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Background/aim The ability to objectively and reliably measure hand performance over time is critical to monitor patient performance and evaluate treatment efficacy. Current spasticity measures are subjective in nature and fail to capture the complexity of the multi-faceted upper motor neuron syndrome. This study examined the test–retest reliability of dynamic computerised hand dynamometry for simultaneously measuring multiple aspects of positive and negative features of the upper motor neuron syndrome during an active grasp and release task. Methods Community-living adults with upper motor neuron syndrome following acquired brain injury attending metropolitan spasticity clinics for management of upper limb spasticity (N = 36; mean age 50 years ±15) and control participants (N = 27, mean age 40 years ±12) completed a computerised hand dynamometry protocol across two testing occasions 5 weeks apart. Objective measurement of Isometric Force, Cycle Duration and Isometric Grip Work, Force Velocity, was completed during a repeated grasp and release test protocol with a computerised hand dynamometer to evaluate the reliability and reproducibility of hand performance. Results Kendall Coefficient of Concordance W scores ranged from W = 0.69–0.98 for motor elements of grasp and release, including Isometric Force, Cycle Duration, Isometric Grip Work and Force Velocity. Conclusions The investigated dynamic computerised hand dynamometry protocol showed fair/good to excellent levels of test–retest reliability in control participants and in subjects with upper motor neuron syndrome following acquired brain injury.

This study aimed to examine outcome in low risk transient ischaemic attack (TIA) patients presenting to emergency departments (ED) in a regional Australian setting discharged on antiplatelet therapy with expedited neurology review. All patients presenting to Gosford or Wyong Hospital ED with TIA, for whom faxed referrals to the neurology department were received between October 2008 and July 2010, were included in this prospective cohort study. Classification of low risk was based on an age, blood pressure, clinical features, duration of symptoms and diabetes (ABCD2) score4 and the absence of high risk features, including known carotid disease, crescendo TIA, or atrial fibrillation. Patients with ABCD2 scoresor =4 or with high risk features were discussed with the neurologist on call (a decision regarding discharge or admission was then made at the neurologist's discretion). Patients were investigated with a brain CT scan and/or CT angiography, routine pathology, and an electrocardiogram. All discharged patients were commenced on antiplatelet therapy and asked to follow up with their local medical officer within 7 days. The patients were contacted by the neurology department to arrange follow-up. Our primary outcome was the number of subsequent strokes occurring within 90 days. Of 200 discharged patients for whom referrals were received, three patients had a stroke within 90 days. None of these would have been prevented through hospitalisation. In conclusion, medical assessment, expedited investigation with immediate commencement of secondary prevention and outpatient neurology review may be a reasonable alternative to admission for low risk patients presenting to the ED with TIA.

Barden HL, Nott MT, Heard R, Chapparo C, Baguley IJ. Clinical assessment of hand motor performance after acquired brain injury with dynamic computerized hand dynamometry: construct, concurrent, and predictive validity. Objective To assess the construct, concurrent, and predictive validity of dynamic computerized hand dynamometry. Design Prospective correlational study between dynamometry and functional upper limb performance. Setting Hospital outpatient spasticity clinics. Participants Adults with upper motor neuron syndrome affecting the upper limb after acquired brain injury (ABI) (n=38; median age, 50y; range, 18–81y) and healthy adult control participants (n=27; median age, 37y; range, 22–62y). Intervention Not applicable. Main Outcome Measures Dynamic computerized dynamometry elements of hand performance (isometric force, force velocity, isometric grip work, contraction and relaxation duration) and the Action Research Arm Test. Results Motor elements of hand performance objectively measured by the dynamic computerized dynamometry protocol achieved moderate to good validity when correlated with standardized measures of functional hand performance. Dynamic computerized dynamometry identified clear differences in hand performance between participants with and without ABI. Within the ABI group, dynamic computerized hand dynamometry achieved fair to moderate predictive validity with regards to whether a participant would be referred for botulinum toxin A injections. Conclusions This study provides support for the construct, concurrent, and predictive validity of the dynamic computerized dynamometry protocol.

We conducted an association study across the human leukocyte antigen (HLA) complex to identify loci associated with multiple sclerosis (MS). Comparing 1927 SNPs in 1618 MS cases and 3413 controls of European ancestry, we identified seven SNPs that were independently associated with MS conditional on the others (each P ≤ 4 x 10(-6)). All associations were significant in an independent replication cohort of 2212 cases and 2251 controls (P ≤ 0.001) and were highly significant in the combined dataset (P ≤ 6 x 10(-8)). The associated SNPs included proxies for HLA-DRB1*15:01 and HLA-DRB1*03:01, and SNPs in moderate linkage disequilibrium (LD) with HLA-A*02:01, HLA-DRB1*04:01 and HLA-DRB1*13:03. We also found a strong association with rs9277535 in the class II gene HLA-DPB1 (discovery set P = 9 x 10(-9), replication set P = 7 x 10(-4), combined P = 2 x 10(-10)). HLA-DPB1 is located centromeric of the more commonly typed class II genes HLA-DRB1, -DQA1 and -DQB1. It is separated from these genes by a recombination hotspot, and the association is not affected by conditioning on genotypes at DRB1, DQA1 and DQB1. Hence rs9277535 represents an independent MS-susceptibility locus of genome-wide significance. It is correlated with the HLA-DPB1*03:01 allele, which has been implicated previously in MS in smaller studies. Further genotyping in large datasets is required to confirm and resolve this association.

OBJECTIVE: To pilot an injury reporting form designed for use in Australian surf lifesaving; the need for such a form is to meet legislative requirements and as an initial step in developing an injury prevention program for volunteer surf lifesavers 4. PARTICIPANTS: Competitors at the National Surf Life Saving Championships (NSLSC) held at Kurrawa Beach, Queensland, in 1998/1999 who reported to the medical tent over the course of the five-day event. Twenty-five volunteers of varying experience staffed the medical tent and included one paramedic coordinator, two doctors, three nurses, three physiotherapists and 16 first-aid officers. METHOD: An injury reporting form was designed using the Australian Sports Injury Data Dictionary 1 and pilot tested at the NSLSC in 1998/1999. The layout and format were based on similar forms used in other sports (eg skiing) with a number of the items altered to be more specific to surf lifesaving competition events. Four strategies were used to assess if the form provided interpretable data: number of forms returned; completeness of data recorded in each section; detailed analysis of difficulties in coding and entering data; detailed feedback from the medical tent personnel about the usability of the form. RESULTS: A total of 433 completed forms were returned and from these both descriptive and injury incidence data were obtained. Medical tent personnel reported the form to be generally usable, though they suggested some changes to it. Conclusions: The injury reporting form was found to be an effective tool to describe injuries and calculate injury incidence. Following minor revisions, a modified form was designed to improve the quality and accuracy of the information obtained; this form has been used nationally since 2001. Language: en

Interleukin 7 receptor alpha chain (IL-7Ralpha) has recently been confirmed as the first non-HLA gene definitively associated with multiple sclerosis (MS). The protective haplotype (haplotype 2) has reduced splicing of exon 6, reduced production of soluble IL-7Ralpha, and therefore reduced interference with receptor binding to its ligands, IL-7, and thymic stromal lymphopoietin (TSLP). From a meta-analysis on 3,376 MS patients, 4,143 controls, and 1,333 trio families, although the most significant association is still seen with haplotype 2 (P = 7 x 10(-10)), the highest odds ratio is seen for haplotype 4 homozygotes (OR = 1.35, P = 0.001). The IL-7Ralpha proximal promoter contains response elements to interferon beta (IFN-beta), the most commonly used immunomodulatory drug in MS. We demonstrate that IL-7Ralpha is up-regulated in response to IFN-beta in vitro for haplotypes 1 and 2, but not 4. This difference can be seen in peripheral blood mononuclear cells (PBMC) from heterozygotes (P0.002, n = 10) and homozygotes (trend only), and in CD4 + CD45RO + and CD4 + CD45RA + cells. In PBMCs, IL-7Ralpha cell surface protein (CD127) is lower in haplotype 4 carriers than non-carriers after incubation with IFN-beta (P0.003, n = 20). Response to IFN-beta includes viral protection and immune modulation, processes that could be pathogenically significant in MS. The haplotype-dependent variation in the regulation of IL-7Ralpha by IFN-beta may contribute to the genetic association of IL-7Ralpha with MS.

Creutzfeldt-Jakob disease (CJD) is a rapidly fatal neurodegenerative disorder belonging to the group of diseases known as transmissible spongiform encephalopathies. It has a stable worldwide incidence of approximately one case per million per year. Case identification relies upon characteristic neurological and EEG features, however, neuropathological assessment is required for confirmation. We have identified four cases of sporadic CJD occurring on the Central Coast of NSW, Australia over a 7 month period during 1997. This represents approximately fifteen times the expected number of cases for the population of 275 000. Multiple co-morbid states particularly in elderly patients, the absence of a reliable diagnostic test and the increasing care of cognitively impaired patients in community institutions are all challenges to accurate case ascertainment. A high index of suspicion for CJD is required and a post-mortem examination should be requested on all patients dying from a consistent clinical illness.

In a recent genome-wide association study (GWAS) based on 12,374 non-synonymous single nucleotide polymorphisms we identified a number of candidate multiple sclerosis susceptibility genes. Here, we describe the extended analysis of 17 of these loci undertaken using an additional 4234 patients, 2983 controls and 2053 trio families. In the final analysis combining all available data, we found that evidence for association was substantially increased for one of the 17 loci, rs34536443 from the tyrosine kinase 2 (TYK2) gene (P=2.7 x 10(-6), odds ratio=1.32 (1.17-1.47)). This single nucleotide polymorphism results in an amino acid substitution (proline to alanine) in the kinase domain of TYK2, which is predicted to influence the levels of phosphorylation and therefore activity of the protein and so is likely to have a functional role in multiple sclerosis.

To identify multiple sclerosis (MS) susceptibility loci, we conducted a genome-wide association study (GWAS) in 1,618 cases and used shared data for 3,413 controls. We performed replication in an independent set of 2,256 cases and 2,310 controls, for a total of 3,874 cases and 5,723 controls. We identified risk-associated SNPs on chromosome 12q13-14 (rs703842, P = 5.4 x 10(-11); rs10876994, P = 2.7 x 10(-10); rs12368653, P = 1.0 x 10(-7)) and upstream of CD40 on chromosome 20q13 (rs6074022, P = 1.3 x 10(-7); rs1569723, P = 2.9 x 10(-7)). Both loci are also associated with other autoimmune diseases. We also replicated several known MS associations (HLA-DR15, P = 7.0 x 10(-184); CD58, P = 9.6 x 10(-8); EVI5-RPL5, P = 2.5 x 10(-6); IL2RA, P = 7.4 x 10(-6); CLEC16A, P = 1.1 x 10(-4); IL7R, P = 1.3 x 10(-3); TYK2, P = 3.5 x 10(-3)) and observed a statistical interaction between SNPs in EVI5-RPL5 and HLA-DR15 (P = 0.001).

Angiotrophic large cell lymphoma (ALCL) is a rare disease characterized by a proliferation of malignant lymphoid cells, usually of B-cell origin, within the lumina of small vessels and frequently involving the central nervous system (CNS). ALCL generally follows a rapidly fatal course and is rarely diagnosed prior to autopsy. Tumour cells are rarely present on examination of peripheral blood, cerebrospinal fluid (CSF) or bone marrow, therefore, an early diagnosis is heavily dependent on recognition of neurological manifestations which are present in over 80% of cases. A pre-mortem diagnosis of ALCL can be made in cases where brain biopsy has been performed. We report a case of a 45-year-old woman demonstrating clinical and laboratory features suggestive of multiple sclerosis associated transverse myelitis (MSA-TM) in whom ALCL was unexpectedly discovered at autopsy. Microscopic examination revealed diffuse CNS vascular involvement by neoplastic cells and prominent myelopathy of the upper thoracic spinal cord associated with ascending and descending tract degeneration of the spinal motor and sensory tracts. Neoplastic cells were immunoreactive for B-cell lymphoid markers. The present case is the first to demonstrate neoplastic B-cell clonality in ALCL using polymerase chain reaction (PCR) to detect abnormal V-D-J immunoglobulin gene rearrangements. ALCL should be considered in the differential diagnosis whenever a transverse myelitis is present in association with global encephalopathy and elevated serum lactate dehydrogenase. The neurological manifestations of ALCL with particular reference to its presentation as MSA-TM is discussed.

The authors report on 3 patients who developed sylvian aqueduct syndrome (SAS) in the context of shunt dysfunction and slit ventricles. All 3 patients had received shunts for adult onset hydrocephalus due to aqueduct stenosis and were stable for years before presenting with loss of upward gaze, convergence-retraction nystagmus, and slit ventricles, all due to shunt overdrainage. All 3 improved after either shunt revision or a third ventriculostomy procedure. Although it is well known that SAS can be caused by shunt blockage producing a transtentorial pressure gradient, these cases emphasize that an identical clinical pattern can occur with a reverse transtentorial pressure gradient and slit ventricles due to shunt overdrainage. The authors propose a simple management plan for patients with shunted hydrocephalus who develop SAS.

To investigate the effectiveness of occupational therapy (OT) with adults demonstrating agitation and post-traumatic amnesia (PTA) following brain injury.Single-system experimental design (ABAB) across subjects.Eight subjects were recruited during acute rehabilitation. Current OT intervention was alternated with the experimental Perceive, Recall, Plan and Perform (PRPP) System approach over 4-weeks. Therapy was conducted daily. Information processing capacity during occupational tasks was measured using the PRPP System of Task Analysis. PTA status was monitored with the Westmead PTA Scale.The PRPP System is a dynamic assessment and intervention approach that directly links results of cognitive task analysis with strategies for intervention. PRPP Intervention adopts an information processing approach that simultaneously focuses on task training, strategy training and strategy application within occupational performance.Seven subjects significantly improved in their application of processing strategies during the PRPP Intervention in comparison to current OT Intervention phases. Large treatment effects favoured the PRPP Intervention. Subjects demonstrated improved information processing strategy use both prior to and following emergence from PTA.Occupational therapy intervention based upon the PRPP System of Task Analysis and Intervention improved subjects' ability to apply information processing strategies during occupational performance when compared to current intervention approaches.

Training specific vocal techniques can be effective in treating nonorganic dysphonias. Evaluation of vocal function in these studies has included auditory-perceptual assessment, aerodynamic measurement, acoustic analysis, self-report, and visual inspection of the larynx. Reliability of judgments made using visual rating tools for nasendoscopic and videostroboscopic visualization of the larynx when diagnosing vocal function and disorder has been the focus of previous research. However, detailed analysis of factors that affect reliability and consistency of perceptual ratings of laryngoscopic footage has not been investigated in voice therapy outcome studies. This study evaluated clinicians' judgments of the effectiveness of training differentiated vocal tract control of false vocal fold activity (FVFA), true vocal fold mass (TVFM) and larynx height (LH). A within-subject, experimental design was used to assess participants' mastery in manipulating FVFA, TVFM, and LH assessed via laryngoscopic visualization of the larynx. Three experienced speech pathologists rated the nasendoscopy footage with accompanying acoustic recordings of 12 speakers. Intrajudge consistency, interjudge reliability, and interjudge agreement of perceptual ratings were investigated. Twelve vocally trained unimpaired speakers used differentiated biomechanical manipulation of various laryngeal muscles to produce eight specific vocal qualities each. These manipulated vocal qualities were rated by three experienced voice clinicians who demonstrated higher levels of intrajudge consistency and interjudge agreement when identifying rather than quantifying the degree of a voice quality based on their visual and auditory perceptions of the different vocal features. The findings suggest that unimpaired speakers can be trained successfully to manipulate and change individual biomechanical aspects of their vocal functions as demonstrated by the visual- and auditory-perceptual judgments of expert voice clinicians. These judgments are vulnerable to issues of reliability and suggests that judges used auditory-perceptual judgments when interpreting laryngoscopic footage, particularly when the view of laryngeal features is compromised.

Background Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS). Although the pathogenesis of MS remains unknown, it is widely regarded as an autoimmune disease mediated by T-lymphocytes directed against myelin proteins and/or other oligodendrocyte epitopes. Methods In this study we investigated the gene expression profiles of peripheral blood cells from patients with RRMS during the relapse and the remission phases utilizing gene microarray technology. Dysregulated genes encoded in regions associated with MS susceptibility from genomic screens or previous trancriptomic studies were identified. The proximal promoter region polymorphisms of two genes were tested for association with disease and expression level. Results Distinct sets of dysregulated genes during the relapse and remission phases were identified including genes involved in apoptosis and inflammation. Three of these dysregulated genes have been previously implicated with MS susceptibility in genomic screens: TGFβ1, CD58 and DBC1. TGFβ1 has one common SNP in the proximal promoter: -508 T>C (rs1800469). Genotyping two Australian trio sets (total 620 families) found a trend for over-transmission of the T allele in MS in females (p < 0.13). Upregulation of CD58 and DBC1 in remission is consistent with their putative roles in promoting regulatory T cells and reducing cell proliferation, respectively. A fourth gene, ALOX5, is consistently found over-expressed in MS. Two common genetic variants were confirmed in the ALOX5 putatve promoter: -557 T>C (rs12762303) and a 6 bp tandem repeat polymorphism (GGGCGG) between position -147 and -176; but no evidence for transmission distortion found. Conclusion The dysregulation of these genes tags their metabolic pathways for further investigation for potential therapeutic intervention.

This study is an extension to previously published work that has linked variation in the human leukocyte antigen (HLA) class I region with susceptibility to multiple sclerosis (MS) in Australians from the Island State of Tasmania. Single nucleotide polymorphism (SNP) mapping was performed on an 865-kb candidate region (D6S1683-D6S265) in 166 Tasmanian MS families, and seven candidate genes [ubiquitin D (UBD), olfactory receptor 2H3 (OR2H3), gamma-aminobutyric acid B receptor 1 (GABBR1), myelin oligodendrocyte glycoprotein (MOG), HLA-F, HLA complex group 4 (HCG4) and HLA-G] were resequenced. SNPs tagging the extended MS susceptibility haplotype were genotyped in an independent sample of 356 Australian MS trios and SNPs in the MOG gene were significantly over-transmitted to MS cases. We identified significant effects on MS susceptibility of HLA-A*2 (OR: 0.51; P = 0.05) and A*3 (OR: 2.85; P = 0.005), and two coding polymorphisms in the MOG gene (V145I: P = 0.01, OR: 2.2; V142L: P = 0.04, OR: 0.45) after full conditioning on HLA-DRB1. We have therefore identified plausible candidates for the causal MS susceptibility allele, and although not conclusive at this stage, our data provide suggestive evidence for multiple class I MS susceptibility genes.

BACKGROUND: The current licensing authority's (Austroads) visual field standards are met when a person demonstrates an intact visual field extending horizontally at least 120 degrees within 10 degrees above and below the horizontal midline. A person cannot be licensed unconditionally if they have a hemianopia, quadrantanopia or any significant visual field loss (scotoma) that is likely to impede driving performance. Despite fairly rigorous implementation of these vision standards by licensing authorities, there is little scientific evidence available to demonstrate that a driver will or will not be safe on road depending on the extent of their visual field. METHODS: This study was developed to examine if the current licensing authority vision standards predict safe on-road driver performance in a cohort of 100 senior drivers. The study consisted of four stages in which participants underwent on-road assessment by a multidisciplinary team including a driving instructor, orthoptist and occupational therapist; off-road occupational therapy cognitive skills assessment using the Visual Recognition Slide Test (VRST-USyd); off-road orthoptic assessment including history, visual acuity and visual fields; and feedback from the team regarding the participant's visual and driving status. Visual fields were assessed using both the Goldmann and Esterman tests. Correlations were calculated to determine the relationship between visual field results and on-road driving performance. RESULTS: Generally it was found that visual field test results did not predict driving performance accurately for both participants with and without visual field loss. CONCLUSION: The results bring into question the current Austroads visual field standards for safe driving. Language: en

Aberrant regulatory T cell populations, characterised by a wide array of CD markers, have been identified in many autoimmune diseases. CD127 has recently been identified as a specific marker for the CD4(+)CD25(Hi) (Tregs) subset. CD127 is the first non-HLA gene to have its association with multiple sclerosis widely replicated. We demonstrate that the regulatory or suppressor T cells CD4(+)CD25(Hi) (Tregs), CD8(+)CD28(-), and CD3(+)CD56(+) (NKT) all produce low levels of CD127, and so could be at a disadvantage in survival and/or proliferation where IL7 is limiting. The remissions seen in relapsing remitting multiple sclerosis (RRMS) could be driven by regulatory T cells, and the absence of remissions seen in primary progressive MS (PPMS) may point to a particularly reduced function of this cell subset. We found that the proportions of CD4(+)FoxP3(+)CD25(Hi) regulatory T cells were not aberrant in PPMS. There was, however, a trend towards reduced FoxP3 expression per cell in this fraction (p0.083), which has been highly correlated with suppressor function. Notably, we found that the target of regulatory T cells, the CD4(+)CD25(-) cells, was in excess (p0.009); and in PPMS a protective CD127 haplotype is correlated with higher CD127 expression (p0.01). These data support further investigations into the regulatory T cell immunophenotype in MS.

Susceptibility to multiple sclerosis (MS) is believed to result from the complex interaction of a number of genes, each with modest effect. Vital to the migration of cells to sites of inflammation, including the central nervous system, are chemokines, many of which are implicated in MS pathogenesis. Most of the CXC chemokine genes are encoded in a cluster on chromosome 4q13.3-21.1, which has been identified in several genome-wide screens as being potentially associated with MS. We conducted a two-stage analysis to investigate the chemokine gene cluster for association with MS. Initially, we sequenced the chemokine genes in several DNA pools to identify common polymorphisms, and then genotyped selected SNPs in 373 Australian MS trio families. We found no evidence that the CXC chemokine gene cluster is genetically associated with MS. However, the existence of common variants conferring small risk factors or rare variants with significant risk cannot be excluded.

A special interdisciplinary project course was offered in the Fall of 2006 within the Carnegie Institute of Technology at Carnegie Mellon University. The course was open to students from across the university, it drew participants from Civil and Environmental Engineering, Engineering and Public Policy, Materials Science and Engineering, Architecture, the School of Design. This multidisciplinary collection of students formed the necessary knowledge base to approach the various tasks of the project. Each student was to rely on their academic experience and talents to contribute to the work, while simultaneously learning from those in other disciplines. The participating material science and engineering were juniors acquainted with fundamental of materials. Some students were taking courses involving steel making process and steel mechanical properties concurrently. Students in civil and mechanical engineering and architecture are familiar with structural design and construction processes. Students in engineering and public policy and environmental engineering have experience with life cycle assessment and environmental impacts. The collaborative group experience introduced students to how disciplines interact in the real world, encouraging them to pursue their own interests in broader areas.The project consisted of three efforts assessing life cycle impact in terms of energy consumption, greenhouse gas emissions, and economic costs of equivalent products made from both steel and wood The first effort involved comparison of steel products versus wood products in existing designs. The second, looked at the optimization of steel products to improve design options and the third tried to identifying opportunities to leverage the use of steel materials in green building design and construction, based on certification requirements established by the US Green Building Council and the Leadership in Energy and Environmental Design (LEED) rating system.At Carnegie Mellon, the Green Design Initiative researchers have been leaders in life cycle assessment methodology development and assessment, and have a history of merging students and faculty from across the university into research teams. This multidisciplinary project was good example of how common topics can be exploited to provide excellent discovery opportunities for undergraduate engineering programs.

Background Globally, with an ageing population, an increase in obesity and a tendency to delay retirement, the absolute numbers and prevalence of people affected by chronic knee pain in the workforce will increase1. A more recent review found strong evidence to indicate a positive association between knee pain or knee osteoarthritis and absenteeism from work. However, data were lacking to demonstrate a clear association with presenteeism2. Also few studies have examined, the influence of the physical or psychological workplace environment or individual or personal factors that may significant influences worker productivity or the decision making process of whether to go to or forgo work among people with knee pain3. Objectives The aims of this study were to evaluate the burden of absenteeism, presenteeism and work transitions and explore the personal and workplace environmental risk factors associated with reduced worker productivity among people with chronic knee pain. Methods A survey containing several validated measures of absenteeism, presenteeism and work transitions as well as individual, disease and work-related demographics was mailed to 496 people who had completed participation in the Long-term Evaluation of Glucosamine Sulfate (LEGS) study. Results A total of 296 (60%) people provided a completed survey with 129 currently in paid employment. Only six (5%) reported absenteeism in the past two months, however 63 (49%) reported presenteeism over a seven day period and 31 (24%) reported making one or more work transitions in the last six months due to knee problems. In multivariate analysis, presenteeism was associated with moderate to severe knee pain (≥3/10) (odds ratio (OR) 2.77, 95% CI 1.30 – 5.8) and reporting problems with other joints (OR 2.32, 95% CI 1.04 – 5.17) while job instability reduced the likelihood (OR 0.40, 95% CI 0.19 – 0.86). Reporting one or more work transitions was associated with moderate to severe knee pain (OR 4.09, 95% CI 1.53 – 10.95), a high co-morbidity score (OR 4.44, 95% CI: 1.02 – 19.32) and low co-worker support (OR 2.79, 95% CI 1.04 – 7.46) while having an occupation involving sitting >30% of the working day reduced the likelihood (OR 0.35, 95% CI 0.12 – 0.97). Conclusions This survey demonstrates the high prevalence of reduced worker productivity among people with chronic knee pain. Allowing access to sitting and promoting positive affiliations between co-workers are likely to provide an enabling workplace environment for these workers. References Woolf AD, Pfleger B. Burden of major musculoskeletal conditions. Bull World Health Organ 2003;81(9):646-56. Agaliotis M, Mackey MG, Jan S, et al. Burden of reduced work productivity among people with chronic knee pain: a systematic review. Occupational and Environmental Medicine 2014. Tang K, Escorpizo R, Beaton DE, et al. Measuring the impact of arthritis on worker productivity: perspectives, methodologic issues, and contextual factors. J Rheumatol 2011;38(8):1776-90. Acknowledgements We thank the LEGS participants for their contributions to our research. This work was supported by Arthritis Australia (The Kevin R James Grant) awarded to Ms Maria Agaliotis. Disclosure of Interest None declared

Objective The present study investigates whether youths with childhood-onset antisocial behavior have higher rates of psychiatric illness, neuropsychological and psychosocial dysfunction than youths who engage in antisocial behavior for the first time in adolescence. Prior studies have generally focused on single domains of function in heterogeneous samples. The present study also examined the extent to which adolescent-onset antisocial behavior can be considered normative, an assumption of Moffitt’s dual taxonomy model. Method Forty-three subjects (34 males, 9 females, mean age = 15.31, age range 12–21) with a diagnosis of conduct disorder (CD) were recruited through Headspace Services and the Juvenile Justice Community Centre. We compared childhood-onset antisocial youths (n = 23) with adolescent-onset antisocial youths (n = 20) with a conduct disorder, across a battery of psychiatric, neuropsychological and psychosocial measures. Neuropsychological function of both groups was also compared with normative scores from control samples. Results The childhood-onset group displayed deficits in verbal learning and memory, higher rates of psychosis, childhood maltreatment and more serious violent behavior, all effects associated with a large effect size. Both groups had impaired executive function, falling within the extremely low range (severely impaired). Conclusions Childhood-onset CD displayed greater cognitive impairment, more psychiatric symptoms and committed more serious violent offences. The finding of severe executive impairment in both childhood- and adolescent-onset groupings challenges the assumption that adolescent-onset antisocial behavior is a normative process.

Contém "Corrigendum", By combining all the data available from the Genetic Analysis of Multiple sclerosis in EuropeanS (GAMES) project, we have been able to identify 17 microsatellite markers showing consistent evidence for apparent association. As might be expected five of these markers map within the Major Histocompatibility Complex (MHC) and are in LD with HLA-DRB1. Individual genotyping of the 12 non-MHC markers confirmed association for three of them--D11S1986, D19S552 and D20S894. Association mapping across the candidate genes implicated by these markers in 937 UK trio families revealed modestly associated haplotypes in JAG1 (p=0.019) on chromosome 20p12.2 and POU2AF1 (p=0.003) on chromosome 11q23.1., This work follows on from the individual GAMES screens that were supported by the Wellcome Trust (grant 057097). The SNP genotyping analysis was supported by a competitive grant awarded by Applied Biosystems and also by grants from the National Multiple Sclerosis Society of the USA (grant RG 3500-A-1) and the Multiple Sclerosis Society of the United Kingdom and Northern Ireland (grant 730/02).

Question Does a modified postural drainage position (horizontal) produce less cardiovascular and respiratory stress than a headdown postural drainage position (30°) in people with severe heart disease? Design A quasi-experimental study. Participants Thirty-one patients (mean age 69 years, SD 13) with severe left ventricular systolic dysfunction (mean ejection fraction 23%, SD 7) who were stable, receiving regular medication and free of acute respiratory illness. Intervention Two manoeuvres were performed – one from long sitting to a modified (horizontal) postural drainage position, and one from long sitting to a head-down (30°) postural drainage position. Outcome measures Cardiovascular responses examined were blood pressure, sphygmocardiographic indices, and cardiac rhythm. Respiratory responses examined were respiratory rate, transcutaneous arterial oxyyhaemoglobin saturation, and dyspnoea. Results Three participants were intolerant to the postural drainage positions – two during head-down and one during modified positioning. The remaining 28 participants maintained their resting cardiac rhythm and did not complain of chest pain or dyspnoea. The changes in cardiovascular responses during the sitting to head-down postural drainage manoeuvre in the tolerant participants were significantly greater ( p < 0.05) than the changes during the sitting to the modified postural drainage manoeuvre for most of the sphygmocardiographic indices. In contrast, there were no significant respiratory responses to either postural drainage manoeuvre. Conclusion Modified positioning is associated with less cardiovascular stress than head-down positioning, yet for most patients with severe heart disease, both positions are generally well tolerated. For a subset of these patients, either position may be inappropriate. This suggests that modified positioning should be attempted first but that a head-down position may be attempted if the modified position proves ineffective. [Naylor JM, McLean A, Chow CM, Heard R, Ting I and Avolio A (2006) A modified postural drainage position produces less cardiovascular stress than a head-down position in patients with severe heart disease: A quasi-experimental study. Australian Journal of Physiotherapy 52: 201–209]

Fragile X syndrome (FXS) is a genetic disorder resulting from CGG trinucleotide repeat lengths greater than 200 and subsequent methylation of the FMR1 gene on the X chromosome. Fragile X associated tremor/ataxia syndrome (FXTAS) is a recently described syndrome of tremor and ataxia in a relative of a FXS patient with clinical signs not seen in typical FXS patients. This syndrome is typically seen in patients over the age of 50 and is thought to be a result of neuronal toxicity from excess mRNA production due to CGG repeat lengths of 55 to 200. We present a 34-year-old gentleman with a previous diagnosis of FXS presenting with phenotypic features of FXTAS including cerebellar ataxia. Genetic testing with methylation assay revealed that he is a FXS and FXTAS mosaic with methylated CGG repeat lengths of 110 and 540 contributing to FXS and unmethylated CGG repeat lengths of 90 and 600 contributing to cerebellar ataxia and diagnosis of FXTAS. Despite the close genotypic relationship between FXS an FXTAS there are distinct phenotypic differences attributable to different methylation state. To our knowledge this is the first case to be reported of FXS/FXTAS mosaicism and adds to the increasing understanding of the role played by methylation in determining phenotypic expression of genetic disorders, in particular the importance of methylation mosaicism. We suggest that in a FXS patient presenting with cerebellar ataxia or tremor without an apparent cause, further genetic testing with methylation analysis should be considered in the diagnostic process.

As with other major autoimmune diseases, susceptibility to multiple sclerosis (MS) is believed to result from the complex interaction of a number of genes, each with modest effect. Extensive research of experimental autoimmune encephalomyelitis in mice and several direct MS studies have implicated NOS2A, which encodes the inducible form of nitric oxide synthase, and the genetic region encoding NOS2A, 17q11.2, has been identified in a number of genome wide screens as being potentially associated with MS. We investigated four single nucleotide polymorphisms in the proximal promoter region of NOS2A, in a case-control group of 100 Australian MS patients and 100 controls and in 203 MS patients and their unaffected parents. We found a trend toward excess transmission of the -277A allele (tag for the AGCC haplotype) to HLA-DRB1*1501-positive MS patients (P (uncorrected)=0.05). We initially discovered a trend toward over-representation of the AGCC haplotype in HLA-DRB1*1501-positive compared to HLA-DRB1*1501-negative MS patients in the case-control cohort. However, when combined with the probands from the transmission disequilibrium analysis, this trend was nullified. Nonetheless, despite the lack of significant evidence of association for the NOS2A promoter polymorphisms with MS, the gene remains an interesting candidate for MS susceptibility, particularly with regard to the HLA-DRB1*1501 haplotype.

Persistent high-titre neutralizing antibodies (NAB) to therapeutic interferon-β (IFNβ) in multiple sclerosis patients reduce therapeutic efficacy. Difficulties in standardization of cell-based bioactivity assays have hindered interlaboratory comparison of NAB titres and the determination of a clinically relevant definition of seropositivity. We determined NAB status in Australasian multiple sclerosis patients receiving IFNβ using both the antiviral cytopathic effect (CPE) assay ( n = 227) and the more specific ELISA for the type I interferon-inducible MxA protein ( n = 350). While the log 10 titres determined in the two assays were highly correlated ( p r = 0.967) with similar distributions, the MxA assay was more sensitive, detecting lower concentrations of NAB than the CPE assay. The range of titres determined in the CPE assay was 10 to > 7290; and 9 to 53,700 in the MxA assay, with ranked titre distribution highlighting the arbitrary nature of currently accepted definitions of NAB seropositivity. Bioactivity of injected IFNβ was significantly reduced in NAB-positive patients ( p = 0.006; NAB MxA titres = 184 to 5340) compared to NAB-negative patients as assessed ex vivo using real-time RT-PCR analysis of MxA gene induction. The range of MxA mRNA levels in healthy controls was remarkably consistent with previously published results, regardless of the assay standardization method [Gilli, F., Sala, A., Marnetto, F., Lindberg, R.L., Leppert, D. and Bertolotto, A. (2003) Comparison of IFNbeta bioavailability evaluations by MxA mRNA using two independent quantification methods. Abstract, ECTRIMS Meeting, Milan, Italy; Pachner, A., Narayan, K., Price, N., Hurd, M. and Dail, D. (2003a) MxA Gene Expression Analysis as an Interferon-beta Bioactivity Measurement in Patients with Multiple Sclerosis and the Identification of Antibody-Mediated Decreased Bioactivity. Mol. Diagn. 7, 17–25]. Assessment of IFNβ response ex vivo accounts for both circulating factors and the cellular response to IFNβ, and the data support the development of the MxA gene induction assay for the routine screening of patients receiving IFNβ.

To test whether Stepping On, a multifaceted community-based program using a small-group learning environment, is effective in reducing falls in at-risk people living at home.A randomized trial with subjects followed for 14 months.The interventions were conducted in community venues, with a follow-up home visit.Three hundred ten community residents aged 70 and older who had had a fall in the previous 12 months or were concerned about falling.The Stepping On program aims to improve fall self-efficacy, encourage behavioral change, and reduce falls. Key aspects of the program are improving lower-limb balance and strength, improving home and community environmental and behavioral safety, encouraging regular visual screening, making adaptations to low vision, and encouraging medication review. Two-hour sessions were conducted weekly for 7 weeks, with a follow-up occupational therapy home visit.The primary outcome measure was falls, ascertained using a monthly calendar mailed by each participant.The intervention group experienced a 31% reduction in falls (relative risk (RR)=0.69, 95% confidence interval (CI)=0.50-0.96; P=.025). This was a clinically meaningful result demonstrating that the Stepping On program was effective for community-residing elderly people. Secondary analysis of subgroups showed that it was particularly effective for men (n=80; RR=0.32, 95% CI=0.17-0.59).The results of this study renew attention to the idea that cognitive-behavioral learning in a small-group environment can reduce falls. Stepping On offers a successful fall-prevention option.

We have investigated the interleukin-7 receptor (IL-7R) alpha-chain gene as a positional and functional candidate gene for susceptibility to multiple sclerosis (MS), in view of its chromosomal location on 5p14-p12, a region that has shown suggestive linkage in MS genome screens, and its role in T- and B-cell proliferation and reactivity. Amplification and DNA sequencing of the IL-7Ralpha gene in pooled and individual samples identified 13 single nucleotide polymorphisms (SNPs), 11 of which are novel, including three in the promoter region, three in exons encoding amino-acid changes (ACC(Thr)66ATC(Ile), ATC(Ile)244ACC(Thr), ATC(Ile)336GTC(Val)), four in introns and one in the 3' untranslated region. Four IL-7R haplotypes were identified for nine SNPs, showing linkage disequilibrium across the gene, and allowing haplotype frequency determination from just three of the nine SNPs. Genotyping of the -504 polymorphism in 101 MS and 90 controls showed a suggestive (P=0.1) association of the T allele with MS; however, this was not supported by transmission disequilibrium testing in 186 MS trio families (P=0.8). There were trends towards an increase of the GTG+ haplotype (odds ratio=1.45), and under-representation of the TTA+ haplotype (OR=0.65) in DRB1*1501-positive MS cases, suggesting that larger sample sizes and comparison in more defined MS patient groups may support an association with the IL-7R gene. These polymorphisms would also be useful for studying genetic associations with other immunologic diseases.

The amount of breast compression that is applied during mammography potentially influences image quality and the discomfort experienced. The aim of this study was to determine the relationship between applied compression force, breast thickness, reported discomfort and image quality. Participants were women attending routine breast screening by mammography at BreastScreen New South Wales Central and Eastern Sydney. During the mammographic procedure, an 'extra' craniocaudal (CC) film was taken at a reduced level of compression ranging from 10 to 30 Newtons. Breast thickness measurements were recorded for both the normal and the extra CC film. Details of discomfort experienced, cup size, menstrual status, existing breast pain and breast problems were also recorded. Radiologists were asked to compare the image quality of the normal and manipulated film. The results indicated that 24% of women did not experience a difference in thickness when the compression was reduced. This is an important new finding because the aim of breast compression is to reduce breast thickness. If breast thickness is not reduced when compression force is applied then discomfort is increased with no benefit in image quality. This has implications for mammographic practice when determining how much breast compression is sufficient. Radiologists found a decrease in contrast resolution within the fatty area of the breast between the normal and the extra CC film, confirming a decrease in image quality due to insufficient applied compression force.

The role of genetic factors in determining susceptibility to multiple sclerosis is well established but, despite the global distribution of the disease, systematic efforts to locate susceptibility genes have concentrated exclusively on populations from the Northern Hemisphere. We performed a genome wide screen of linkage in the Australian population using a panel of 397 microsatellite markers in 54 affected sibling-pairs. Multipoint linkage analysis revealed four regions of suggestive linkage (on chromosomes 2p13, 4q26-28, 6q26 and Xp11) and 18 additional regions of potential linkage (at 1q43-44, 3q13-24, 4q24, 4q31-34, 5q11-13, 6q27, 7q33-35, 8p23-21, 9q21, 13q31-32, 16p13, 16p11, 16q23-24, 17p13, 18p11, 20p12-11, Xp21-11 and Xq23-28). Our results contribute to the available data adding new provisional regions of linkage as well as increasing support for areas previously implicated in genetic susceptibility to multiple sclerosis.

PurposeAcoustic and perceptual studies show a number of differences between the voices of radio performers and controls. Despite this, the vocal fold kinematics underlying these differences are largely unknown. Using high-speed videoendoscopy, this study sought to determine whether the vocal vibration features of radio performers differed from those of non-performing controls.MethodUsing high-speed videoendoscopy, recordings of a mid-phonatory/i/ in 16 male radio performers (aged 25-52 years) and 16 age-matched controls (aged 25-52 years) were collected. Videos were extracted and analysed semi-automatically using High-Speed Video Program, obtaining measures of fundamental frequency (f0), open quotient and speed quotient. Post-hoc analyses of sound pressure level (SPL) were also performed (n = 19). Pearson's correlations were calculated between SPL and both speed and open quotients.ResultsMale radio performers had a significantly higher speed quotient than their matched controls (t = 3.308, p = 0.005). No significant differences were found for f0 or open quotient. No significant correlation was found between either open or speed quotient with SPL.DiscussionA higher speed quotient in male radio performers suggests that their vocal fold vibration was characterised by a higher ratio of glottal opening to closing times than controls. This result may explain findings of better voice quality, higher equivalent sound level and greater spectral tilt seen in previous research. Open quotient was not significantly different between groups, indicating that the durations of complete vocal fold closure were not different between the radio performers and controls. Further validation of these results is required to determine the aetiology of the higher speed quotient result and its implications for voice training and clinical management in performers.

A 42-year-old white man presented with cognitive impairment and behavioral changes followed by rapidly progressive motor and gait impairment. Magnetic resonance imaging revealed striking multifocal white matter signal change, areas of restricted diffusion, diffuse callosal signal change, and atrophy and hyperintensity of the corticospinal tracts. A broad range of etiologies warrant consideration in this case, including degenerative, vascular, inflammatory, metabolic, and neoplastic diseases.

This study focused on susceptibility to MS within the b-chain of the T-cell antigen receptor (TCRB locus, 7q35) in a cohort of 122 RR-MS patients compared with 96 normal individuals using biallelic polymorphisms across the bv8s1(Vb8.1) to bv11s1 (Vb11) TCRB subregion. The markers bv6s5, bv8s1, bv10s1, bv15s1 and bv3s1 were studied for allele and genotype frequencies; haplotypes were assigned with combinations of two of these markers and stratification for HLA-DR15 was also performed. Linkage disequilibrium was found between alleles of the bv8s1, bv10s1/bv15s1 and bv3s1 loci in both patients and controls. An increase among RR-MS patients in the allele frequency of bv8s1*2 (P=0.03) and the haplotype bv8s1*2/bv3s1*1 (P=0.006) was noted and both were found to be statistically significant. In the DR15-positive group, the association between TCRB and MS was seen with the bv8s1*2 allele (Puc=0.05) and the bv8s1*2/bv10s1 haplotypes (Puc=0.048), while the haplotype associations seen among DR15-negative RR-MS patients included the bv3s1*1 allele (bv10s1*1/bv3s1*1, Puc=0.022; bv8s1*2/bv3s1*1, Puc=0.048). These results support the involvement of the TCRB region in MS susceptibility and encourage further study of the variable gene segments in this region.

The pathogenesis of multiple sclerosis is under strong genetic control involving several or more genes each of modest effect. Whilst the mechanisms underlying the pathogenesis of MS remain unknown, it has been hypothesised that either decreased apoptosis of autoreactive T cells in the CNS, or increased apoptosis of oligodendrocytes may play an important role. The Apo-1/Fas antigen (CD95), the gene for which is located in a chromosomal region showing linkage in MS genome screens, is a critical inducer of apoptosis and studies have shown aberrant expression of this molecule in MS, correlating with a decrease in T cell apoptosis or increase in CNS tissue damage. This study investigated an Mva I polymorphism in the Apo-1/Fas promoter region in a group of 124 Australian patients with relapsing-remitting MS and in 183 normal controls. Whilst there were increases in the Mva I*2 allele in MS individuals overall (59% vs 52%, P not corrected=0.08), and in HLA-DRB1*1501 negative MS patients (62% vs 55%), these were not significantly different from controls. Interactions were investigated between the Mva I alleles and T cell receptor beta chain variable region (TCRBV) germline polymorphisms, with a trend in MS individuals towards a decrease of the Mva I*1 allele when combined with the TCRBV3S1*2 allele (Relative Risk=0.25, P=0.067), and with the TCRBV8S1*1 allele (Relative Risk=0.44, P=0.12). Overall, the findings of this study indicate a possible effect of the Apo-1/Fas promoter Mva I polymorphism in MS susceptibility, which needs to be confirmed in further studies. Multiple Sclerosis (2000) 6 14 - 18

OBJECTIVES—There have been many studies reporting restricted patterns of T cell receptor usage in established multiple sclerosis and these have led to clinical trials of immunomodulation directed at deleting clonal T cell populations. The present study aims to test the hypothesis that highly restricted T cell populations are also present in the CSF in the earliest clinical stages of acute demyelinating disease of the CNS. METHODS—T cell receptor Vβ (TCRBV) gene expression was studied in CSF and blood in nine patients with acute optic neuritis within 7 days of onset of symptoms, six patients with an acute relapse of multiple sclerosis, and 13 control subjects. RNA was extracted and cDNA synthesised from unstimulated CSF and blood lymphocytes, and TCRBV gene segments were amplified from the cDNA by polymerase chain reaction (PCR) using 21 family specific primers. PCR products were separated by polyacrylamide gel electrophoresis and detected via a labelled oligonucleotide probe. A semiquantitative analysis of band intensity was performed by laser densitometry. RESULTS—TCRBV mRNA was detected in the CSF of eight of nine patients with optic neuritis, six of six patients with multiple sclerosis, and five of 13 controls, and was closely correlated with the presence of oligoclonal IgG. Usage of a single TCRBV family was demonstrated in two of nine patients with optic neuritis and two of six patients with multiple sclerosis. The number of TCRBV families expressed in the other patients ranged between 5 and 15 (optic neuritis) and 4 and 17 (multiple sclerosis). CONCLUSIONS—There is a relative lack of restriction of TCRBV usage by CSF lymphocytes in the very earliest stages (

Genetic susceptibility to multiple sclerosis (MS) has so far been strongly localized to the MHC class II region encoding the alleles of the haplotype HLA-DRB1∗1501, -DQA1∗0102, -DQB1∗0602. However, this haplotype is not carried by approximately 40% of MS patients; a potential explanation could be that they carry other MHC class II alleles with similar function due to the sharing of nucleotide sequences encoding critical amino acid residues. The DRB1 gene is polymorphic at residue 86, encoding valine or glycine. In view of the increasing evidence for a functional role for DRB1 aa86 in the binding and presentation of autoantigenic peptides such as myelin basic protein, this study investigated associations with the residue 86 polymorphism in an Australian MS population. A significant increase in the Val 86 /Val 86 genotype was observed in the MS patients, which was still present in the absence of the DRB1∗1501 allele ( p = 0.032). This suggests that DRB1 aa86 may have an independent role in contributing to MS susceptibility. The Val 86 /Val 86 genotype was correlated with genotyping for other putative MS susceptibility genes, including T cell receptor beta chain germline polymorphisms, HLA-DMB alleles, and -DQA1 and -DQB1 alleles encoding critical amino acid residues, with a significant interaction only observed with DQB1 Leu 26 ( p = 0.014). Additional studies of the HLA-DRB1 aa86 polymorphism in MS, and its function, are needed to more fully understand this association.

Background With an ageing population and increased trend to delay retirement worldwide, the number of people in the workforce affected by knee osteoarthritis will increase(1). There is a paucity of research examining the burden of work disability among people with knee osteoarthritis(2). Previous population and patient-based surveys have mostly been limited to evaluating absenteeism and have all required lengthy recall periods(2). Objectives To determine the burden and risk factors associated with work disability (absenteeism and presenteeism) among people with chronic knee pain. Methods A longitudinal study nested within a randomised controlled trial evaluating the long-term effect of dietary supplements. The study cohort consisted of the 336 (55%) trial participants in paid employment. A Participant Diary required reporting on days off work (absenteeism) and reduced productivity while at work (presenteeism) for seven days, every two months over a 12 month follow up period. Baseline risk factors included knee pain, patient global assessment, occupational group, radiographic disease severity, physical activity, body mass index, health-related quality of life (SF-12) and self-reported co-morbidity. Results Among the 336 participants in paid employment, 36 (12%) withdrew from the LEGS study during the 12 month follow up period. A total of 219 (65%) completed all six Participant Diaries while 269 (80%) completed at least five of the six Participant Diaries. Most participants were in professional and managerial roles (46%) and less than 60 years of age (69%). While all participants had medial tibiofemoral joint space narrowing in at least one knee, most knees were Kellgren and Lawrence grade 1 or 2 (∼90%) indicating mild to moderate radiographic disease(3). Over the 12 month follow up period, 44 (13%) participants reported 1 or more days off work due to knee problems. Almost half (43%) of the cohort reported Conclusions This longitudinal study demonstrated marked work disability among people with chronic knee pain, but mostly only mild radiographic disease severity. Physical disability, older age, manual labour and knee pain were clearly associated with reduced productivity while at work. References Woolf AD, Pfleger B. Burden of major musculoskeletal conditions. [Review] [69 refs]. Bull World Health Organ 2003;81:646-56. Bieleman HJ, Oosterveld FG, Oostveen JC, Reneman MF, Groothoff JW. Work participation and health status in early osteoarthritis of the hip and/or knee: a comparison between the Cohort Hip and Cohort Knee and the Osteoarthritis Initiative. Arthritis Care Res 2010;62:683-9. Kellgren JH, Lawrence JS. Radiological assessment of osteo-arthrosis. Ann Rheum Dis 1957;16:494-502. Disclosure of Interest None Declared

PCR-RFLP typing methods for DQA1 and DQB1 in conjunction with the analysis of heteroduplex and homoduplex patterns have allowed a simple method for typing all of the major DQA1 and DQB1 alleles. This method has advantages over PCR amplification with sequence-specific primers (PCR-SSP), PCR hybridization with sequence-specific oligonucleotide probes (PCR-SSO) and other PCR-RFLP strategies for typing DQ alleles. The analysis of heteroduplex and homoduplex patterns can be used in conjunction with other PCR typing systems such as PCR-SSP as a confirmatory step with little additional work. In addition, a PCR-RFLP strategy was designed for resolving the DQB1*0602 and DQB1*0603 alleles, which involved the use of a primer containing a base mutation, creating a new restriction site which distinguished the two alleles. These techniques have enabled resolution of the major homozygous and heterozygous combinations of these DQA1 and DQB1 alleles. The PCR-RFLP technique does not require the large number of oligonucleotides that are necessary for both the PCR-SSP and PCR-SSO techniques and is thus both time and cost effective for infrequent or small numbers of samples.

BackgroundSeveral lines of evidence suggest that transcription factors are involved in the pathogenesis of Multiple Sclerosis (MS) but complete mapping of the whole network has been elusive. One of the reasons is that there are several clinical subtypes of MS and transcription factors that may be involved in one subtype may not be in others. We investigate the possibility that this network could be mapped using microarray technologies and contemporary bioinformatics methods on a dataset derived from whole blood in 99 untreated MS patients (36 Relapse Remitting MS, 43 Primary Progressive MS, and 20 Secondary Progressive MS) and 45 age-matched healthy controls.Methodology/principal findingsWe have used two different analytical methodologies: a non-standard differential expression analysis and a differential co-expression analysis, which have converged on a significant number of regulatory motifs that are statistically overrepresented in genes that are either differentially expressed (or differentially co-expressed) in cases and controls (e.g., V$KROX_Q6, p-value Conclusions/significanceOur analysis uncovered a network of transcription factors that potentially dysregulate several genes in MS or one or more of its disease subtypes. The most significant transcription factor motifs were for the Early Growth Response EGR/KROX family, ATF2, YY1 (Yin and Yang 1), E2F-1/DP-1 and E2F-4/DP-2 heterodimers, SOX5, and CREB and ATF families. These transcription factors are involved in early T-lymphocyte specification and commitment as well as in oligodendrocyte dedifferentiation and development, both pathways that have significant biological plausibility in MS causation.

Interferon beta (IFNbeta) is the most common immunomodulatory treatment for relapsing-remitting multiple sclerosis (RRMS). However, some patients fail to respond to treatment. In this study, we identified putative clinical response markers in the serum and plasma of people with multiple sclerosis (MS) treated with IFNbeta. In a discovery-driven approach, we use 2D-difference gel electrophoresis (DIGE) to identify putative clinical response markers and apply power calculations to identify the sample size required to further validate those markers. In the process we have optimized a DIGE protocol for plasma to obtain cost effective and high resolution gels for effective spot comparison. APOA1, A2M, and FIBB were identified as putative clinical response markers. Power calculations showed that the current DIGE experiment requires a minimum of 10 samples from each group to be confident of 1.5 fold difference at the p

Most literature reporting the impressive results from knee and hip replacement derives from international data. Few Australian studies have comprehensively compared outcomes after joint replacement up to 1 year. This paper compares the patterns of recovery across physical and patient-centred outcomes following knee or hip replacement in an Australian cohort. One hundred and twenty-two consecutive patients undergoing knee or hip replacement were prospectively followed. Serial assessments were conducted (preoperatively, and 2, 6, 12, 26 and 52 weeks postsurgery). Joint pain, patient?s global improvement, timed mobility, and complications were monitored. English-proficient patients completed WOMAC (Western Ontario and McMaster Universities Osteoarthritis Index) and SF-36v2 (Medical Outcomes Short-Form 36 version 2) questionnaires. At 1 year, 81% (55 knee, 44 hip) were available for follow-up. Significant, large improvements (up to 254%) were evident for most outcomes. Global improvement was reported by 97%. Recovery for both surgical groups was greatest within the first 26 weeks, but hip patients improved more quickly in most outcomes. Wound disturbances were the most common complication (23 in total, 23%) and 13 patients (13%) were readmitted for complications. Recovery patterns were similar to that observed elsewhere. The physical and patientcentred outcomes provide a useful Australian reference for clinicians of the temporal aspects of recovery as well the differences between hip and knee surgeries. Complication and readmission rates appeared high, possibly partly explained by the rigorous capture method.

To provide a definitive linkage map for multiple sclerosis, we have genotyped the Illumina BeadArray linkage mapping panel (version 4) in a data set of 730 multiplex families of Northern European descent. After the application of stringent quality thresholds, data from 4,506 markers in 2,692 individuals were included in the analysis. Multipoint nonparametric linkage analysis revealed highly significant linkage in the major histocompatibility complex (MHC) on chromosome 6p21 (maximum LOD score [MLS] 11.66) and suggestive linkage on chromosomes 17q23 (MLS 2.45) and 5q33 (MLS 2.18). This set of markers achieved a mean information extraction of 79.3% across the genome, with a Mendelian inconsistency rate of only 0.002%. Stratification based on carriage of the multiple sclerosis-associated DRB1*1501 allele failed to identify any other region of linkage with genomewide significance. However, ordered-subset analysis suggested that there may be an additional locus on chromosome 19p13 that acts independent of the main MHC locus. These data illustrate the substantial increase in power that can be achieved with use of the latest tools emerging from the Human Genome Project and indicate that future attempts to systematically identify susceptibility genes for multiple sclerosis will have to involve large sample sizes and an association-based methodology.

Genome-wide association studies involve several hundred thousand markers and, even when quality control is scrupulous, are invariably confounded by residual uncorrected errors that can falsely inflate the apparent difference between cases and controls (so-called genomic inflation). As a consequence such studies inevitably generate false positives alongside genuine associations. By use of Bayesian logic and empirical data, the Wellcome Trust Case Control Consortium suggested that association studies in complex disease should involve at least 2000 cases and 2000 controls, at which level they predicted that p values of less than 5×10 −7 would more commonly signify true positives than false positives.

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system with a multifactorial aetiology and highly variable natural history. A growing understanding of the immunopathogenesis of the condition has led to an expanding array of therapies for this previously untreatable disease. While a cure for MS remains elusive, the potential to reduce inflammatory disease activity by preventing relapses and minimising disease progression is achievable. The importance of early treatment in minimising long-term disability is increasingly recognised. Most of the newer, more effective therapies are associated with risks and practical problems that necessitate an active management strategy and continuous vigilance. While the initiation of these therapies is likely to remain the responsibility of neurologists, other specialist physicians and general practitioners will be involved in the identification and management of adverse effects.

Background A high prevalence of symptoms of mental disorders (SOMD) has been found among people living with HIV/AIDS (PLHIV). Additionally, SOMD may impact on the prevalence of high-risk health behaviours (HRB). This study investigates the relationship between SOMD and HRB in a large sample of Vietnamese HIV positive outpatients. Methods A cross-sectional study was conducted with 400 outpatients at two HIV/AIDS clinics in Ho Chi Minh City, Vietnam, selected using a systematic sampling technique. Validated scales were used to measure SOMD, specifically symptoms of depression, anxiety, alcohol use disorder (AUD), substance use disorder (SUD) and HIV associated dementia (HAD). Participants completed a self-report questionnaire assessing HRB during the preceding 12 months including unsafe sexual practices and illicit drug use. Multivariable logistic regression models were used to evaluate associations between SOMD and HRB. Results The majority of participants (63.5%) were male and the median age was 34.0 years. Unsafe sexual practices and illicit drug use were reported by 13.8 and 5.5% of participants. The prevalences of HAD, depression, AUD, anxiety and SUD symptoms were 39.8, 36.5, 13.3 10.5, 3.3% respectively. There was no association between SOMD and HRB either with or without adjusting for correlates of HRB, except between symptoms of SUD and illicit drug use. PLHIV who had symptoms of SUD were more likely to use illicit drugs (adjusted Odds Ratio 81.14, 95% CI 12.55–524.47). Conclusions While the prevalence of SOMD among HIV positive outpatients was high, most SOMD were not associated with increased HRB. Only illicit drug use was predicted by symptoms of SUD. Screening PLHIV for symptoms of SUD may be useful for detecting people likely to be engaging in illicit drug use to reduce the risk of secondary disease transmission.

The few loci associated with multiple sclerosis (MS) are all related to immune function. We report a GWA study identifying a new locus replicated in 2,679 cases and 3,125 controls. An rs10492972[C] variant located in the KIF1B gene was associated with MS with an odds ratio of 1.35 (P = 2.5 x 10(-10)). KIF1B is a neuronally expressed gene plausibly implicated in the irreversible axonal loss characterizing MS in the long term.

To monitor daily shift-by-shift changes in agitated behaviour during adult brain injury rehabilitation.A prospective, descriptive study.Eight participants were monitored daily for up to 28 days. The Agitated Behaviour Scale (ABS) evaluated behaviour during three nursing shifts (morning, afternoon, night). Severity of agitation, peak intensity and concomitant behaviours were calculated. Shift differences and patterns of behavioural changes were analysed.Four hundred and seven recordings were taken with the ABS. All participants demonstrated multiple agitated behaviours (between 3-13 concomitant behaviours per person); the most common behaviours were representative of the ABS Disinhibition sub-scale. Weekly peak intensity ranged from 14-55 on the ABS. Mean ABS scores were highest during the afternoon shift and lowest at night. Improved cognition was associated with resolving agitated behaviour; while persistent agitated behaviour was associated with low levels of cognition. Minimal agitated behaviour was observed in participants who emerged from post-traumatic amnesia.Agitated behaviour during acute brain injury rehabilitation has a complex clinical presentation. High levels of agitation observed during the afternoon shift may be associated with low levels of structured activities available at that time, higher levels of environmental stimuli during visiting times and increased cognitive fatigue. Lower cognitive ability was related to consistently higher levels of agitated behaviour and vice-versa.

Background and Purpose. Isolated head-down postural drainage is assumed to acutely load the cardiovascular system. Consequently, it is considered a relative contraindication in the presence of severe cardiovascular disease. Evidence demonstrating that the head-down manoeuvre as used by physiotherapists does significantly load the cardiovascular system is lacking. The present study documents the cardiovascular responses to short-term 30° head-down positioning in healthy subjects. The results are a point of reference for respiratory patients with and without cardiovascular disease. Method. A quasi-experimental research design was used, with multiple measurements obtained at rest (long sitting) and in the head-down position. Twenty-one young subjects (mean age 25 years (standard deviation, (SD) 3 years)) and 19 older subjects (mean age 66 years (SD 6 years)) were studied. Applanation tonometry and sphygmocardiography were used to measure temporal and pressure variables, and indices that estimate myocardial work and coronary blood flow. Results. Absolute differences existed between the two age groups for all variables at rest (p 0.05). Serial measures in the head-down position did not vary across time (p>0.05). Small (