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Favaloro E.J.,Westmead Hospital | Chapman K.,Hunter Area Pathology Service | Meiring M.,University of the Free State | Funk Adcock D.,Esoterix Inc.
Journal of Thrombosis and Haemostasis | Year: 2012

Background von Willebrand disease (VWD), the most common inherited bleeding disorder, is caused by deficiencies and/or defects in von Willebrand factor (VWF). An effective diagnostic and VWD typing strategy requires plasma testing for factor VIII, and VWF antigen plus one or more VWF 'activity' assays. VWF activity is classically assessed by using VWF ristocetin cofactor activity (VWF:RCo), although VWF collagen-binding (VWF:CB) and VWF mAb-based (VWF activity [VWF:Act]) assays are used by some laboratories. Objective: To perform a cross-laboratory study to specifically evaluate these three VWF activity assays for comparative sensitivity to loss of high molecular weight (HMW) VWF, representing the form of VWF that is most functionally active and that is absent in some types of VWD, namely 2A and 2B. Methods: A set of eight samples, including six selectively representing stepwise reduction in HMW VWF, were tested by 51 different laboratories using a variety of assays. Results: The combined data showed that the VWF:CB and VWF:RCo assays had higher sensitivity to the loss of HMW VWF than did the VWF:Act assay. Moreover, within-method analysis identified better HMW VWF sensitivity of some VWF:CB assays than of others, with all VWF:CB assays still showing better sensitivity than the VWF:Act assay. Differences were also identified between VWF:RCo methodologies on the basis of either platelet aggregometry or as performed on automated analyzers. Conclusions: We believe that these results have significant clinical implications for the diagnosis of VWD and monitoring of its therapy, as well as for the future diagnosis and therapy monitoring of thrombotic thrombocytopenic purpura. © 2012 International Society on Thrombosis and Haemostasis.


Chen J.,University of Houston | Pande M.,University of Houston | Huang Y.-J.,University of Houston | Wei C.,University of Houston | And 9 more authors.
Carcinogenesis | Year: 2013

Heterogeneity in age of onset of colorectal cancer in individuals with mutations in DNA mismatch repair genes (Lynch syndrome) suggests the influence of other lifestyle and genetic modifiers. We hypothesized that genes regulating the cell cycle influence the observed heterogeneity as cell cycle-related genes respond to DNA damage by arresting the cell cycle to provide time for repair and induce transcription of genes that facilitate repair. We examined the association of 1456 single nucleotide polymorphisms (SNPs) in 128 cell cycle-related genes and 31 DNA repair-related genes in 485 non-Hispanic white participants with Lynch syndrome to determine whether there are SNPs associated with age of onset of colorectal cancer. Genotyping was performed on an Illumina GoldenGate platform, and data were analyzed using Kaplan-Meier survival analysis, Cox regression analysis and classification and regression tree (CART) methods. Ten SNPs were independently significant in a multivariable Cox proportional hazards regression model after correcting for multiple comparisons (P < 5 × 10-4). Furthermore, risk modeling using CART analysis defined combinations of genotypes for these SNPs with which subjects could be classified into low-risk, moderate-risk and high-risk groups that had median ages of colorectal cancer onset of 63, 50 and 42 years, respectively. The age-associated risk of colorectal cancer in the high-risk group was more than four times the risk in the low-risk group (hazard ratio = 4.67, 95% CI = 3.16-6.92). The additional genetic markers identified may help in refining risk groups for more tailored screening and follow-up of non-Hispanic white patients with Lynch syndrome. © The Author 2012. Published by Oxford University Press. All rights reserved.


Papeix G.,Manning Base Hospital | Zardawi I.M.,University of Newcastle | Douglas C.D.,Breast Center | Clark D.A.,Breast Center | Braye S.G.,Hunter Area Pathology Service
Acta Cytologica | Year: 2012

Background and Objective: The literature on fine-needle aspiration (FNA) cytology for papillary lesions presents a very mixed picture. Many authors advocate mandatory excision of these lesions. This recommendation is largely based on the 'atypical' nature of the FNA report. The aim of this work is to see if breast papillomas can be treated conservatively. Study Design: We report a retrospective study of outcomes for patients with a provisional diagnosis of a 'papillary breast lesion' based on assessment by palpation (no clinically suspicious features), sonography (benign or probably benign according to the Breast Imaging Reporting and Data System 'BI-RADS®'), and FNA (benign cytological category with a papillary architecture) findings from one integrated breast service. Results: Thirty-six cases were identified over a period of 6 years. Thirty-four of the patients had surgical excision. All of the 34 surgical cases were confirmed to be benign in nature on histopathology (intraduct papilloma). The remaining 2 cases were stable on follow-up. Conclusion: We believe that a policy of mandatory excision of papillary lesions of the breast is unnecessarily cautious. © 2012 S. Karger AG, Basel.


Sapkota Y.,QIMR Berghofer Medical Research Institute | Low S.-K.,QIMR Berghofer Medical Research Institute | Low S.-K.,RIKEN | Attia J.,QIMR Berghofer Medical Research Institute | And 19 more authors.
Human Reproduction | Year: 2015

STUDY QUESTION Are single-nucleotide polymorphisms (SNPs) at the interleukin 1A (IL1A) gene locus associated with endometriosis risk? SUMMARY ANSWER We found evidence for strong association between IL1A SNPs and endometriosis risk. WHAT IS KNOWN ALREADY Genetic factors contribute substantially to the complex aetiology of endometriosis and the disease has an estimated heritability of ∼51%. We, and others, have conducted genome-wide association (GWA) studies for endometriosis, which identified a total of nine independent risk loci. Recently, two small Japanese studies reported eight SNPs (rs6542095, rs11677416, rs3783550, rs3783525, rs3783553, rs2856836, rs1304037 and rs17561) at the IL1A gene locus as suggestively associated with endometriosis risk. There is also evidence of a link between inflammation and endometriosis. STUDY DESIGN, SIZE, DURATION We sought to further investigate the eight IL1A SNPs for association with endometriosis using an independent sample of 3908 endometriosis cases and 8568 controls of European and Japanese ancestry. The study was conducted between October 2013 and July 2014. PARTICIPANTS/MATERIALS, SETTING, METHODS By leveraging GWA data from our previous multi-ethnic GWA meta-Analysis for endometriosis, we imputed variants in the IL1A region, using a recent 1000 Genomes reference panel. After combining summary statistics for the eight SNPs from our European and Japanese imputed data with the published results, a fixed-effect meta-Analysis was performed. An additional meta-Analysis restricted to endometriosis cases with moderate-to-severe (revised American Fertility Society stage 3 or 4) disease versus controls was also performed. MAIN RESULTS AND THE ROLE OF CHANCE All eight IL1A SNPs successfully replicated at P < 0.014 in the European imputed data with concordant direction and similar size to the effects reported in the original Japanese studies. Of these, three SNPs (rs6542095, rs3783550 and rs3783525) also showed association with endometriosis at a nominal P < 0.05 in our independent Japanese sample. Fixed-effect meta-Analysis of the eight SNPs for moderate-to-severe endometriosis produced a genome-wide significant association for rs6542095 (odds ratio = 1.21; 95% confidence interval = 1.13-1.29; P = 3.43 × 10-8). LIMITATIONS, REASONS FOR CAUTION The meta-Analysis for moderate-to-severe endometriosis included results of moderate-to-severe endometriosis cases from our European data sets and all endometriosis cases from the Japanese data sets, as disease stage information was not available for endometriosis cases in the Japanese data sets. WIDER IMPLICATIONS OF THE FINDINGS SNP rs6542095 is located ∼2.3 kb downstream of the IL1A gene and ∼6.9 kb upstream of cytoskeleton-Associated protein 2-like (CKAP2L) gene. The IL1A gene encodes the IL1a protein, a member of the interleukin 1 cytokine family which is involved in various immune responses and inflammatory processes. These results provide important replication in an independent Japanese sample and, for the first time, association of the IL1A locus in endometriosis patients of European ancestry. SNPs within the IL1A locus may regulate other genes, but if IL1A is the target, our results provide supporting evidence for a link between inflammatory responses and the pathogenesis of endometriosis. STUDY FUNDING/COMPETING INTEREST(S) The research was funded by grants from the Australian National Health and Medical Research Council and Wellcome Trust. None of the authors has competing interests for the study. © 2014 © The Author 2014. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved.


PubMed | University of Newcastle, Hunter Medical Research Institute and Hunter Area Pathology Service
Type: Journal Article | Journal: Dementia and geriatric cognitive disorders extra | Year: 2014

Autoimmunity is considered an uncommon but under-recognised cause of cognitive decline.Serum samples from 3,253 randomly selected subjects enrolled in the Hunter Community Study, aged 55-85 years, were assayed for thyrotropin stimulatory hormone, anti-thyroid peroxidase antibodies (TPO-Ab), anti-nuclear antibodies (ANA) and extractable nuclear antigens (ENA). Cognitive function was assessed using the Audio Recorded Cognitive Screen (ARCS) tool.TPO-Ab were found in 8.4% and ANA in 27.9% of the study population, of whom 3% had positive ENA findings. No relationship was found between the ARCS score and either TPO-Ab (coefficient = 0.133; 95% CI -0.20, 0.82, p = 0.616), ANA at a low (coefficient = 1.01; 95% CI -2.58, 0.55, p = 0.203) or a high titre (coefficient = -0.65; 95% CI -2.59, 1.28, p = 0.508), or ENA antibodies (coefficient = 5.12; 95% CI -0.53, 10.77; p = 0.076).Autoantibody findings are common in an aging population and are not associated with cognitive decline.


Kamien B.,Hunter Genetics | Kamien B.,University of Newcastle | Lionel A.C.,Applied Genomics | Lionel A.C.,University of Toronto | And 5 more authors.
American Journal of Medical Genetics, Part A | Year: 2014

We report on two patients with intragenic deletions of RBFOX1 and one patient with an intragenic duplication of RBFOX1. These patients, by report, all had autism spectrum disorder and/or developmental delay and had strong family histories of these conditions. We initially hypothesized that RBFOX1 was another susceptibility locus for autism spectrum disorder or developmental delay. However, epidemiological evidence examining large numbers of individuals did not support this hypothesis and the data presented here suggests that RBFOX1 intragenic copy number variants are not pathogenic. This contradicts previous reports that examined smaller numbers of patients and controls. © 2014 Wiley Periodicals, Inc.


Tran H.,Hunter Region Mail Center | Tran H.,University of Newcastle | Jones T.,Hunter Area Pathology Service | Ianna E.,Hunter Area Pathology Service | And 2 more authors.
Endocrine Practice | Year: 2013

Objective: Hepatitis C virus (HCV) infection is one of the major epidemics afflicting young people in both developed and developing countries. The most common endocrine disorder associated with this infection, especially in conjunction with interferon-α (IFN-α)-based therapy, is thyroid disease (TD). This review examines the development of TD before, during, and after the completion of treatment with combination IFN-α and ribavirin (RBV) for chronic HCV infection. We also summarize the current understanding of the natural history of the condition and propose management and follow-up guidelines.Methods: PubMed was searched up to June 30, 2011 for English-language publications that contained the search terms "hepatitis C virus," "chronic hepatitis C," "HCV," "thyroid disease," "thyroiditis," "autoimmunity," "interferon-alpha," and "ribavirin." Additional publications were identified from the reference lists of identified papers. The included studies were original research publications and included combination IFN-α and RBV use in patients that developed TD.Results: The prevalence of TD before combination IFN-α and RBV therapy ranges from 4.6 to 21.3%; during therapy, 1.1 to 21.3%; and after therapy, 6.7 to 21.3%. The most common TD is thyroiditis. Thyroid function testing (TFT) frequency and diagnostic criteria for various thyroid conditions are not standardized, and many of the existing studies are retrospective.Conclusion: Patients undergoing this therapy should be assessed with a standardized protocol to appropriately detect and manage developed TD. Based on the currently available literature, we recommend that patients receiving combination interferon-α and RBV therapy undergo monthly thyrotropin (TSH) level testing. © 2013 AACE.


Berry N.K.,Calvary Materials Hospital | Berry N.K.,University of Newcastle | Bain N.L.,Hunter Area Pathology Service | Enjeti A.K.,Calvary Materials Hospital | And 2 more authors.
Journal of Clinical Pathology | Year: 2014

Aim: To evaluate the role of whole genome comparative genomic hybridisation microarray (array-CGH) in detecting genomic imbalances as compared to conventional karyotype (GTG-analysis) or myeloma specific fluorescence in situ hybridisation (FISH) panel in a diagnostic setting for plasma cell dyscrasia (PCD). Methods: A myeloma-specific interphase FISH (i-FISH) panel was carried out on CD138 PC-enriched bone marrow (BM) from 20 patients having BM biopsies for evaluation of PCD. Whole genome array-CGH was performed on reference (control) and neoplastic (test patient) genomic DNA extracted from CD138 PC-enriched BM and analysed. Results: Comparison of techniques demonstrated a much higher detection rate of genomic imbalances using array-CGH. Genomic imbalances were detected in 1, 19 and 20 patients using GTG-analysis, i-FISH and array-CGH, respectively. Genomic rearrangements were detected in one patient using GTG-analysis and seven patients using i-FISH, while none were detected using array-CGH. I-FISH was the most sensitive method for detecting gene rearrangements and GTG-analysis was the least sensitive method overall. All copy number aberrations observed in GTG-analysis were detected using array-CGH and i-FISH. Conclusions: We show that array-CGH performed on CD138-enriched PCs signi ficantly improves the detection of clinically relevant and possibly novel genomic abnormalities in PCD, and thus could be considered as a standard diagnostic technique in combination with IGH rearrangement i-FISH.


Dwight T.,Kolling Institute of Medical Research | Dwight T.,University of Sydney | Benn D.E.,Kolling Institute of Medical Research | Benn D.E.,University of Sydney | And 9 more authors.
American Journal of Surgical Pathology | Year: 2013

Succinate dehydrogenase-deficient gastrointestinal stromal tumors (SDH-deficient GISTs) are a unique class of GIST defined by negative immunohistochemical staining for succinate dehydrogenase B (SDHB). SDH-deficient GISTs show distinctive clinical and pathologic features including absence of KIT and PDGFRA mutations, exclusive gastric location, common lymph node metastasis, a prognosis not predicted by size and mitotic rate, and indolent behavior of metastases. They may be syndromal with some being associated with the Carney Triad or germline SDHA, SDHB, SDHC, or SDHD mutations (Carney-Stratakis syndrome). It is normally recommended that genetic testing for SDHA, SDHB, SDHC, and SDHD be offered whenever an SDH-deficient GIST is encountered. However, testing for all 4 genes is burdensome and beyond the means of most centers. In this study we performed SDHA mutation and immunohistochemical analyses for SDHA on 10 SDH-deficient GISTs. Three showed negative staining for SDHA, and all of these were associated with germline SDHA mutations. In 2 tumors, 3 novel mutations were identified (p.Gln54X, p.Thr267Met, and c.1663+3G>C), none of which have previously been reported in GISTs or other SDH-associated tumors. Seven showed positive staining for SDHA and were not associated with SDHA mutation. In conclusion, 30% of SDH-deficient GISTs in this study were associated with germline SDHA mutation. Negative staining for SDHA can be used to triage formal genetic testing for SDHA when an SDH-deficient GIST is encountered. © 2012 by Lippincott Williams & Wilkins.


Williams M.,Royal Melbourne Hospital | Izzard L.,Geelong Hospital | Graves S.R.,Hunter Area Pathology Service | Stenos J.,Geelong Hospital | And 2 more authors.
Medical Journal of Australia | Year: 2011

Human infection with Rickettsia felis has been reported in most parts of the world, and R. felis has recently been confirmed in cat fleas in Western Australia. The clinical presentations of R. typhi and R. felis are similar, and in the past, the incidence of R. felis infection may have been underestimated. We describe the first reported cases of probable human R. felis infection in Australia. Two adults and three children in Victoria contracted a rickettsial disease after exposure to fleas from kittens. Molecular testing of fleas demonstrated the presence of R. felis but not R. typhi.

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