Uloga adrenalnih žlijezda u nastanku promjena u metabolizmu ugljikohidrata izazvanih diazinonom u štakora

Treatment of rats with diazinon (40 mg/kg, i.p.) resulted in hyper-glycaemia and depletion of glycogen from the brain and peripheral tissues two hours after administration. The activities of glycogen phosphorylase and phosphoglucomutase were significantly higher in the brain and liver; that of glucose-6-phosphatase was not altered. The activities of the glycolytic enzymes hexokinase and lactate dehydrogenase were increased only in the brain. The cholinesterase activity in the brain was reduced by treatment with diazinon. The activities of the hepatic gluconeogenic enzymes fructose I.6-diphosphatase and phosphoenolpyruvate carboxykinase were significantly increased. The lactate level was increased in the brain and blood, whereas that of pyruvate was not changed. The activity of glucose-6-phosphate dehydrogenase was not changed to any major extent. Cholesterol and ascorbic acid contents of adrenals were depleted in diazinon-treated animals. The changes were pronounced after intraperitoneal administration of 40 mg/kg diazinon, they were slight but significant after 20 mg/kg, and absent after l0 mg/kg. Hyperglycaemia and changes in carbohydrate metabolism were abolished by adrenalectomy suggesting possible involvement of adrenals.U štakora koji su dobivali diazinon (40 mg/kg) intraperitonealno dva sata nakon pnm1ene utvrđena je hiperglikemija i smanjenje nivoa glikogena u tkivima mozga i živaca. Aktivnosti glikogen fosforilaze i fosfoglukomutaze u mozgu i jetri bile su značajno više, dok se aktivnost glukoza-6-fosfataze nije promijenila. Glikolitski enzimi heksokinaza i laktat dehidrogenaza imali su povišenu aktivnost samo u mozgu. Tretman diazinonom doveo je do smanjene aktivnosti kolinesteraze u mozgu. Aktivnosti glukoneogenih enzima jetre fruktoza 1,6-difosfataze i fosfoenolpiruvatne karboksikinaze značajno su porasle. Nivo laktata bio je povišen u mozgu i krvi, dok je koncentracija piruvata ostala nepromijenjena. Aktivnost glukoza-6-fosfatne dehidrogenaze nije se bitno promijenila. Sadržaj kolesterola i askorbinske kiseline u nadbubrežnim žlijezdama bioje niži u životinja koje su primale diazinon, Promjene su bile najizraženije nakon doze od 40 mg kg diazinona, male ali značajne nakon doze od 20 mg/kg, a nije ih bilo nakon doze od 10 mg/kg. Hiperglikemija i promjene u metabolizmu ugljikohidrata bile su spriječene adrenalektomijom što ukazuje na moguću ulogu nadbubrežnih žlijezda u biokemijskim promjenama izazvanima diazinonom

GLP-1 receptor agonists for the reduction of atherosclerotic cardiovascular risk in patients with type 2 diabetes

Patients with type 2 diabetes are at high risk for development of cardiovascular disease, including myocardial infarction, stroke, heart failure, and cardiovascular death. Multiple large cardiovascular outcome trials with novel glucose-lowering agents, namely SGLT2i (SGLT2 inhibitors) and GLP-1 RA (GLP-1 receptor agonists), have demonstrated robust and significant reductions of major adverse cardiovascular events and additional cardiovascular outcomes, such as hospitalizations for heart failure. This evidence has changed the landscape for treatment of patients with type 2 diabetes. Both diabetes and cardiology guidelines and professional societies have responded to this paradigm shift by including strong recommendations to use SGLT2i and/or GLP-1 RA, with evidence-based benefits to reduce cardiovascular risk in high-risk individuals with type 2 diabetes, independent of the need for additional glucose control. GLP-1 RA were initially developed as glucose-lowering drugs because activation of the GLP-1 receptor by these agents leads to a reduction in blood glucose and an improvement in postprandial glucose metabolism. By stimulating GLP-1R in hypothalamic neurons, GLP-1 RA additionally induce satiety and lead to weight loss. Data from cardiovascular outcome trials demonstrated a robust and consistent reduction in atherothrombotic events, particularly in patients with established atherosclerotic cardiovascular disease. Despite the consistent evidence of atherosclerotic cardiovascular disease benefit from these trials, the number of patients receiving these drugs remains low. This overview summarizes the experimental and clinical evidence of cardiovascular risk reduction offered by GLP-1 RA, and provides practical information on how these drugs should be implemented in the treatment of type 2 diabetes in the cardiology community

Incidence of COVID-19 among returning travelers in quarantine facilities: A longitudinal study and lessons learned

This article is made available for unrestricted research re-use and secondary analysis in any form or be any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.Introduction: The emergence of the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) had resulted in an unpresented global pandemic. In the initial events, the Kingdom of Saudi Arabia implemented mandatory quarantine of returning travelers in order to contain COVID-19 cases. Materials and methods: This is a longitudinal study of the arriving travelers to Quarantine facilities and the prevalence of positive SARS-CoV-2 as detected by RT-PCR. Results: During the study period, there was a total of 1928 returning travelers with 1273 (66%) males. The age range was 28 days–69 years. Of all the travelers, 23 (1.2%) tested positive for SARS-CoV-2. Of the first swab, 14/1928 (0.7%) tested positive. The positivity rate was 0.63% and 0.92% among males and females, respectively (P = 0.57). The second swab was positive in 9 (0.5%) of the other 1914 who were initially negative with a positivity rate of 0.39% and 0.62% among males and females, respectively (P = 0.49). There was no statistical difference in the positivity rates between first and second swab (P = 0.4). Of all travelers, 40 (n = 26, 1.3%) were admitted from the quarantine facility to the hospital due to COVID-19 related positive results or development of symptoms such as fever, cough, and respiratory symptoms; and 14 (0.7%) were admitted due to non-COVID-19 related illness. Conclusion: This study showed the efforts put for facility quarantine and that such activity yielded a lower incidence of positive cases. There was a need to have a backup healthcare facility to accommodate those developing a medical need for evaluation and admission for non-COVID-19 related illnesses

WNT10B/β-catenin signalling induces HMGA2 and proliferation in metastatic triple-negative breast cancer

Wnt/β-catenin signalling has been suggested to be active in basal-like breast cancer. However, in highly aggressive metastatic triple-negative breast cancers (TNBC) the role of β-catenin and the underlying mechanism(s) for the aggressiveness of TNBC remain unknown. We illustrate that WNT10B induces transcriptionally active β-catenin in human TNBC and predicts survival-outcome of patients with both TNBC and basal-like tumours. We provide evidence that transgenic murine Wnt10b-driven tumours are devoid of ERα, PR and HER2 expression and can model human TNBC. Importantly, HMGA2 is specifically expressed during early stages of embryonic mammogenesis and absent when WNT10B expression is lost, suggesting a developmentally conserved mode of action. Mechanistically, ChIP analysis uncovered that WNT10B activates canonical β-catenin signalling leading to up-regulation of HMGA2. Treatment of mouse and human triple-negative tumour cells with two Wnt/β-catenin pathway modulators or siRNA to HMGA2 decreases HMGA2 levels and proliferation. We demonstrate that WNT10B has epistatic activity on HMGA2, which is necessary and sufficient for proliferation of TNBC cells. Furthermore, HMGA2 expression predicts relapse-free-survival and metastasis in TNBC patients

Saving and Empowering young lives in PAKistan (SEPAK): An Exploratory Cluster Randomized Controlled Trial (cRCT)

IntroductionSuicide is a leading cause of death among young people and most deaths by suicide occur in low and middle-income countries. School is the best place where we can identify and respond to youth suicide risk. School-based interventions for suicide prevention in young people have been successful across US, Europe and Australia, but require adaptations to be acceptable and feasible in Pakistan.ObjectivesTo develop and test culturally adapted preventative interventions for suicidal behaviours among pupils in secondary schools in Pakistan. The qualitative component aimed at exploring the views of students, parents, teachers and general practitioners on cultural adaptation, experience of participation, areas of improvement and suggestions for scale-up of the school-based suicide prevention program (SEPAK).MethodsA clustered randomised controlled trial. The four culturally modified interventions 1) Linking Education and Awareness of Depression and Suicide Awareness (LEADS) Training for pupils (students=260) 2) the Question, Persuade, and Refer (QPR) for teachers (students=203) 3) QPR for parents (students=445); 4) Screening by Professionals (Profscreen) (students=260) were compared against control intervention (educational posters) (students=227). Structured questionnaires were administered at baseline and 1-month post-intervention to assess suicidal behaviours, psychological well-being and quality of life. A total of 8 focus groups (FGs) were conducted at pre and post intervention stage with each stakeholders.ResultsPatient and public involvement and Engagement (PPIE) was strongly embedded in the project to ensure meaningful benefits for participants. A total of 40 schools were recruited from 8 cities across Pakistan. A total of 243 students attended LEADS intervention, 92 teachers and 304 parents completed QPR training, and 9 general practitioners were trained in ProfScreen. The retention rate at follow-up was 99% that shows feasibility of delivering intervention package in Pakistan. All participants marked SEPAK as effective in identifying risk of and preventing self-harm and suicide in young people and in improving pathways to treatment. Interventions were perceived as helpful in improving knowledge about mental health, impact of mental health difficulties on functioning, reducing stigma, equipping stakeholders to identify and signpost at-risk people. Improvement in clinical and teaching practice as well as understanding others behaviors were also reported.ConclusionsThis study suggest feasibility of integrating a suicide prevention program in existing educational system and highlights positive role of creating awareness about suicide in youth, introduction of school-based mental health programs, parental counseling and strengthening of the health system by training general practitioners in early identification of suicide risk and promoting suicide prevention strategiesDisclosure of InterestNone Declared</jats:sec

Surgical Standards for Management of the Axilla in Breast Cancer Clinical Trials with Pathological Complete Response Endpoint.

Advances in the surgical management of the axilla in patients treated with neoadjuvant chemotherapy, especially those with node positive disease at diagnosis, have led to changes in practice and more judicious use of axillary lymph node dissection that may minimize morbidity from surgery. However, there is still significant confusion about how to optimally manage the axilla, resulting in variation among practices. From the viewpoint of drug development, assessment of response to neoadjuvant chemotherapy remains paramount and appropriate assessment of residual disease-the primary endpoint of many drug therapy trials in the neoadjuvant setting-is critical. Therefore decreasing the variability, especially in a multicenter clinical trial setting, and establishing a minimum standard to ensure consistency in clinical trial data, without mandating axillary lymph node dissection, for all patients is necessary. The key elements which include proper staging and identification of nodal involvement at diagnosis, and appropriately targeted management of the axilla at the time of surgical resection are presented. The following protocols have been adopted as standard procedure by the I-SPY2 trial for management of axilla in patients with node positive disease, and present a framework for prospective clinical trials and practice

Erratum: Author Correction: Surgical Standards for Management of the Axilla in Breast Cancer Clinical Trials with Pathological Complete Response Endpoint.

[This corrects the article DOI: 10.1038/s41523-018-0074-6.]