Investigation of the role of ANKH in ankylosing spondylitis

Objective The ank/ank mouse develops a phenotype similar to ankylosing spondylitis (AS) in humans. ANKH, the human homolog of the mutated gene in the ank/ank mouse, has been implicated in familial autosomal-dominant chondrocalcinosis and autosomal-dominant craniometaphyseal dysplasia. This study was undertaken to investigate the role of ANKH in susceptibility to and clinical manifestations of AS. Methods Sequence variants were identified by genomic sequencing of the 12 ANKH exons and their flanking splice sites in 48 AS patients; variants were then screened in 233 patients and 478 controls. Linkage to the ANKH locus was assessed in 185 affected-sibling-pair families. Results Five single-nucleotide polymorphisms were identified within the coding region and flanking splice sites. No association between either susceptibility to AS or its clinical manifestations and these novel polymorphisms, or between disease susceptibility and 3 known promoter variants, was seen. No linkage between the ANKH locus and AS was observed. Multipoint exclusion mapping rejected the hypothesis of a locus of a magnitude λ≥1.4 (logarithm of odds score <-2) (equivalent to a genetic contribution of >10% to the AS sibling recurrence risk ratio) within this area contributing to AS. Conclusion These findings indicate that ANKH is not significantly involved in susceptibility to or clinical manifestations of AS.

Ratcheting and wear behavior of Australian rail steel: Experimental investigation of material properties and sampling method

To The ratcheting behavior of high-strength rail steel (Australian Standard AS1085.1) is studied in this work for the purpose of predicting wear and damage to the rail surface. Historically, researchers have used circular test coupons obtained from the rail head to conduct cyclic load tests, but according to hardness profile data, considerable variation exists across the rail head section. For example, the induction-hardened rail (AS1085.1) shows high hardness (400-430 HV100) up to four-millimeters into the rail head’s surface, but then drops considerably beyond that. Given that cyclic test coupons five millimeters in diameter at the gauge area are usually taken from the rail sample, there is a high probability that the original surface properties of the rail do not apply across the entire test coupon and, therefore, data representing only average material properties are obtained. In the literature, disks (47 mm in diameter) for a twin-disk rolling contact test machine have been obtained directly from the rail sample and used to validate rolling contact fatigue wear models. The question arises: How accurate are such predictions? In this research paper, the effect of rail sampling position on the ratcheting behavior of AS1085.1 rail steel was investigated using rectangular shaped specimens. Uniaxial stress-controlled tests were conducted with samples obtained at four different depths to observe the ratcheting behaviour of each. Micro-hardness measurements of the test coupons were carried out to obtain a constitutive relationship to predict the effect of depth on the ratcheting behaviour of the rail material. This work ultimately assists the selection of valid material parameters for constitutive models in the study of rail surface ratcheting.

Experimental investigation of wear modes of hardened rail material used in Australian heavy-haul railways

This work investigates the effects of contact pressure and geometry in rolling-contact wear tests by using discs with different radii of curvature to simulate the varying contact conditions that may be typically found in the field. The tests were conducted without any significant amount of traction, but micro slip was still observed due to contact deformation. Moreover, variation of contact pressure was observed due to contact patch elongation and diameter reduction. Rolling contact fatigue, adhesive and sliding wear were observed on the curved contact interface. The development of different wear regimes and material removal phenomena were analyzed using microscopic images in order to broaden the understanding of the wear mechanisms occurring in the rail-wheel contact.

A multimarker approach to diagnose and stratify heart failure

Background We have previously demonstrated that circulating NT-proBNP is truncated at the N and C termini. Aims of this study are three-fold: firstly to determine whether the NT-proBNP levels correlate with NYHA functional classes when measuring with different antibody pairs; secondly to evaluate the diagnostic potential of ProBNP and; thirdly to investigate whether combining NT-proBNP assays with or without ProBNP would lead to better diagnostic accuracies. Methods Plasma samples were collected from healthy controls (n = 52) and HF patients (n = 46). Customized AlphaLISA® immunoassays were developed and validated to measure the concentrations of proBNP and NT-proBNP (with antibodies targeting 13–45, 13–76, 28–76). The diagnostic performance and predictive value of proBNP and NT-proBNP assays and their combinations were evaluated. Results Plasma proBNP assay showed acceptable diagnostic performance. NT-proBNP13–76 assay is useful in diagnosing and stratifying HF patients. The diagnostic performance of NT-proBNP13–76 demonstrated improvement over commercial NT-proBNP tests. The combination of NT-proBNP13–76 with NT-proBNP28–76 assays gave the best diagnostic assay performance. Conclusion Our results demonstrate that while there is major heterogeneity in circulating NT-proBNP, specific epitopes of the peptides are extraordinarily stable, providing ideal targets for clinically useful diagnostic assays. Future new clinical diagnostic clinical trials should include a multimarker approach rather than using a single marker to diagnose HF.

A preliminary investigation into adrenal responsiveness and outcomes in patients with cardiogenic shock after acute myocardial infarction

PURPOSE: This study investigated the significance of baseline cortisol levels and adrenal response to corticotropin in shocked patients after acute myocardial infarction (AMI). METHODS: A short corticotropin stimulation test was performed in 35 patients with cardiogenic shock after AMI by intravenously injecting of 250 μg of tetracosactrin (Synacthen). Blood samples were obtained at baseline (T0) before and at 30 (T30) and 60 (T60) minutes after the test to determine plasma total cortisol (TC) and free cortisol concentrations. The main outcome measure was in-hospital mortality and its association with T0 TC and maximum response to corticotropin (maximum difference [Δ max] in cortisol levels between T0 and the highest value between T30 and T60). RESULTS: The in-hospital mortality was 37%, and the median time to death was 4 days (interquartile range, 3-9 days). There was some evidence of an increased mortality in patients with T0 TC concentrations greater than 34 μg/dL (P=.07). Maximum difference by itself was not an independent predictor of death. Patients with a T0 TC 34 μg/dL or less and Δ max greater than 9 μg/dL appeared to have the most favorable survival (91%) when compared with the other 2 groups: T0 34 μg/dL or less and Δ max 9 μg/dL or less or T0 34 μg/dL or higher and Δ max greater than 9 μg/dL (75%; P=.8) and T0 greater than 34 μg/dL and Δ max 9 μg/dL or less (60%; P=.02). Corticosteroid therapy was associated with an increased mortality (P=.03). There was a strong correlation between plasma TC and free cortisol (r=0.85). CONCLUSIONS: A high baseline plasma TC was associated with a trend toward increased mortality in patients with cardiogenic shock post-AMI. Patients with lower baseline TC, but with an inducible adrenal response, appeared to have a survival benefit. A prognostic system based on basal TC and Δ max similar to that described in septic shock appears feasible in this cohort. Corticosteroid therapy was associated with adverse outcomes. These findings require further validation in larger studies.

An investigation into the effectiveness of sensory modulation in reducing seclusion within an acute mental health unit

In this paper we report the findings from an evaluation of the introduction of sensory modulation (SM) in an acute mental health inpatient unit. It was expected that SM could be used to help settle patients experiencing high levels of disturbance and that as a result, there would be less need for use of more restrictive seclusion practices. The evaluation took place in a hospital in south-east Queensland, Australia. SM was introduced in one acute unit while the other served as a control. The evaluation comprised two studies. In the first study we aimed to determine whether SM reduced the level of disturbance among patients given the opportunity to use it. In the second study we aimed to find out whether the introduction of SM reduced the frequency and duration of seclusion. In study 1, we found that most patients reported marked reduction in disturbance after using SM and there was a very large effect size for the group as a whole. In study 2, we found that frequency of seclusion dropped dramatically in the unit that introduced SM but rose slightly in the unit that did not have access to SM. The change in seclusion rate was highly significant (χ2 = 49.1, df = 1, p < 0.001). Results are discussed, having reference to the limitations inherent in a naturalistic study.

A process mining-based investigation of adverse events in care processes

This paper proposes the Clinical Pathway Analysis Method (CPAM) approach that enables the extraction of valuable organisational and medical information on past clinical pathway executions from the event logs of healthcare information systems. The method deals with the complexity of real-world clinical pathways by introducing a perspective-based segmentation of the date-stamped event log. CPAM enables the clinical pathway analyst to effectively and efficiently acquire a profound insight into the clinical pathways. By comparing the specific medical conditions of patients with the factors used for characterising the different clinical pathway variants, the medical expert can identify the best therapeutic option. Process mining-based analytics enables the acquisition of valuable insights into clinical pathways, based on the complete audit traces of previous clinical pathway instances. Additionally, the methodology is suited to assess guideline compliance and analyse adverse events. Finally, the methodology provides support for eliciting tacit knowledge and providing treatment selection assistance.

Optimal management of the critically Ill: Anaesthesia, monitoring, data capture, and point-of-care technological practices in ovine models of critical care

Animal models of critical illness are vital in biomedical research. They provide possibilities for the investigation of pathophysiological processes that may not otherwise be possible in humans. In order to be clinically applicable, the model should simulate the critical care situation realistically, including anaesthesia, monitoring, sampling, utilising appropriate personnel skill mix, and therapeutic interventions. There are limited data documenting the constitution of ideal technologically advanced large animal critical care practices and all the processes of the animal model. In this paper, we describe the procedure of animal preparation, anaesthesia induction and maintenance, physiologic monitoring, data capture, point-of-care technology, and animal aftercare that has been successfully used to study several novel ovine models of critical illness. The relevant investigations are on respiratory failure due to smoke inhalation, transfusion related acute lung injury, endotoxin-induced proteogenomic alterations, haemorrhagic shock, septic shock, brain death, cerebral microcirculation, and artificial heart studies. We have demonstrated the functionality of monitoring practices during anaesthesia required to provide a platform for undertaking systematic investigations in complex ovine models of critical illness.

Investigation of the mechanical behavior of kangaroo humeral head cartilage tissue by a porohyperelastic model based on the strain-rate-dependent permeability

Solid–interstitial fluid interaction, which depends on tissue permeability, is significant to the strain-rate-dependent mechanical behavior of humeral head (shoulder) cartilage. Due to anatomical and biomechanical similarities to that of the human shoulder, kangaroos present a suitable animal model. Therefore, indentation experiments were conducted on kangaroo shoulder cartilage tissues from low (10−4/s) to moderately high (10−2/s) strain-rates. A porohyperelastic model was developed based on the experimental characterization; and a permeability function that takes into account the effect of strain-rate on permeability (strain-rate-dependent permeability) was introduced into the model to investigate the effect of rate-dependent fluid flow on tissue response. The prediction of the model with the strain-rate-dependent permeability was compared with those of the models using constant permeability and strain-dependent permeability. Compared to the model with constant permeability, the models with strain-dependent and strain-rate-dependent permeability were able to better capture the experimental variation at all strain-rates (p<0.05). Significant differences were not identified between models with strain-dependent and strain-rate-dependent permeability at strain-rate of 5×10−3/s (p=0.179). However, at strain-rate of 10−2/s, the model with strain-rate-dependent permeability was significantly better at capturing the experimental results (p<0.005). The findings thus revealed the significance of rate-dependent fluid flow on tissue behavior at large strain-rates, which provides insights into the mechanical deformation mechanisms of cartilage tissues.

Transformation of public space in contemporary urban neighbourhoods of Kathmandu Valley, Nepal: An investigation of changing provision, use and meaning

This research examined the transformation of public space in contemporary urban neighbourhoods of the Kathmandu Valley in Nepal. The development of neighbourhood public space remains a considerable challenge in the present changing context, with significant consequences for public life and social interaction. The findings will aid policy makers, urban planners and designers in addressing the adverse effects of the current urban growth and change, and in winning back public space for the well-being of the local community.

Consensus statement on the investigation and management of non-radiographic axial spondyloarthritis (nr-axSpA)

Aim Non-radiographic axial spondyloarthritis (nr-axSpA) is axial inflammatory arthritis where plain radiographic damage is not evident. An unknown proportion of these patients will progress to ankylosing spondylitis (AS). The increasing recognition of nr-axSpA has been greatly assisted by the widespread use of magnetic resonance imaging. The aim of this article was to construct a set of consensus statements based on a literature review to guide investigation and promote best management of nr-axSpA. Methods A literature review using Medline was conducted covering the major investigation modalities and treatment options available. A group of rheumatologists and a radiologist with expertise in investigation and management of SpA reviewed the literature and formulated a set of consensus statements. The Grade system encompassing the level of evidence and strength of recommendation was used. The opinion of a patient with nr-axSpA and a nurse experienced in the care of SpA patients was also sought and included. Results The literature review found few studies specifically addressing nr-axSpA, or if these patients were included, their results were often not separately reported. Fourteen consensus statements covering investigation and management of nr-axSpA were formulated. The level of agreement was high and ranged from 8.1 to 9.8. Treatment recommendations vary little with established AS, but this is primarily due to the lack of available evidence on the specific treatment of nr-axSpA. Conclusion The consensus statements aim to improve the diagnosis and management of nr-axSpA. We aim to raise awareness of this condition by the public and doctors and promote appropriate investigation and management.

High-resolution SNP microarray investigation of copy number variations on chromosome 18 in a control cohort

Copy number variations (CNVs) as described in the healthy population are purported to contribute significantly to genetic heterogeneity. Recent studies have described CNVs using lymphoblastoid cell lines or by application of specifically developed algorithms to interrogate previously described data. However, the full extent of CNVs remains unclear. Using high-density SNP array, we have undertaken a comprehensive investigation of chromosome 18 for CNV discovery and characterisation of distribution and association with chromosome architecture. We identified 399 CNVs, of which loss represents 98%, 58% are less than 2.5 kb in size and 71% are intergenic. Intronic deletions account for the majority of copy number changes with gene involvement. Furthermore, one-third of CNVs do not have putative breakpoints within repetitive sequences. We conclude that replicative processes, mediated either by repetitive elements or microhomology, account for the majority of CNVs in the healthy population. Genomic instability involving the formation of a non-B structure is demonstrated in one region.

Finite element analysis investigation of response of pumpkin tissue under uniaxial loading

Finite element analysis (FEA) models of uniaxial loading of pumpkin peel and flesh tissues were developed and validated using experimental results. The tensile model was developed for both linear elastic and plastic material models, the compression model was develop d only with the plastic material model. The outcomes of force versus time curves obtained from FEA models followed similar pattern to the experimental curves however the curve resulted with linear elastic material properties had a higher difference with the experimental curves. The values of predicted forces were determined and compared with the experimental curve. An error indicator was introduced and computed for each case and compared. Additionally Root Mean Square Error (RMSE) values were also calculated for each model and compared. The results of modelling were used to develop material model for peel and flesh tissues in FEA modelling of mechanical peeling of tough skinned vegetables.

Investigation of the role of ENPP1 and TNAP genes in chondrocalcinosis

Objectives. Extracellular inorganic pyrophosphate (ePPi) inhibits certain forms of pathological mineralization while promoting others. Three molecules involved in ePPi regulation are important candidates for the development of calcium pyrophosphate dihydrate chondrocalcinosis (CPPD CC). These include ANKH, ectonucleotide pyrophosphatase (ENPP1) and TNAP. We have previously showed that genetic variation in ANKH is a cause of autosomal dominant familial CC and also some sporadic cases of CPPD CC. We now investigate the possible role of ENPP1 and TNAP in CPPD CC. Methods. Exons, untranslated regions (UTR) and exon-intron boundaries of ENPP1 and TNAP were sequenced using ABI Big Dye chemistry on automated sequencers. Sixteen variants were identified (3 in ENPP1 and 13 in TNAP) and were subsequently genotyped in 128 sporadic Caucasian CPPD CC patients and 600 healthy controls using a combination of polymerase chain reaction/restriction fragment-length polymorphism analysis or using Taqman. Allele and genotype frequencies were compared between cases and controls using the χ 2 test. Linkage disequilibrium, haplotype and the single nucleotide polymorphism-specific analyses were also performed. This study had 80% power to detect an odds ratio of 2.2 or more at these loci. Results. No difference was observed in the allele or genotype frequencies between patients and controls at either ENPP1 or TNAP. Conclusions. Polymorphisms of ENPP1 and TNAP are not major determinants of susceptibility to CC in the population studied. Further studies of the aetiology of sporadic CPPD CC are required to determine its causes.

Acute liver failure in children : a regional experience

Objective: To review the outcome of acute liver failure (ALF) and the effect of liver transplantation in children in Australia. Methodology: A retrospective review was conducted of all paediatric patients referred with acute liver failure between 1985 and 2000 to the Queensland Liver Transplant Service, a paediatric liver transplant centre based at the Royal Children's Hospital, Brisbane, that is one of three paediatric transplant centres in Australia. Results: Twenty-six patients were referred with ALF. Four patients did not require transplantation and recovered with medical therapy while two were excluded because of irreversible neurological changes and died. Of the 20 patients considered for transplant, three refused for social and/or religious reasons, with 17 patients listed for transplantation. One patient recovered spontaneously and one died before receiving a transplant. There were 15 transplants of which 40% (6/15) were < 2 years old. Sixty-seven per cent (10/15) survived > 1 month after transplantation. Forty per cent (6/15) survived more than 6 months after transplant. There were only four long term survivors after transplant for ALF (27%). Overall, 27% (6/22) of patients referred with ALF survived. Of the 16 patients that died, 44% (7/16) were from neurological causes. Most of these were from cerebral oedema but two patients transplanted for valproate hepatotoxicity died from neurological disease despite good graft function. Conclusions: Irreversible neurological disease remains a major cause of death in children with ALF. We recommend better patient selection and early referral and transfer to a transplant centre before onset of irreversible neurological disease to optimize outcome of children transplanted for ALF.