Rare chromosome disorders and their developmental consequences

Professionals working in disability services often encounter clients who have chromosome disorders such as Williams, Angelman or Down syndromes. As chromosome testing becomes increasingly sophisticated, however, more people are being diagnosed with very rare chromosome disorders that are identified not by a syndrome name, but rather by a description of the number, size and shape of their chromosomes (called the karyotype) or by a report of chromosome losses and gains detected through an advanced process known as microarray-based comparative genomic hybridisation (array CGH). For practitioners who work with individuals with rare chromosome disorders and their families, a basic level of knowledge about the evolving field of genetics, as well as specific knowledge about chromosome abnormalities, is essential since they must be able to demonstrate their knowledge and skills to clients (Simic & Turk, 2004). In addition, knowledge about the developmental consequences of various rare chromosome disorders is important for guiding prognoses, expectations, decisions and interventions. The current article provides information that aims to help practitioners work more effectively with this population. It begins by presenting essential information about chromosomes and their numerical and structural abnormalities and then considers the developmental consequences of rare chromosome disorders through a critical review of relevant literature.

End-of-life care pathways for improving outcomes in caring for the dying (Review)

Background In many clinical areas, integrated care pathways are utilised as structured multidisciplinary care plans which detail essential steps in caring for patients with specific clinical problems. Particularly, care pathways for the dying have been developed as a model to improve the end-of-life care of all patients. They aim to ensure that the most appropriate management occurs at the most appropriate time and that it is provided by the most appropriate health professional. Clinical pathways for end-of-life care management are used widely around the world and have been regarded as the gold standard. Therefore, there is a significant need for clinicians to be informed about the utilisation of end-of-life care pathways with a systematic review. Objectives To assess the effects of end-of-life care pathways, compared with usual care (no pathway) or with care guided by another end-of-life care pathway across all healthcare settings (e.g. hospitals, residential aged care facilities, community). Search strategy The Cochrane Register of controlled Trials (CENTRAL), the Pain, Palliative and Supportive Care Review group specialised register,MEDLINE, EMBASE, review articles and reference lists of relevant articles were searched. The search was carried out in September 2009. Selection criteria All randomised controlled trials (RCTs), quasi-randomised trial or high quality controlled before and after studies comparing use versus non-use of an end-of-life care pathway in caring for the dying. Data collection and analysis Results of searches were reviewed against the pre-determined criteria for inclusion by two review authors. Main results The search identified 920 potentially relevant titles, but no studies met criteria for inclusion in the review. Authors’ conclusions Without further available evidence, recommendations for the use of end-of-life pathways in caring for the dying cannot be made. RCTs or other well designed controlled studies are needed for evaluating the use of end-of-life care pathways in caring for dying people.

Effect of amblyopia on the developmental eye movement test in children

Purpose. To investigate the functional impact of amblyopia in children, the performance of amblyopic and age-matched control children on a clinical test of eye movements was compared. The influence of visual factors on test outcome measures was explored. Methods. Eye movements were assessed with the Developmental Eye Movement (DEM) test, in a group of children with amblyopia (n = 39; age, 9.1 ± 0.9 years) of different causes (infantile esotropia, n = 7; acquired strabismus, n = 10; anisometropia, n = 8; mixed, n = 8; deprivation, n = 6) and in an age-matched control group (n = 42; age, 9.3 ± 0.4 years). LogMAR visual acuity (VA), stereoacuity, and refractive error were also recorded in both groups. Results. No significant difference was found between the amblyopic and age-matched control group for any of the outcome measures of the DEM (vertical time, horizontal time, number of errors and ratio(horizontal time/vertical time)). The DEM measures were not significantly related to VA in either eye, level of binocular function (stereoacuity), history of strabismus, or refractive error. Conclusions. The performance of amblyopic children on the DEM, a commonly used clinical measure of eye movements, has not previously been reported. Under habitual binocular viewing conditions, amblyopia has no effect on DEM outcome scores despite significant impairment of binocular vision and decreased VA in both the better and worse eye.

Paving pathways : shaping the public health workforce through tertiary education

Public health educational pathways in Australia have traditionally been the province of Universities, with the Master of Public Health (MPH) recognised as the flagship professional entry program. Public health education also occurs within the fellowship training of the Faculty of Public Health Medicine, but within Australia this remains confined to medical graduates. In recent years, however, we have seen a proliferation of undergraduate degrees as well as an increasing public health presence in the Vocational Education and Training (VET) sector. ----- Following the 2007 Australian Federal election, the new Labour government brought with it a refreshing commitment to a more inclusive and strategic style of government. An important example of this was the 2020 visioning process that identified key issues of public health concern, including an acknowledgment that it was unacceptable to allocate less than 2% of the health budget towards disease prevention. This led to the recommendation for the establishment of a national preventive health agency (Australia: the healthiest country by 2020 National Preventative Health Strategy, Prepared by the Preventative Health Taskforce 2009). ----- The focus on disease prevention places a spotlight on the workforce that will be required to deliver the new investment in health prevention, and also on the role of public health education in developing and upskilling the workforce. It is therefore timely to reflect on trends, challenges and opportunities from a tertiary sector perspective. Is it more desirable to focus education efforts on selected lead issues such as the “obesity epidemic”, climate change, Indigenous health and so on, or on the underlying theory and skills that build a flexible workforce capable of responding to a range of health challenges? Or should we aspire to both? ----- This paper presents some of the key discussion points from 2008 – 2009 of the Public Health Educational Pathways workshops and working group of the Australian Network of Public Health Institutions. We highlight some of the competing tensions in public health tertiary education, their impact on public health training programs, and the educational pathways that are needed to grow, shape and prepare the public health workforce for future challenges.

Building resilience to prevent mental health problems in young people : The resourceful adolescent programme (RAP)

This chapter describes an evidence-based programme called the Resourceful Adolescent Program (RAP), which has been successful in building resilience in young people to prevent depressive symptoms developing.The programme adopts a strengths-focused approach. It aims to build a range of coping resources that foster teenagers’ abilities to maintain a positive sense of self and regulate emotions in the face of the vicissitudes of everyday struggles and difficult life events.This groupbased programme can be implemented routinely in schools or by counselling professionals as an early intervention or prevention programme. While there is no universal definition, ‘resilience’ generally means the process of avoiding the negative trajectories associated with exposure to risk factors (Fergus and Zimmerman, 2005). Current models of resilience are also very clear that there ‘are many pathways to resilience’ (Bonanno, 2004) and there is no

Effects of lead exposure on hippocampal metabotropic glutamate receptor subtype 3 and 7 in developmental rats

Background A complete explanation of the mechanisms by which Pb2+ exerts toxic effects on developmental central nervous system remains unknown. Glutamate is critical to the developing brain through various subtypes of ionotropic or metabotropic glutamate receptors (mGluRs). Ionotropic N-methyl-D-aspartate receptors have been considered as a principal target in lead-induced neurotoxicity. The relationship between mGluR3/mGluR7 and synaptic plasticity had been verified by many recent studies. The present study aimed to examine the role of mGluR3/mGluR7 in lead-induced neurotoxicity. Methods Twenty-four adult and female rats were randomly selected and placed on control or 0.2% lead acetate during gestation and lactation. Blood lead and hippocampal lead levels of pups were analyzed at weaning to evaluate the actual lead content at the end of the exposure. Impairments of short -term memory and long-term memory of pups were assessed by tests using Morris water maze and by detection of hippocampal ultrastructural alterations on electron microscopy. The impact of lead exposure on mGluR3 and mGluR7 mRNA expression in hippocampal tissue of pups were investigated by quantitative real-time polymerase chain reaction and its potential role in lead neurotoxicity were discussed. Results Lead levels of blood and hippocampi in the lead-exposed rats were significantly higher than those in the controls (P < 0.001). In tests using Morris Water Maze, the overall decrease in goal latency and swimming distance was taken to indicate that controls had shorter latencies and distance than lead-exposed rats (P = 0.001 and P < 0.001 by repeated-measures analysis of variance). On transmission electron microscopy neuronal ultrastructural alterations were observed and the results of real-time polymerase chain reaction showed that exposure to 0.2% lead acetate did not substantially change gene expression of mGluR3 and mGluR7 mRNA compared with controls. Conclusion Exposure to lead before and after birth can damage short-term and long-term memory ability of young rats and hippocampal ultrastructure. However, the current study does not provide evidence that the expression of rat hippocampal mGluR3 and mGluR7 can be altered by systemic administration of lead during gestation and lactation, which are informative for the field of lead-induced developmental neurotoxicity noting that it seems not to be worthwhile to include mGluR3 and mGluR7 in future studies. Background

Morphologic and genomic characterisation of the koala Chlamydia pneumoniae strain

Chlamydia pneumoniae is a common human and animal pathogen associated with a wide range of upper and lower respiratory tract infections. In more recent years there has been increasing evidence to suggest a link between C. pneumoniae and chronic diseases in humans, including atherosclerosis, stroke and Alzheimer’s disease. C. pneumoniae human strains show little genetic variation, indicating that the human-derived strain originated from a common ancestor in the recent past. Despite extensive information on the genetics and morphology processes of the human strain, knowledge concerning many other hosts (including marsupials, amphibians, reptiles and equines) remains virtually unexplored. The koala (Phascolarctos cinereus) is a native Australian marsupial under threat due to habitat loss, predation and disease. Koalas are very susceptible to chlamydial infections, most commonly affecting the conjunctiva, urogenital tract and/or respiratory tract. To address this gap in the literature, the present study (i) provides a detailed description of the morphologic and genomic architecture of the C. pneumoniae koala (and human) strain, and shows that the koala strain is microscopically, developmentally and genetically distinct from the C. pneumoniae human strain, and (ii) examines the genetic relationship of geographically diverse C. pneumoniae isolates from human, marsupial, amphibian, reptilian and equine hosts, and identifies two distinct lineages that have arisen from animal-to-human cross species transmissions. Chapter One of this thesis explores the scientific problem and aims of this study, while Chapter Two provides a detailed literature review of the background in this field of work. Chapter Three, the first results chapter, describes the morphology and developmental stages of C. pneumoniae koala isolate LPCoLN, as revealed by fluorescence and transmission electron microscopy. The profile of this isolate, when cultured in HEp-2 human epithelial cells, was quite different to the human AR39 isolate. Koala LPCoLN inclusions were larger; the elementary bodies did not have the characteristic pear-shaped appearance, and the developmental cycle was completed within a shorter period of time (as confirmed by quantitative real-time PCR). These in vitro findings might reflect biological differences between koala LPCoLN and human AR39 in vivo. Chapter Four describes the complete genome sequence of the koala respiratory pathogen, C. pneumoniae LPCoLN. This is the first animal isolate of C. pneumoniae to be fully-sequenced. The genome sequence provides new insights into genomic ‘plasticity’ (organisation), evolution and biology of koala LPCoLN, relative to four complete C. pneumoniae human genomes (AR39, CWL029, J138 and TW183). Koala LPCoLN contains a plasmid that is not shared with any of the human isolates, there is evidence of gene loss in nucleotide salvage pathways, and there are 10 hot spot genomic regions of variation that were previously not identified in the C. pneumoniae human genomes. Sequence (partial-length) from a second, independent, wild koala isolate (EBB) at several gene loci confirmed that the koala LPCoLN isolate was representative of a koala C. pneumoniae strain. The combined sequence data provides evidence that the C. pneumoniae animal (koala LPCoLN) genome is ancestral to the C. pneumoniae human genomes and that human infections may have originated from zoonotic infections. Chapter Five examines key genome components of the five C. pneumoniae genomes in more detail. This analysis reveals genomic features that are shared by and/or contribute to the broad ecological adaptability and evolution of C. pneumoniae. This analysis resulted in the identification of 65 gene sequences for further analysis of intraspecific variation, and revealed some interesting differences, including fragmentation, truncation and gene decay (loss of redundant ancestral traits). This study provides valuable insights into metabolic diversity, adaptation and evolution of C. pneumoniae. Chapter Six utilises a subset of 23 target genes identified from the previous genomic comparisons and makes a significant contribution to our understanding of genetic variability among C. pneumoniae human (11) and animal (6 amphibian, 5 reptilian, 1 equine and 7 marsupial hosts) isolates. It has been shown that the animal isolates are genetically diverse, unlike the human isolates that are virtually clonal. More convincing evidence that C. pneumoniae originated in animals and recently (in the last few hundred thousand years) crossed host species to infect humans is provided in this study. It is proposed that two animal-to-human cross species events have occurred in the context of the results, one evident by the nearly clonal human genotype circulating in the world today, and the other by a more animal-like genotype apparent in Indigenous Australians. Taken together, these data indicate that the C. pneumoniae koala LPCoLN isolate has morphologic and genomic characteristics that are distinct from the human isolates. These differences may affect the survival and activity of the C. pneumoniae koala pathogen in its natural host, in vivo. This study, by utilising the genetic diversity of C. pneumoniae, identified new genetic markers for distinguishing human and animal isolates. However, not all C. pneumoniae isolates were genetically diverse; in fact, several isolates were highly conserved, if not identical in sequence (i.e. Australian marsupials) emphasising that at some stage in the evolution of this pathogen, there has been an adaptation/s to a particular host, providing some stability in the genome. The outcomes of this study by experimental and bioinformatic approaches have significantly enhanced our knowledge of the biology of this pathogen and will advance opportunities for the investigation of novel vaccine targets, antimicrobial therapy, or blocking of pathogenic pathways.

Socioeconomic inequality profiles in physical and developmental health from 0-7 years : Australian National Study

Background: Early and persistent exposure to socioeconomic disadvantage impairs children’s health and wellbeing. However, it is unclear at what age health inequalities emerge or whether these relationships vary across ages and outcomes. We address these issues using cross-sectional Australian population data on the physical and developmental health of children at ages 0-1, 2-3, 4-5 and 6-7 years. Methods: 10 physical and developmental health outcomes were assessed in 2004 and 2006 for two cohorts each comprising around 5000 children. Socioeconomic position was measured as a composite of parental education, occupation and household income. Results: Lower socioeconomic position was associated with increased odds for poor outcomes. For physical health outcomes and socio-emotional competence, associations were similar across age groups and were consistent with either threshold effects (for poor general health, special healthcare needs and socio-emotional competence) or gradient effects (for illness with wheeze, sleep problems and injury). For socio-emotional difficulties, communication, vocabulary and emergent literacy, stronger socioeconomic associations were observed. The patterns were linear or accelerated and varied across ages. Conclusions: From very early childhood, social disadvantage was associated with poorer outcomes across most measures of physical and developmental health and showed no evidence of either strengthening or attenuating at older compared to younger ages. Findings confirm the importance of early childhood as a key focus for health promotion and prevention efforts.

Diagnostic and treatment pathways for men with prostate cancer in Queensland : investigating spatial and demographic inequalities

Background: Patterns of diagnosis and management for men diagnosed with prostate cancer in Queensland, Australia, have not yet been systematically documented and so assumptions of equity are untested. This longitudinal study investigates the association between prostate cancer diagnostic and treatment outcomes and key area-level characteristics and individual-level demographic, clinical and psychosocial factors.---------- Methods/Design: A total of 1064 men diagnosed with prostate cancer between February 2005 and July 2007 were recruited through hospital-based urology outpatient clinics and private practices in the centres of Brisbane, Townsville and Mackay (82% of those referred). Additional clinical and diagnostic information for all 6609 men diagnosed with prostate cancer in Queensland during the study period was obtained via the population-based Queensland Cancer Registry. Respondent data are collected using telephone and self-administered questionnaires at pre-treatment and at 2 months, 6 months, 12 months, 24 months, 36 months, 48 months and 60 months post-treatment. Assessments include demographics, medical history, patterns of care, disease and treatment characteristics together with outcomes associated with prostate cancer, as well as information about quality of life and psychological adjustment. Complementary detailed treatment information is abstracted from participants’ medical records held in hospitals and private treatment facilities and collated with health service utilisation data obtained from Medicare Australia. Information about the characteristics of geographical areas is being obtained from data custodians such as the Australian Bureau of Statistics. Geo-coding and spatial technology will be used to calculate road travel distances from patients’ residences to treatment centres. Analyses will be conducted using standard statistical methods along with multilevel regression models including individual and area-level components.---------- Conclusions: Information about the diagnostic and treatment patterns of men diagnosed with prostate cancer is crucial for rational planning and development of health delivery and supportive care services to ensure equitable access to health services, regardless of geographical location and individual characteristics. This study is a secondary outcome of the randomised controlled trial registered with the Australian New Zealand Clinical Trials Registry (ACTRN12607000233426)

Differential roles of the pRb and Arf/p53 pathways in murine naevus and melanoma genesis

We report on a systematic analysis of genotype-specific melanocyte (MC) UVR responses in transgenic mouse melanoma models along with tumour penetrance and comparative histopathology. pRb or p53 pathway mutations cooperated with NrasQ61K to transform MCs. We previously reported that MCs migrate from the follicular outer root sheath into the epidermis after neonatal UVR. Here, we found that Arf or p53 loss markedly diminished this response. Despite this, mice carrying these mutations developed melanoma with very early age of onset after neonatal UVR. Cdk4R24C did not affect the MC migration. Instead, independent of UVR exposure, interfollicular dermal MCs were more prevalent in Cdk4R24C mice. Subsequently, in adulthood, these mutants developed dermal MC proliferations reminiscent of superficial congenital naevi. Two types of melanoma were observed in this model. The location and growth pattern of the first was consistent with derivation from the naevi, while the second appeared to be of deep dermal origin. In animals carrying the Arf or p53 defects, no naevi were detected, with all tumours ostensibly skipping the benign precursor stage in progression.