-1.05) and higher for stroke (aHR = 1.11, 95% CI = 1.09-1.13). Compared to Brazilian-born individuals, international migrants had 18% lower all-cause mortality (aHR = 0.82, 95% CI = 0.80-0.84), with up to 50% lower mortality from interpersonal violence among men (aHR = 0.50, 95% CI = 0.40-0.64), but higher mortality from avoidable causes related to maternal health (aHR = 2.17, 95% CI = 1.17-4.05). Interpretation: Although internal migrants had similar all-cause mortality, international migrants had lower all-cause mortality compared to non-migrants. Further investigations using intersectional approaches are warranted to understand the marked variations by migration status, age, and sex for specific causes of death, such as elevated maternal mortality and male lower interpersonal violence-related mortality among international migrants. Funding: The Wellcome Trust.

Subacute administration of cilostazol modulates PLC-γ/PKC-α/p38/NF-kB pathway and plays vascular protective effects through eNOS activation in early stages of atherosclerosis development.

AIMS: Hypercholesterolemia is an important risk factor for development of cardiovascular disturbances, such as atherosclerosis, and its treatment remains challenging in modern medicine. Cilostazol is a selective inhibitor of phosphodiesterase 3 clinically prescribed for intermittent claudication treatment. Due to its pleiotropic properties, such as lipid lowering, anti-inflammatory, and antioxidant effects, the therapeutic repurposing of cilostazol has become a strategic approach for atherosclerosis treatment. This study aimed to investigate the effects of subacute administration of cilostazol on the aortas of hypercholesterolemic rats, focusing on the signaling pathways involved in these actions. MAIN METHODS: A murine model of hypercholesterolemia was employed to mimic the early stages of atherosclerosis development. Vascular reactivity assays were performed on thoracic aorta rings to assess the vascular response, as well as the non-invasive blood pressure was evaluated by plethysmography method. Pro-inflammatory markers and malondialdehyde (MDA) levels were measured to investigate the anti-inflammatory and antioxidant effects of cilostazol. Western Blot analysis was performed in aortas homogenates to evaluate the role of cilostazol on PLC-γ/PKC-α/p38-MAPK/IκB-α/NF-кB and PKA/eNOS/PKG pathways. KEY FINDINGS: The hypercholesterolemic diet induced the production of pro-inflammatory mediators such as TNF-α, TXB2, VCAM, and worsened vascular function, marked by increased contractile response, decreased maximum relaxation, and elevated systolic and diastolic blood pressure. Cilostazol seems to counteract the deleterious effects promoted by hypercholesterolemic diet, showing important anti-inflammatory and vasculoprotective properties possibly through the inhibition of the PLC-γ/PKC-α/p38-MAPK/IκB-α/NF-кB pathway and activation of the PKA/eNOS/PKG pathway. SIGNIFICANCE: Cilostazol suppressed hypercholesterolemia-induced vascular dysfunction and inflammation. Our data suggest the potential repurposing of cilostazol as a pharmacological treatment for atherosclerosis.