Mode of action of iron (III) chelators as antimalarials: II. Evidence for differential effects on parasite iron-dependent nucleic acid synthesis

Iron chelation treatment of red blood cells infected with Plasmodium falciparum selectively intervenes with iron-dependent metabolism of malaria parasites and inhibits their development. Highly permeant hydroxamate iron chelator RSFileum2 affects all parasite stages when cultures are continuously exposed to drug, but affects primarily ring stages when assessed for irreversible effects, ie, sustained inhibition remaining after drug removal. On the other hand, the hydrophilic and poorly permeant desferrioxamine (DFO) affects primarily trophozoite/schizont stages when tested either in the continuous mode or irreversible mode. Unlike parasites, mammalian cells subjected to similar drug treatment show complete growth recovery once drugs are removed. Our studies indicate that parasites display a limited capacity to recover from intracellular iron depletion evoked by iron chelators. Based on these findings we provide a working model in which the irreversible effects of RSFs on rings are explained by the absence of pathways for iron acquisition/utilization by early forms of parasites. Trophozoite/schizonts can partially recover from RSFileum2 treatments, but show no DNA synthesis following DFO treatment even after drug removal and iron replenishment by permeant iron carriers. At trophozoite stage, the parasite uses a limited pathway for refurnishing its iron-containing enzymes, thus overcoming iron deprivation caused by permeant RSFileum2, but not by DFO because this latter drug is not easily removable from parasites. Their DNA synthesis is blocked by the hydroxamate iron chelators probably by affecting synthesis of ribonucleotide reductase (RNRase). Presumably in parasites, prolonged repression of the enzyme leads also to irreversible loss of activity. The action profiles of RSFileum2 and DFO presented in this study have implications for improved chemotherapeutic performance by combined drug treatment and future drug design based on specific intervention at parasite DNA synthesis.     

Small steps: barriers and facilitators to physical health self-management by people living with mental illness

It has been established that people with mental illness experience mortality and morbidity from all the major health conditions at 2–3 times the rate of those without mental illness. One way to overcome this problem is to encourage consumers of mental health services to self-manage their physical health. The purpose of the study was to investigate the facilitators and barriers to physical health self-management by people living with a mental illness. The study was underpinned by a hermeneutic phenomenological framework and utilised focus groups for data collection. A total of 27 participants, who lived in the community, had a diagnosed mental illness and who also had a co-morbid chronic physical health condition were included in one of three focus groups. The collected data were thematically analysed to identify common experiences and difficulties. It was found that participants were well aware of the need to attend to physical health issues. However, a number of factors at the individual, social and system levels impeded their ability to do so. Barriers to self-management included the debilitating nature of mental illness, poor physical health literacy, stigma from medical staff and social isolation, which resulted in a lack of support. Whereas informal peer networks, group participation and where it was offered, the support and encouragement from healthcare professionals facilitated health self-management.     

Small steps: physical health promotion for people living with mental illness

Physical health promotion for people with mental illness is vital if the life expectancy of this population group is to be improved. While there is promising evidence of physical health promotion initiatives in the literature in this population group, it is unclear whether these have resulted in long-term gains and actually reduced morbidity and mortality. We aimed to identify which physical health promotion strategies and resources were most likely to resonate with people who have long-term mental health problems and live in the community. We facilitated three focus groups in metropolitan Perth with 27 participants who experienced long-term serious mental health problems for this qualitative study. Participants were clear about which health promotion resources and approaches they did or did not consider would engage them. Participants wanted health messages that were positive, clear and not too wordy. They tended to dislike pamphlets and preferred DVDs. They also preferred to participate in health promotion activities in groups. Participants were aware of the need to engage in health protective behaviours but were often overwhelmed by their mental health problems. Health promotion for this population group ought to capitalise on therapeutic alliances with staff and informal peer networks already established in drop-in centres and clubhouses.     

Fatigue of dental ceramics

Objectives

Clinical data on survival rates reveal that all-ceramic dental prostheses are susceptible to fracture from repetitive occlusal loading. The objective of this review is to examine the underlying mechanisms of fatigue in current and future dental ceramics.

Data/sources

The nature of various fatigue modes is elucidated using fracture test data on ceramic layer specimens from the dental and biomechanics literature.

Conclusions

Failure modes can change over a lifetime, depending on restoration geometry, loading conditions and material properties. Modes that operate in single-cycle loading may be dominated by alternative modes in multi-cycle loading. While post-mortem examination of failed prostheses can determine the sources of certain fractures, the evolution of these fractures en route to failure remains poorly understood. Whereas it is commonly held that loss of load-bearing capacity of dental ceramics in repetitive loading is attributable to chemically assisted ‘slow crack growth’ in the presence of water, we demonstrate the existence of more deleterious fatigue mechanisms, mechanical rather than chemical in nature. Neglecting to account for mechanical fatigue can lead to gross overestimates in predicted survival rates.

Clinical significance

Strategies for prolonging the clinical lifetimes of ceramic restorations are proposed based on a crack-containment philosophy.     

Chipping resistance of graded zirconia ceramics for dental crowns

A serious drawback of veneering porcelains is a pronounced susceptibility to chipping. Glass-infiltrated dense zirconia structures can now be produced with esthetic quality, making them an attractive alternative. In this study, we examined the hypothesis that such infiltrated structures are much more chip-resistant than conventional porcelains, and at least as chip-resistant as non-infiltrated zirconia. A sharp indenter was used to produce chips in flat and anatomically correct glass-infiltrated zirconia crown materials, and critical loads were measured as a function of distance from the specimen edge (flat) or side wall (crown). Control data were obtained on zirconia specimens without infiltration and on crowns veneered with porcelains. The results confirmed that the resistance to chipping in graded zirconia is more than 4 times higher than that of porcelain-veneered zirconia and is at least as high as that of non-veneered zirconia.     

Setting priorities in global child health research investments: assessment of principles and practice

This article reviews theoretical and practical approaches for setting priorities in global child health research investments. It also provides an overview of previous attempts to develop appropriate tools and methodologies to define priorities in health research investments. A brief review of the most important theoretical concepts that should govern priority setting processes is undertaken, showing how different perspectives, such as medical, economical, legal, ethical, social, political, rational, philosophical, stakeholder driven, and others will necessarily conflict each other in determining priorities. We specially address present research agenda in global child health today and how it relates to United Nation's (UN) Millennium Development Goal 4, which is to reduce child mortality by two-thirds between 1990 and 2015. The outcomes of these former approaches are evaluated and their benefits and shortcomings presented. The case for a new methodology for setting priorities in health research investments is presented, as proposed by Child Health and Nutrition Research Initiative, and a need for its implementation in global child health is outlined. A transdisciplinary approach is needed to address all the perspectives from which investments into health research can be seen as priorities. This prioritization requires a process that is transparent, systematic, and that would take into account many perspectives and build on advantages of previous approaches.     

Understanding the business versus care paradox in gambling venues: a qualitative study of the perspectives from gamblers,venue staff and counsellors

Background

In recent years, greater emphasis has been placed on gambling venues to identify potential problem gamblers, respond appropriately and refer to treatment. In seeking the perspectives of problem gamblers, venue staff and treatment providers, this qualitative study investigates how problem gamblers experience being identified and referred for treatment by venue staff.

Methods

A semi-structured interview guide focusing on experiences and perceptions of problem gambling identification and referral for treatment in gaming venues was used to conduct 4 focus groups and 9 semi-structured in-depth interviews. Participants comprised 22 problem gamblers, 10 gambling venue staff and 8 problem gambling counsellors. Audio recordings were transcribed verbatim, and an interpretive phenomenological analysis was conducted.

Results

‘Role conflict’ was identified as a considerable source of stress for venue staff who described conflicting priorities in responding to problem gamblers whilst maintaining employer profit margins. Problem gamblers described offers of help from venue staff as hypocritical and disingenuous. Venue staff also described reluctance to make moral judgements through the identification of and engagement with problem gamblers, and gamblers described resentment in being singled out and targeted as a problem gambler. Being approached and offered referral to a counselling service was a rare occurrence among problem gamblers. This corresponded with reports by gambling counsellors.

Conclusions

Role conflict experienced by gambling venue staff and patrons alike inhibits effective referral of potential problem gamblers into treatment. Reducing the need for gambling venue staff to make a perceived moral judgement about the gambling behaviours of specific patrons may improve the reception of responsible gambling information and promote help-seeking.