Examining the potential contribution of social theory to developing and supporting Australian Indigenous-mainstream health service partnerships

Introduction: The substantial gap in life expectancy between Indigenous and non-Indigenous Australians has been slow to improve, despite increased dedicated funding. Partnerships between Australian Indigenous and mainstream Western biomedical organisations are recognised as crucial to improved Indigenous health outcomes. However, these partnerships often experience challenges, particularly in the context of Australia’s race and political relations. Methods: We examined the relevant literature in order to identify the potential role for social theory and theoretical models in developing and maintaining intercultural partnerships. Having identified relevant theoretical models, terms and possible key words, a range of databases were searched and relevant articles selected for inclusion. An integrative approach brought together theoretical models and practical considerations about working in partnership, to inform our analysis of the literature. Findings: Considering partnerships between Australian Indigenous and mainstream health organisations as 'bi-cultural' is simplistic: rather they are culturally diverse across social and professional levels. As such, partnerships between Australian Indigenous and mainstream health organisations may be better conceptualised as 'intercultural', operating across diverse and shifting cultural frames of reference. Theories identified by this review as useful to guide partnerships include power relations, reflexivity and dialogue, borders and strangeness and the intercultural or third space. This paper examines how these theoretical approaches can develop understanding and improve intercultural engagement between mainstream and Australian Indigenous partners in healthcare.Conclusions: Rather than viewing partnerships merely as arrangements between disembodied entities, sometimes contractual in nature, they are better seen as activities between people and organisations and essentially dependent on relationships, occurring in an intercultural space that is complex, dynamic and subject to changes in power relations. Theoretical models aiming to understand and improve partnerships indicate the complexity of building and maintaining such partnerships and stress the importance of understanding factors that can strengthen or derail their effectiveness. While the theories presented here are by no means exhaustive, they nonetheless provide a series of entry points through which to engage with the issue and expand the discourse. This approach allows the transformative nature of Australian Indigenous-mainstream 'culture' to be explored and understood in its lived expression; rather than relegated to prescriptive categories

Spatiotemporal variation in harbor porpoise distribution and foraging across a landscape of fear

Funding information: Marine Alliance for Science and Technology for Scotland; Marine Scotland Science; University of AberdeenPeer reviewedPublisher PD

Host-parasite interactions between Lernaeocera branchialis (Copepoda: Pennellidae) and its host Gadus morhua (Teleosti: Gadidae)

Lernaeocera branchialis (Linnaeus, 1767) is a parasitic copepod possessing a complex dual-host lifecycle. The “definitive” gadoid hosts, including Gadus morhua (Atlantic cod), Melanogrammus aeglefinus (haddock) and Merlangius merlangus (whiting), are infected by the fertilised female, which penetrates the host’s ventral aorta or bulbus arteriosus whilst undertaking extensive metamorphosis and a haematophagous lifestyle. The pathogenic effects of this activity upon the host have been well documented and mortality may occur, especially when multiple parasites are present. These negative impacts on cod, particularly juveniles, by L. branchialis have the potential to adversely affect cod aquaculture in the future, and already vulnerable wild cod stocks. This PhD project therefore, investigated the immune response of wild haddock and cultured-cod post-infection by L. branchialis, and the possible mechanisms by which the parasite modulates/evades the host’s immune response. The systemic immune response of both wild haddock and cultured-cod post-infection by L. branchialis depended on the maturation stage of the parasite, and in the former host species, upon the infection intensity. Wild haddock harbouring fully metamorphosed females showed an increase in circulating thrombocytes and a decrease in serum protein levels however; if multiple mature L. branchialis were present the haddock possessed reduced circulating monocytes, and increased circulating thrombocytes and serum anti-trypsin activity. Infection by L. branchialis was also associated with a suppressive effect on haddock serum spontaneous haemolytic activity. These responses were thought to be due to the host trying to counteract the increased damage caused by the massive increase in size and the feeding of the mature parasite, which is more pronounced when multiple parasites are present, resulting in the increase in some parameters and the ‘consumption’ of others. However, the effect of parasite-derived secretions and other pathogens due to observations on wild fish could not be discounted. The laboratory-infection of cultured-cod from two different sources was also performed in order to study the immune response over time. The two groups of cod showed differences in their immune response to L. branchialis. The first group showed suppressed respiratory burst activity of phagocytes, as the parasite reached the early penella sub-stage, whilst no suppression in phagocyte respiratory burst activity was found in the second group. The parasite was found to migrate along the afferent branchial artery of the cod where a thrombus formed and was present throughout its migration into the ventral aorta. At 14 d post-infection, leukocytes expressing Interleukin 8 mRNA were observed within the free-flowing blood at the periphery of the organising thrombus within the lumen of the ventral aorta. This was speculated to aid the recruitment and activation of leukocytes to the site, and the maturation and neovascularisation of granulation tissue. The infection of the second group subsided with the death of the parasite, and none of the parasites metamorphosed past the early penella sub-stage. The live parasites infecting the first group of cod did not possess IgM or complement component C3 binding on their cuticle, however, both IgM and C3 binding occurred on the dead parasites in the second infection trial. This may highlight the importance of these opsonins and the cytotoxic effect of phagocytes in the elimination of L. branchialis by some cod. However, the first infection was terminated as the parasite reached the early penella sub-stage due to a loss of stock cod prior to the study, so the long-term success of the infection can not be concluded. Therefore, the immune response to infection needs to be determined over the entire metamorphosis of L. branchialis to determine whether the infection was successful or not, and preferably in populations with varying susceptibility to L. branchialis. This will not be possible without further studies into the resistance of different stocks of cultured-cod. Many arthropod parasites, such as ticks and salmon lice, have been previously documented to produce pharmacologically active secretions, aiding host invasion and parasite feeding, preventing the host immune response from working effectively against the parasite, all aimed at improving survival of the parasite. Therefore, the effects of the secretory/excretory products (SEPs) produced during the initial infective stage and by the mature, fully metamorphosed female on the immune response of cultured-cod in vitro, and the location of exocrine glands associated with the oral region of the parasite were investigated. The SEPs from the infective stage of the parasite were found not to affect the intracellular hydrogen peroxide (H2O2) production of phagocytes. The practical difficulties in collecting large quantities of the SEPs from the infective stage meant that their effects could not be tested on the other host immune parameters studied. The SEPs from fully metamorphosed female L. branchialis, however, had a number of suppressive effects on the host immune response in vitro including: 1) suppression of the intracellular production of cytotoxic H2O2 during the respiratory burst of phagocytic leukocytes post-PMA stimulation, 2) suppression of the production of macrophage activating factor by leukocytes with a priming effect on naïve phagocyte function, and 3) suppression of the chemo-attraction ‘power’ of zymosan activated cod serum, i.e. anaphylatoxin activity, on head kidney-derived leukocytes. These effects were dose-dependent, and highlight the capacity of L. branchialis to suppress its host’s innate immune response at the local feeding area. Further work is required to establish the mechanisms by which the parasite-derived SEPs suppress these host immune parameters, and to identify which molecules produced by the parasite are responsible. The correlation between these in vitro results, and systemic immune parameters measured from laboratory-infected Atlantic cod and wild infected haddock are discussed. Host immuno-modulation by other arthropod parasites is mediated by pharmacologically active secretions produced by exocrine glands. Therefore, the exocrine glands of the infective and fully metamorphosed female L. branchialis were also investigated in order to identify those that might be responsible for the secretion of host-modifying products. Adult female exocrine glands were mapped using diaminobenzidine (DAB), most commonly known to stain peroxidases and catalases. These compounds are known to be involved in the neutralisation of harmful free radicals which are released during the respiratory burst and tissue damage. Such products may therefore be important protective secretory components at the site of feeding / infection. Exocrine glands were located in the infective stage associated with the oral region, one pair termed the anterior gland complex (AGC), and the other pair extending either side of the oral cone termed the circum-oral glands (CG). These were further investigated using light microscopy and transmission electron microcopy. The AGC and CGs possessed multi-component secretions and they possessed secretory vesicles, abundant and highly active rough endoplasmic reticulum and Golgi apparatus suggesting that protein is an important component of the secretory products. These glands were also observed in the fully metamorphosed females where they had increased in size within the cephalothorax post-metamorphosis. It is hoped that the identification of these glandular structures, which are thought to secrete within the local vicinity of the oral cone, will aid future studies regarding the identification and secretion kinetics of parasite-derived molecules during the infection and feeding process.EThOS - Electronic Theses Online ServiceFisheries Society of the British IslesGBUnited Kingdo

Examination of Fluconazole-Induced Alopecia in an Animal Model and Human Cohort.

Fluconazole-induced alopecia is a significant problem for patients receiving long-term therapy. We evaluated the hair cycle changes of fluconazole in a rat model and investigated potential molecular mechanisms. Plasma and tissue levels of retinoic acid were not found to be causal. Human patients with alopecia attributed to fluconazole also underwent detailed assessment and in both our murine model and human cohort fluconazole induced telogen effluvium. Future work further examining the mechanism of fluconazole-induced alopecia should be undertaken

Increased axonal bouton dynamics in the aging mouse cortex

Aging is a major risk factor for many neurological diseases and is associated with mild cognitive decline. Previous studies suggest that aging is accompanied by reduced synapse number and synaptic plasticity in specific brain regions. However, most studies, to date, used either postmortem or ex vivo preparations and lacked key in vivo evidence. Thus, whether neuronal arbors and synaptic structures remain dynamic in the intact aged brain and whether specific synaptic deficits arise during aging remains unknown. Here we used in vivo two-photon imaging and a unique analysis method to rigorously measure and track the size and location of axonal boutons in aged mice. Unexpectedly, the aged cortex shows circuit-specific increased rates of axonal bouton formation, elimination, and destabilization. Compared with the young adult brain, large (i.e., strong) boutons show 10-fold higher rates of destabilization and 20-fold higher turnover in the aged cortex. Size fluctuations of persistent boutons, believed to encode long-term memories, also are larger in the aged brain, whereas bouton size and density are not affected. Our data uncover a striking and unexpected increase in axonal bouton dynamics in the aged cortex. The increased turnover and destabilization rates of large boutons indicate that learning and memory deficits in the aged brain arise not through an inability to form new synapses but rather through decreased synaptic tenacity. Overall our study suggests that increased synaptic structural dynamics in specific cortical circuits may be a mechanism for age-related cognitive decline

Microgravity induces proteomics changes involved in endoplasmic reticulum stress and mitochondrial protection

On Earth, biological systems have evolved in response to environmental stressors, interactions dictated by physical forces that include gravity. The absence of gravity is an extreme stressor and the impact of its absence on biological systems is ill-defined. Astronauts who have spent extended time under conditions of minimal gravity (microgravity) experience an array of biological alterations, including perturbations in cardiovascular function. We hypothesized that physiological perturbations in cardiac function in microgravity may be a consequence of alterations in molecular and organellar dynamics within the cellular milieu of cardiomyocytes. We used a combination of mass spectrometry-based approaches to compare the relative abundance and turnover rates of 848 and 196 proteins, respectively, in rat neonatal cardiomyocytes exposed to simulated microgravity or normal gravity. Gene functional enrichment analysis of these data suggested that the protein content and function of the mitochondria, ribosomes, and endoplasmic reticulum were differentially modulated in microgravity. We confirmed experimentally that in microgravity protein synthesis was decreased while apoptosis, cell viability, and protein degradation were largely unaffected. These data support our conclusion that in microgravity cardiomyocytes attempt to maintain mitochondrial homeostasis at the expense of protein synthesis. The overall response to this stress may culminate in cardiac muscle atrophy

Asfotase alfa therapy for children with hypophosphatasia

Background. Hypophosphatasia (HPP) is caused by loss-of-function mutation(s) of the gene that encodes the tissue-nonspecific isoenzyme of alkaline phosphatase (TNSALP). Consequently, cell-surface deficiency of TNSALP phosphohydrolase activity leads to extracellular accumulation of inorganic pyrophosphate, a natural substrate of TNSALP and inhibitor of mineralization. Children with HPP can manifest rickets, skeletal pain, deformity, fracture, muscle weakness, and premature deciduous tooth loss. Asfotase alfa is a recombinant, bone-targeted, human TNSALP injected s.c. to treat HPP. In 2012, we detailed the 1-year efficacy of asfotase alfa therapy for the life-threatening perinatal and infantile forms of HPP. Methods. Here, we evaluated the efficacy and safety of asfotase alfa treatment administered to children 6–12 years of age at baseline who were substantially impaired by HPP. Two radiographic scales quantitated HPP skeletal disease, including comparisons to serial radiographs from similarly affected historical control patients. Results. Twelve children receiving treatment were studied for 5 years. The 6-month primary endpoint was met, showing significant radiographic improvement. Additional significant improvements included patient growth, strength, motor function, agility, and quality of life, which for most patients meant achieving normal values for age- and sex-matched peers that were sustained at 5 years of treatment. For most, pain and disability resolved. Mild to moderate injection-site reactions were common and were sometimes associated with lipohypertrophy. Low anti–asfotase alfa antibody titers were noted in all patients. No evidence emerged for clinically important ectopic calcification or treatment resistance. Conclusions. Asfotase alfa enzyme replacement therapy has substantial and sustained efficacy with a good safety profile for children suffering from HPP. Trial Registration. ClinicalTrials.gov NCT00952484 (https://clinicaltrials.gov/ct2/show/NCT00952484) and NCT01203826 (https://clinicaltrials.gov/ct2/show/NCT01203826). Funding. Alexion Pharmaceuticals Inc. and Shriners Hospitals for Children

cAMP-Signalling Regulates Gametocyte-Infected Erythrocyte Deformability Required for Malaria Parasite Transmission.

Blocking Plasmodium falciparum transmission to mosquitoes has been designated a strategic objective in the global agenda of malaria elimination. Transmission is ensured by gametocyte-infected erythrocytes (GIE) that sequester in the bone marrow and at maturation are released into peripheral blood from where they are taken up during a mosquito blood meal. Release into the blood circulation is accompanied by an increase in GIE deformability that allows them to pass through the spleen. Here, we used a microsphere matrix to mimic splenic filtration and investigated the role of cAMP-signalling in regulating GIE deformability. We demonstrated that mature GIE deformability is dependent on reduced cAMP-signalling and on increased phosphodiesterase expression in stage V gametocytes, and that parasite cAMP-dependent kinase activity contributes to the stiffness of immature gametocytes. Importantly, pharmacological agents that raise cAMP levels in transmissible stage V gametocytes render them less deformable and hence less likely to circulate through the spleen. Therefore, phosphodiesterase inhibitors that raise cAMP levels in P. falciparum infected erythrocytes, such as sildenafil, represent new candidate drugs to block transmission of malaria parasites

Magnetic resonance imaging protocols for paediatric neuroradiology

Increasingly, radiologists are encouraged to have protocols for all imaging studies and to include imaging guidelines in care pathways set up by the referring clinicians. This is particularly advantageous in MRI where magnet time is limited and a radiologist’s review of each patient’s images often results in additional sequences and longer scanning times without the advantage of improvement in diagnostic ability. The difficulties of imaging small children and the challenges presented to the radiologist as the brain develops are discussed. We present our protocols for imaging the brain and spine of children based on 20 years experience of paediatric neurological MRI. The protocols are adapted to suit children under the age of 2 years, small body parts and paediatric clinical scenarios

Dynamics of Galactic Disks and Mergers at z~1.6: Spatially Resolved Spectroscopy with Keck Laser Guide Star Adaptive Optics

We present 0.2" resolution near-infrared integral field spectroscopy of H-alpha emission from six star forming galaxies at z~1.6 (look-back time of ~9.6 Gyr). These observations were obtained with OSIRIS using the Keck Laser Guide Star Adaptive Optics system. All sources have a compact spatial extent of ~1", with an average half light radius of r=2.9 kpc and average dereddened star formation rate of 22 Msolar per year. Based on H-alpha kinematics we find that these six galaxies are dynamically distinguishable, and we classify them as either merger or disk candidate systems. We find three merger systems (HDF-BX1287, HDF-BX1315, and Q1623-BX491) with varying geometries and dynamical properties. Three galaxies (HDF-BMZ1299, Q2343-BX344, and Q2343-BM145) are well-fit by an inclined-disk model with low velocity residuals (20 to 46 km/sec). An average plateau velocity of v_p=185 km/sec is achieved within 1.0 kpc. The majority of observed velocity dispersions (~88 km/sec) can be explained by the residual seeing halo, and are not intrinsic to our sources. However, one merger and one disk candidate have high velocity dispersions (> 200 km/sec) that cannot be solely explained by beam smearing. For two disk candidates, we detect [NII] emission and are able to map the [NII]/H-alpha ratio on kiloparsec scales. In both cases, [NII] emission is more concentrated than H-alpha emission (< 0.2"), and peak ratios are best explained by the presence of an AGN. These are among the weakest known AGN at high redshift, however their emission is strong enough to impact high redshift metallicity studies that use nebular ratios. All disk candidates have likely completed only a few orbital periods, and if left unperturbed are excellent candidates to become present-day spiral galaxies.Comment: 45 pages, 12 figures, resubmitted to Ap