Kolling Institute of Medical Research

Sydney, Australia

Kolling Institute of Medical Research

Sydney, Australia
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Gossan N.,University of Manchester | Zeef L.,University of Manchester | Hensman J.,University of Sheffield | Hughes A.,University of Manchester | And 7 more authors.
Arthritis and Rheumatism | Year: 2013

Objective To characterize the circadian clock in murine cartilage tissue and identify tissue-specific clock target genes, and to investigate whether the circadian clock changes during aging or during cartilage degeneration using an experimental mouse model of osteoarthritis (OA). Methods Cartilage explants were obtained from aged and young adult mice after transduction with the circadian clock fusion protein reporter PER2::luc, and real-time bioluminescence recordings were used to characterize the properties of the clock. Time-series microarrays were performed on mouse cartilage tissue to identify genes expressed in a circadian manner. Rhythmic genes were confirmed by quantitative reverse transcription-polymerase chain reaction using mouse tissue, primary chondrocytes, and a human chondrocyte cell line. Experimental OA was induced in mice by destabilization of the medial meniscus (DMM), and articular cartilage samples were microdissected and subjected to microarray analysis. Results Mouse cartilage tissue and a human chondrocyte cell line were found to contain intrinsic molecular circadian clocks. The cartilage clock could be reset by temperature signals, while the circadian period was temperature compensated. PER2::luc bioluminescence demonstrated that circadian oscillations were significantly lower in amplitude in cartilage from aged mice. Time-series microarray analyses of the mouse tissue identified the first circadian transcriptome in cartilage, revealing that 615 genes (∼3.9% of the expressed genes) displayed a circadian pattern of expression. This included genes involved in cartilage homeostasis and survival, as well as genes with potential importance in the pathogenesis of OA. Several clock genes were disrupted in the early stages of cartilage degeneration in the DMM mouse model of OA. Conclusion These results reveal an autonomous circadian clock in chondrocytes that can be implicated in key aspects of cartilage biology and pathology. Consequently, circadian disruption (e.g., during aging) may compromise tissue homeostasis and increase susceptibility to joint damage or disease. © 2013 The Authors. Arthritis & Rheumatism is published by Wiley Periodicals, Inc. on behalf of the American College of Rheumatology.


Trinh A.T.,Hung Vuong Hospital | Khambalia A.,Kolling Institute of Medical Research | Ampt A.,Kolling Institute of Medical Research | Morris J.M.,Royal North Shore Hospital | Roberts C.L.,Kolling Institute of Medical Research
Bulletin of the World Health Organization | Year: 2013

Objective To describe the use of episiotomy among Vietnamese-born women in Australia, including risk factors for, and pregnancy outcomes associated with, episiotomy. Methods This population-based, retrospective cohort study included data on 598 305 singleton, term (i.e. ≥ 37 weeks' gestation) and vertex-presenting vaginal births between 2001 and 2010. Data were obtained from linked, validated, population-level birth and hospitalization data sets. Contingency tables and multivariate analysis were used to compare risk factors and pregnancy outcomes in women who did or did not have an episiotomy. Findings The episiotomy rate in 12 208 Vietnamese-born women was 29.9%, compared with 15.1% in Australian-born women. Among Vietnamese-born women, those who had an episiotomy were significantly more likely than those who did not to be primiparous, give birth in a private hospital, have induced labour or undergo instrumental delivery. In these women, having an episiotomy was associated with postpartum haemorrhage (adjusted odds ratio, aOR: 1.26; 95% confidence interval, CI: 1.08-1.46) and postnatal hospitalization for more than 4 days (aOR: 1.14; 95% CI: 1.00-1.29). Among multiparous women only, episiotomy was positively associated with a third- or fourth-degree perineal tear (aOR: 2.00; 95% CI: 1.31-3.06); in contrast, among primiparous women the association was negative (aOR: 0.47; 95% CI: 0.37-0.60). Conclusion Episiotomy was performed in far fewer Vietnamese-born women giving birth in Australia than in Viet Nam, where more than 85% undergo the procedure, and was not associated with adverse outcomes. A lower episiotomy rate should be achievable in Viet Nam.


Girgis C.M.,Garvan Institute of Medical Research | Girgis C.M.,University of Sydney | Clifton-Bligh R.J.,University of Sydney | Clifton-Bligh R.J.,Kolling Institute of Medical Research | And 7 more authors.
Endocrinology | Year: 2014

Vitamin D deficiency is linked to a range of muscle disorders including myalgia, muscle weakness, and falls. Humans with severe vitamin D deficiency and mice with transgenic vitamin D receptor (VDR) ablation have muscle fiber atrophy. However, molecular mechanisms by which vitamin D influences muscle function and fiber size remain unclear. A central question is whether VDR is expressed in skeletal muscle and is able to regulate transcription at this site. To address this, we examined key molecular and morphologic changes in C2C12 cells treated with 25-hydroxyvitamin D (25OHD) and 1,25-dihydroxyvitamin D (1,25(OH)2D). As well as stimulating VDR expression, 25(OH)D and 1,25(OH)2D dose-dependently increased expression of the classic vitamin D target cytochrome P450, family 24, subfamily A, polypeptide 1 (CYP24A1), demonstrating the presence of an autoregulatory vitamin D-endocrine system in these cells. Luciferase reporter studies demonstrated that cytochrome P450, family 27, subfamily B, polypeptide 1 (CYP27B1) was functional in these cells. Both 25OHD and 1,25(OH)2D altered C2C12 proliferation and differentiation. These effects were related to the increased expression of genes involved in G0/G1 arrest (retinoblastoma protein [Rb], 1.3-fold; ATM, 1.5-fold, both P < .05), downregulation of mRNAs involved in G1/S transition, including myc and cyclin-D1 (0.7- and 0.8-fold, both P < .05) and reduced phosphorylation of Rb protein (0.3-fold, P < .005). After serum depletion, 1,25(OH)2D (100nM) suppressed myotube formation with decreased mRNAs for key myogenic regulatory factors (myogenin, 0.5- fold; myf5, 0.4-fold, P < .005) but led to a 1.8-fold increase in cross-sectional size of individual myotubes associated with markedly decreased myostatin expression (0.2-fold, P < .005). These data show that vitamin D signaling alters gene expression in C2C12 cells, with effects on proliferation, differentiation, and myotube size. Copyright © 2014 by the Endocrine Society.


Singh P.,Kolling Institute of Medical Research | Wig J.D.,Government Medical College and Hospital | Srinivasan R.,Jawaharlal Institute of Postgraduate Medical Education & Research
Indian Journal of Cancer | Year: 2011

One of the major signaling pathways that determine the tumor aggression and patient outcome in pancreatic cancer is the transforming growth factor-beta (TGF-ß) pathway. It is inactivated at various levels in pancreatic cancer and plays a dual role in tumor initiation and progression. The Smad family of proteins transduce signals from the TGF-ß superfamily ligands that regulate cell proliferation, differentiation and death through activation of receptor serine/threonine kinases. This review discusses the structure, function and regulation of various participating Smad family members, and their individual roles in determining the progression and outcome of pancreatic cancer patients, with a special emphasis on Smad4.


Downey A.,University of Sydney | Jackson C.,Kolling Institute of Medical Research | Harun N.,Westmead Millennium Institute | Cooper A.,Royal North Shore Hospital
Journal of the American Academy of Dermatology | Year: 2012

Toxic epidermal necrolysis (TEN) is a severe cutaneous drug reaction with a mortality rate of approximately 30%. The hallmark of TEN is widespread epidermal sloughing due to keratinocyte apoptosis. Multiple genetic associations between TEN and specific ethnic populations have been determined. The pathophysiology of TEN has yet to be fully elucidated; however, current pathogenic models implicate Fas ligand, granulysin, and reactive oxygen species. The value of current therapies, such as intravenous immunoglobulin and corticosteroids, remains under evaluation. © 2011 by the American Academy of Dermatology, Inc.


Khambalia A.Z.,Kolling Institute of Medical Research | Khambalia A.Z.,University of Sydney | Dickinson S.,University of Sydney | Hardy L.L.,University of Sydney | And 3 more authors.
Obesity Reviews | Year: 2012

Schools are an attractive and popular setting for implementing interventions for children. There is a growing body of empirical research exploring the efficacy of school-based obesity prevention programs. While there have been several reviews on the topic, findings remain mixed. To examine the quality of evidence and compare the findings from existing systematic reviews and meta-analyses of school-based programs in the prevention and control of childhood obesity. This paper systematically appraises the methodology and conclusions of literature reviews examining the effectiveness of school-based obesity interventions published in English in peer-reviewed journals between January 1990 and October 2010. Eight reviews were examined, three meta-analyses and five systematic reviews. All of the reviews recognized that studies were heterogeneous in design, participants, intervention and outcomes. Intervention components in the school setting associated with a significant reduction of weight in children included long-term interventions with combined diet and physical activity and a family component. Several reviews also found gender differences in response to interventions. Of the eight reviews, five were deemed of high quality and yet limited evidence was found on which to base recommendations. As no single intervention will fit all schools and populations, further high-quality research needs to focus on identifying specific program characteristics predictive of success. © 2011 The Authors. obesity reviews © 2011 International Association for the Study of Obesity.


Khambalia A.Z.,Kolling Institute of Medical Research | Roberts C.L.,Kolling Institute of Medical Research | Bowen J.R.,University of Sydney | Nassar N.,Kolling Institute of Medical Research
Journal of Paediatrics and Child Health | Year: 2012

Aim: The aim of this study was to compare maternal and infant characteristics by mode of VK administration. Methods: De-identified computerised birth files of all babies born in New South Wales (NSW), Australia between January 2007 and December 2009 (when VK prophylaxis was measured) were included in the present study. The outcome variable, mode of VK prophylaxis, was recorded by checkbox as oral, IM injection, none or not stated. Results: We analysed population-based birth data from 2007 to 2009 in NSW, Australia and found that IM injection was the most prevalent mode of administration (96.3%, n = 263, 555), followed by oral (2.6%, n = 7023) and none (1.2%, n = 3136). Compared to neonates receiving IM VK, those with oral or none were more likely to have vaginal births without medical interventions at birth centres or planned home births and were less likely to receive hepatitis B vaccination. Among neonates administered oral VK, a larger proportion were preterm births and breastfed at discharge compared to neonates administered VK as an IM injection. Neonates with no VK recorded were more likely to be admitted to neonatal intensive care, but may have received VK later in the birth admission. Conclusions: A small proportion of the Australian neonates may be at risk of inadequate protection from VKBD due to parental concerns about the safety of IM injection of VK to neonates. © 2012 The Authors. Journal of Paediatrics and Child Health © 2012 Paediatrics and Child Health Division (Royal Australasian College of Physicians).


Nguyen T.G.,Kolling Institute of Medical Research | Ward C.M.,Kolling Institute of Medical Research | Morris J.M.,Kolling Institute of Medical Research | Morris J.M.,University of Sydney
Clinical and Experimental Immunology | Year: 2013

Maternal immune responses during pregnancy are critical in programming the future health of a newborn. The maternal immune system is required to accommodate fetal immune tolerance as well as to provide a protective defence against infections for the immunocompromised mother and her baby during gestation and lactation. Natural immunity and antibody production by maternal B cells play a significant role in providing such immunoprotection. However, aberrations in the B cell compartment as a consequence of maternal autoimmunity can pose serious risks to both the mother and her baby. Despite their potential implication in shaping pregnancy outcomes, the role of B cells in human pregnancy has been poorly studied. This review focuses on the role of B cells and the implications of B cell depletion therapy in pregnancy. It highlights the evidence of an association between aberrant B cell compartment and obstetric conditions. It also alludes to the potential mechanisms that amplify these B cell aberrances and thereby contribute to exacerbation of some maternal autoimmune conditions and poor neonatal outcomes. Clinical and experimental evidence suggests strongly that maternal autoantibodies contribute directly to the pathologies of obstetric and neonatal conditions that have significant implications for the lifelong health of a newborn. The evidence for clinical benefit and safety of B cell depletion therapies in pregnancy is reviewed, and an argument is mounted for further clinical evaluation of B cell-targeted therapies in high-risk pregnancy, with an emphasis on improving neonatal outcomes and prevention of neonatal conditions such as congenital heart block and fetal/neonatal alloimmune thrombocytopenia. © 2012 British Society for Immunology.


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.


Khambalia A.Z.,Kolling Institute of Medical Research
Diabetic medicine : a journal of the British Diabetic Association | Year: 2013

To determine occurrence and recurrence rates of gestational diabetes among women having at least two consecutive pregnancies. Risk factors for recurrence of gestational diabetes and rates of second/third pregnancy pre-existing diabetes mellitus were also assessed. Population-based study using longitudinally linked hospital discharge and birth records (2001-2009) in NSW, Australia. Participants included women without a pre-existing diagnosis of Type 1 or Type 2 diabetes at time of first pregnancy and with at least a first and second birth. Factors associated with recurrence of gestational diabetes were examined using multivariate log-binomial models to adjust for correlation within mothers and estimate relative risks and 95% confidence intervals. First occurrence of gestational diabetes was 3.7% (5315/142 843) in the first pregnancy and 2.7% (3689/137 528) in the second pregnancy. The recurrence rate of gestational diabetes in a second consecutive pregnancy was 41.2%. Risk of pre-existing diabetes in a pregnancy subsequent to one with first occurrence of gestational diabetes was 2.2% and 2.0% in the second or third pregnancy, respectively. Among women with a diagnosis of gestational diabetes in the first pregnancy, independent predictors of gestational diabetes recurrence were maternal age ≥ 35 years, ethnicity (Middle East/North Africa and Asia), pregnancy hypertension, large for gestational age infant and preterm birth in the first pregnancy, longer inter-pregnancy birth interval and pregnancy hypertension and multiple pregnancy in the second pregnancy. Gestational diabetes in a previous pregnancy is a strong indicator of future risk and a useful clinical marker for identifying women at elevated risk in a subsequent pregnancy. © 2013 The Authors. Diabetic Medicine © 2013 Diabetes UK.

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