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Shoubridge C.,SA Pathology at the Womens and Childrens Hospital
Advances in experimental medicine and biology | Year: 2012

Expansion of polyalanine tracts cause at least 9 inherited human diseases. Eight of these nine diseases are due to expansions in transcription factors and give rise to congenital disorders, many with neurocognitive phenotypes. Disease-causing expansions vary in length dependingupon the gene in question, with the severity of the associated clinical phenotype generally increasing with length of the polyalanine tract. The past decade has seen considerable progress in the understanding on how these mutations may arise and the functional effect of expanded polyalanine tracts on the resulting protein. Despite this progress, the pathogenic mechanism of expanded polyalanine tracts contributing to the associated disease states remains poorly understood. Gaining insights into the mechanisms that underlie the pathogenesis of different expanded polyalanine tract mutations will be a necessary step on the path to the design of potential treatment strategies for the associated diseases.

Skoien R.,University of Queensland | Richardson M.M.,University of Queensland | Jonsson J.R.,University of Queensland | Powell E.E.,University of Queensland | And 14 more authors.
Liver International | Year: 2013

Background: Adult non-alcoholic fatty liver disease (NAFLD) involves lobular necroinflammatory activity and fibrosis is typically centrilobular, whereas paediatric NAFLD has predominantly portal fibrosis. The reasons for these differences are unclear. We aimed to determine (a) how centrilobular and portal fibrosis in children relate to histological parameters; and (b) whether atypical fibrosis patterns exist in adults that are unexplained by current fibrogenesis models. Methods: Histological features of paediatric (n = 38) and adult (n = 56) NAFLD were assessed using conventional scoring systems. Keratin-7 immunostaining was used to assess hepatic progenitor cell numbers and the ductular reaction. Centrilobular and portal components of fibrosis were independently scored and fibrosis patterns were classified according to accepted types. Post-treatment (rosiglitazone/gastric banding) biopsies were also examined in adults. Results: Twenty-six children (68.4%) had portal-predominant fibrosis, although the typical "adult" pattern was seen in 11 (28.9%). Portal fibrosis was associated with a ductular reaction (P = 0.021) and hepatic progenitor cell expansion (P < 0.001), whereas centrilobular fibrosis was associated with lobular inflammation (P = 0.026) and ballooning (P = 0.001). Before intervention, six adults (10.7%) had atypical fibrosis including 3 (5.4%) with a previously unrecognized pattern of very fine, non-zonal sinusoidal fibrosis. Despite improvements in steatosis and inflammation, more patients developed this unusual pattern after intervention with most having had surgery (9 of 10 adults; P < 0.001). Conclusion: Differing associations with portal and centrilobular fibrosis in children and atypical fibrosis patterns in adults suggest that multiple fibrogenic pathways exist in NAFLD. This has implications for therapy and understanding pathogenesis. © 2013 John Wiley & Sons A/S.

Dibbens L.M.,University of South Australia | Hodgson B.L.,University of South Australia | Helbig K.L.,University of Melbourne | Oliver K.L.,University of Melbourne | And 5 more authors.
Epilepsy Research | Year: 2012

Levetiracetam, a broad spectrum antiepileptic drug, binds to membrane protein SV2A. The protein coding region of SV2A was sequenced in 158 patients with focal or generalized epilepsies divided into three groups based on their response to levetiracetam: responders (>75% decrease), exacerbators (50% increase) and non-responders. Nonsynonymous coding variation within SV2A was extremely rare, suggesting that rare variation is not likely to account for the individual differences in response to levetiracetam. © 2012 Elsevier B.V.

Qutob A.F.,King Abdulaziz University | Qutob A.F.,University of Adelaide | Gue S.,University of Adelaide | Revesz T.,SA Pathology at the Womens and Childrens Hospital | And 2 more authors.
Oral Oncology | Year: 2013

This systematic review investigated, critically appraised, and rated the evidence on agents used to prevent oral mucositis in children. A comprehensive search of the relevant literature was performed up to December 2011. Articles were included according to the inclusion/exclusion criteria and were critically appraised for validation and quality assessment using a checklist consisting of 18 categories. Each article was then rated for its strength of evidence. 16,471 articles were retrieved from 19 different databases and then reduced to 27 articles that fit the inclusion criteria. Five articles on oral care protocols supported their use to prevent oral mucositis in children. Seven articles on chlorhexidine mouthwash and three on laser therapy had conflicting evidence of its use. The preventative agents that were supported by one or two articles included: benzydamine mouthwash, iseganan mouthwash, granulocyte-macrophage colony-stimulating factor (GM-CSF) mouthwash, oral/enteral glutamine, oral propantheline and cryotherapy, oral cryotherapy, oral sucralfate suspension, prostaglandin E2 tablets, and chewing gum. The reduction in the rates of occurrence of oral mucositis when using agents of fair (B) to good (A) evidence ranged from 22% to 52%. In conclusion, this review suggests the use of oral care protocols to prevent oral mucositis in children because of their strength of evidence (fair to good). The authors suggest avoiding agents with fair to good evidence against their use (oral sucralfate suspension, prostaglandin E2 tablets, and GM-CSF mouthwash). Agents with conflicting evidence (chlorhexidine mouthwash (used solely), laser therapy, and glutamine) should also be avoided until further research confirms their efficacy. © 2012 Elsevier Ltd. All rights reserved.

Mouton J.W.,Radboud University Nijmegen | Mouton J.W.,Nijmegen Institute for Infection | Ambrose P.G.,Institute for Clinical Pharmacodynamics Inc. | Canton R.,CIBER ISCIII | And 5 more authors.
Drug Resistance Updates | Year: 2011

There is a growing need to optimize the use of old and new antibiotics to treat serious as well as less serious infections. The topic of how to use pharmacokinetic and pharmacodynamic (PK/PD) knowledge to conserve antibiotics for the future was elaborated on in a workshop of the conference (The conference "The Global Need for Effective Antibiotics - moving towards concerted action", ReAct, Uppsala, Sweden, 2010). The optimization of dosing regimens is accomplished by choosing the dose and schedule that results in the antimicrobial exposure that will achieve the microbiological and clinical outcome desired while simultaneously suppressing emergence of resistance. PK/PD of antimicrobial agents describe how the therapeutic drug effect is dependent on the potency of a drug against a microorganism and the exposure (the concentration of antimicrobial available for effect over time). The description and modeling of these relationships quantitatively then allow for a rational approach to dose optimization and several strategies to that purpose are described. These strategies include not only the dosing regimen itself but also the duration of therapy, preventing collateral damage through inappropriate use and the application of PK/PD in drug development. Furthermore, PK/PD relationships of older antibiotics need to be urgently established. The need for global harmonization of breakpoints is also suggested and would add efficacy to antibiotic therapy. For each of the strategies, a number of priority actions are provided. © 2011 Elsevier Ltd. All Rights Reserved.

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