A comparative study of atenolol, nifedipine and their combination in the treatment of hypertension

The antihypertensive effects, as assessed by clinical and ambulatory blood pressure measurement, of nifedipine slowrelease (SR), atenolol and the two In combination were evaluated In 28 known hypertenslv88 In a placebo-controlled, double-blind, randomlsed cross-over trial. Clinical blood pressure was significantly lower on combination therapy (P< 0,025) than on either agent alone, although all therapeutic agents reduced blood pressure significantly when compared with placebo (P< 0,01). All ambulatory blood pressure measurements obtained on any therapeutic agent were significantly lower than those obtained on placebo (P < 0,01). The mean daytime (08h00 17h00) ambulatory blood pressure measurement as well as the percentage of this monitoring period dUring which patients were hypertensive were significantly lower (P < 0,01) on combination therapy than on nifedipine SR. A similar pattern was observed for 24-hour ambulatory blood pressure measurements. Headache was the most significant adverse effect. This was most common with nHedlplne SR, less common with combination therapy and least common with atenolol. Combination therapy with nifedipine SR and atenolol is therefore a viable therapeutic alternative in the treatment of patients with benign essential hypertension

Towards a new philosophy of engineering: structuring the complex problems from the sustainability discourse

This dissertation considers three broad issues which emerge from the sustainability discourse. First is the nature of the discourse itself, particularly the underlying philosophical positions which are represented. Second, is the nature of the highly complex types of problem which the discourse exposes. And third is whether the engineering profession, as it is practised currently, is adequate to deal with such problems. The sustainability discourse exposes two distinct, fundamentally irreconcilable philosophical positions. The first, “sustainable development”, considers humanity to be privileged in relation to all other species and ecosystems. It is only incumbent upon us to look after the environment to the extent to which it is in our interests to do so. The second, “sustainability”, sees humanity as having no special moral privilege and recognises the moral status of other species, ecosystems, and even wilderness areas. Thus, sustainability imposes upon us a moral obligation to take their status into account and not to degrade or to destroy them. These two conflicting positions give rise to extremely complex problems. An innovative taxonomy of problem complexity has been developed which identifies three broad categories of problem. Of particular interest in this dissertation is the most complex of these, referred to here as the Type 3 problem. The Type 3 problem recognises the systemic complexity of the problem situation but also includes differences of the domain of interests as a fundamental, constituent part of the problem itself. Hence, established systems analysis techniques and reductionist approaches do not work. The domain of interests will typically have disparate ideas and positions, which may be entirely irreconcilable. The dissertation explores the development of philosophy of science, particularly in the last 70 years. It is noted that, unlike the philosophy of science, the philosophy of engineering has not been influenced by developments of critical theory, cultural theory, and postmodernism, which have had significant impact in late 20th-century Western society. This is seen as a constraint on the practice of engineering. Thus, a set of philosophical principles for sustainable engineering practice is developed. Such a change in the philosophy underlying the practice of engineering is seen as necessary if engineers are to engage with and contribute to the resolution of Type 3 problems. Two particular challenges must be overcome, if Type 3 problems are to be satisfactorily resolved. First, issues of belief, values, and morals are central to this problem type and must be included in problem consideration. And second, the problem situation is usually so complex that it challenges the capacity of human cognition to deal with it. Consequently, extensive consideration is given to cognitive and behavioural psychology, in particular to choice, judgement and decision-making in uncertainty. A novel problem-structuring approach is developed on three levels. A set philosophical foundation is established; a theoretical framework, based on general systems theory and established behavioural and cognitive psychological theory, is devised; and a set of tools is proposed to model Type 3 complex problems as a dynamic systems. The approach is different to other systems approaches, in that it enables qualitative exploration of the system to plausible, hypothetical disturbances. The problem-structuring approach is applied in a case study, which relates to the development of a water subsystem for a major metropolis (Sydney, Australia). The technique is also used to critique existing infrastructure planning processes and to propose an alternative approach

The impact of RIPK1 kinase inhibition on atherogenesis : a genetic and a pharmacological approach

RIPK1 (receptor-interacting serine/threonine-protein kinase 1) enzymatic activity drives both apoptosis and necroptosis, a regulated form of necrosis. Because necroptosis is involved in necrotic core development in atherosclerotic plaques, we investigated the effects of a RIPK1(S25D/S25D) mutation, which prevents activation of RIPK1 kinase, on atherogenesis in ApoE(−/−) mice. After 16 weeks of western-type diet (WD), atherosclerotic plaques from ApoE(−/−) RIPK1(S25D/S25D) mice were significantly larger compared to ApoE(−/−) RIPK1(+/+) mice (167 ± 34 vs. 78 ± 18 × 10(3) µm(2), p = 0.01). Cell numbers (350 ± 34 vs. 154 ± 33 nuclei) and deposition of glycosaminoglycans (Alcian blue: 31 ± 6 vs. 14 ± 4%, p = 0.023) were increased in plaques from ApoE(−/−) RIPK1(S25D/S25D) mice while macrophage content (Mac3: 2.3 ± 0.4 vs. 9.8 ± 2.4%, p = 0.012) was decreased. Plaque apoptosis was not different between both groups. In contrast, pharmacological inhibition of RIPK1 kinase with GSK’547 (10 mg/kg BW/day) in ApoE(−/−) Fbn1(C1039G+/−) mice, a model of advanced atherosclerosis, did not alter plaque size after 20 weeks WD, but induced apoptosis (TUNEL: 136 ± 20 vs. 62 ± 9 cells/mm(2), p = 0.004). In conclusion, inhibition of RIPK1 kinase activity accelerated plaque progression in ApoE(−/−) RIPK1(S25D/S25D) mice and induced apoptosis in GSK’547-treated ApoE(−/−) Fbn1(C1039G+/−) mice. Thus, without directly comparing the genetic and pharmacological studies, it can be concluded that targeting RIPK1 kinase activity does not limit atherogenesis

Sevikar (R): Combination therapy for the treatment of hypertension

Hypertension is a highly prevalent disease and one of the most important modifiable risk factors for cardiovascular disease. Hypertension remains the leading cause of mortality and the third largest cause of disability in both developed and developing countries. Although recent guidelines and advisory statements are recommending lower thresholds and goals for antihypertensive treatment, approximately two thirds of patients do not achieve the goals. In the United States only 36.8% of hypertensive patients achieve the goal o