Bcl-2 genes and growth factors in the pathology of ischaemic acute renal failure

For the past decade, an attempt has been made by many research groups to define the roles of the growing number of Bcl-2 gene family proteins in the apoptotic process. The Bcl-2 family consists of pro-apoptotic (or cell death) and anti-apoptotic (or cell survival) genes and it is the balance in expression between these gene lineages that may determine the death or survival of a cell. The majority of studies have analysed the role/s of the Bcl-2 genes in cancer development. Equally important is their role in normal tissue development, homeostasis and non-cancer disease states. Bcl-2 is crucial for normal development in the kidney, with a deficiency in Bcl-2 producing such malformation that renal failure and death result. As a corollary, its role in renal disease states in the adult has been sought. Ischaemia is one of the most common causes of both acute and chronic renal failure. The section of the kidney that is most susceptible to ischaemic damage is the outer zone of the outer medulla. Within this zone the proximal tubules are most sensitive and often die by necrosis or desquamate. In the distal nephron, apoptosis is the more common form of cell death. Recent results from our laboratory have indicated that ischaemia-induced acute renal failure is associated with up-regulation of two anti-apoptotic Bcl-2 proteins (Bcl-2 and Bcl-XL) in the damaged distal tubule and occasional up-regulation of Bax in the proximal tubule. The distal tubule is a known reservoir for several growth factors important to renal growth and repair, such as insulin-like growth factor-1 (IGF-1) and epidermal growth factor (EGF). One of the likely possibilities for the anti-cell death action of the Bcl-2 genes is that the protected distal cells may be able to produce growth factors that have a further reparative or protective role via an autocrine mechanism in the distal segment and a paracrine mechanism in the proximal cells. Both EGF and IGF-1 are also up-regulated in the surviving distal tubules and are detected in the surviving proximal tubules, where these growth factors are not usually synthesized. As a result, we have been using in vitro methods to test: (i) the relative sensitivities of renal distal and proximal epithelial cell populations to injury caused by mechanisms known to act in ischaemia-reperfusion; (ii) whether a Bcl-2 anti-apoptotic mechanism acts in these cells; and (iii) whether an autocrine and/or paracrine growth factor mechanism is initiated. The following review discusses the background to these studies as well as some of our preliminary results.

Determination of urinary thymidine glycol using affinity chromatography, HPLC and post-column reaction detection : a biomarker of oxidative DNA damage upon kidney transplantation

Reactive oxygen species are generated during ischaemia-reperfusion of tissue. Oxidation of thymidine by hydroxyl radicals (HO) leads to the formation of 5,6-dihydroxy-5,6-dihydrothymidine (thymidine glycol). Thymidine glycol is excreted in urine and can be used as biomarker of oxidative DNA damage. Time dependent changes in urinary excretion rates of thymidine glycol were determined in six patients after kidney transplantation and in six healthy controls. A new analytical method was developed involving affinity chromatography and subsequent reverse-phase high-performance liquid chromatography (RP-HPLC) with a post-column chemical reaction detector and endpoint fluorescence detection. The detection limit of this fluorimetric assay was 1.6 ng thymidine glycol per ml urine, which corresponds to about half of the physiological excretion level in healthy control persons. After kidney transplantation the urinary excretion rate of thymidine glycol increased gradually reaching a maximum around 48 h. The excretion rate remained elevated until the end of the observation period of 10 days. Severe proteinuria with an excretion rate of up to 7.2 g of total protein per mmol creatinine was also observed immediately after transplantation and declined within the first 24 h of allograft function (0.35 + 0.26 g/mmol creatinine). The protein excretion pattern, based on separation of urinary proteins on sodium dodecyl sulphate-polyacrylamide gel electrophorosis (SDS-PAGE), as well as excretion of individual biomarker proteins, indicated nonselective glomerular and tubular damage. The increased excretion of thymidine glycol after kidney transplantation may be explained by ischaemia-reperfusion induced oxidative DNA damage of the transplanted kidney.

Injury prevention in Queensland : report to Queensland Injury Prevention Council

Injury is the fourth leading cause of death in Australia. Injury rates in Queensland are amongst the highest in Australia and 21.5% of people surveyed for this research reported that their lifestyle or that of an immediate family member had been permanently affected by injury. Injury results in over 40,000 hospital admissions and 200,000 attendances at hospital Emergency Departments in Queensland each year. Queensland's death rate from injuries is higher than the national average, with consistently higher rates of deaths related to transport injuries. Queensland statistics also show higher than national average rates of injuries due to falls, homicide and accidental drowning. (Pike, Muller, Baade & Ward, 2000) In 2000-01 injuries represented over $4 billion (or 8%) of total health system expenditure, and 185,000 disability-adjusted life years (DALYs), or 7% of the total morbidity burden of disease and injury in Australia in 2003. (Begg, Vos, Barker, Stevenson, Stanley & Lopez, 2007). Injury is one of seven key health areas identified by the Commonwealth, state and territory governments for priority attention as National Health Priority Areas

Teaching young people first aid skills to reduce injury

Background First aid given immediately after a motor vehicle crash can have considerable benefits. Less understood however is first aid training as a prevention strategy for reducing risk-taking. A first step is to understand whether first aid skills are associated with risk-taking and injury experiences. Further, students and teachers who undergo or deliver such training offer important perspectives about implementation. Aims The research has two aims: (i) to identify whether first aid knowledge is associated with road risk-taking and injury and (ii) to examine teachers’ and students’ experiences of first aid activities within a school-based injury prevention and control program. Method Participants were 173 Year 9s (47% male) who completed a survey which included demographic information, first aid knowledge and risk-taking behaviour and injury experiences. Focus groups were held with 8 teachers who delivered, and 70 students who participated in, a school-based injury prevention and control program. Results Results showed a relationship between greater first aid knowledge and reduced engagement in risk-taking and injury experiences. Both students and teachers reported favourably on first aid however teachers also acknowledged challenges in delivering practical activities. Discussion & Conclusion It appears that first aid can be implemented within the school setting, particularly at the Year 9 level, and that both students and teachers involved in such training identify multiple benefits and positive experiences with first aid training. In addition, the findings suggest that first aid knowledge could be an important part of a prevention program.

Reduction of Secondary Degeneration after Spinal Cord Injury by Acute Delivery of Proinflammatory Growth Factors

INTRODUCTION Inflammation is a protective attempt to facilitate the removal of damaged tissue and to initiate the healing response in other tissues. However, after spinal cord injury (SCI), this response is prolonged leading to secondary degeneration and glial scarring. Here, we investigate the potential of sustained delivery of pro-inflammatory factors vascular endothelial growth factor (VEGF) and platelet derived growth factor (PDGF) to increase early inflammatory events and promote inflammatory resolution. Method Animal ethics approval was obtained from the Queensland University of Technology. Adult Wistar-Kyoto rats (12-16 weeks old) were subjected to laminectomies and T10 hemisections. Animals were then randomised to treatment (implantation of osmotic pump (Alzet) loaded with 5ug VEGF & 5 ug PDGF) or control groups (lesion control or lesion plus pump delivering PBS). Rats were sacrificed at one month and the spinal cords were harvested and examined by immunohistology, using anti-neurofilament-200(NF200) and anti- ionized calcium binding adapter molecule 1 (Iba1). One way ANOVA was used for statistic analysis. Results At 1 month, active pump-treated cords showed a high level of axonal filament throughout the defects as compared to the control groups. The mean lesion size, as measured by NF200, was 0.47mm2 for the lesion control, 0.39mm2 for the vehicle control and 0.078mm2 for the active pump group. Significant differences were detected between the active pump group and the two control groups (AP vs LC p= 0.017 AG vs VC p= 0.004). Iba-1 staining also showed significant differences in the post-injury inflammatory response. Discussion We have shown that axons and activated microglia are co-located in the lesion of the treated cord. We hypothesise the delivery of VEGF/PDGF increases the local vessel permeability to inflammatory cells and activates these along with the resident microglia to threshold population, which ultimately resolved the prolonged inflammation. Here, we have shown that maintaining the inflammatory signals for at least 7 days improved the morphology of the injured cord. Conclusion This study has shown that boosting inflammation, by delivery VEGF/PDGF, in the early phase of SCI helps to reduce secondary degeneration and may promote inflammation resolution. This treatment may provide a platform for other neuro-regenrative therapies.

Targeting injury prevention strategies to adolescents of Pacific Islander descent : what will work?

Background: Ethnicity is rarely considered in injury prevention program development, even though this is known to impact on participation in injury risk behaviour. An understanding of injury, risk behaviour and risk and protective factors specific to adolescents of Pacific Islander descent will inform the development of prevention strategies appropriate to this group.----- Aims: To determine patterns of injury and associated risk behaviour among adolescents of Pacific Islander descent, and to understand the risk and protective factors that influence injury rates among this group.----- Methods: A total of 875 Year 9 students from five Queensland high schools completed a survey during health classes. Seventy-one students (n = 38 male) identified as Pacific Islander. The survey consisted of scales examining injury, risk taking behaviour, and relationships with family, school and police.----- Results: The leading causes of injury among adolescents of Pacific Islander descent were sports (48%) and transport (e.g. 45% reported bicycle injuries). Interpersonal violence related injuries were also relatively frequent, with 28% having been injured in a fight. Reports of alcohol use were relatively low (20% c.f. 40% of the remaining sample), however reports of other risk behaviours were relatively high (e.g. 43% c.f. 25% of remaining sample reported a group fight).----- Discussion and conclusions: Conclusions will be drawn regarding risk-related injuries reported by adolescents of Pacific Islander descent and those of other ethnic backgrounds. Additionally, risk and protective factors relating to family, school and police will be explored, in order to inform prevention strategies appropriate to this group.

The importance of school connectedness in adolescent risk taking and injury prevention

Background: Injury is the leading cause of mortality for young people in Australia (AIHW, 2008). Adolescent injury mortality is consistently associated with risk taking behaviour, including transport and interpersonal violence (AIHW, 2003), which often occurs in the context of alcohol and other substance use. A rapid increase in risk taking and injury through early to late adolescence highlights the need for effective school based interventions. Aim: The aim of the current research was to examine the relationship between school connectedness and adolescent risk and injury, in order to inform effective prevention approaches. School connectedness, or students’ feelings of belongingness to school, has been shown to be a critical protective factor in adolescence which can be targeted effectively through teacher interventions. Despite evidence linking low school connectedness with increased health risk behaviour, including substance use and violence, research has not yet addressed possible links between connectedness and a broader range of risk taking behaviours (e.g. transport risks) or injury. Method: This study involved background data collection to inform the development of an intervention. A total of 595 Year 9 students (aged 13-14 years) from 5 Southeast Queensland high schools completed questionnaires that included measures of school connectedness, risk taking behaviour, alcohol and other substance use, and injuries. Results: Increased school connectedness was found to be associated with fewer transport risk behaviours and with decreased alcohol and other substance use for both males and females. Similarly, increased school connectedness was associated with fewer passenger and motorcycle injuries for male participants. Both males and females with increased school connectedness reported fewer alcohol related injuries. Implications: These results indicate that school connectedness appears to have protective effects for early adolescence. These findings may also hold for older adolescents and indicate that it may be an important factor to target in school based risk and injury prevention programs. A school connectedness intervention is currently being designed, focusing on teacher professional development. The intervention will be implemented in conjunction with a curriculum based injury prevention program for Year 9 students and will be evaluated through a large scale cluster randomised trial involving 26 schools.

The inclusion of first aid in an injury prevention curriculum

Prompt first aid can have considerable benefits. The Skills for Preventing Injury in Youth (SPIY) program aims to teach, in part, first aid skills along with additional injury prevention strategies. The approach to including first aid is both as an injury prevention strategy and a way in which to reduce the severity of injuries once they occur. This paper outlines an implementation trial of the SPIY program with particular emphasis on the delivery and implementation of first aid skills. SPIY demonstrated effectiveness with regard to first aid knowledge and as an injury prevention program. SPIY is taught in the Year 9 Health curriculum by HPE teachers. Students and teachers who undergo or deliver such training offer important perspectives about implementation. In addition independent observation of delivery provides further information about the program. The research aimed to examine teachers‟ and students‟ experiences of first aid activities within a school-based injury prevention and control program and identify key issues in delivery from independent observation of the program. Focus groups were held with 8 teachers who delivered, and 70 students who participated in the SPIY curriculum program. Results showed favourable reports on the delivery of first aid material however teachers noted challenges in delivering practical activities. In sum, first aid can be effectively implemented within the high school setting and both students and teachers identified multiple benefits and positive experiences after undertaking first aid training.

Health outcomes of adults 3 months after injury

Background: Injury is a leading cause of preventable mortality and morbidity in Australia and the world. Despite this there is little research examining the health related quality of life of adults following general trauma. Methods: A prospective cohort design was used to study adults who presented to hospital following injury. Data regarding injury and demographic details was collected through the routine operation of the Queensland Trauma Registry (QTR). In addition, the short form 36 (SF-36) was mailed to patients approximately 3 months following injury. Results: Participants included 339 injured patients who were hospitalised for ≥24 h in March-June 2003. A secondary group of 145 patients completed the SF-36, but did not have QTR data collected due to hospitalisation being <24 h. Both groups of participants reported significantly lower scores on all subscales of the SF-36 when compared to Australian norms. Conclusions: Health related quality of life of injured survivors is markedly reduced 3 months after injury. Ongoing treatment and support is necessary to improve these health outcomes.