Medicine, Dentistry & Health Sciences Collected Works - Research Publications
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ItemSkulduggery in the museum, Remnants of Piltdown Man in the Harry Brookes Allen Museum of Anatomy and Pathology(Cultural Collections Unit, University of Melbourne Library, 2019)
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Item'Not man, but man-like’ Early 20th-century anthropological plaster casts in the Harry Brookes Allen Museum of Anatomy and Pathology(Cultural Collections Unit, University of Melbourne Library, 2019)A description of early 20th-century plaster casts of skulls and bones of primates and prehistoric humans (hominins) within The Harry Brookes Allen Museum of Anatomy and Pathology collections.
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ItemCharacterization of the ATP4 ion pump in Toxoplasma gondii(AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC, 2019-04-05)The Plasmodium falciparum ATPase PfATP4 is the target of a diverse range of antimalarial compounds, including the clinical drug candidate cipargamin. PfATP4 was originally annotated as a Ca2+ transporter, but recent evidence suggests that it is a Na+ efflux pump, extruding Na+ in exchange for H+ Here we demonstrate that ATP4 proteins belong to a clade of P-type ATPases that are restricted to apicomplexans and their closest relatives. We employed a variety of genetic and physiological approaches to investigate the ATP4 protein of the apicomplexan Toxoplasma gondii, TgATP4. We show that TgATP4 is a plasma membrane protein. Knockdown of TgATP4 had no effect on resting pH or Ca2+ but rendered parasites unable to regulate their cytosolic Na+ concentration ([Na+]cyt). PfATP4 inhibitors caused an increase in [Na+]cyt and a cytosolic alkalinization in WT but not TgATP4 knockdown parasites. Parasites in which TgATP4 was knocked down or disrupted exhibited a growth defect, attributable to reduced viability of extracellular parasites. Parasites in which TgATP4 had been disrupted showed reduced virulence in mice. These results provide evidence for ATP4 proteins playing a key conserved role in Na+ regulation in apicomplexan parasites.
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ItemA multilevel study of neighborhood disadvantage, individual socioeconomic position, and body mass index: Exploring cross-level interaction effects(ELSEVIER, 2019-06)This study examined associations between neighborhood disadvantage and body mass index (BMI), and tested whether this differed by level of individual socioeconomic position (SEP). Data were from 9953 residents living in 200 neighborhoods in Brisbane, Australia in 2007. Multilevel linear regression analyses were undertaken by gender to determine associations between neighborhood disadvantage, individual SEP (education, occupation and household income) and BMI (from self-reported height and weight); with cross-level interactions testing whether the relationship between neighborhood disadvantage and BMI differed by level of individual SEP. Both men (Quintile 4, where Quintile 5 is the most disadvantaged β = 0.66 95%CI 0.20, 1.12) and women (Quintile 5 β = 1.32 95%CI 0.76, 1.87) from more disadvantaged neighborhoods had a higher BMI. BMI was significantly higher for those with lower educational attainment (men β = 0.71 95%CI 0.36, 1.07 and women β = 1.66 95%CI 0.78, 1.54), and significantly lower for those in blue collar occupations (men β = -0.67 95%CI -1.09, -0.25 and women β = -0.71 95%CI -1.40, -0.01). Among men, those with a lower income had a significantly lower BMI, while the opposite was found among women. None of the interaction models had a significantly better fit than the random intercept models. The relationship between neighborhood disadvantage and BMI did not differ by level of education, occupation, or household income. This suggests that individual SEP is unlikely to be an effector modifier of the relationship between neighborhood disadvantage and BMI. Further research is required to assist policy-makers to make more informed decisions about where to intervene to counteract BMI-inequalities.
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ItemJAK2 is dispensable for maintenance of JAK2 mutant B-cell acute lymphoblastic leukemias(COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT, 2018-06-01)Activating JAK2 point mutations are implicated in the pathogenesis of myeloid and lymphoid malignancies, including high-risk B-cell acute lymphoblastic leukemia (B-ALL). In preclinical studies, treatment of JAK2 mutant leukemias with type I JAK2 inhibitors (e.g., Food and Drug Administration [FDA]-approved ruxolitinib) provided limited single-agent responses, possibly due to paradoxical JAK2Y1007/1008 hyperphosphorylation induced by these agents. To determine the importance of mutant JAK2 in B-ALL initiation and maintenance, we developed unique genetically engineered mouse models of B-ALL driven by overexpressed Crlf2 and mutant Jak2, recapitulating the genetic aberrations found in human B-ALL. While expression of mutant Jak2 was necessary for leukemia induction, neither its continued expression nor enzymatic activity was required to maintain leukemia survival and rapid proliferation. CRLF2/JAK2 mutant B-ALLs with sustained depletion or pharmacological inhibition of JAK2 exhibited enhanced expression of c-Myc and prominent up-regulation of c-Myc target genes. Combined indirect targeting of c-Myc using the BET bromodomain inhibitor JQ1 and direct targeting of JAK2 with ruxolitinib potently killed JAK2 mutant B-ALLs.
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ItemThe Frequency and Spectrum of Chromosomal Translocations in a Cohort of Sri Lankans.(Hindawi Limited, 2019)Translocations are the most common type of structural chromosomal abnormalities. Unbalanced translocations are usually found in children who present with congenital abnormalities, developmental delay, or intellectual disability. Balanced translocations are usually found in adults who frequently present with reproductive failure; either subfertility, or recurrent pregnancy loss. Herein, we report the spectrum and frequency of translocations in a Sri Lankan cohort. A database of patients undergoing cytogenetic testing was maintained prospectively from January 2007 to December 2016 and analyzed, retrospectively. A total of 15,864 individuals were tested. Among them, 277 (1.7%) had translocations. There were 142 (51.3%) unbalanced translocations and 135 (48.7%) balanced translocations. Majority (160; 57.8%) were Robertsonian translocations. There were 145 (52.3%) children and adolescents aged less than 18 years with translocations, and 142 (97.9%) were unbalanced translocations. Majority [138 (95.2%)] were referred due to congenital abnormalities, developmental delay, or intellectual disability, and 91 were children with translocation Down syndrome. All adults aged 18 years or above (132) had balanced translocations. Subfertility and recurrent pregnancy loss [84 (63.6%)] and offspring(s) with congenital abnormalities [48 (36.4%)] were the most common indications in this group. Majority (68.2%) in this group were females with reciprocal translocations (55.3%). Chromosomes 21, 14, and 13 were the most commonly involved with rob(14q21q) [72 (26%)], rob(21q21q) [30 (13.7%)], and rob(13q14q) [34 (12.3%)] accounting for 52% of the translocations. Chromosomes 1, 8, 11, and 18 were most commonly involved in reciprocal translocations. The observed high frequency of chromosomal translocations in our cohort highlights the importance of undertaking cytogenetic evaluation and providing appropriate genetic counseling for individuals with the phenotypes associated with these translocations.
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ItemProteome Analysis of Human Neutrophil Granulocytes From Patients With Monogenic Disease Using Data-independent Acquisition(ELSEVIER, 2019-04)Neutrophil granulocytes are critical mediators of innate immunity and tissue regeneration. Rare diseases of neutrophil granulocytes may affect their differentiation and/or functions. However, there are very few validated diagnostic tests assessing the functions of neutrophil granulocytes in these diseases. Here, we set out to probe omics analysis as a novel diagnostic platform for patients with defective differentiation and function of neutrophil granulocytes. We analyzed highly purified neutrophil granulocytes from 68 healthy individuals and 16 patients with rare monogenic diseases. Cells were isolated from fresh venous blood (purity >99%) and used to create a spectral library covering almost 8000 proteins using strong cation exchange fractionation. Patient neutrophil samples were then analyzed by data-independent acquisition proteomics, quantifying 4154 proteins in each sample. Neutrophils with mutations in the neutrophil elastase gene ELANE showed large proteome changes that suggest these mutations may affect maturation of neutrophil granulocytes and initiate misfolded protein response and cellular stress mechanisms. In contrast, only few proteins changed in patients with leukocyte adhesion deficiency (LAD) and chronic granulomatous disease (CGD). Strikingly, neutrophil transcriptome analysis showed no correlation with its proteome. In case of two patients with undetermined genetic causes, proteome analysis guided the targeted genetic diagnostics and uncovered the underlying genomic mutations. Data-independent acquisition proteomics may help to define novel pathomechanisms in neutrophil diseases and provide a clinically useful diagnostic dimension.
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ItemTelepractice delivery of an autism communication intervention to parent groups: A feasibility study.(Speech Pathology Australia, 2019)Evidence suggests that early intervention improves communication and developmental skills in children with autism. Families face barriers accessing intervention including geographic isolation, service availability and cost. Telepractice can address these barriers and expanding telepractice services may enable more families to access intervention. This research investigated the feasibility of telepractice to deliver intervention based on Hanen More Than Words (HMTW) to groups of parents of children with autism. Suitable technologies, design implications and participant perceptions were evaluated. Assessment of technology preceded delivery of intervention. Observation of telepractice sessions and participant interviews enabled qualitative analysis of telepractice delivery and participant perceptions. The intervention, including group training and individual video feedback, was delivered via telepractice to two parents. Participants expressed satisfaction with the approach and parents reported increased confidence in helping their children communicate. Telepractice delivery of HMTW-based intervention was feasible. Results indicated that delivery to larger groups is viable, with potential to increase parent intervention skills and child social-communication outcomes.
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ItemAnti-TNF Drugs for Chronic Uveitis in Adults-A Systematic Review and Meta-Analysis of Randomized Controlled Trials(FRONTIERS MEDIA SA, 2019-05-24)Background: We aimed to assess efficacy and safety of anti-tumor necrosis factor (TNF) drugs for adult chronic non-infectious uveitis (NIU). Methods: CENTRAL, MEDLINE, and EMBASE, were searched from inception to January 2019. Double-masked randomized placebo-controlled trials, assessing any anti-TNF vs. best medical intervention/standard of care in adults with chronic NIU were considered. The PRISMA and SAMPL guidelines were followed. The risk of bias was assessed using the Cochrane risk of bias tool. Overall quality of the evidence was assessed according to GRADE. PROSPERO registration: #CRD42016039068. The primary efficacy and safety outcomes were preservation of visual acuity (VA) and withdrawals due to adverse events, respectively. Meta-analysis of efficacy analysis was not performed due to significant clinical heterogeneity between studies' population and interventions. Results: A total of 1,157 references were considered and 3 studies were included. The overall risk of bias was moderate. In active NIU, adalimumab group showed an increased likelihood of VA preservation (risk ratio (RR) 1.75, 95%CI 1.32 to 2.32, n = 217), whereas the etanercept group did not (RR 0.81, 95%CI 0.57 to 1.14, n = 20). In inactive NIU, adalimumab was associated with increased likelihood of VA preservation (RR 1.31, 95%CI 1.12 to 1.53, n = 226). The rate of adverse events did not differ between anti-TNF and control arms (RR 1.03, 95%CI 0.94 to 1.13, n = 410). Conclusions: There is high quality evidence that adalimumab decreases the risk of worsening VA in active and inactive NIU and very low quality evidence that the risk of etanercept worsening VA in inactive NIU is not different from placebo. Moderate quality evidence suggests that anti-TNF agents are not different from placebo on the risk of study withdrawal.
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ItemMorphology of Peeled Internal Limiting Membrane in Macular Hole Surgery(HINDAWI LTD, 2019)PURPOSE: The aim of this work was to describe the ultrastructure and behavior of peeled internal limiting membrane (ILM) in macular hole (MH) surgery. METHODS: Seven patients with MH were included, and vitrectomy with ILM peeling was performed in all patients. The ILM inverted flap technique was used. Two other flaps of ILM of the same patient were collected and studied using light and transmission electron microscopy (TEM). ILM cell type, distribution, and morphology were analyzed, and the proliferation or fusion potential of the ILM interface was evaluated. RESULTS: ILM vitreous sides in apposition showed signs of proliferative fibrotic activity, producing a basal membrane that merges ILM sides. CONCLUSIONS: Epiretinal cells in ILM show proliferative capacity, with formation of microfibrils between adjacent sides of the ILM, which may explain adherence of ILM flaps to the hole border, contributing to closure of the hole in MH surgery. This trail is registered with NCT03799575.