Peroxynitrite-mediated inactivation of heme oxygenases

BACKGROUND: Endogenous nitric oxide (NO) and carbon monoxide (CO) are generated by nitric oxide synthase and heme oxygenase, respectively. Like NO, CO has been accepted as an important cellular signaling molecule in biological systems. An up-regulation in both gene and protein expression of heme oxygenase-1 (HO-1) under oxidative/nitrosative stress has been well documented, and the protective role of HO-1 and HO-2 against oxidative damage is proposed. However, data on the direct effect of reactive oxygen/nitrogen species (ROS/RNS) on HO function is incomplete. Using gas chromatography to quantify carbon monoxide (CO) formation from heme oxidation, we investigated the effects of peroxynitrite (ONOO(-)) on the in vitro catalytic activity of rat spleen (HO-1) and brain (HO-2) microsomal heme oxygenases. RESULTS: Exposure to ONOO(- )led to concentration-dependent but reversible decreases in the activity of microsomal rat spleen and brain HO activity. Spleen HO activity was 100-fold more sensitive to ONOO(-)-dependent inactivation compared to that of the brain, with IC(50 )values of 0.015 ± 0.005 mM and 1.25 ± 0.25 mM respectively. Inhibition of both rat spleen and brain microsomal HO activity was also observed with tetra-nitromethane, a tyrosine nitrating agent, as well as two NO donors, S-nitrosoglutathione (GSNO) and diethylamine NONOate (DEA-NONOate). However, no additive effect was found following the application of NO donors and ONOO(- )together. CONCLUSION: These results indicate that ONOO(- )may regulate HO-1 and HO-2 activities by mechanisms that involve different interactions with these proteins. It is suggested that while nitration of tyrosine residues and oxidation of sulfhydryl groups may be involved, consideration should be given to other facets of ONOO(- )chemistry. This inhibition of HO activity offers a mechanism for cross talk between the nitric oxide synthase and HO systems

Insurance claims in Uganda: A Critical Analysis of the Motor Vehicle Insurance (Third Party Risks) Act Cap 214

“Insurance is an ingenious modern game of chance in which the player is permitted to enjoy the comfortable conviction that he is beating the man who keeps the table” (Bierce, 1911)A total of 9,000 people lost their lives in road accidents in the last three years according to the recent Traffic Police reports while the 2017 Ministry of Works and Transport reported that at least 10 people die every day due to bodaboda-related accidents. Kiva (2018, p. 4). This is in addition to a big number of individuals who have suffered bodily injuries in road accidents and who are not usually tracked. Taking the case study of the Gaagaa bus accident which took place along Kiryandogo road, the government of Uganda compensated the families of the accident victims with shs.5,000,000/= (Five Million Uganda Shillings Only) and shs.3,000,000/= (Three Million Uganda Shillings only) for the relatives of deceased and injured victims respectively. Surprisingly, there is no indication that the motor vehicles involved in this accident were government-owned or uninsured as to entitle victims involved to compensation from the government. Besides, the amount compensated was above the statutory limit of shs.150,000/= (One Hundred and Fifty Thousand Uganda Shillings) inclusive of costs incidental to the judgment!!!The dilemma of third-party insurance compensation policy is embedded in the fact that there is a big number of victims who are not compensated as there are also many policyholders who have not benefited from the cover because they have not caused or been involved in an accident. This calls for a critical analysis of the insurance claims in Uganda in light of the Motor Vehicle Insurance (Third Party Risks) Act Cap 214 to address this injustice.This article presents the current legal framework for compensation against the insured. It analyses the challenges of insurers with the said legal framework. It recommends among others the amendment of S.39 of the Motor Vehicle Insurance (Third Party Risks) Act Cap 214 to establish a compensation policy that can benefit policyholders and to establish a Motor Insurance Information Centre which can facilitate the third-party suits against insurers. Keywords: Third-party, Insurance, Compensation, Indemnity. DOI: 10.7176/JLPG/110-04 Publication date:June 30th 202

A systematic review of experimental evidence for antiviral effects of ivermectin and an in silico analysis of ivermectin's possible mode of action against SARS-CoV-2

Viral infections remain a major cause of economic loss with an unmet need for novel therapeutic agents. Ivermectin is a putative antiviral compound; the proposed mechanism is the inhibition of nuclear translocation of viral proteins, facilitated by mammalian host importins, a necessary process for propagation of infections. We systematically reviewed the evidence for the applicability of ivermectin against viral infections including SARS-CoV-2 regarding efficacy, mechanisms and selective toxicity. The SARS-CoV-2 genome was mined to determine potential nuclear location signals for ivermectin and meta-analyses for in vivo studies included all comparators over time, dose range and viral replication in multiple organs. Ivermectin inhibited the replication of many viruses including those in Flaviviridae, Circoviridae and Coronaviridae families in vitro. Real and mock nuclear location signals were identified in SARS-CoV-2, a potential target for ivermectin and predicting a sequestration bait for importin β, stopping infected cells from reaching a virus-resistant state. While pharmacokinetic evaluations indicate that ivermectin could be toxic if applied based on in vitro studies, inhibition of viral replication in vivo was shown for Porcine circovirus in piglets and Suid herpesvirus in mice. Overall standardized mean differences; 95% confidence intervals for ivermectin versus controls were: -4.43 (-5.81, -3.04), P < 0.00001. Based on current results, the potential for repurposing ivermectin as an antiviral agent is promising. However, further work is needed to reconcile in vitro studies with clinical efficacy. Developing ivermectin as an additional antiviral agent should be pursued with an emphasis on pre-clinical trials in validated models of infection

Utilisation and evaluation of cooperative case-based teaching for integration of microbiology and pharmacology in veterinary education

Purpose: Integrating basic sciences with clinical disciplines while fostering clinical reasoning capabilities is difficult. We investigated the utilisation of diagnostic specimens and, a cooperative, case-based learning and teaching model to integrate principles of antimicrobial drug pharmacology and microbiology in the fifth year of a veterinary course. Methods: In small groups, students were assigned diagnostic specimens from which they isolated and identified clinically relevant microorganisms and then performed antimicrobial susceptibility tests based on a review of pharmacology, microbiology and pathophysiology. Results were recorded and analysed followed by a student-led integrative tutorial. Learning outcomes were assessed via individually written reports discussing the disease process, interpretation of diagnostic results and, recommendations and rationales for therapeutic interventions. Results: This approach yielded high quality student reports that conformed to antimicrobial prescription guidelines with consistently high summative assessment scores. Mean scores for the final report in this learning activity were: 82 ± 12%, 80 ± 12% and 80 ± 11% for 2015, 2016 and 2017 cohorts respectively; over the same time period, 98 ± 1% of students indicated that these learning activities facilitated the development of confidence, professional knowledge and skills. Discussion: This was a consistent approach for integrating principles of veterinary pharmacology and microbiology in clinical disciplines. These data illustrate the benefit of a systematic application of a cooperative, case-based learning and teaching model in integrating pre-clinical and clinical disciplines in a bachelor of veterinary science course

Maintaining normal blood pressure in a renovascular stenosis model of hypertension in adult Lewis rats: putative physiological modulation of the renin-angiotensin system

Prolonged unilateral renal artery stenosis using a Goldblatt Two-Kidney-One Clip (2K1C) technique is a validated scientific approach to inducing experimental hypertension in laboratory animals. This patho-physiological modulation is associated with the activation of the renin-angiotensin system with increased renin and angiotensin II release to initiate hypertension. This mode of experimental hypertension has been demonstrated for many rat strains including Sprague Dawley, Brown Norway and Wistar Kyoto but has not been fully characterized in syngeneic Lewis rats. The objective of this study was to develop and characterize a unilateral renal artery stenosis model of hypertension in adult male Lewis rats using a 2K1C method for hypertension studies in our laboratory. Thirty animals were randomly assigned to two groups to undergo sham or the 2K1C surgical procedure under isoflurane-induced anesthesia; approval was granted by our institutional animal ethics committee (A2404, n =15 per group). Hemodynamic parameters including heart rate; systolic and diastolic blood pressure were monitored weekly for 6 weeks, using a volume-pressure tail cuff and a CODA pressure computer. Plasma concentrations of critical biomarkers of the renin-angiotensin system were quantified using standard ELISA assays and renal histopathological changes were assessed microscopically. Unilateral renal arterial stenosis caused marked renal atrophy, glomerulosclerosis and interstitial fibrosis, but a compensatory renal hypertrophy was observed in contralateral kidneys. Interestingly, unilateral renal arterial stenosis failed to induce hypertension over the six week period. The resistance to develop hypertension in the 2K1C group was associated with a significant decrease in total plasma renin (P = 0.023), an increase in the ratio of plasma angiotensin (1-7) to total renin (P = 0.034) and a decrease in the ratio of angiotensin II to total renin (P = 0.013). There were no changes in plasma electrolytes, glucose, creatinine or urea. These data demonstrate that adult male Lewis rats may have physiologically modulated the activation of the renin-angiotensin system to maintain a homeostatic balance and resist hypertension following unilateral renal artery stenosis

Assessment of urban solid waste logistics systems: the case of Kampala, Uganda

Many cities, especially in developing countries, are facing challenges in the management of solid waste. The aim of the study was to develop effective logistics systems for solid waste management in urban areas of developing countries, with a specific focus on Kampala, Uganda. This thesis contains an assessment of the reverse logistics systems that enable effective recapturing of valuable products from urban solid waste. The study mapped the waste collection systems in Kampala using a geographic information system (GIS), i.e. ArcGIS software, and examined the existing models of waste collection to the final disposal destinations. It was found that food and yard wastes constitute 92.7 % of the waste that reaches landfills in Kampala. Recyclables and other special wastes constitute only 7.3 % of the total waste. The generation rate of solid wastes on average from poor areas, upscale wealthier areas, business centres and market areas was 582, 169, 105 and 90 tonnes/day respectively. The study optimised travel distances, number of vehicles and collection time, while maximising total waste collection for environmental sustainability. Results showed that, an increase from a 6-tonne truck to a 10-tonne one reduced the travel distance by 39 %, while an increase from a 10-tonne truck to an 18-tonne truck reduced the travel distance by 34 % considering the current 40 % waste collection. Suggestions regarding the best waste collection routes and a suitable vehicle fleet and capacity to be used by Kampala Capital City Authority (KCCA) have been provided in this study. The research study further developed an overview of reverse logistics at the Kiteezi landfill. The study analysed in detail the collection, re-processing, re-distribution and final markets of these products into a reversed supply chain network of products delivered to the landfill. Of the products at the Kiteezi landfill, 14 % was channelled into the reverse chain, 63 % could be included in the distribution chain but were left out and disposed of while the remaining 23 % was buried straightaway. The main conclusion of the work was that solid waste management in Kampala is characterised by inefficient collection methods, insufficient coverage of the collection system and improper disposal of municipal solid waste. The existing system pertaining to reverse logistics suffers from unfavourable economics and legislative, technical and operational constraints that affect the recycling rate in Kampala compared to developed countries. This study presented large-scale data that can be used to improve solid waste management in other cities in developing countries

Inclusive Higher Education and Employment: A Secondary Analysis of Program Components

Through secondary analyses of quantitative data obtained from the Transition and Postsecondary Programs for Students with Intellectual Disabilities (TPSID) National Coordinating Center database from the first cohort (2010-2015) of model demonstration sites in Florida, this study examined components of the postsecondary education programs for students with intellectual disabilities that are correlated with employment upon program exit. This study adds to the emergent knowledge base on inclusive higher education by identifying the programmatic components of the postsecondary education programs for students with intellectual disability most correlated with successful transition from college to employment. This information can be used to inform program development and refinement to foster employment upon exit, a worthy outcome that leads to greater quality of life. The academic access program component of inclusive coursework was found to have the strongest correlation with the post-school outcome of paid, competitive employment upon exit. This program component aligns with the established predictors of post-school success for students with disabilities (Mazzotti et al., 2016) and employment for people with intellectual disabilities (Southward & Kyzar, 2017). Areas of agreement are discussed as well as implications for a number of stakeholders

Testudines as sentinels for monitoring the dissemination of antibiotic resistance in marine environments: an integrative review

Dissemination of antibiotic resistance (AR) in marine environments is a global concern with a propensity to affect public health and many ecosystems worldwide. We evaluated the use of sea turtles as sentinel species for monitoring AR in marine environments. In this field, antibiotic resistant bacteria have been commonly identified by using standard culture and sensitivity tests, leading to an overrepresentation of specific, culturable bacterial classes in the available literature. AR was detected against all major antibiotic classes, but the highest cumulative global frequency of resistance in all represented geographical sites was against the beta-lactam class by a two-fold difference compared to all other antibiotics. Wastewater facilities and turtle rehabilitation centres were associated with higher incidences of multidrug-resistant bacteria (MDRB) accounting for an average of 58% and 49% of resistant isolates, respectively. Furthermore, a relatively similar prevalence of MDRB was seen in all studied locations. These data suggest that anthropogenically driven selection pressures for the development of AR in sea turtles and marine environments are relatively similar worldwide. There is a need, however, to establish direct demonstrable associations between AR in sea turtles in their respective marine environments with wastewater facilities and other anthropogenic activities worldwide

Towards a sanitation selection algorithm for enhancing decentralized service delivery

In Uganda, sanitation coverage is estimated at 53% and 39% for urban and rural areas respectively. The national coverage is 41%. Lack of proper sanitation potentially leads to environmental health problems, which in many cases cost lives and impact on health of a community and family income as more money is spent on medication. This leads to a vicious circle of poverty. The objective of this study was to collect information on the current practices in selection of sanitation arrangements and use it to develop a simple algorithm for use by decision makers and district staff to advise households on selection of appropriate sanitation systems. Currently, there is no streamlined criterion used. People select systems based on what they are used to. Consequently, traditional pit latrines are the commonest sanitation system used. These toilet systems however, are disadvantageous due to: difficult soils (rocky, collapsing formations and areas with high water table); when full, require that new pits are dug, which is expensive and in the dense settlements this is inhibited by lack of space for new pits. As a starting point, we have proposed a simple algorithm that can be used by decentralized districts to give guidance to households in the selection of sanitation systems. The principle of the sanitation ladder, where people choose from the whole range of options, and select systems based on site conditions, affordability as well as user acceptance and perceptions applies. At the next phase, we intend to carry out detailed consultations to get specific information on user preferences, develop costs for all categories and package the information in an easy to use document for awareness creation, advocacy and promotion of sanitation

Are interactions between epicardial adipose tissue, cardiac fibroblasts and cardiac myocytes instrumental in atrial fibrosis and atrial fibrillation?

Atrial fibrillation is very common among the elderly and/or obese. While myocardial fibrosis is associated with atrial fibrillation, the exact mechanisms within atrial myocytes and surrounding non-myocytes are not fully understood. This review considers the potential roles of myocardial fibroblasts and myofibroblasts in fibrosis and modulating myocyte electrophysiology through electrotonic interactions. Coupling with (myo)fibroblasts in vitro and in silico prolonged myocyte action potential duration and caused resting depolarization; an optogenetic study has verified in vivo that fibroblasts depolarized when coupled myocytes produced action potentials. This review also introduces another non-myocyte which may modulate both myocardial (myo)fibroblasts and myocytes: epicardial adipose tissue. Epicardial adipocytes are in intimate contact with myocytes and (myo)fibroblasts and may infiltrate the myocardium. Adipocytes secrete numerous adipokines which modulate (myo)fibroblast and myocyte physiology. These adipokines are protective in healthy hearts, preventing inflammation and fibrosis. However, adipokines secreted from adipocytes may switch to pro-inflammatory and pro-fibrotic, associated with reactive oxygen species generation. Pro-fibrotic adipokines stimulate myofibroblast differentiation, causing pronounced fibrosis in the epicardial adipose tissue and the myocardium. Adipose tissue also influences myocyte electrophysiology, via the adipokines and/or through electrotonic interactions. Deeper understanding of the interactions between myocytes and non-myocytes is important to understand and manage atrial fibrillation