A randomized controlled trial comparing the Thompson hemiarthroplasty with the Exeter polished tapered stem and Unitrax modular head in the treatment of displaced intracapsular fractures of the hip: the WHiTE 3: HEMI Trial.

Aims: This study aimed to compare the change in health-related quality of life of patients receiving a traditional cemented monoblock Thompson hemiarthroplasty compared with a modern cemented modular polished-taper stemmed hemiarthroplasty for displaced intracapsular hip fractures. Patients and Methods: This was a pragmatic, multicentre, multisurgeon, two-arm, parallel group, randomized standard-of-care controlled trial. It was embedded within the WHiTE Comprehensive Cohort Study. The sample size was 964 patients. The setting was five National Health Service Trauma Hospitals in England. A total of 964 patients over 60 years of age who required hemiarthroplasty of the hip between February 2015 and March 2016 were included. A standardized measure of health outcome, the EuroQol (EQ-5D-5L) questionnaire, was carried out on admission and at four months following the operation. Results: Of the 964 patients enrolled, 482 died or were lost to follow-up (50%). No significant differences were noted in EQ-5D between groups, with a mean difference at four months of 0.037 in favour of the Exeter/Unitrax implant (95% confidence interval (CI) 0.014 to 0.087, p = 0.156), rising to 0.045 (95% CI 0.007 to 0.098, p = 0.09) when patients who died were excluded. The minimum clinically important difference for EQ-5D-5L used in this study is 0.08, therefore any benefit between implants is unlikely to be noticeable to the patient. There was no difference in mortality or mobility score. Conclusion: Allowing for the high rate of loss to follow-up, the use of the traditional Thompson hemiarthroplasty in the treatment of the displaced intracapsular hip fracture shows no difference in health outcome when compared with a modern cemented hemiarthroplasty. Cite this article: Bone Joint J 2018;100-B:352-60.

Predicting the risk of cucurbit downy mildew in the eastern United States using an integrated aerobiological model.

Cucurbit downy mildew caused by the obligate oomycete, Pseudoperonospora cubensis, is considered one of the most economically important diseases of cucurbits worldwide. In the continental United States, the pathogen overwinters in southern Florida and along the coast of the Gulf of Mexico. Outbreaks of the disease in northern states occur annually via long-distance aerial transport of sporangia from infected source fields. An integrated aerobiological modeling system has been developed to predict the risk of disease occurrence and to facilitate timely use of fungicides for disease management. The forecasting system, which combines information on known inoculum sources, long-distance atmospheric spore transport and spore deposition modules, was tested to determine its accuracy in predicting risk of disease outbreak. Rainwater samples at disease monitoring sites in Alabama, Georgia, Louisiana, New York, North Carolina, Ohio, Pennsylvania and South Carolina were collected weekly from planting to the first appearance of symptoms at the field sites during the 2013, 2014, and 2015 growing seasons. A conventional PCR assay with primers specific to P. cubensis was used to detect the presence of sporangia in rain water samples. Disease forecasts were monitored and recorded for each site after each rain event until initial disease symptoms appeared. The pathogen was detected in 38 of the 187 rainwater samples collected during the study period. The forecasting system correctly predicted the risk of disease outbreak based on the presence of sporangia or appearance of initial disease symptoms with an overall accuracy rate of 66 and 75%, respectively. In addition, the probability that the forecasting system correctly classified the presence or absence of disease was ≥ 73%. The true skill statistic calculated based on the appearance of disease symptoms in cucurbit field plantings ranged from 0.42 to 0.58, indicating that the disease forecasting system had an acceptable to good performance in predicting the risk of cucurbit downy mildew outbreak in the eastern United States.

Thompson hemiarthroplasty versus modular unipolar implants for patients requiring hemiarthroplasty of the hip: A systematic review of the evidence.

OBJECTIVES: The objective of this study was to assess all evidence comparing the Thompson monoblock hemiarthroplasty with modular unipolar implants for patients requiring hemiarthroplasty of the hip with respect to mortality and complications. METHODS: A literature search was performed to identify all relevant literature. The population consisted of patients undergoing hemiarthroplasty of the hip for fracture. The intervention was hemiarthroplasty of the hip with a comparison between Thompson and modular unipolar prostheses.Pubmed, Embase, CINAHL, Web of Science, PROSPERO and the Cochrane Central Register of Controlled Trials.The study designs included were randomised controlled trials (RCTs), well designed case control studies and retrospective or prospective cohort studies. Studies available in any language, published at any time until September 2015 were considered. Studies were included if they contained mortality or complications. RESULTS: The initial literature search identified 4757 items for examination. Four papers were included in the final review. The pooled odds ratio for mortality was 1.3 (95% confidence Interval 0.78 to 2.46) favouring modular designs. The pooled odds ratio for post-operative complications was 1.1 (95% CI 0.79 to 1.55) favouring modular designs. Outcomes were reported at 12 or six months. These papers all contained potential sources of bias and significant clinical heterogeneity. CONCLUSION: The current evidence comparing monoblock versus modular implants in patients undergoing hemiarthroplasty is weak. Confidence intervals around the pooled odds ratios are broad and incorporate a value of one. Direct comparison of outcomes from these papers is fraught with difficulty and, as such, may well be misleading. A well designed randomised controlled trial would be helpful to inform evidence-based implant selection.Cite this article: A. L. Sims, A. J. Farrier, M. R. Reed, T. A. Sheldon. Thompson hemiarthroplasty versus modular unipolar implants for patients requiring hemiarthroplasty of the hip: A systematic review of the evidence. Bone Joint Res 2017;6:-513. DOI: 10.1302/2046-3758.68.BJR-2016-0256.R1.

Prevalence and management of recurrent respiratory papillomatosis (RRP) in the UK: cross-sectional study.

OBJECTIVES: To estimate the number of patients with recurrent respiratory papillomatosis currently managed in secondary and tertiary health care in the UK and the frequency of its treatment with radiofrequency cold ablation (Coblation™ ). DESIGN: Cross-sectional survey of ENT consultants in the UK with validation using Hospital Episode Statistics (HES) inpatient data. SETTING: Online survey. PARTICIPANTS: ENT consultants in the UK. MAIN OUTCOME MEASURES: Number of recurrent respiratory papillomatosis patients currently managed in acute care in the UK and frequency of use of Coblation. RESULTS: A total of 283 ENT consultants from 128 UK NHS healthcare trusts and health boards completed the online survey. Responses were received from 86% of surveyed organisations, and an estimated 45% of all ENT consultants in UK. The estimated number of recurrent respiratory papillomatosis patients from the cross-sectional survey was 918 (at August 2015) which included 730 patients in England. The number of recurrent respiratory papillomatosis patients in England estimated from Hospital Episode Statistics (2014/15 financial year) was up to 741. A total of 42 Coblation procedures conducted in the UK were identified from the cross-sectional survey; 36 were conducted in England compared with 34 identified from Hospital Episode Statistics. CONCLUSIONS: The numbers of recurrent respiratory papillomatosis patients and Coblation procedures identified in England from a cross-sectional survey and Hospital Episode Statistics were in broad agreement. Our study estimated 1.42 recurrent respiratory papillomatosis patients per 100 000 in the general UK population. We also estimated that Coblation procedures accounted for 3% of interventional treatments conducted in the UK recurrent respiratory papillomatosis population.

The World Hip Trauma Evaluation Study 3: Hemiarthroplasty Evaluation by Multicentre Investigation - WHITE 3: HEMI - An Abridged Protocol.

BACKGROUND: Approximately half of all hip fractures are displaced intracapsular fractures. The standard treatment for these fractures is either hemiarthroplasty or total hip arthroplasty. The recent National Institute for Health and Care Excellence (NICE) guidance on hip fracture management recommends the use of 'proven' cemented stem arthroplasty with an Orthopaedic Device Evaluation Panel (ODEP) rating of at least 3B (97% survival at three years). The Thompsons prosthesis is currently lacking an ODEP rating despite over 50 years of clinical use, likely due to the paucity of implant survival data. Nationally, adherence to these guidelines is varied as there is debate as to which prosthesis optimises patient outcomes. DESIGN: This study design is a multi-centre, multi-surgeon, parallel, two arm, standard-of-care pragmatic randomised controlled trial. It will be embedded within the WHiTE Comprehensive Cohort Study (ISRCTN63982700). The main analysis is a two-way equivalence comparison between Hemi-Thompson and Hemi-Exeter polished taper with Unitrax head. Secondary outcomes will include radiological leg length discrepancy measured as per Bidwai and Willett, mortality, re-operation rate and indication for re-operation, length of index hospital stay and revision at four months. This study will be supplemented by the NHFD (National Hip Fracture Database) dataset. DISCUSSION: Evidence on the optimum choice of prosthesis for hemiarthroplasty of the hip is lacking. National guidance is currently based on expert opinion rather than empirical evidence. The incidence of hip fracture is likely to continue to increase and providing high quality evidence on the optimumCite this article: A. L. Sims. The World Hip Trauma Evaluation Study 3: Hemiarthroplasty Evaluation by Multicentre Investigation - WHITE 3: HEMI - An Abridged Protocol. Bone Joint Res 2016;5:18-25. doi: 10.1302/2046-3758.51.2000473.

Performance of three cognitive screening tools in a sample of older New Zealanders.

BACKGROUND: With the ubiquitous Mini-Mental State Exam now under copyright, attention is turning to alternative cognitive screening tests. The aim of the present study was to investigate three common cognitive screening tools: the Montreal Cognitive Assessment (MoCA), the Rowland Universal Dementia Assessment Scale (RUDAS), and the recently revised Addenbrooke's Cognitive Assessment Version III (ACE-III). METHODS: The ACE-III, MoCA and RUDAS were administered in random order to a sample of 37 participants with diagnosed mild dementia and 47 comparison participants without dementia. The diagnostic accuracy of the three tests was assessed. RESULTS: All the tests showed good overall accuracy as assessed by area under the ROC Curve, 0.89 (95% CI = 0.80-0.95) for the ACE-III, 0.84 (0.75-0.91) for the MoCA, and 0.86 (0.77-0.93) for RUDAS. The three tests were strongly correlated: r(84) = 0.85 (0.78-0.90) between the ACE-III and MoCA, 0.70 (0.57-0.80) between the ACE-III and RUDAS; and 0.65 (0.50-0.76) between the MoCA and RUDAS. The data derived optimal cut-off points for were lower than the published recommendations for the ACE-III (optimal cut-point ≤76, sensitivity = 81.1%, specificity = 85.1%) and the MoCA (≤20, sensitivity = 78.4%, specificity = 83.0%), but similar for the RUDAS (≤22, sensitivity = 78.4%, specificity = 85.1%). CONCLUSIONS: All three tools discriminated well overall between cases of mild dementia and controls. To inform interpretation of these tests in clinical settings, it would be useful for future research to address more inclusive and potentially age-stratified local norms.

Cemented Thompson's hemiarthroplasty in patients with intracapsular neck of femur fractures: survival analysis of 1,670 procedures.

Cemented Thompson's prostheses have been used to treat elderly patients with displaced intracapsular hip fractures at our two units for the last 15 years, amid growing support for the use of newer implant designs for hip hemiarthroplasty. This provided us with an opportunity to investigate survival of the Thompson's stem in our patients. A retrospective cohort study was set up to review previously collected data on patients who underwent Thompson's hemiarthroplasty over a 7-year period. These were linked to surgical notes, clinical letters and radiographs to record post-operative course and subsequent admissions and procedures. The identifiers were then linked to mortality data from the Office of 'National Statistics. Kaplan-Meier survival analyses were done for implants and patients. A total of 1,632 patients (mean age 82.7 years) underwent 1,670 procedures. Five-year implant survival was 95.4 %. A total of 36 stems were revised, including 14 revisions to total hip arthroplasty and 22 excision arthroplasties. Reasons for revision included infection (2.1 %), dislocation (1.1 %) and aseptic loosening (0.5 %). Symptomatic aseptic loosening and acetabular erosion occurred late (mean time 3.2 and 5.7 years, respectively following surgery). Aseptic loosening and erosion following hemiarthroplasty are relatively late complications.

Changes in PIK3CA mutation status are not associated with recurrence, metastatic disease or progression in endocrine-treated breast cancer.

The phosphatidylinositol-3-kinase pathway plays an important role in proliferation, migration and survival in breast cancer and may play a role in resistance to endocrine therapy. Pathway activation occurs as a result of mutations in PIK3CA or loss of functional PTEN. Matched primary and recurrent samples from 120 breast cancer patients treated with endocrine therapy were profiled with a qPCR-based mutation assay covering eight mutational hotspots in PIK3CA. PTEN was assayed by immunohistochemistry. Samples were well characterized with respect to anatomic location of recurrence (metastatic nodal or local recurrence as opposed to contralateral or ipsilateral new primary cancers). In total, 43 % of patients had at least one PIK3CA mutation at diagnosis, and 41 % had a mutation at the time of recurrence. Only 8 % of patients with local recurrence, metastatic disease or progression on primary endocrine treatment changed their PIK3CA mutation status (four gains, two losses, total 76). The most common changes in PIK3CA mutation status were seen in patients who developed a new cancer either in the treated or contralateral breast (64 %, three gains, four losses, total 11). PIK3CA mutation status does not change in the majority of patients with breast cancer and the acquisition of mutations in PIK3CA is not responsible for the development of endocrine resistance. PTEN loss at diagnosis is associated with a significantly shorter time to progression compared with tumours in which PTEN was retained. These are the most comprehensive data currently available correlating PIK3CA status, site of recurrence and endocrine resistance.

Effect of procedure volume on outcomes after iliac artery angioplasty and stenting.

BACKGROUND: Service reorganization to concentrate complex vascular services in hospitals with high caseload volume aims to reduce mortality and complication rates. The present study assessed the relationship between caseload volume and outcome for iliac artery angioplasty and stenting in England using a routinely available national data set (Hospital Episode Statistics, HES). METHODS: Routine administrative data for iliac artery angioplasty and stent procedures performed in England between 2007 and 2011 were analysed. Associations between centre volume and outcomes (death, complications and duration of hospital stay) were tested and compared for two methods of stratification (quartiles and quintiles) and two statistical tests (odds ratios and the Cochran-Armitage test for trend). Multivariable analysis was also performed. RESULTS: There were 23,308 episodes of care recorded in HES with Office of Population Censuses and Surveys Classification of Surgical Operations and Procedures, fourth revision, codes L54.1 or L54.4 corresponding to iliac artery intervention. There was a gradual increase year by year in number of procedures performed. Univariable and multivariable analysis showed no association between centre volume and either death or complications (multivariable odds ratio, OR 1.00, 95 per cent confidence interval 1.00 to 1.00) for elective and non-elective procedures. Age was associated with higher mortality and complication rates in elective procedures, and with mortality in non-elective procedures. The risk of death after elective iliac angioplasty or stenting was significantly higher in women (multivariable OR 4.98, 2.09 to 13.26). CONCLUSION: There was no association between the outcomes of endovascular iliac artery intervention and centre volume, but outcomes were significantly worse with increasing age and female sex.

Characterization of the ultrasound beam produced by the MIST therapy, wound healing system.

The MIST Therapy wound healing device (Celleration, Eden Prairie, MN, USA), which uses low-frequency ultrasound to deliver an atomized saline spray to acute wounds, was evaluated in a laboratory environment. The output of the MIST device was characterized by its frequency, transmission in the presence and absence of the saline spray and intensity. When measured up to 500 mm away from the transducer tip, the transmission of 39.5 kHz ultrasound was not significantly attenuated by the saline itself. In the absence of the saline spray, the acoustic intensity range of the MIST device was calculated to be 429-188 mW cm(-2) across the manufacturer-specified treatment range (12.5-20 mm). Because of the acoustic impedance mismatch between air and soft tissue, the MIST Therapy device would deliver only 0.1% of this incident intensity into the wound site.

KIBRA exhibits MST-independent functional regulation of the Hippo signaling pathway in mammals.

The Salvador/Warts/Hippo (Hippo) signaling pathway defines a novel signaling cascade regulating cell contact inhibition, organ size control, cell growth, proliferation, apoptosis and cancer development in mammals. The upstream regulation of this pathway has been less well defined than the core kinase cassette. KIBRA has been shown to function as an upstream member of the Hippo pathway by influencing the phosphorylation of LATS and YAP, but functional consequences of these biochemical changes have not been previously addressed. We show that in MCF10A cells, loss of KIBRA expression displays epithelial-to-mesenchymal transition (EMT) features, which are concomitant with decreased LATS and YAP phosphorylation, but not MST1/2. In addition, ectopic KIBRA expression antagonizes YAP via the serine 127 phosphorylation site and we show that KIBRA, Willin and Merlin differentially regulate genes controlled by YAP. Finally, reduced KIBRA expression in primary breast cancer specimens correlates with the recently described claudin-low subtype, an aggressive sub-group with EMT features and a poor prognosis.

Defining the molecular response to trastuzumab, pertuzumab and combination therapy in ovarian cancer.

BACKGROUND: Trastuzumab and pertuzumab target the Human Epidermal growth factor Receptor 2 (HER2). Combination therapy has been shown to provide enhanced antitumour activity; however, the downstream signalling to explain how these drugs mediate their response is not clearly understood. METHODS: Transcriptome profiling was performed after 4 days of trastuzumab, pertuzumab and combination treatment in human ovarian cancer in vivo. Signalling pathways identified were validated and investigated in primary ovarian xenografts at the protein level and across a timeseries. RESULTS: A greater number and variety of genes were differentially expressed by the combination of antibody therapies compared with either treatment alone. Protein levels of cyclin-dependent kinase inhibitors p21 and p27 were increased in response to both agents and further by the combination; pERK signalling was inhibited by all treatments; but only pertuzumab inhibited pAkt signalling. The expression of proliferation, apoptosis, cell division and cell-cycle markers was distinct in a panel of primary ovarian cancer xenografts, suggesting the heterogeneity of response in ovarian cancer and a need to establish predictive biomarkers. CONCLUSION: This first comprehensive study of the molecular response to trastuzumab, pertuzumab and combined therapy in vivo highlights both common and distinct downstream effects to agents used alone or in combination, suggesting that complementary pathways may be involved.

Remote measurement of the leak around the uncuffed tracheal tube: objective measurement and physical characteristics.

BACKGROUND: We have developed a technique for measuring a characteristic of the tracheal tube (TT)-trachea interface: the leak conductance (LC). This study aimed to validate the technique in the laboratory and to compare LC with measurements of fractional volume loss (FVL) in neonates undergoing mechanical ventilation. METHODS: LC, expressed as leak flow at a lung pressure of 10 cm H(2)O, was derived remotely from ventilator pressure and flow signals. Validation was by simulating breathing circuits for 10 models in which LC was measured directly. LC was compared with FVL for different settings of PEEP, inspired pressure, and time at plateau pressure. Clinically, LC was measured for 135 infants admitted to paediatric intensive care after cardiac surgery and compared with FVL. RESULTS: No significant differences were found between direct and remote laboratory measurements of LC (P>0.05). FVL varied with PEEP, plateau pressure, and time at plateau (P<0.05) but LC did not (P>0.05). The between-patient standard deviation (sd) of LC (0.4 litre min(-1)) exceeded the within-patient sd of lc (0.05 litre min(-1); P<0.05); the between-patient sd of FVL (22.1%) exceeded the within-patient sd of FVL (1.3%; P<0.05). The median LC was 0.38 (inter-quartile range 0.29-0.46) litre min(-1). LC was correlated with FVL (r=0.82; 95% confidence interval 0.76-0.88) but wide ranges of FVL were observed for patients with similar LC. CONCLUSIONS: LC can be derived remotely and was correlated with FVL, a conventional proxy for tube fit. It may be a better measure of TT fit than FVL.

A gene on the HER2 amplicon, C35, is an oncogene in breast cancer whose actions are prevented by inhibition of Syk.

BACKGROUND: C35 is a 12 kDa membrane-anchored protein endogenously over-expressed in many invasive breast cancers. C35 (C17orf37) is located on the HER2 amplicon, between HER2 and GRB7. The function of over-expressed C35 in invasive breast cancer is unknown. METHODS: Tissue microarrays containing 122 primary human breast cancer specimens were used to examine the association of C35 with HER2 expression. Cell lines over-expressing C35 were generated and tested for evidence of cell transformation in vitro. RESULTS: In primary breast cancers high levels of C35 mRNA expression were associated with HER2 gene amplification. High levels of C35 protein expression were associated with hallmarks of transformation, such as, colony growth in soft agar, invasion into collagen matrix and formation of large acinar structures in three-dimensional (3D) cell cultures. The transformed phenotype was also associated with characteristics of epithelial to mesenchymal transition, such as adoption of spindle cell morphology and down-regulation of epithelial markers, such as E-cadherin and keratin-8. Furthermore, C35-induced transformation in 3D cell cultures was dependent on Syk kinase, a downstream mediator of signalling from the immunoreceptor tyrosine-based activation motif, which is present in C35. CONCLUSION: C35 functions as an oncogene in breast cancer cell lines. Drug targeting of C35 or Syk kinase might be helpful in treating a subset of patients with HER2-amplified breast cancers.

Elastic and viscoelastic properties of porcine subdermal fat using MRI and inverse FEA.

There is a scarcity of investigation into the mechanical properties of subdermal fat. Recently, progress has been made in the determination of subdermal stress and strain distributions. This requires accurate constitutive modelling and consideration of the subdermal tissues. This paper reports the results of a study to estimate non-linear elastic and viscoelastic properties of porcine subdermal fat using a simple constitutive model. High-resolution magnetic resonance imaging (MRI) was used to acquire a time series of coincident images during a confined indentation experiment. Inverse finite element analysis was used to estimate the material parameters. The Neo Hookean model was used to represent the elastic behaviour (µ = 0.53 ± 0.31 kPa), while a single-element Prony series was used to model the viscoelastic response (α = 0.39 ± 0.03, τ = 700 ± 255 s).

Bioinformatics and breast cancer: what can high-throughput genomic approaches actually tell us?

High-throughput genomic technology has rapidly become a major tool for the study of breast cancer. Gene expression profiling has been applied to many areas of research from basic science to translational studies, with the potential to identify new targets for treatment, mechanisms of resistance and to improve on current tools for the analysis of prognosis. However, the sheer scale of the data generated along with the number of different protocols, platforms and analysis methods can make these studies difficult for clinicians to comprehend. Similarly, computational scientists and statisticians that may be called upon to analyse the data generated are often unaware of the processes involved in sample collection or the relevance and impact of genetics and pathological characteristics. There is a pressing need for better understanding of the challenges and limitations of microarray approaches, both in experimental design and data analysis. Holistic, whole-genome approaches are still relatively new and critics have been quick to highlight non-overlapping results from groups testing similar hypotheses. However, it is often subtle differences in the experimental design and technology that underpin the variation between these studies. Rather than indicating that the data are meaningless, this suggests that many findings are real, but highly context dependent. This review explores both the current state and potential of bioinformatics to bring meaning to high-throughput genomic approaches in the understanding of breast cancer.

Fine mapping of the MHC Class III region demonstrates association of AIF1 and rheumatoid arthritis.

OBJECTIVES: The heritability of RA has been estimated to be approximately 55%, of which the MHC contributes about one-third. HLA-DRB1 alleles are strongly associated with RA, but it is likely that significant non-DRB1 MHC genetic susceptibility factors are involved. Previously, we identified two three-marker haplotypes in a 106-kb region in the MHC class III region immediately centromeric to TNF, which are strongly associated with RA on HLA-DRB1*0404 haplotypes. In the present study, we aimed to refine these associations further using a combination of genotyping and gene expression studies. METHODS: Thirty-nine nucleotide polymorphisms (SNPs) were genotyped in 95 DRB1*0404 carrying unrelated RA cases, 125 DRB1*0404-carrying healthy controls and 87 parent-case trio RA families in which the affected child carried HLA-DRB1*04. Quantitative RT-PCR was used to assess the expression of the positional candidate MHC class III genes APOM, BAT2, BAT3, BAT4, BAT5, AIF1, C6orf47, CSNK2beta and LY6G5C, and the housekeeper genes, hypoxanthine-guanine phosphoribosyltransferase (HPRT) and beta(2)-microglobulin (B2M) in 31 RA cases and 21 ethnically, age- and sex-matched healthy controls. Synovial membrane specimens from RA, PsA and OA cases were stained by an indirect immunoperoxidase technique using a mouse-anti-human AIF1 monoclonal antibody. RESULTS: Association was observed between RA and single markers or two marker haplotypes involving AIF1, BAT3 and CSNK. AIF1 was also significantly overexpressed in RA mononuclear cells (1.5- to 1.9-fold difference, P = 0.02 vs HPRT, P = 0.002 vs B2M). AIF1 protein was clearly expressed by synovial macrophages in all the inflammatory synovial samples in contrast to the non-inflammatory OA samples. CONCLUSIONS: The results of the genotyping and expression studies presented here suggest a role for AIF1 in both the aetiology and pathogenesis of RA.

Prospective meta-analysis of interleukin 1 gene complex polymorphisms confirms associations with ankylosing spondylitis.

OBJECTIVES: The aim of the current study was to determine the contribution of interleukin (IL)1 gene cluster polymorphisms previously implicated in susceptibility for ankylosing spondylitis (AS) to AS susceptibility in different populations worldwide. METHODS: Nine polymorphisms in the IL1 gene cluster members IL1A (rs2856836, rs17561 and rs1894399), IL1B (rs16944), IL1F10 (rs3811058) and IL1RN (rs419598, the IL1RA VNTR, rs315952 and rs315951) were genotyped in 2675 AS cases and 2592 healthy controls recruited in 12 different centres in 10 countries. Association of variants with AS was tested by Mantel-Haenszel random effects analysis. RESULTS: Strong association was observed with three single nucleotide polymorphisms (SNPs) in the IL1A gene (rs2856836, rs17561, rs1894399, p = 0.0036, 0.000019 and 0.0003, respectively). There was no evidence of significant heterogeneity of effects between centres, and no evidence of non-combinability of findings. The population attributable risk fraction of these variants in Caucasians is estimated at 4-6%. CONCLUSIONS: This study confirms that IL1A is associated with susceptibility to AS. Association of the other IL1 gene complex members could not be excluded in specific populations. Prospective meta-analysis is a useful tool in confirmation studies of genes associated with complex genetic disorders such as AS, providing sufficiently large sample sizes to produce robust findings often not achieved in smaller individual cohorts.

TPD52 and NFKB1 gene expression levels correlate with G2 chromosomal radiosensitivity in lymphocytes of women with and at risk of hereditary breast cancer.

PURPOSE: To evaluate a transcriptomic approach to identify healthy women at increased risk of breast cancer due to G2-radiosensitivity and look at transcripts that are differentially expressed between individuals. MATERIALS AND METHODS: We perform the first study to assess the association of G2 radiosensitivity with basal gene expression in cultured T-lymphocytes from 11 women with breast cancer and 12 healthy female relatives using Affymetrix GeneChips. RESULTS: Transcripts associated with radiosensitivity and breast cancer risk were predominantly involved in innate immunity and inflammation, such as interleukins and chemokines. Genes differentially expressed in radiosensitive individuals were more similarly expressed in close family members than in un-related individuals, suggesting heritability of the trait. The expression of tumour protein D52 (TPD52), a gene implicated in cell proliferation, apoptosis, and vesicle trafficking was the most strongly correlated with G2 score while nuclear factor (kappa)-B (NFKB1) was highly inversely correlated with G2 score. NFKB1 is known to be activated by irradiation and its inhibition has been previously shown to increase radiosensitivity. CONCLUSIONS: Gene expression analysis of lymphocytes may provide a quantitative measure of radiation response potential and is a promising marker of breast cancer susceptibility.