Forearm blood flow in individuals with CHF and age-matched healthy volunteers : a study and historical review

This study examined forearm blood flow (FBF) in individuals with chronic heart failure (CHF) at rest, moderate exercise, and following limb occlusion. FBF was measured by venous occlusion plethysmography in CHF patients (n = 43) and healthy age-matched volunteers (n = 8) at rest and during exercise consisting of intermittent isometric hand squeezing at 15, 30, and 45% of maximum voluntary contraction (MVC). Peak vasodilatory capacity was also determined following the release of an occluding arm cuff. FBF was lower in CHF patients during exercise and during peak reactive hyperemia (PRH) compared to healthy volunteers, but there was no significant difference between groups at rest. Peak vasodilatory capacity was significantly higher in healthy volunteers than the CHF group ((30.6 ± 8.6 ml±100 mL^-1±min^-1 and 18.3 ± 6.9 ml±100 mL^-1±min^-1, respectively). Local blood flow stimulation in response to exercise or limb occlusion is reduced in individuals with CHF, however, there was no difference in resting flows between the two groups, suggesting vasodilatory medication may restore resting blood flow to healthy values.

Angiotensin I-converting enzyme transition state stabilization by HIS1089 : evidence for a catalytic mechanism distinct from other gluzincin metalloproteinases

Angiotensin (Ang) I-converting enzyme (ACE) is a member of the gluzincin family of zinc metalloproteinases that contains two homologous catalytic domains. Both the N- and C-terminal domains are peptidyl-dipeptidases that catalyze Ang II formation and bradykinin degradation. Multiple sequence alignment was used to predict His¹⁰⁸⁹ as the catalytic residue in human ACE C-domain that, by analogy with the prototypical gluzincin, thermolysin, stabilizes the scissile carbonyl bond through a hydrogen bond during transition state binding. Site-directed mutagenesis was used to change His¹⁰⁸⁹ to Ala or Leu. At pH 7.5, with Ang I as substrate, k_cat/K_m values for these Ala and Leu mutants were 430 and 4,000-fold lower, respectively, compared with wild-type enzyme and were mainly due to a decrease in catalytic rate (k_cat) with minor effects on ground state substrate binding (K_m). A 120,000-fold decrease in the binding of lisinopril, a proposed transition state mimic, was also observed with the His¹⁰⁸⁹ --> Ala mutation. ACE C-domain-dependent cleavage of AcAFAA showed a pH optimum of 8.2. H1089A has a pH optimum of 5.5 with no pH dependence of its catalytic activity in the range 6.5-10.5, indicating that the His¹⁰⁸⁹ side chain allows ACE to function as an alkaline peptidyl-dipeptidase. Since transition state mutants of other gluzincins show pH optima shifts toward the alkaline, this effect of His¹⁰⁸⁹ on the ACE pH optimum and its ability to influence transition state binding of the sulfhydryl inhibitor captopril indicate that the catalytic mechanism of ACE is distinct from that of other gluzincins.

Arg1098 is critical for the chloride dependence of human angiotensin I-converting enzyme C-domain catalytic activity

Angiotensin (Ang) I-converting enzyme (ACE) is a Zn²+ metalloprotease with two homologous catalytic domains. Both the N- and C-terminal domains are peptidyl dipeptidases. Hydrolysis by ACE of its decapeptide substrate Ang I is increased by Cl−, but the molecular mechanism of this regulation is unclear. A search for single substitutions to Gln among all conserved basic residues (Lys/Arg) in human ACE C-domain identified R1098Q as the sole mutant that lacked Cl− dependence. Cl−dependence is also lost when the equivalent Arg in the N-domain, Arg⁵⁰⁰, is substituted with Gln. The Arg¹⁰⁹⁸ to Lys substitution reduced Cl− binding affinity by ∼100-fold. In the absence of Cl−, substrate binding affinity (1/K m) of and catalytic efficiency (k cat/K m) for Ang I hydrolysis are increased 6.9- and 32-fold, respectively, by the Arg¹⁰⁹⁸ to Gln substitution, and are similar (<2-fold difference) to the respective wild-type C-domain catalytic constants in the presence of optimal [Cl−]. The Arg¹⁰⁹⁸ to Gln substitution also eliminates Cl− dependence for hydrolysis of tetrapeptide substrates, but activity toward these substrates is similar to that of the wild-type C-domain in the absence of Cl−. These findings indicate that: 1) Arg¹⁰⁹⁸ is a critical residue of the C-domain Cl−-binding site and 2) a basic side chain is necessary for Cl− dependence. For tetrapeptide substrates, the inability of R1098Q to recreate the high affinity state generated by the Cl−-C-domain interaction suggests that substrate interactions with the enzyme-bound Cl− are much more important for the hydrolysis of short substrates than for Ang I. Since Cl− concentrations are saturating under physiological conditions and Arg¹⁰⁹⁸ is not critical for Ang I hydrolysis, we speculate that the evolutionary pressure for the maintenance of the Cl−-binding site is its ability to allow cleavage of short cognate peptide substrates at high catalytic efficiencies.

The economic analysis of prevention in mental health programs

This article introduces the role economics can play in deciding whether programs designed to prevent mental disorders, which carry large disease and economic burdens, are a worthwhile use of limited healthcare resources. Fortunately, preventive interventions for mental disorders exist; however, which interventions should be financed is a common issue facing decision makers, and economic evaluation can provide answers. Unfortunately, existing economic evaluations of preventive interventions have limited applicability to local healthcare contexts. An approach to priority setting largely based on economic techniques— Assessing Cost-Effectiveness (ACE)—has been developed and used in Australia to answer questions regarding the economic credentials of competing interventions. Eleven preventive interventions for mental disorders and suicide, mostly psychological in nature, have been evaluated using this approach, with many meeting the criteria of good value for money. Interventions targeting the prevention of suicide, adult and childhood depression, childhood anxiety, and early psychosis have particular merit.

Angiotensin converting enzyme inhibition lowers body weight and improves glucose tolerance in C57BL/6J mice maintained on a high fat diet

The renin–angiotensin system (RAS) is functional within adipose tissue and angiotensin II, the active component of RAS, has been implicated in adipose tissue hypertrophy and insulin resistance. In this study, captopril, an angiotensin converting enzyme (ACE) inhibitor that prevents angiotensin II formation, was used to study the development of diet-induced obesity and insulin resistance in obesity prone C57BL/6J mice. The mice were fed a high fat diet (w/w 21% fat) and allowed access to either water or water with captopril added (0.2 mg/ml). Body weight was recorded weekly and water and food intake daily. Glucose tolerance was determined after 11–12 weeks. On completion of the study (after 16 weeks of treatment), the mice were killed and kidney, liver, epididymal fat and extensor digitorum longus muscle (EDL) were weighed. Blood samples were collected and plasma analysed for metabolites and hormones. Captopril treatment decreased body weight in the first 2 weeks of treatment. Food intake of captopril-treated mice was similar to control mice prior to weight loss and was decreased after weight loss. Glucose tolerance was improved in captopril-treated mice. Captopril-treated mice had less epididymal fat than control mice. Relative to body weight, captopril-treated mice had increased EDL weight. Relative to control mice, mice administered captopril had a higher plasma concentration of adiponectin and lower concentrations of leptin and non-esterified fatty acids (NEFA). The results indicate that captopril both induced weight loss and improved insulin sensitivity. Thus, captopril may eventually be used for the treatment of obesity and Type 2 diabetes.

Sustaining Victorian certificate of applied learning (VCAL) educators

This paper draws on emerging data from in-progress analysis of interviews with 22 teachers/educators who teach the Victorian Certificate of Applied Learning (VCAL) in the settings of schools, Adult Community Education (ACE) and Technical and Further Education (TAFE). The development and implementation of VCAL occurred in 2002 as a response to Victorian government policy initiatives resulting from the Kirby (2000) Report. The VCAL is offered alongside the Victorian Certificate of Education (VCE), in years 11 and 12 of school, as another pathway into employment or further education and training. VCAL is also offered in the settings of TAFE and ACE. The VCAL curriculum uses applied learning as a pedagogical foundation to engage students in relevant, meaningful and authentic learning. In schools VCAL is delivered by qualified and registered teachers. In the TAFE and ACE sectors VCAL is taught by staff who are not necessarily teacher trained. Many pre-service teaching courses (including Certificate IV in Workplace Training and Assessment) do not include applied learning pedagogy in the curriculum. Since VCALʼs implementation there have been calls for greater consultation with, and support given to, VCAL teachers and organisations (Knipe, Ling, Bottrell and Keamy, 2003, p. 6; Harrison, 2006). Additionally VCAL teachers are frequently ill prepared professionally to manage a cohort which includes a high concentration of disengaged young people demonstrating challenging behaviours and attitudes (Pritchard & Anderson, 2006, p.1). Emerging data from the interviews with VCAL educators indicates these issues have not been addressed and many educators and teachers continue to feel unprepared and poorly supported. This is particularly significant in the light of a recent Victorian government announcement that, despite rising VCAL enrolments, VCAL coordination funding to schools is to be cut in 2012. (VALA, 2011, para. 4). To compensate for a lack of structured support and preparation, VCAL educators are frequently sustaining professional practice by their own agency in adapting already held life-skills and knowledge.

Improving the cost-effectiveness of cardiovascular disease prevention in Australia : a modelling study

Background : Cardiovascular disease is the leading cause of death worldwide. Like many countries, Australia is currently changing its guidelines for cardiovascular disease prevention from drug treatment for everyone with 'high blood pressure' or 'high cholesterol', to prevention based on a patient's absolute risk. In this research, we model cost-effectiveness of cardiovascular disease prevention with blood pressure and lipid drugs in Australia under three different scenarios: (1) the true current practice in Australia; (2) prevention as intended under the current guidelines; and (3) prevention according to proposed absolute risk levels. We consider the implications of changing to absolute risk-based cardiovascular disease prevention, for the health of the Australian people and for Government health sector expenditure over the long term.

Methods : We evaluate cost-effectiveness of statins, diuretics, ACE inhibitors, calcium channel blockers and beta-blockers, for Australian men and women, aged 35 to 84 years, who have never experienced a heart disease or stroke event. Epidemiological changes and health care costs are simulated by age and sex in a discrete time Markov model, to determine total impacts on population health and health sector costs over the lifetime, from which we derive cost-effectiveness ratios in 2008 Australian dollars per quality-adjusted life year.

Results : Cardiovascular disease prevention based on absolute risk is more cost-effective than prevention under the current guidelines based on single risk factor thresholds, and is more cost-effective than the current practice, which does not follow current clinical guidelines. Recommending blood pressure-lowering drugs to everyone with at least 5% absolute risk and statin drugs to everyone with at least 10% absolute risk, can achieve current levels of population health, while saving $5.4 billion for the Australian Government over the lifetime of the population. But savings could be as high as $7.1 billion if Australia could match the cheaper price of statin drugs in New Zealand.

Conclusions : Changing to absolute risk-based cardiovascular disease prevention is highly recommended for reducing health sector spending, but the Australian Government must also consider measures to reduce the cost of statin drugs, over and above the legislated price cuts of November 2010.