Nedlands, Australia
Nedlands, Australia

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Hurt A.C.,World Health Organization | Leang S.K.,World Health Organization | Speers D.J.,Path West Laboratory Medicine | Barr I.G.,World Health Organization | And 3 more authors.
Emerging Infectious Diseases | Year: 2012

Analysis of mutations I117V and I117M in the neuraminidase of influenza A pandemic (H1N1) 2009 viruses showed that I117V confers a mild reduction in oseltamivir sensitivity and has a synergistic effect of further increasing resistance when combined with H275Y. Contrary to recent reports, the I117M mutation does not alter oseltamivir sensitivity.


Dingle K.E.,University of Oxford | Dingle K.E.,National Health Research Institute | Elliott B.,University of Western Australia | Elliott B.,Path West Laboratory Medicine | And 23 more authors.
Genome Biology and Evolution | Year: 2014

The symptoms of Clostridium difficile infection are caused by toxins expressed from its 19 kb pathogenicity locus (Pa Loc). Stable integration of the Pa Loc is suggested by its single chromosomal location and the clade specificity of its different genetic variants. However, the Pa Loc is variably present, even among closely related strains, and thus resembles a mobile genetic element. Our aim was to explain these apparently conflicting observations by reconstructing the evolutionary history of the Pa Loc. Phylogenetic analyses and annotation of the regions spanning the Pa Loc were performed using C. difficile population-representative genomes chosen from a collection of 1,693 toxigenic (Pa Loc present) and non toxigenic (Pa Loc absent) isolates. Comparison of the core genome and Pa Loc phylogenies demonstrated aneventful evolutionary history, with distinct Pa Loc variants acquired clade specifically after divergence. In particular, our data suggest a relatively recent Pa Loc acquisitionin clade 4. Exchanges and losses of the Pa Loc DNA have also occurred, via long homologous recombination events involving flanking chromosomal sequences. The most recent loss event occurred ∼30 years ago within a clade 1 genotype. The genetic organization of the clade 3 Pa Loc was unique in containing a stably integrated novel trans poson (designated Tn6218), variants of which were found at multiple chromosomal locations. Tn6218 elements were Tn916-related but non conjugative and occasionally contained genes conferring resistance to clinically relevant antibiotics. The evolutionary histories of two contrasting but clinically important genetic elements were thus characterized: the Pa Loc, mobilized rarely via homologous recombination, and Tn6218, mobilized frequently through transposition. © The Author(s) 2013.


Peckova K.,University Hospital Plzen | Vanecek T.,University Hospital Plzen | Martinek P.,University Hospital Plzen | Spagnolo D.,Path West Laboratory Medicine | And 16 more authors.
Annals of Diagnostic Pathology | Year: 2014

T(6;11) renal cell carcinoma (RCC) has been recognized as a rare andmostly nonaggressive tumor (NAT). The criteria for distinguishing aggressive tumors (AT) from NATs are notwell established. A total of 6 cases were selected for the study. Five cases of t(6;11) RCCs behaved nonaggressively, and 1 was carcinoma with aggressive behavior. The tumors were analyzed morphologically using immunohistochemistry and by molecular-genetic methods. The specimen of aggressive t(6;11) RCC was from a 77-year-old woman who died of the disease 2.5 months after diagnosis. The specimens of nonaggressive t(6;11) RCCswere from 3women and 2menwhose ages range between 15 and 54 years. Follow-up was available in all cases (2.5 months-8 years). The tumor size ranged from 3 to 14 cm in nonaggressive t(6;11) RCC. In the aggressive carcinoma, the tumor size was 12 cm. All tumors (6/6) were well circumscribed. Aggressive t(6;11) RCC was widely necrotic. Six (100%) of 6 all tumors displayed a solid/alveolar architecture with occasional tubules and pseudorosettes. Pseudopapillary formations lined by bizarre polymorphic cells were found focally in the aggressive t(6;11) RCC case. Mitoses, though rare, were found as well. All cases (AT and NAT) were positive for HMB-45, Melan-A, Cathepsin K, and cytokeratins. CD117 positivity was seen in 4 of 5 NATs, as well as in the primary and metastatic lesions of the AT. mTOR was positive in 2 of 5 NATs and vimentin in 4 of 5 NATs. Vimentin was negative in the primary lesion of the AT, as well as in the metastasis found in the adrenal gland. Translocation t(6;11)(Alpha-TFEB) or TFEB breakwas detected in 4 of 5 NATs and in the AT case. Aggressive tumor showed amplification of TFEB locus. Losses of part of chromosome 1 and chromosome 22were found in 1 of 5 NATs and in the AT. Conclusions: (1) Aggressive t(6;11) RCCs generally occur in the older population in comparison with their indolent counterparts. (2) In regard to the histologic findings in ATs, 3 of 5 so far published cases were morphologically not typical for t(6;11) RCC. Of the 3 cases, 2 cases lacked a small cell component and 1 closely mimicked clear cell-type RCC. (3) Necroseswere only present in aggressive t(6;11) RCC. (4) Amplification of TFEB locus was also found only in the aggressive t(6;11) RCC. © 2014 Elsevier Inc. All rights reserved.


Alfonso H.,University of Western Australia | Franklin P.,University of Western Australia | Ching S.,University of Western Australia | Croft K.,University of Western Australia | And 9 more authors.
Respirology | Year: 2015

Background and objective Many of the pathological consequences in the lung following inhalation of asbestos fibres arise as a consequence of persistent oxidative stress and inflammation. Inflammatory responses can be observed in asymptomatic asbestos-exposed individuals. There are currently no interventions to reduce inflammatory or oxidative responses to asbestos before disease develops. We investigated the effects of oral N-acetylcysteine (NAC) on indicators of inflammation or oxidative stress in asymptomatic people previously exposed to asbestos. Methods A double-blind, randomized, placebo-controlled study was conducted to assess the effectiveness and safety of 1800 mg of NAC given orally over a period of 4 months. This was a proof of principle study. Effectiveness was assessed using indicators of inflammation or oxidation as primary end-points. Serum levels of total combined thiols (cysteine, cysteinylglycine, glutathione and homocysteine) were used to monitor the NAC supplementation. Results Thirty-four subjects were randomly allocated to NAC and 32 to placebo. Serum levels of total combined thiols were similar between the groups after intervention. There were no differences in levels of inflammatory or oxidative stress end-points between the groups. No adverse effects were identified. Conclusions No evidence was found that NAC supplementation replenishes total combined thiols in the blood of healthy subjects with a history of asbestos exposure. There was also no evidence of reduced indicators of inflammation or oxidative stress. Further studies should determine the conditions required to increase levels of total anti-oxidant capacity in the blood and in the lungs of subjects with either asbestos-related diseases or subclinical lung inflammation. © 2015 Asian Pacific Society of Respirology.

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