Ear and hearing health in Aboriginal and Torres Strait Islander people aged 15 years and older: A scoping review.

OBJECTIVE: Review empirical research investigating the prevalence, experiences and management of hearing loss and ear disease in Aboriginal and Torres Strait Islander adults. DESIGN: Scoping review. STUDY SAMPLES: Searches of four electronic databases, Advanced Google, and key webpages identified 16,373 studies - 21 met inclusion criteria: original research relating to hearing/ear health and Aboriginal and Torres Strait Islander adults. RESULTS: Fourteen studies measured prevalence of hearing loss or middle-ear dysfunction, with a rate of hearing loss at an estimated 50% (reports ranging from 8% to 100%). Five studies reported views, attitudes, and experiences of hearing loss, with results showing hearing loss negatively impacted individual experiences in health and justice systems, and health professionals had limited understanding of the socioeconomic risk factors of middle ear disease. No articles directly reported on hearing loss management. CONCLUSIONS: There is a lack of research into the hearing health of Aboriginal and Torres Strait Islander adults, despite its critical importance in addressing health and social inequities. Given the widely varying and imprecise estimated rates of hearing loss detected, urgent action is needed to obtain accurate prevalence estimates and, in partnership with Aboriginal and Torres Strait Islander communities, identify the best methods of screening and managing hearing loss.

Aboriginal and Torres Strait Islander oral health and its impact among adults: A cross-sectional study.

BACKGROUND: Robust oral health epidemiological information for Aboriginal and Torres Strait Islander adults is scant. Set within a large urban population, this study describes self-reported oral health behaviours, status and impact assessed through computerized health checks (HC), stratified by age groups and sex, and identifies associations with dental appearance satisfaction. METHODS: This was a cross-sectional study of Aboriginal and Torres Strait Islander adults (aged ≥20 years) attending the Southern Queensland Centre of Excellence in Aboriginal and Torres Strait Islander Primary Health Care between 1 January 2014 and 31 December 2015 who had HC and provided research consent. RESULTS: There were 945 patients, 466 (49.3%) female, with an average age of 41.3 years (range, 20-82). Overall, 97.3% owned a toothbrush and 56.2% brushed two or more times/day. Despite self-reporting a significant oral health burden, only 28.8% visited a dentist within 12 months, mostly due to problems (84.3%). Surprisingly, only 28.4% reported dental appearance dissatisfaction, likely a result of community normalization whereby people are resigned to poor oral health. CONCLUSIONS: Under-utilization of dental services remains problematic for Aboriginal and Torres Strait Islander adults. To close the oral heath gap, culturally appropriate, acceptable and safe integrated primary health systems, with co-located dental services, demand consideration.

When a patient's ethnicity is declared, medical students' decision-making processes are affected.

BACKGROUND: Disparity in health status and healthcare outcomes is widespread and well known. This holds true for Indigenous peoples in many settings including Australia and Hawaii. While multi-factorial, there is increasing evidence of health practitioner contribution to this disparity. This research explored senior medical students' clinical decision-making processes. METHODS: A qualitative study was conducted in 2014 with 30 final year medical students from The University of Melbourne, Australia, and The John Burns Medical School, Hawaii, USA. Each student responded to questions about a paper-based case, first in writing and elaborated further in an interview. Half the students were given a case of a patient whose ethnicity was not declared; the other half considered the patient who was Native Hawaiian or Australian Aboriginal. A systematic thematic analysis of the interview transcripts was conducted. RESULTS: The study detected subtle biases in students' ways of talking about the Indigenous person and their anticipation of interacting with her as a patient. Four main themes emerged from the interview transcripts: the patient as a person; constructions of the person as patient; patient-student/doctor interactions; and the value of various education settings. There was a strong commitment to the patient's agenda and to the element of trust in the doctor-patient interaction. CONCLUSION: These findings will help to advance medical curricula so that institutions graduate physicians who are increasingly able to contribute to equitable outcomes for all patients in their care. The study also draws attention to subtle biases based on ethnicity that may be currently at play in physicians' practices.

Model of care for the management of complex Type 2 diabetes managed in the community by primary care physicians with specialist support: an open controlled trial.

AIMS: To evaluate patient outcomes for a novel integrated primary/specialist model of community care for complex Type 2 diabetes mellitus management compared with outcomes for usual care at a tertiary hospital for diabetes outpatients. METHODS: This was a prospective open controlled trial performed in a primary and tertiary care setting in Australia. A total of 330 patients with Type 2 diabetes aged >18 years were allocated to an intervention (n=185) or usual care group (n=145). The intervention arm was a community-based model of care led by a general practitioner with advanced skills and an endocrinologist partnership. Usual care was provided via the hospital diabetes outpatient department. The primary end point was HbA(1c) concentration at 12 months. Secondary end points included serum lipids and blood pressure. RESULTS: The mean change in HbA1c concentration in the intervention group was -9 mmol/mol (-0.8%) at 12 months and in the usual care group it was -2 mmol/mol (-0.2%) (95% CI -5,1). The percentage of patients in the intervention group achieving the HbA(1c) target of ≤53 mmol/mol (7%) increased from 21 to 42% (P<0.001); for the usual care group there was a 1% increase to 39% of patients attaining this target (P=0.99). Patients in the intervention group experienced significant improvements in blood pressure and total cholesterol compared with those in the usual care group. The percentage of patients achieving clinical targets was greater in the intervention group for the combined target of HbA(1c) concentration, blood pressure and LDL cholesterol. CONCLUSIONS: A community-based, integrated model of complex diabetes care, delivered by general practitioners with advanced skills, produced clinical and process benefits compared with a tertiary diabetes outpatient clinic.

Strategies for assessing the degree of photodamage to skin: a systematic review of the literature.

As our understanding of the role of ultraviolet (UV) radiation exposure in causing skin cancer continues to be enhanced, it is important that clinicians and researchers are familiar with the various methods for assessing photodamage to skin. This paper provides a systematic review of the published literature on invasive and noninvasive methods used to quantify lifetime UV exposure ('photoageing'). Clinical examination, histopathology, immunohistochemistry, skin surface topography and ultrasound, in addition to newer technologies such as reflectance confocal microscopy, optical coherence tomography and multiphoton tomography, are reviewed. It is concluded that histopathological solar elastosis alone should not be viewed as a 'gold standard' diagnostic test and that there is no single method available to give accurate quantification of the degenerative changes associated with photodamage. Although additional research into sensitivity and specificity is still needed, skin surface topography currently has the most support in the literature as a valid and reliable noninvasive tool for the assessment of photoageing.

Intracellular and extracellular serpins modulate lung disease.

An imbalance between peptidases and their inhibitors leads to pulmonary disease. Imbalances occur in the adult and the neonate at risk for a specific set of lung pathologies. Serpins (serine peptidase inhibitors) make up the major source of antipeptidase activity in the lung. The purpose of this review is to describe the serpin mechanism of inhibition, their roles in the normal and pathological lung and their potential as therapeutic agents.

Thermotolerance and virulence of Aspergillus fumigatus: role of the fungal nucleolus.

The ability to thrive at 37 degrees C is characteristic of all human pathogens and has long been suspected to play a role in the pathogenesis of aspergillosis. As a thermotolerant fungus, Aspergillus fumigatus is capable of growth at temperatures that approach the upper limit for all eukaryotes, suggesting that the organism has evolved unique mechanisms of stress resistance that may be relevant to its ability to adapt to the stress of growth in the host. High temperature is a strain on many biological systems, particularly those involved in complex macromolecular assemblies such as ribosomes. This review will discuss the relationship between thermotolerance and virulence in pathogenic fungi, emphasizing the link to ribosome biogenesis in A. fumigatus. Future work in this area will help determine how rapid growth is accomplished at elevated temperature and may offer new avenues for the development of novel antifungals that disrupt thermotolerant ribosome assembly.

Effect of Pseudomonas-induced chronic lung inflammation on specific cytotoxic T-cell responses to adenoviral vectors in mice.

A mouse model of chronic Pseudomonas-induced bronchopulmonary inflammation that mimics chronic cystic fibrosis (CF) lung disease was employed to determine whether this inflammatory milieu influences immune responses to adenoviral vectors. Pseudomonas-infected and control mice were inoculated intranasally with a second-generation type 2 adenovirus (Ad2) vector (Ad2/betagal-2). After 3 weeks, serum and airway Ad2-specific antibodies and Ad2 vector-directed, cytotoxic T-lymphocyte (CTL) activity in splenocytes were measured. No differences in humoral immunity were observed between Pseudomonas-infected mice and controls. However, there was a two- to three-fold increase in Ad-specific CTL activity in the Pseudomonas-infected mice compared to control mice. MHC class I-dependent antigen presentation by antigen-presenting cells (APC) from lungs of Pseudomonas-infected mice was also significantly increased compared to APC from control mice, suggesting a mechanism that may contribute to increased Ad-specific CD8+ CTL responses. It was concluded that Ad-specific CTL activity is enhanced in the setting of pre-existing chronic Pseudomonas-induced lung inflammation similar to CF lung disease, and that increased antigen presentation via MHC class I in this setting may be one underlying mechanism. These findings underscore the importance of considering the influence of the disease milieu when evaluating modes of gene therapy for such diseases in animal models.

Human clade B serpins (ov-serpins) belong to a cohort of evolutionarily dispersed intracellular proteinase inhibitor clades that protect cells from promiscuous proteolysis.

Serpins are unique among the various types of active site proteinase inhibitors because they covalently trap their targets by undergoing an irreversible conformational rearrangement. Members of the serpin superfamily are present in the three major domains of life (Bacteria, Archaea and Eukarya) as well as several eukaryotic viruses. The human genome encodes for at least 35 members that segregate evolutionarily into nine (A-I) distinct clades. Most of the human serpins are secreted and circulate in the bloodstream where they reside at critical checkpoints intersecting self-perpetuating proteolytic cascades such as those of the clotting, thrombolytic and complement systems. Unlike these circulating serpins, the clade B serpins (ov-serpins) lack signal peptides and reside primarily within cells. Most of the human clade B serpins inhibit serine and/or papain-like cysteine proteinases and protect cells from exogenous and endogenous proteinase-mediated injury. Moreover, as sequencing projects expand to the genomes of other species, it has become apparent that intracellular serpins belonging to distinct phylogenic clades are also present in the three major domains of life. As some of these serpins also guard cells against the deleterious effects of promiscuous proteolytic activity, we propose that this cytoprotective function, along with similarities in structure are common features of a cohort of intracellular serpin clades from a wide variety of species.

SERPINB12 is a novel member of the human ov-serpin family that is widely expressed and inhibits trypsin-like serine proteinases.

Members of the human serpin family regulate a diverse array of serine and cysteine proteinases associated with essential biological processes such as fibrinolysis, coagulation, inflammation, cell mobility, cellular differentiation, and apoptosis. Most serpins are secreted and attain physiologic concentrations in the blood and extracellular fluids. However, a subset of the serpin superfamily, the ov-serpins, also resides intracellularly. Using high throughput genomic sequence, we identified a novel member of the human ov-serpin gene family, SERPINB12. The gene mapped to the ov-serpin cluster at 18q21 and resided between SERPINB5 (maspin) and SERPINB13 (headpin). The presence of SERPINB12 in silico was confirmed by cDNA cloning. Expression studies showed that SERPINB12 was expressed in many tissues, including brain, bone marrow, lymph node, heart, lung, liver, pancreas, testis, ovary, and intestines. Based on the presence of Arg and Ser at the reactive center of the RSL, SERPINB12 appeared to be an inhibitor of trypsin-like serine proteinases. This hypothesis was confirmed because recombinant SERPINB12 inhibited human trypsin and plasmin but not thrombin, coagulation factor Xa, or urokinase-type plasminogen activator. The second-order rate constants for the inhibitory reactions were 2.5 +/- 1.6 x 10(5) and 1.6 +/- 0.2 x 10(4) M(-1) S(-1), respectively. These data show that SERPINB12 encodes for a new functional member of the human ov-serpin family.

Research output of Australian general practice: a comparison with medicine, surgery and public health.

OBJECTIVES: To compare the productivity of Australian general practice in terms of research publications with the productivity of other medical disciplines. DESIGN: A survey of Australian general practice, medicine, surgery and public health publications carried out by manual searching of specific journals and an electronic search of the US National Library of Medicine's "PubMed" database. MAIN OUTCOME MEASURES: The number of original research publications by Australian general practitioners, physicians, surgeons and public health physicians during 1999; the relative publication rate of Australian general practice, medicine, surgery and public health over the period 1990-1999. RESULTS: Of original research articles published in 1999, GPs authored 65% (17/26) in Australian Family Physician and 3% (3/90) in the Medical Journal of Australia; physicians published 4% and 37%, respectively. The electronic search identified 54 research articles relating to Australian general practice published in 1999 in 21 different journals, only two of which were primary care journals. Over the period 1990-1999, there was a publication rate of one general practice [discipline] article per 1000 GPs in practice per year. Corresponding rates for medicine, surgery and public health were 105/1000, 61/1000 and 148/1000, respectively. CONCLUSIONS: There is considerable disparity between the level of research output of general practice and that of the disciplines of medicine, surgery and public health. If we are to have effective general practice research, we urgently need to develop research skills, a supportive infrastructure and a culture that nurtures research.

Identification of genes of Aspergillus fumigatus up-regulated during growth on endothelial cells.

Aspergillus fumigatus is an important opportunistic fungal pathogen that can cause acute invasive disease in neutropenic hosts. Invasive aspergillosis is being diagnosed with increasing frequency, and morbidity and mortality remain high despite prompt antifungal therapy. Because little is known about the virulence factors used by A. fumigatus, a tissue culture model was developed to mimic the interaction of the fungus with the endothelium. Differential display was used to compare gene expression in fungal cells grown on endothelial cells with that of cells grown in the absence of endothelial cell contact, and genes that were up-regulated were selected for analysis as putatively virulence-related genes. Two of these up-regulated genes were chosen for further study and were identified as genes encoding the regulatory subunit of cyclic adenosine monophosphate (cAMP)-dependent protein kinase and a member of the ras gene family, both of which are involved in cAMP-mediated signaling in fungi. This model system provides a new approach to the identification of potentially virulence-related genes induced in A. fumigatus by the interaction with host cells.

Molecular cloning of cgrA, the gene encoding the Aspergillus nidulans ortholog of Saccharomyces cerevisiae CGR1.

Saccharomyces cerevisiae CGR1 encodes a 120-amino acid protein with a predominant nucleolar localization. In this study we report the identification and cloning of the ortholog, cgrA, from Aspergillus nidulans. The cgrA gene is comprised of three exons on A. nidulans Chromosome 7. The cDNA contains a single open reading frame (ORF) that would encode a protein of 114 amino acids with 44% sequence identity to yeast Cgr1p. A plasmid expressing cgrA complemented the impaired growth phenotype of a yeast strain that can be inducibly depleted of CGR1, and a green fluorescent protein (GFP)-tagged CgrA protein had the same nucleolar localization as the corresponding yeast protein. These results identify cgrA as the A. nidulans ortholog of yeast CGR1 and suggest evolutionary conservation of nucleolar localization mechanisms used by these proteins.

Systemic deficits in transporter for antigen presentation (TAP)-1 or proteasome subunit LMP2 have little or no effect on tumor incidence.

Some tumor cells have deficits in class I MHC antigen processing, suggesting that T cells exert selective pressure on tumor cells. Previous studies have not revealed increased tumor incidence in mice with deficits in T-cell immunity, including mice lacking TAP1 (a subunit of the transporter for antigen presentation) or LMP2 (a regulated subunit of the 20S proteasome). The incidence of spontaneous tumors in these mice, however, is too low to assess differences in host resistance to tumors. To increase tumor incidence and better assess the role of systemic expression of TAP1 and LMP2 in responses to tumors, TAP1-/- and LMP2-/- mice were bred with p53-/- mice to create TAP1-/-p53-/- and LMP2-/-p53-/- double knockout mice. Lymphomas and sarcomas (malignant fibrous histiocytoma and angiosarcoma) occurred with high incidence in all p53-deficient populations. Tumor incidence and death rate were similar in TAP1-/-p53-/- mice and closely matched control TAP1+/+p53-/- mice. Tumor incidence and death rate were slightly accelerated in LMP2-/-p53-/- mice relative to control LMP2+/+p53-/- mice, but the biological significance of this difference was unclear. The relative incidence of lymphomas vs. sarcomas was not significantly altered by variation in TAP1 or LMP2. In conclusion, systemic absence of TAP1 did not alter tumor incidence, while absence of LMP2 was associated with only a slight acceleration of tumor incidence of uncertain significance. These observations are consistent with other evidence that normal T-cell responses do not effectively limit tumorigenesis. Even though T cells can attack some tumor cells, the ability of tumors to alter their immunogenicity and evade T-cell surveillance may render the native immune system ineffective at providing a rate-limiting barrier to tumorigenesis and preventing cancer.

Cgr1p, a novel nucleolar protein encoded by Saccharomyces cerevisiae orf YGL0292w.

Saccharomyces cerevisiae open reading frame (ORF) YGL029w (CGR1) encodes a small hydrophilic protein of unknown function. To investigate the role of this gene, we have determined the intracellular localization of the encoded product and examined the effects of Cgr1p depletion on cell growth. Tagging Cgr1p with the green fluorescent protein (GFP) or the myc epitope showed focal accumulation of the fusion protein in the yeast nucleolus, and this localization overlapped with the distribution of the nucleolar protein Nop1p. Cells depleted of CGR1 mRNA were growth impaired and hypersensitive to the translational inhibitor paromomycin, and this phenotype was complemented by episomal expression of the CGR1-GFP fusion gene. These results identify Cgr1p as a novel component of the yeast nucleolus and suggest a potential role in ribosome biogenesis.

Molecular cloning of Aspergillus fumigatus CgrA, the ortholog of a conserved fungal nucleolar protein.

In this report we describe the cloning of cgrA, the Aspergillus fumigatus ortholog of the yeast nucleolar protein Cgr1p. The cgrA complementary DNA (cDNA) contains a single open reading frame that would encode a protein of 114 amino acids that has 42% sequence identity to yeast Cgrlp. Heterologous expression of a green fluorescent protein (GFP)-tagged A. fumigatus cgrA gene demonstrated that the CgrA protein could localize to the yeast nucleolus. Moreover, the cgrA cDNA complemented the growth deficiency caused by inducible depletion of intracellular Cgr1p levels in yeast. These results support an orthologous relationship between the CgrA and Cgr1 proteins, and open the way for future studies into the potential value of nucleolar proteins as antifungal targets.

CpG DNA induces maturation of dendritic cells with distinct effects on nascent and recycling MHC-II antigen-processing mechanisms.

Murine bone marrow cultured with GM-CSF produced dendritic cells (DCs) expressing MHC class II (MHC-II) but little CD40, CD80, or CD86. Oligodeoxynucleotides (ODN) containing CpG motifs enhanced DC maturation, increased MHC-II expression, and induced high levels of CD40, CD80, and CD86. When added with Ag to DCs for 24 h, CpG ODN enhanced Ag processing, and the half-life of peptide:MHC-II complexes was increased. However, Ag processing was only transiently enhanced, and exposure of DCs to CpG ODN for 48 h blocked processing of hen egg lysozyme (HEL) to HEL(48-61):I-A(k) complexes. Processing of this epitope required newly synthesized MHC-II and was blocked by brefeldin A (BFA), suggesting that reduced MHC-II synthesis could explain decreased processing. Real-time quantitative PCR confirmed that CpG ODN decreased I-A(beta)(k) mRNA in DCs. In contrast, RNase(42-56):I-A(k) complexes were generated via a different processing mechanism that involved recycling MHC-II and was partially resistant to BFA. Processing of RNase(42-56):I-A(k) persisted, although at reduced levels, after CpG-induced maturation of DCs, and this residual processing by mature DCs was completely resistant to BFA. Changes in endocytosis, which was transiently enhanced and subsequently suppressed by CpG ODN, may affect Ag processing by both nascent and recycling MHC-II mechanisms. In summary, CpG ODN induce DC maturation, transiently increase Ag processing, and increase the half-life of peptide-MHC-II complexes to sustain subsequent presentation. Processing mechanisms that require nascent MHC-II are subsequently lost, but those that use recycling MHC-II persist even in fully mature DCs.

Identification of a cell type-specific silencer in the first exon of the His-1 gene.

The His-1 gene is developmentally expressed in the murine choroid plexus but is silenced in the adult brain. To test the hypothesis that the gene contains cis-acting elements that contribute to this repression, we have analyzed segments of the proximal promoter for negative regulatory sequences by transient transfection analysis. The activity of the proximal promoter was moderately influenced by positively and negatively acting sequences located from -335 to -168 and -617 to -335, respectively. A strong His-1-positive regulatory element (HPRE, +18 to +29) was essential for maximal promoter activity and could also enhance the activity of the heterologous SV40 promoter in an orientation-dependent manner. The HPRE contains homology to the neuronal restrictive silencer element (NRSE) but interacted with nuclear proteins that were distinct from the NRSE-binding factor (NRSF). By contrast, a potent negative regulatory sequence (HNRE) was identified in the first exon that repressed either the His-1 or SV40 promoters by greater than 80%. This negative regulatory sequence interacted with nuclear proteins from cells that contain a silent His-1 gene but showed no interaction with nuclear proteins from cells that actively transcribe the endogenous gene. HNRE-mediated repression was orientation independent; most of this activity was mapped to a minimal 26-bp sequence. These findings suggest that the first exon of the His-1 gene contains a cell type-specific silencer that contributes to the regulation of His-1 transcription.

Characterization of Apt- cell lines exhibiting cross-resistance to glucocorticoid- and Fas-mediated apoptosis.

Apoptosis induction by staurosporine, ceramide, and Fas stimulation was investigated in the mouse thymoma cell line W7.2 and a panel of dexamethasone (dex)-resistant W7.2 mutant cell lines, Apt3.8, Apt4.8 and Apt5.8, and a Bcl-2 transfected W7.2 cell line (Wbcl2). While W7. 2 cells were found to be sensitive to these apoptosis inducers, the Apt- mutants and Wbcl2 cells were shown to be resistant to some or all of the treatments. Specifically, all three Apt- mutants and Wbcl2 cells were found to be resistant to ceramide and Fas-mediated apoptosis, whereas, Apt4.8 and Apt5.8 were sensitive to staurosporine-induced apoptosis under conditions in which Apt3.8 and Wbcl2 cells were resistant. Measurements of caspase activity and cytochrome c release in cytosolic extracts of dex and staurosporine-treated cells indicated that the recessive Apt- mutations effect steps upstream of mitochondrial dysfunction. Steady-state RNA levels of apoptosis-associated gene transcripts showed that the observed differential resistance of the Apt- cell lines could not be explained by altered expression of numerous Bcl-2 or Fas related genes. Transient transfection of human Fas gene coding sequences into the Apt- mutants and Wbcl2 cells did not induce apoptosis, even though these same cell lines were sensitive to ectopic expression of the FADD and caspase 8 genes. Taken together, these data provide genetic evidence for the existence of shared components in the dex- and Fas-mediated apoptotic pathways in W7.2 cells.