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.

Concordance of disease severity among family members with ankylosing spondylitis?

Objective. The heritability of disease activity and function in ankylosing spondylitis (AS) have been estimated at 0.51 and 0.63 (i.e., 51% and 63%), respectively. We examined the concordance of disease severity among family members in terms of disease activity, function, radiological change, prevalence of iritis, and juvenile onset. Methods. Disease activity and functional impairment due to AS were studied using the Bath AS Disease Activity Index (BASDAI) and Functional Index (BASFI) self-administered questionnaires; radiographic involvement was measured using the Bath AS Radiology Index (BASRI) scale. Familial correlation of BASDAI and BASFI was assessed in 406 families with 2 or more cases, using the program PAP. Parent-child and sibling-sibling concordance for iritis and juvenile AS were also studied in these families. Heritability of radiological disease severity based on the BASRI was assessed in 29 families containing 60 affected individuals using the program SOLAR. Results. Correlations between parent-child pairs for disease activity and function were 0.07 for both. Correlations between sibling pairs for disease activity and function were 0.27 and 0.36, respectively. The children of AS parents with iritis were more likely to develop iritis [27/71 (38%)] than children of non-iritis AS parents [13/70 (19%)] (p = 0.01). Parents with JAS were more likely to have children with JAS [17/30 (57%) compared to non-JAS parents 34/111 (30%)] (p = 0.002). The heritability of radiological disease severity based on the BASRI was 0.62. Conclusion. While correlation in severity between parent and child is poor, siblings do resemble each other in terms of severity, supporting the findings of segregation studies indicating significant genetic dominance in the heritable component of disease activity. Significant parent-child concordance for iritis and juvenile disease onset suggest that there are genetic risk factors for these traits independent of those determining the risk of AS itself. The finding of significant heritability of radiological change (BASRI) provides support using an objective measure for the observed heritability of the questionnaire-assessed disease severity scores, ASDAI and BASFI.

Polymorphisms of the CYP2D6 gene increase susceptibility to ankylosing spondylitis

Ankylosing spondylitis (AS) is a common and highly familial rheumatic disorder. The sibling recurrence risk ratio for the disease is 63 and heritability assessed in twins > 90%. Although MHC genes, including HLA-B27, contribute only 20-50% of the genetic risk for the disease, no non-MHC gene has yet been convincingly demonstrated to influence either susceptibility to the disease or its phenotypic expression. Previous linkage and association studies have suggested the presence of a susceptibility gene for AS close to, or within, the cytochrome P450 2D6 gene (CYP2D6, debrisoquine hydroxylase) located at chromosome 22q13.1. We performed a linkage study of chromosome 22 in 200 families with AS affected sibling-pairs. Association of alleles of the CYP2D6 gene was examined by both case-control and within-family means. For case-control studies, 617 unrelated individuals with AS (361 probands from sibling-pair and parent-case trio families and 256 unrelated non-familial sporadic cases) and 402 healthy ethnically matched controls were employed. For within-family association studies, 361 families including 161 parent-case trios and 200 affected sibling-pair families were employed. Homozygosity for poor metabolizer alleles was found to be associated with AS. Heterozygosity for the most frequent poor metabolizer allele (CYP2D6*4) was not associated with increased susceptibility to AS. Significant within-family association of CYP2D6*4 alleles and AS was demonstrated. Weak linkage was also demonstrated between CYP2D6 and AS. We postulate that altered metabolism of a natural toxin or antigen by the CYP2D6 gene may increase susceptibility to AS.

Bearing capacity of cold-formed unlipped channels with restrained flanges under EOF and IOF load cases

Bearing failure is a form of localized failure that occurs when thin-walled cold-formed steel sections are subjected to concentrated loads or support reactions. To determine the bearing capacity of cold-formed channel sections, a unified design equation with different bearing coefficients is given in the current North American specification AISI S100 and the Australian/New Zealand standard AS/NZS 4600. However, coefficients are not available for unlipped channel sections that are normally fastened to supports through their flanges. Eurocode 3 Part 1.3 includes bearing capacity equations for different load cases, but does not distinguish between fastened and unfastened support conditions. Therefore, an experimental study was conducted to determine the bearing capacities of these sections as used in floor systems. Twenty-eight web bearing tests on unlipped channel sections with restrained flanges were conducted under End One Flange (EOF) and Interior One Flange (IOF) load cases. Using the results from this study, a new equation was proposed within the AISI S100 and AS/NZS 4600 guidelines to determine the bearing capacities of cold-formed unlipped channels with flanges fastened to supports. A new design rule was also proposed based on the direct strength method.

Medical negligence, causation and 'exceptional cases' under the civil liability legislation

Under the civil liability legislation enacted in most Australian jurisdictions, factual causation will be established if, on the balance of probabilities, the claimant can prove that the defendant's negligence was 'a necessary condition of the occurrence of the [claimant's] harm'. Causation will then be satisfied by showing that the harm would not have occurred 'but for' the defendant's breach of their duty of care. However, in an exceptional or appropriate case, sub-section 2 of the legislation provides that if the 'but for' test is not met, factual causation may instead be determined in accordance with other 'established principles'. In such a case, 'the court is to consider (amongst other relevant things) whether or not and why responsibility for the harm should be imposed' on the negligent party.

Comparison of Radiation Doses for Catheter Ablation Procedures for Atrial Fibrillation with Percutaneous Coronary Intervention Cases

Background: Catheter ablation procedures for atrial fibrillation (AF) may frequently require long fluoroscopic times. We sought to undertake a review of radiation safety practice in our Cardiac Electrophysiology Laboratory and implement changes to minimize fluoroscopic doses. We also sought to compare the results with radiation doses for percutaneous coronary intervention (PCI) cases performed in our hospital. Methods: Fluoroscopic times and doses for AF ablation procedures performed by a single operator on a Philips Integris H3000 image-intensifier were analysed for 11-month period. Results were compared with all PCI procedures performed over a similar period by multiple operators on a Philips Integris Allura FD system. Comprehensive review of radiation practice in the Electrophysiology laboratory identified the potential to reduce pulse frame rates and doses, and to narrow the field of interest without impacting the performance of the procedure. These changes were implemented and results analysed after a further 11 months. Results: In the pre-intervention period 50 AF catheter ablations had a mean fluoroscopic time of 86.4 min and mean fluoroscopic dose 68.4 Gy/cm2. Post-intervention 75 procedures had a mean fluorosocopic time of 68.9 min (p < 0.0001) and mean dose of 14.3 Gy/cm2 (p < 0.0001) 128 PCI procedures had a mean combined fluoroscopic and image acquisition time of 10.0 min and mean total dose 38.8 Gy/cm2. Conclusions: Catheter ablation procedures for AF may require lengthy use of fluoroscopy but simple modifications to radiation practice can result in marked reductions in radiation dose that compare favourably with PCI case doses

Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same region.

A large-scale analysis of genetic variants within putative miRNA binding sites in prostate cancer

Prostate cancer is the second most common malignancy among men worldwide. Genome-wide association studies have identified 100 risk variants for prostate cancer, which can explain approximately 33% of the familial risk of the disease. We hypothesized that a comprehensive analysis of genetic variations found within the 3' untranslated region of genes predicted to affect miRNA binding (miRSNP) can identify additional prostate cancer risk variants. We investigated the association between 2,169 miRSNPs and prostate cancer risk in a large-scale analysis of 22,301 cases and 22,320 controls of European ancestry from 23 participating studies. Twenty-two miRSNPs were associated (P<2.3×10(-5)) with risk of prostate cancer, 10 of which were within 7 genes previously not mapped by GWAS studies. Further, using miRNA mimics and reporter gene assays, we showed that miR-3162-5p has specific affinity for the KLK3 rs1058205 miRSNP T-allele, whereas miR-370 has greater affinity for the VAMP8 rs1010 miRSNP A-allele, validating their functional role. SIGNIFICANCE Findings from this large association study suggest that a focus on miRSNPs, including functional evaluation, can identify candidate risk loci below currently accepted statistical levels of genome-wide significance. Studies of miRNAs and their interactions with SNPs could provide further insights into the mechanisms of prostate cancer risk.

Strategically Pleading Intentional Torts in medical cases

The opportunities and challenges faced by litigants who strategically plead intentional torts are borne out by two recent medical cases. Both arose out of dental treatment. Dean v Phung established some key principles which were clarified in White v Johnston. Before considering those two cases it is worth examining the environment in which such intentional torts claims now exist. Following the Ipp Review of the Law of Negligence, non-uniform legislative changes to the law of negligence were introduced across Australia which have imposed limitations on liability and quantum of damages in cases where a person has been injured through the fault of another. While it seems that, given the limitation of the scope of the review and recommendations to negligently caused damage, the Ipp Review reforms were meant to be limited to injury resulting from negligent acts rather than intentional torts, the extent to which the civil liability legislation applies to intentional torts differs across Australia.

Osseointegrated total knee replacement connected to a lower limb prosthesis: 4 cases

Background and purpose — Osseointegrated implants are an alternative for prosthetic attachment in individuals with amputation who are unable to wear a socket. However, the load transmitted through the osseointegrated fixation to the residual tibia and knee joint can be unbearable for those with transtibial amputation and knee arthritis. We report on the feasibility of combining total knee replacement (TKR) with an osseointegrated implant for prosthetic attachment. Patients and methods — We retrospectively reviewed all 4 cases (aged 38–77 years) of transtibial amputations managed with osseointegration and TKR in 2012–2014. The below-the-knee prosthesis was connected to the tibial base plate of a TKR, enabling the tibial residuum and knee joint to act as weight-sharing structures. A 2-stage procedure involved connecting a standard hinged TKR to custom-made implants and creation of a skin-implant interface. Clinical outcomes were assessed at baseline and after 1–3 years of follow-up using standard measures of health-related quality of life, ambulation, and activity level including the questionnaire for transfemoral amputees (Q-TFA) and the 6-minute walk test. Results — There were no major complications, and there was 1 case of superficial infection. All patients showed improved clinical outcomes, with a Q-TFA improvement range of 29–52 and a 6-minute walk test improvement range of 37–84 meters. Interpretation — It is possible to combine TKR with osseointegrated implants.

A high-density association screen of 155 ion transport genes for involvement with common migraine

The clinical overlap between monogenic Familial Hemiplegic Migraine (FHM) and common migraine subtypes, and the fact that all three FHM genes are involved in the transport of ions, suggest that ion transport genes may underlie susceptibility to common forms of migraine. To test this leading hypothesis, we examined common variation in 155 ion transport genes using 5257 single nucleotide polymorphisms (SNPs) in a Finnish sample of 841 unrelated migraine with aura cases and 884 unrelated non-migraine controls. The top signals were then tested for replication in four independent migraine case-control samples from the Netherlands, Germany and Australia, totalling 2835 unrelated migraine cases and 2740 unrelated controls. SNPs within 12 genes (KCNB2, KCNQ3, CLIC5, ATP2C2, CACNA1E, CACNB2, KCNE2, KCNK12, KCNK2, KCNS3, SCN5A and SCN9A) with promising nominal association (0.00041 < P < 0.005) in the Finnish sample were selected for replication. Although no variant remained significant after adjusting for multiple testing nor produced consistent evidence for association across all cohorts, a significant epistatic interaction between KCNB2 SNP rs1431656 (chromosome 8q13.3) and CACNB2 SNP rs7076100 (chromosome 10p12.33) (pointwise P = 0.00002; global P = 0.02) was observed in the Finnish case-control sample. We conclude that common variants of moderate effect size in ion transport genes do not play a major role in susceptibility to common migraine within these European populations, although there is some evidence for epistatic interaction between potassium and calcium channel genes, KCNB2 and CACNB2. Multiple rare variants or trans-regulatory elements of these genes are not ruled out.

Evidence for an X-linked genetic component in familial typical migraine

Migraine is a common complex disorder that shows strong familial aggregation. There is a general increased prevalence of migraine in females compared with males, with recent studies indicating that migraine affects 18% of females compared with 6% of males. This preponderance of females among migraine sufferers coupled with evidence of an increased risk of migraine in first degree relatives of male probands but not in relatives of female probands suggests the possibility of an X-linked dominant gene. We report here the localization of a typical migraine susceptibility locus to the X chromosome. Of three large multigenerational migraine pedigrees two families showed significant excess allele sharing to Xq markers (P = 0.031 and P = 0.012). Overall analysis of data from all three pedigrees gave significant evidence in support of linkage and heterogeneity (HLOD = 3.1). These findings provide conclusive evidence that familial typical migraine is a heterogeneous disorder. We suggest that the localization of a migraine susceptibility locus to the X chromosome could in part explain the increased risk of migraine in relatives of male probands and may be involved in the increased female prevalence of this disorder.

Effect of temperature and precipitation on salmonellosis cases in South-East Queensland, Australia: An observational study

Objective Foodborne illnesses in Australia, including salmonellosis, are estimated to cost over $A1.25 billion annually. The weather has been identified as being influential on salmonellosis incidence, as cases increase during summer, however time series modelling of salmonellosis is challenging because outbreaks cause strong autocorrelation. This study assesses whether switching models is an improved method of estimating weather–salmonellosis associations. Design We analysed weather and salmonellosis in South-East Queensland between 2004 and 2013 using 2 common regression models and a switching model, each with 21-day lags for temperature and precipitation. Results The switching model best fit the data, as judged by its substantial improvement in deviance information criterion over the regression models, less autocorrelated residuals and control of seasonality. The switching model estimated a 5°C increase in mean temperature and 10 mm precipitation were associated with increases in salmonellosis cases of 45.4% (95% CrI 40.4%, 50.5%) and 24.1% (95% CrI 17.0%, 31.6%), respectively. Conclusions Switching models improve on traditional time series models in quantifying weather–salmonellosis associations. A better understanding of how temperature and precipitation influence salmonellosis may identify where interventions can be made to lower the health and economic costs of salmonellosis.

The Situated Cases

In this chapter, we meet the eight children whose documented lives are the heart of this book. The children are spread across 6 continents, so we have some textual traveling to do. We find each child in a local school. There they venture into literacy along official paths negotiated with their teachers and, also, along unofficial paths tied to their desire for peer companionship and social belonging (Corsaro, 2011; Nelson, 2007). We are most interested in their literate productions—their composing, be it with stick and dirt, pencil, crayons, and paper, tablet computer, or chalk and slate. Each child is a unique story, and each story is told by an author with particular interests in the goings-on in school, that is, with a particular angle of vision. All the authors, though, take us into a child’s educational circumstance; they give us a sense of the school’s physical site and its official curricular guidelines. Most importantly, they collectively allow us a global view of children as symbol users and social participants in the official and the unofficial worlds of school. No matter where young children go to school, they are expected to learn to “write” (although writing, as the cases illustrate, does not always mean “composing”)...