Serum brain natriuretic peptide (BNP) and N-terminal brain natriuretic peptide (NT-proBNP) in heart valve disease

Serum levels of natriuretic peptides (BNP and NT- proBNP) are known to increase in cardiac failure, and aid in the diagnosis and management of such patients. BNP and NT-proBNP also increase in patients with heart valve lesions, and may contribute to the assessment and management of these patients. There appears to be a general trend towards higher BNP values in more severe heart valve lesions, but the exact implication of a raised BNP or NTproBNP appears to be different for each specific valve lesion. In aortic valve stenosis increased levels of BNP/NT-proBNP correlate with the degree of stenosis, symptoms and prognosis. In addition, the increased natriuretic peptide levels seem to reflect left ventricular dysfunction, as high levels predict poor long-term outcomes in conservatively treated patients as well as post-operative death and poor functional recovery in those who survive the valve replacement procedure. In mitral regurgitation natriuretic peptide levels correlate with the degree of valvular regurgitation, and seem to reflect subclinical left ventricular dysfunction. Serum natriuretic peptide levels are elevated in patients with mitral stenosis, and correlate with the degree of valvular stenosis and increased pulmonary pressure. Serum levels of natriuretic peptides are elevated in other heart valve lesions, such as aortic valve regurgitation, as well as different forms of mixed valvular disease, but very little is known about the relationship between the serum levels of natriuretic peptides and the latter valve lesions. The practical application of our knowledge concerning serum natriuretic peptides and heart valve disease is limited at this stage, and no specific cut-off values to guide patient management have been incorporated into any official guidelines as yet. This review aims to summarise current knowledge on serum BNP and NT–proBNP levels in patients with heart valve disease. The impact of this information on current clinical decision making in patients with different heart valve lesions, as well as evolving concepts concerning its potential future use, will be discussed

Turnover-Dependent Covalent Inactivation of Staphylococcus aureus Coenzyme A-Disulfide Reductase by Coenzyme A-Mimetics: Mechanistic and Structural Insights

Disruption of the unusual thiol-based redox homeostasis mechanisms in Staphylococcus aureus represents a unique opportunity to identify new metabolic processes, and new targets for intervention. Targeting uncommon aspects of CoASH biosynthetic and redox functions in S. aureus, the antibiotic CJ-15,801 has recently been demonstrated to be an antimetabolite of the CoASH biosynthetic pathway in this organism; CoAS-mimetics containing α,β-unsaturated sulfone and carboxyl moieties have also been exploited as irreversible inhibitors of S. aureus coenzyme A-disulfide reductase (SaCoADR). In this work we have determined the crystal structures of three of these covalent SaCoADR-inhibitor complexes, prepared by inactivation of wild-type enzyme during turnover. The structures reveal the covalent linkage between the active-site Cys43-Sγ and Cβ of the vinyl sulfone or carboxyl moiety. The full occupancy of two inhibitor molecules per enzyme dimer, together with kinetic analyses of the wild-type/C43S heterodimer, indicates that half-sites-reactivity is not a factor during normal catalytic turnover. Further, we provide the structures of SaCoADR active-site mutants; in particular, Tyr419′-OH plays dramatic roles in directing intramolecular reduction of the Cys43-SSCoA redox center, in the redox asymmetry observed for the two FAD per dimer in NADPH titrations, and in catalysis. The two conformations observed for the Ser43 side chain in the C43S mutant structure lend support to a conformational switch for Cys43-Sγ during its catalytic Cys43-SSCoA/Cys43-SH redox cycle. Finally, the structures of the three inhibitor complexes provide a framework for design of more effective inhibitors with therapeutic potential against several major bacterial pathogens

Drug treatment of hypercholesterolaemia report on Logos University programme, 3-5 February 1995

[No abstract available]Articl

Thyroid hormone and the heart

Thyroid hormone has important cardiovascular effects, and abnormalities of its production cause cardiovascular morbidity. The role of both excessive and insufficient thyroid hormone production in the pathogenesis of clinical cardiac diseases can be deduced from thyroid hormone-induced molecular changes. Thyroid hormone regulates the expression of myocardial genes regulating the handling of calcium, which affects both systolic and diastolic myocardial function. Thyroid hormone also has indirect and direct effects on peripheral vascular smooth muscle tone, and alters the coupling of the left ventricle and arterial system. Excessive production of thyroid hormone results in an increased cardiac output as well as increased cardiac work efficiency, but reduced cardiac reserve. Amiodarone therapy for cardiac rhythm can cause both hyper- and hypothyroidism. Amiodarone-induced thyrotoxicosis (AIT) can be due to either excessive thyroid hormone production (type I AIT) or thyroid hormone release due to an inflammatory condition (type II AIT). Classification of AIT is helpful in guiding therapy. Amiodarone causes changes in the thyroid function tests of euthyroid patients on therapy - it inhibits the conversion of T4 to T3, which results in decreased T3 and slightly increased T4 serum levels in euthyroid patients. Baseline thyroid functions should therefore be determined before starting amiodarone therapy, and at 6-monthly intervals thereafter.Revie

Technical audit of rehabilitation works on unpaved rural access roads

Paper presented at the 24th Annual Southern African Transport Conference 11 - 13 July 2005 "Transport challenges for 2010", CSIR International Convention Centre, Pretoria, South Africa.This paper was transferred from the original CD ROM created for this conference. The material on the CD ROM was published using Adobe Acrobat technology. The original CD ROM was produced by Document Transformation Technologies Postal Address: PO Box 560 Irene 0062 South Africa. Tel.: +27 12 667 2074 Fax: +27 12 667 2766 E-mail: [email protected] URL: http://www.doctech.co.z

Aerodrome functions, challenges and opportunities within the north west aviation system

Individual aerodromes support different types of aviation functions and activities, and thereby contribute to the overall operational capacity and efficiency of the bigger aviation system. The functions of an aerodrome can include commercial air transport services (both scheduled and / or unscheduled services) and general aviation. General aviation is all civil aviation operations other than scheduled air services and non-scheduled air transport operations for remuneration or hire and include non-commercial business aviation, instructional flying, pleasure flying and aerial work. Aerodromes providing general aviation operations are faced with various challenges ranging from lack of funding for infrastructure maintenance, compliance to licensing conditions, contractual arrangements with the owner of the aerodrome (typically a municipality) and property issues. The North West Province is home to 13 licensed aerodromes and six registered aerodromes. Of these, four airports receive scheduled commercial services, with the remainder providing a general aviation function. The North West Department of Community Safety and Transport Management developed an Aviation Master Plan for the province during 2018. This plan considered the role played by each aerodrome within the provincial and regional aviation system. The plan also identified the typical challenges faced by aerodromes and opportunities for maintaining and growing the general aviation market. This paper presents a view on the functions of licensed and registered aerodromes in North West Province as part of a bigger aviation system and considers the main challenges and key opportunities for specifically the general aviation focused aerodromes in the province.Papers presented virtually at the 39th International Southern African Transport Conference on 05 -07 July 202

The role of β-adrenergic receptors in the cardioprotective effects of beta-preconditioning (βPC)

Aim To determine the mechanism whereby transient stimulation of the β-adrenergic receptor subtypes (β-AR) elicit cardioprotection against subsequent ischaemia. Methods Isolated rat hearts were subjected to 35 min regional ischaemia (RI) and reperfusion and infarct size (IS) determined. Hearts were preconditioned with 5 min isoproterenol (β1/β2-AR agonist), denopamine (β1-AR agonist), formoterol hemifumarate (β2-AR agonist) or BRL37344 (β3-AR agonist) and 5 min reperfusion. The roles of the β-ARs, NO, PKA, and PI3-K were explored by using selective antagonists/blockers. Pertussis toxin was administered i.p., 48 h prior to experimentation. Results IS of hearts preconditioned with either isoproterenol, denopamine or formoterol (% of area at risk: 23.6 ± 1.26; 24.52 ± 0.89; 20.74 ± 0.85 respectively) were significantly smaller than that of non-preconditioned hearts (41.7 ± 1.65) and associated with improvement in postischaemic mechanical performance. The β3-AR agonist BRL37344 could not reduce IS. The β1- and β2-AR blockers CGP-20712A and ICI-118551 abolished the reduction in IS and improvement in mechanical recovery during reperfusion induced by isoproterenol preconditioning, while the β3-AR blocker SR59230A was without effect. Both Rp-8-CPT-cAMPs and wortmannin significantly increased IS when administered before and during β1/β2-AR preconditioning and reduced mechanical recovery. PTX pretreatment had no significant effect on the reduction in IS induced by β1/β2-AR or β2-AR preconditioning, but reduced mechanical recovery in β2-AR preconditioning. Similarly the NOS inhibitors L-NAME and LNNA had no effect on IS in β1/β2-AR preconditioning, but depressed mechanical recovery. Conclusion Protection afforded by β-ARs stimulation, depends on activation of both β1-AR and β2-ARs but not β3-AR. With functional recovery as endpoint, results suggest involvement of NO in β1/β2-AR preconditioning and the Gi protein in β2-AR preconditioning. Both PKA and PI3-K activation were essential for β1/β2-AR cardio-protection. © Springer Science+Business Media, LLC 2010.Articl

Opioid receptor stimulation acts as mediator of protection in ischaemic preconditioning

Involvement of the opioid receptors in preconditioning-induced protection has recently been described. The aims of this study were to establish whether: (i) opioid receptor stimulation acts as a trigger (during the preconditioning protocol) or as a mediator (during sustained ischaemia) of cardioprotection using either morphine or [D-ala2, D-leu5] enkephalin (DADLE), a synthetic δ-opioid receptor agonist; (ii) the beneficial effects of DADLE are protein kinase C (PKC)-mediated; and (iii) inhibitory 'cross-talk' occurs between the β-adrenergic and phosphatidylinositol pathways activated by release of endogenous catecholamines and opioids respectively during sustained ischaemia. The isolated, perfused working rat heart, subjected to 25 minutes' global ischaemia and 30 minutes' reperfusion, was used as the experimental model. The results showed that δ-opioid receptor stimulation with DADLE (10-8 M), when administered for 3 × 5 minutes, had no effect, while when given 10 minutes before sustained ischaemia the drug significantly improved functional recovery during reperfusion. This indicates that opioid receptor stimulation acts as a mediator rather than a trigger in the protection elicited. Morphine (3 × 10-7) when administered in the same manner was without effect. Opioid receptor stimulation caused a marked reduction in the β-adrenergic response to isoproterenol, indicating inhibitory cross-talk between the phosphatidyl-inositol and β-adrenergic signal transduction pathways. However, reduction of the β-adrenergic response to ischaemia does not appear to be the mechanism of opioid-induced protection, as indicated by 3′,5′-cyclic adenosine monophosphate (cAMP) levels at the end of 25 minutes' global ischaemia. Opioid receptor-mediated protection against ischaemic damage is PKC-dependent, since DADLE-induced protection could be abolished by the inhibitor chelerythrine.Articl

Cyclosporin as a treatment for interstitial lung disease of unknown aetiology

Ten patients with progressive, symptomatic interstitial lung disease of unknown aetiology who were treated with cyclosporin A were reviewed. Five had clinical and histopathological features of cryptogenic fibrosing alveolitis and five a progressive restrictive lung disease characterised by interstitial infiltration with lymphocytes and minimal fibrosis, which could not be classified precisely. Three patients with lymphocytic infiltration showed a response to initial treatment with cyclosporin A alone at high dosage, but toxicity precluded further treatment. All 10 patients then received low doses of cyclosporin A and prednisone. Three of the patients with cryptogenic fibrosing alveolitis and all five patients with lymphocytic infiltration responded with a reduction in dyspnoea or an increase in vital capacity, or both; cyclosporin A appeared to be effective, or at least to have a corticosteroid potentiating effect. A high incidence of side effects occurred, though these do not necessarily prohibit the long term use of cyclosporin A when it is indicated clinically. Cyclosporin A may be effective in the treatment of interstitial lung disease of unknown aetiology. Further studies are required to determine the long term outcome of treatment.Articl

Ischaemic preconditioning does not protect hypertrophied myocardium against ischaemia

Objectives. Because ischaemic preconditioning elicits a potent endogenous protective mechanism against the development of myocardial infarction, it is important to explore its utilisation in clinical situations. The aim of this study was to examine whether the myocardium of rats with genetic hypertension could be protected by ischaemic preconditioning. Methods. Male New Zealand genetically hypertensive rats (GH-Wistar-derived) and normotensive Wistar controls (WAG-Wistar-derived), aged 12 months, were used. Isolated perfused hearts were preconditioned by 3 periods of 5 minutes' global ischaemia, interspersed with 5 minutes' reperfusion, and subsequently subjected to 25 minutes' global ischaemia, followed by 30 minutes' reperfusion. Results. Heart and body mass were significantly higher in GH rats. Although the heart/body mass ratios of GH rats were higher than those of WAG rats, the difference was not significant. The reperfusion coronary flow pattern during the preconditioning protocol differed markedly between the 2 groups. Only normotensive WAG hearts demonstrated protective effects of preconditioning on post-ischaemic function and tissue creatine phosphate content, while the GH hearts could not be preconditioned. Conclusions. An explanation for the failure of preconditioning in GH hearts is not yet available. The data caution against implementation of preconditioning in patients with angina pectoris and left ventricular hypertrophy.Articl