Diabetes and the cardiac dysfunction caused by experimental sepsis

PhDSepsis is the leading cause of death in ICU patients. Patients with sepsis may develop sepsis-related cardiac dysfunction. The presence of this cardiac dysfunction can increase the mortality rate from 40% to 70%. Diabetes is a chronic disease that manifests as an elevation in blood glucose. Patients with diabetes are more susceptible to, and at increasing risk of developing, infections and subsequently sepsis. Activation of the NF-ĸB pathway plays a crucial role in the pathophysiology of sepsis-associated cardiac dysfunction and diabetic cardiomyopathy. The effect of diabetes on outcomes in patients with sepsis is highly controversial and it is still unclear whether pre-existing T2DM augments the cardiac dysfunction associated with sepsis and whether activation of NF-ĸB drives the cardiac dysfunction in T2DM/sepsis patients. In this thesis, I have first developed two models of high fat diet (HFD)-induced diabetes and diabetic cardiomyopathy in mice. Then, I developed two models of sepsis associated cardiac dysfunction using lipopolysaccharide (LPS) or caecumligation and puncture (CLP) in diabetic mice. I have demonstrated that mice with pre-existing T2DM exhibit a significantly greater cardiac (organ) dysfunction after challenge with either (low dose) LPS or mild CLP surgery. The exacerbated cardiac dysfunction was accompanied by an increase in NF-ĸB activation and reduction in Akt phosphorylation in the heart and an increase in the serum levels of proinflammatory cytokines. The increase in cardiac dysfunction, as well as the increase in the activation of NF-ĸB, caused by sepsis in animals with T2DM was largely attenuated by treatment with a selective IĸB kinase inhibitor (IKK-16) or a DPP-4 inhibitor (linagliptin). Thus, excessive activation of NF-ĸB in animals with diabetes/sepsis drives the observed excessive cardiac dysfunction, and that inhibition of NF-ĸB may be a useful target to treat the excessive inflammation and sepsis associated cardiac (organ) dysfunction in patients with T2DM and sepsis.Al-Balqa’ Applied University

Table1_Generic switching: Do future physicians in Jordan have enough knowledge and a positive attitude?.DOCX

Background: Generic switching is a policy that has shown success in minimising pharmaceutical costs. It has also been used to mitigate recurrent and sudden drug shortages. Not all countries have policies that allow pharmacists to switch to generic drugs independently. In Jordan, only pharmacists at Ministry of Health hospitals automatically switch to generics if doctors had not already done INN prescribing.Objectives: This study targeted medical students to assess their experience with generic switching as patients, their knowledge of the subject as students, and their attitude towards it as future prescribers and policymakers.Methods: This is a descriptive, cross-sectional study conducted online. Eligibility criteria were being a fourth, fifth, or sixth-year medical school student enrolled at any of the six Jordanian universities. The questionnaire was developed by the researchers after a careful review of the relevant literature.Results: Three hundred and ninety students responded to the online questionnaire. Most participants were females (244, 62.6%), senior students in their final (6th) year (162, 41.5%) and with very good academic achievement (166, 42.6%). The highest knowledge scores concerned patient rights (0.73/1.00), followed by knowledge about monitoring after generic switching (0.66/1.00), and patients with known drug allergies (0.66/1.00). Almost half of the participants believe that pharmacists should not be given the right to do generic switching and only 16% stated that they would choose generic drugs if they needed treatment in the future. Multivariate linear regression analysis showed that significant predictors of knowledge were gender, GPA, and family income. No correlations were found between participants’ knowledge scores and their attitudes towards giving pharmacists the right to independently switch drugs, or whether they would accept a substitute from pharmacists rather than having to refer to the physician.Conclusion: Medical students in Jordan lack sufficient knowledge about generic switching. Students need to be more aware of the current policies and regulations of this practice, and the role of each healthcare worker involved in it. They also need to have a more positive attitude toward generic drugs and generic switching practice to facilitate its future implementation.</p

SARS-CoV-2 and Coronavirus Disease Mitigation: Treatment Options, Vaccinations and Variants

COVID-19 is caused by a novel coronavirus (2019-nCoV), which was declared as a pandemic after it emerged in China 2019. A vast international effort has been conducted to prevent and treat COVID-19 due to its high transmissibility and severe morbidity and mortality rates, particularly in individuals with chronic co-morbidities. In addition, polymorphic variants increased the need for proper vaccination to overcome the infectivity of new variants that are emerging across the globe. Many treatment options have been proposed and more than 25 vaccines are in various stages of development; however, the infection peaks are oscillating periodically, which raises a significant question about the effectiveness of the prevention measures and the persistence of this pandemic disease. In this review, we are exploring the most recent knowledge and advances in the treatment and vaccination options as well as the new emerging variants of 2019-nCoV and the possible mitigation of one of the most aggressive pandemics in the last centuries

A Synthetic Peptide Designed to Neutralize Lipopolysaccharides Attenuates Metaflammation and Diet-Induced Metabolic Derangements in Mice

Metabolic endotoxemia has been suggested to play a role in the pathophysiology of metaflammation, insulin-resistance and ultimately type-2 diabetes mellitus (T2DM). The role of endogenous antimicrobial peptides (AMPs), such as the cathelicidin LL-37, in T2DM is unknown. We report here for the first time that patients with T2DM compared to healthy volunteers have elevated plasma levels of LL-37. In a reverse-translational approach, we have investigated the effects of the AMP, peptide 19-2.5, in a murine model of high-fat diet (HFD)-induced insulin-resistance, steatohepatitis and T2DM. HFD-fed mice for 12 weeks caused obesity, an impairment in glycemic regulations, hypercholesterolemia, microalbuminuria and steatohepatitis, all of which were attenuated by Peptide 19-2.5. The liver steatosis caused by feeding mice a HFD resulted in the activation of nuclear factor kappa light chain enhancer of activated B cells (NF-ĸB) (phosphorylation of inhibitor of kappa beta kinase (IKK)α/β, IκBα, translocation of p65 to the nucleus), expression of NF-ĸB-dependent protein inducible nitric oxide synthase (iNOS) and activation of the NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome, all of which were reduced by Peptide 19-2.5. Feeding mice, a HFD also resulted in an enhanced expression of the lipid scavenger receptor cluster of differentiation 36 (CD36) secondary to activation of extracellular signal-regulated kinases (ERK)1/2, both of which were abolished by Peptide 19-2.5. Taken together, these results demonstrate that the AMP, Peptide 19-2.5 reduces insulin-resistance, steatohepatitis and proteinuria. These effects are, at least in part, due to prevention of the expression of CD36 and may provide further evidence for a role of metabolic endotoxemia in the pathogenesis of metaflammation and ultimately T2DM. The observed increase in the levels of the endogenous AMP LL-37 in patients with T2DM may serve to limit the severity of the disease