Loading compliance of static load bearing exercises performed by transfemoral amputees fitted with an osseointegrated implant

Background To date bone-anchored prostheses are used to alleviate the concerns caused by socket suspended prostheses and to improve the quality of life of transfemoral amputees (TFA). Currently, two implants are commercially available (i.e., OPRA (Integrum AB, Sweden), ILP (Orthodynamics GmbH, Germany)). [1-17]The success of the OPRA technique is codetermined by the rehabilitation program. TFA fitted with an osseointegrated implant perform progressive mechanical loading (i.e. static load bearing exercises (LBE)) to facilitate bone remodelling around the implant.[18, 19] Aim This study investigated the trustworthiness of monitoring the load prescribed (LP) during experimental static LBEs using the vertical force provided by a mechanical bathroom scale that is considered a surrogate of the actual load applied. Method Eleven unilateral TFAs fitted with an OPRA implant performed five trials in four loading conditions. The forces and moments on the three axes of the implant were measured directly with an instrumented pylon including a six-channel transducer. The “axial” and “vectorial” comparisons corresponding to the difference between the force applied on the long axis of the fixation and LP as well as the resultant of the three components of the load applied and LP, respectively were analysed Results For each loading condition, Wilcoxon One-Sample Signed Rank Tests were used to investigate if significant differences (p<0.05) could be demonstrated between the force applied on the long axis and LP, and between the resultant of the force and LP. The results demonstrated that the raw axial and vectorial differences were significantly different from zero in all conditions (p<0.05), except for the vectorial difference for the 40 kg loading condition (p=0.182). The raw axial difference was negative for all the participants in every loading condition, except for TFA03 in the 10 kg condition (11.17 N). Discussion & Conclusion This study showed a significant lack of axial compliance. The load applied on the long axis was significantly smaller than LP in every loading condition. This led to a systematic underloading of the long axis of the implant during the proposed experimental LBE. Monitoring the vertical force might be only partially reflective of the actual load applied, particularly on the long axis of the implant.

Fine mapping and replication of genetic risk Loci in primary sclerosing cholangitis

Background and aims. Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease characterized by progressive inflammation and fibrosis of the bile ducts eventually leading to biliary cirrhosis. Recent genetic studies in PSC have identified associations at 2q13, 2q35, 3p21, 4q27, 13q31 and suggestive association at 10p15. The aim of this study was to further characterize and refine the genetic architecture of PSC. Methods. We analyzed previously reported associated SNPs at four of these non-HLA loci and 59 SNPs tagging the IL-2/IL-21 (4q27) and IL2RA (10p15) loci in 992 UK PSC cases and 5162 healthy UK controls. Results. The most associated SNPs identified were rs3197999 (3p21 (MST1), p = 1.9 × 10 -6, OR A vs G = 1.28, 95% CI (1.16-1.42)); rs4147359 (10p15 (IL2RA), p = 2.6 × 10 -4, OR A vs G = 1.20, 95% CI (1.09-1.33)) and rs12511287 (4q27 (IL-2/IL-21), p = 3.0 × 10 -4, OR A vs T = 1.21, 95% CI (1.09-1.35)). In addition, we performed a meta-analysis for selected SNPs using published summary statistics from recent studies. We observed genome-wide significance for rs3197999 (3p21 (MST1), P combined = 3.8 × 10 -12) and rs4147359 (10p15 (IL2RA), P combined = 1.5 × 10 -8). Conclusion. We have for the first time confirmed the association of PSC with genetic variants at 10p15 (IL2RA) locus at genome-wide significance and replicated the associations at MST1 and IL-2/IL-21 loci in a large homogeneous UK population. These results strongly implicate the role of IL-2/IL2RA pathway in PSC and provide further confirmation of MST1 association. © Informa Healthcare.

Novel ANKH amino terminus mutation (Pro5Ser) associated with early-onset calcium pyrophosphate disease with associated phosphaturia

This report describes a 32-year-old woman presenting since childhood with progressive calcium pyrophosphate disease (CPPD), characterized by severe arthropathy and chondrocalcinosis involving multiple peripheral joints and intervertebral disks. Because ANKH mutations have been previously described in familial CPPD, the proband's DNA was assessed at this locus by direct sequencing of promoter and coding regions and revealed 3 sequence variants in ANKH. Sequences of exon 1 revealed a novel isolated nonsynonymous mutation (c.13 C>T), altering amino acid in codon 5 from proline to serine (CCG>TCG). Sequencing of parental DNA revealed an identical mutation in the proband's father but not the mother. Subsequent clinical evaluation demonstrated extensive chondrocalcinosis and degenerative arthropathy in the proband's father. In summary, we report a novel mutation, not previously described, in ANKH exon 1, wherein serine replaces proline, in a case of early-onset severe CPPD associated with metabolic abnormalities, with similar findings in the proband's father.

Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis

Multiple sclerosis is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurological disturbance followed by progressive accumulation of disability. Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals, and systematic attempts to identify linkage in multiplex families have confirmed that variation within the major histocompatibility complex (MHC) exerts the greatest individual effect on risk. Modestly powered genome-wide association studies (GWAS) have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects have a key role in disease susceptibility. Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the analysis of sample sizes that are beyond the numbers currently available to individual research groups. In a collaborative GWAS involving 9,772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci. Within the MHC we have refined the identity of the HLA-DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the class I region. Immunologically relevant genes are significantly overrepresented among those mapping close to the identified loci and particularly implicate T-helper-cell differentiation in the pathogenesis of multiple sclerosis. © 2011 Macmillan Publishers Limited. All rights reserved.

Genome-wide study of familial juvenile hyperuricaemic (gouty) nephropathy (FJHN) indicates a new locus, FJHN3, linked to chromosome 2p22.1-p21

Familial juvenile hyperuricaemic (gouty) nephropathy (FJHN), is an autosomal dominant disease associated with a reduced fractional excretion of urate, and progressive renal failure. FJHN is genetically heterogeneous and due to mutations of three genes: uromodulin (UMOD), renin (REN) and hepatocyte nuclear factor-1beta (HNF-1β) on chromosomes 16p12, 1q32.1, and 17q12, respectively. However, UMOD, REN or HNF-1β mutations are found in only ~45% of FJHN probands, indicating the involvement of other genetic loci in ~55% of probands. To identify other FJHN loci, we performed a single nucleotide polymorphism (SNP)-based genome-wide linkage analysis, in six FJHN families in whom UMOD, HNF-1β and REN mutations had been excluded. Parametric linkage analysis using a 'rare dominant' model established linkage in five of the six FJHN families, with a LOD score >+3, at 0% recombination, between FJHN and SNPs at chromosome 2p22.1-p21. Analysis of individual recombinants in two unrelated affected individuals defined a ~5.5 Mbp interval, flanked telomerically by SNP RS372139 and centromerically by RS896986 that contained the locus, designated FJHN3. The interval contains 28 genes, and DNA sequence analysis of the most likely candidate, solute carrier family 8 member 1 (SLC8A1), did not identify any abnormalities in the FJHN3 probands. FJHN3 is likely located within a ~5.5 Mbp interval on chromosome 2p22.1-p21, and identifying the genetic abnormality will help to further elucidate mechanisms predisposing to gout and renal failure.

The multiple sclerosis whole blood mRNA transcriptome and genetic associations indicate dysregulation of specific T cell pathways in pathogenesis

Multiple sclerosis (MS) is an autoimmune disease with a genetic component, caused at least in part by aberrant lymphocyte activity. The whole blood mRNA transcriptome was measured for 99 untreated MS patients: 43 primary progressive MS, 20 secondary progressive MS, 36 relapsing remitting MS and 45 age-matched healthy controls. The ANZgene Multiple Sclerosis Genetics Consortium genotyped more than 300 000 SNPs for 115 of these samples. Transcription from genes on translational regulation, oxidative phosphorylation, immune synapse and antigen presentation pathways was markedly increased in all forms of MS. Expression of genes tagging T cells was also upregulated (P < 10-12) in MS. A T cell gene signature predicts disease state with a concordance index of 0.79 with age and gender as co-variables, but the signature is not associated with clinical course or disability. The ANZgene genome wide association screen identified two novel regions with genome wide significance: one encoding the T cell co-stimulatory molecule, CD40; the other a region on chromosome 12q13-14. The CD40 haplotype associated with increased MS susceptibility has decreased gene expression in MS (P < 0.0007). The second MS susceptibility region includes 17 genes on 12q13-14 in tight linkage disequilibrium. Of these, only 13 are expressed in leukocytes, and of these the expression of one, FAM119B, is much lower in the susceptibility haplotype (P tdthomlt; 10-14). Overall, these data indicate dysregulation of T cells can be detected in the whole blood of untreated MS patients, and supports targeting of activated T cells in therapy for all forms of MS.

A recurrent mutation in the BMP type I receptor ACVR1 causes inherited and sporadic fibrodysplasia ossificans progressiva

Fibrodysplasia ossificans progressiva (FOP) is a rare autosomal dominant disorder of skeletal malformations and progressive extraskeletal ossification. We mapped FOP to chromosome 2q23-24 by linkage analysis and identified an identical heterozygous mutation (617G→A; R206H) in the glycine-serine (GS) activation domain of ACVR1, a BMP type I receptor, in all affected individuals examined. Protein modeling predicts destabilization of the GS domain, consistent with constitutive activation of ACVR1 as the underlying cause of the ectopic chondrogenesis, osteogenesis and joint fusions seen in FOP.

The purposes of history? Curriculum studies, invisible objects and twenty-first century societies

A new intellectual epoch has generated new enterprises to suit changed beliefs and circumstances. A widespread sentiment in both formal historiography and curriculum studies reduces the “new” to the question of how knowledge is recognized as such, how it is gained, and how it is represented in narrative form. Whether the nature of history and conceptions of knowledge are, or ought to be, central considerations in curriculum studies and reducible to purposes or elevated as present orientated requires rethinking. This paper operates as an incitement to discourse that disrupts the protection and isolation of primary categories in the field whose troubling is overdue. In particular, the paper moves through several layers that highlight the lack of settlement regarding the endowment of objects for study with the status of the scientific. It traces how some “invisible” things have been included within the purview of curriculum history as objects of study and not others. The focus is the making of things deemed invisible into scientific objects (or not) and the specific site of analysis is the work of William James (1842-1910). James studied intensely both child mind and the ghost, the former of which becomes scientized and legitimated for further study, the latter abjected. This contrast opens key points for reconsideration regarding conditions of proof, validation criteria, and subject matters and points to opportunities to challenge some well-rehearsed foreclosures within progressive politics and education.

The Post-Illumination Pupil Response (PIPR)

Purpose The post-illumination pupil response (PIPR) has been quantified using four metrics, but the spectral sensitivity of only one is known; here we determine the other three. To optimize the human PIPR measurement, we determine the protocol producing the largest PIPR, the duration of the PIPR, and the metric(s) with the lowest coefficient of variation. Methods The consensual pupil light reflex (PLR) was measured with a Maxwellian view pupillometer. - Experiment 1: Spectral sensitivity of four PIPR metrics [plateau, 6 s, area under curve (AUC) early and late recovery] was determined from a criterion PIPR to a 1s pulse and fitted with Vitamin A1 nomogram (λmax = 482nm). - Experiment 2: The PLR was measured as a function of three stimulus durations (1s, 10s, 30s), five irradiances spanning low to high melanopsin excitation levels (retinal irradiance: 9.8 to 14.8 log quanta.cm-2.s-1), and two wavelengths, one with high (465nm) and one with low (637nm) melanopsin excitation. Intra and inter-individual coefficients of variation (CV) were calculated. Results The melanopsin (opn4) photopigment nomogram adequately describes the spectral sensitivity of all four PIPR metrics. The PIPR amplitude was largest with 1s short wavelength pulses (≥ 12.8 log quanta.cm-2.s-1). The plateau and 6s PIPR showed the least intra and inter-individual CV (≤ 0.2). The maximum duration of the sustained PIPR was 83.0±48.0s (mean±SD) for 1s pulses and 180.1±106.2s for 30s pulses (465nm; 14.8 log quanta.cm-2.s-1). Conclusions All current PIPR metrics provide a direct measure of the intrinsic melanopsin photoresponse. To measure progressive changes in melanopsin function in disease, we recommend that the PIPR be measured using short duration pulses (e.g., ≤ 1s) with high melanopsin excitation and analyzed with plateau and/or 6s metrics. Our PIPR duration data provide a baseline for the selection of inter-stimulus intervals between consecutive pupil testing sequences.

The post-illumination pupil response of melanopsin expressing retinal ganglion cells

Purpose The post-illumination pupil response (PIPR) has been quantified in the literature by four metrics. The spectral sensitivity of only one metric is known and this study quantifies the other three. To optimize the measurement of the PIPR in humans, we also determine the stimulus protocol producing the largest PIPR, the duration of the PIPR, and the metric(s) with the lowest coefficient of variation. Methods The consensual pupil light reflex (PLR) was measured with a Maxwellian view pupillometer (35.6° diameter stimulus). - Experiment 1: Spectral sensitivity of four PIPR metrics [plateau, 6 s, area under curve (AUC) early and late recovery] was determined from a criterion PIPR (n = 2 participants) to a 1 s pulse at five wavelengths (409-592nm) and fitted with Vitamin A nomogram (ƛmax = 482 nm). - Experiment 2: The PLR was measured in five healthy participants [29 to 42 years (mean = 32.6 years)] as a function of three stimulus durations (1 s, 10 s, 30 s), five irradiances spanning low to high melanopsin excitation levels (retinal irradiance: 9.8 to 14.8 log quanta.cm-2.s-1), and two wavelengths, one with high (465 nm) and one with low (637 nm) melanopsin excitation. Intra and inter-individual coefficients of variation (CV) were calculated. Results The melanopsin (opn4) photopigment nomogram adequately described the spectral sensitivity derived from all four PIPR metrics. The largest PIPR amplitude was observed with 1 s short wavelength pulses (retinal irradiance ≥ 12.8 log quanta.cm-2.s-1). Of the 4 PIPR metrics, the plateau and 6 s PIPR showed the least intra and inter-individual CV (≤ 0.2). The maximum duration of the sustained PIPR was 83.4 ± 48.0 s (mean ± SD) for 1 s pulses and 180.1 ± 106.2 s for 30 s pulses (465 nm; 14.8 log quanta.cm-2.s-1). Conclusions All current PIPR metrics provide a direct measure of intrinsic melanopsin retinal ganglion cell function. To measure progressive changes in melanopsin function in disease, we recommend that the intrinsic melanopsin response should be measured using a 1 s pulse with high melanopsin excitation and the PIPR should be analyzed with the plateau and/or 6 s metrics. That the PIPR can have a sustained constriction for as long as 3 minutes, our PIPR duration data provide a baseline for the selection of inter-stimulus intervals between consecutive pupil testing sequences.

Fatigue crack growth under pulsatile pressure and plaque rupture

Identification of vulnerable plaque pre-rupture is extremely important for patient risk stratification. The mechanism of plaque rupture is still not entirely clear, but it is thought to be a process involving multiple factors. From a biomechanical viewpoint, plaque rupture is usually seen as a structural failure when the plaque cannot resist the hemodynamic blood pressure and shear stress exerted on it. However, the cardiovascular system is naturally a cyclical hemodynamic environment, and myocardial infarction can be a symptomatically quiescent but potentially progressive process when plaque ruptures at stresses much lower than its strength. Therefore, fatigue accumulation is a possible mechanism for plaque rupture. In this study, a crack growth model was developed, and the previously-mentioned hypothesis was tested by conducting a comparative study between 18 symptomatic and 16 asymptomatic patients with carotid stenosis.

MRI-based fatigue analysis predicts plaque vulnerability: A study comparing symptomatic and asymptomatic individuals

BACKGROUND: Rupture of atheromatous plaque in the carotid artery often leads to thrombosis and subsequent stroke. The mechanism of plaque rupture is not entirely clear but is thought to be a multi-factorial process involving thinning and weakening of the fibrous cap and biomechanical stress as the trigger leading to plaque rupture. As the cardiovascular system is a classic fatigue environment, the weakening of plaque leading to rupture may be a fatigue process, which is a symptomatically quiescent but potentially progressive failure process. In this study, we used a fatigue analysis based on in vivo magnetic resonance imaging (MRI) to investigate the rupture initiation location, crack propagation path and fatigue life within plaques of asymptomatic and symptomatic individuals. METHODS: Forty non-consecutive subjects (20 symptomatic and 20 asymptomatic) underwent high-resolution multi-sequence in vivo MRI of the carotid bifurcation. Fatigue analysis was performed based on the plaque geometry derived from in vivo MRI of the carotid artery at the point of maximum stenosis. Paris’ Law in fracture mechanics is adopted to determine the fatigue crack growth rate. Incremental crack propagation was dynamically simulated based on stress distributions. Plaque initiation location, crack propagation path and fatigue cycle of symptomatic and asymptomatic individuals were compared. RESULTS: Cracks were often found to begin at the lumen wall at areas of stress concentration. The preferred rupture direction was radial from the lumen center. The crack initially advanced slowly but accelerated as it developed, depending on plaque morphology. The fatigue cycles of symptomatic plaques were significantly less than those in the asymptomatic group (2.3 ± 0.9 vs 3.1 ± 0.7 (x106); p = 0.003). CONCLUSIONS: The number of cycles to rupture in symptomatic patients was higher than those predicted in asymptomatic patients by fatigue analysis, suggesting the possibility that plaques with a less fatigue life may be more prone to be symptomatic and rupture. If further validated by large-scale longitudinal studies, fatigue analysis based on high resolution in vivo MRI could potentially act as a useful tool for risk assessment of carotid atheroma.

Social media in selected Australian federal and state election campaigns, 2010-15

Campaigning in Australian election campaigns at local, state, and federal levels is fundamentally affected by the fact that voting is compulsory in Australia, with citizens who are found to have failed to cast their vote subject to fines. This means that - contrary to the situation in most other nations – elections are decided not by which candidate or party has managed to encourage the largest number of nominal supporters to make the effort to cast their vote, but by some 10-20% of genuine ‘swinging voters’ who change their party preferences from one election to the next. Political campaigning is thus aimed less at existing party supporters (so-called ‘rusted on’ voters whose continued support for the party is essentially taken for granted) than at this genuinely undecided middle of the electorate. Over the past decades, this has resulted in a comparatively timid, vague campaigning style from both major party blocs (the progressive Australian Labor Party [ALP] and the conservative Coalition of the Liberal and National Parties [L/NP]). Election commitments that run the risk of being seen as too partisan and ideological are avoided as they could scare away swinging voters, and recent elections have been fought as much (or more) on the basis of party leaders’ perceived personas as they have on stated policies, even though Australia uses a parliamentary system in which the Prime Minister and state Premiers are elected by their party room rather than directly by voters. At the same time, this perceived lack of distinctiveness in policies between the major parties has also enabled the emergence of new, smaller parties which (under Australia’s Westminster-derived political system) have no hope of gaining a parliamentary majority but could, in a close election, come to hold the balance of power and thus exert disproportionate influence on a government which relies on their support.

Partial intervertebral fusion secures successful outcomes after thoracoscopic anterior scoliosis correction: A low-dose computed tomography study

Study Design Retrospective review of prospectively collected data. Objectives To analyze intervertebral (IV) fusion after thoracoscopic anterior spinal fusion (TASF) and explore the relationship between fusion scores and key clinical variables. Summary of Background Information TASF provides comparable correction with some advantages over posterior approaches but reported mechanical complications, and their relationship to non-union and graft material is unclear. Similarly, the optimal combination of graft type and implant stiffness for effecting successful radiologic union remains undetermined. Methods A subset of patients from a large single-center series who had TASF for progressive scoliosis underwent low-dose computed tomographic scans 2 years after surgery. The IV fusion mass in the disc space was assessed using the 4-point Sucato scale, where 1 indicates <50% and 4 indicates 100% bony fusion of the disc space. The effects of rod diameter, rod material, graft type, fusion level, and mechanical complications on fusion scores were assessed. Results Forty-three patients with right thoracic major curves (mean age 14.9 years) participated in the study. Mean fusion scores for patient subgroups ranged from 1.0 (IV levels with rod fractures) to 2.2 (4.5-mm rod with allograft), with scores tending to decrease with increasing rod size and stiffness. Graft type (autograft vs. allograft) did not affect fusion scores. Fusion scores were highest in the middle levels of the rod construct (mean 2.52), dropping off by 20% to 30% toward the upper and lower extremities of the rod. IV levels where a rod fractured had lower overall mean fusion scores compared to levels without a fracture. Mean total Scoliosis Research Society (SRS) questionnaire scores were 98.9 from a possible total of 120, indicating a good level of patient satisfaction. Conclusions Results suggest that 100% radiologic fusion of the entire disc space is not necessary for successful clinical outcomes following thoracoscopic anterior selective thoracic fusion.

Total body potassium in cystic fibrosis

To further evaluate the nature of malnutrition, define at-risk groups, and confirm the efficacy of nutritional supplementation on body composition in cystic fibrosis (CF), we have conducted longitudinal and cross-sectional studies of total body potassium (TBK) in 161 unselected CF subjects aged 1 month to 17 years. TBK was determined by measurement of40K in a whole body counter, reflecting body cell mass (BCM), the vital work-performing and growing cellular component of the body. Compared with normal TBK data for age and sex from pooled measurements of 1,629 healthy children aged 1 week to 17 years, CF infants (n = 12) diagnosed by newborn screening were depleted in TBK at diagnosis and showed catch-up with therapy by 1 year; CF children aged 2-17 years (n = 140) showed a tendency for inadequate accretion of TBK (and thus BCM) with increasing age, although the normal correlation between TBK and weight and height was maintained in the majority suggesting a pattern of nutritional stunting of growth; and malnourished CF children (n = 9) showed significant catchup in TBK with long-term nutritional rehabilitation (85-98% of TBK predicted for weight and height). These studies suggest that potentially serious, but possibly correctable deficits, in the growth of the body cell mass as measured by TBK occur commonly in CF. These deficits may be established very early in life and if not corrected lead to progressive nutritional growth retardation with increasing age. © 1989 Raven Press, Ltd., New York.