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1.  Revision Arthroplasty in the Haemophiliac Patient 
Case Reports in Orthopedics  2013;2013:348080.
Arthroplasty in the haemophiliac patient is associated with higher rates of infection and is traditionally performed in a younger age group. Despite this there is little evidence in the literature regarding revision arthroplasty in this cohort of patients. We describe the case of a periprosthetic fracture in a haemophiliac patient requiring revision arthroplasty, who did not consent to receiving blood products due to religious beliefs, with a successful outcome.
doi:10.1155/2013/348080
PMCID: PMC3659652  PMID: 23738171
2.  Attitudes of undergraduate health science students towards patients with intellectual disability, substance abuse, and acute mental illness: a cross-sectional study 
BMC Medical Education  2010;10:71.
Background
There is a long history of certain medical conditions being associated with stigma, stereotypes, and negative attitudes. Research has shown that such attitudes can have a detrimental effect on patients presenting with stigmatised medical conditions and can even flow on to impact their family. The objective of this study was to measure the attitudes of undergraduate students enrolled in six different health-related courses at Monash University toward patients with intellectual disability, substance abuse, and acute mental illness.
Methods
A convenience sample of undergraduate students enrolled in six health-related courses in first, second and third years at Monash University were surveyed. The Medical Condition Regard Scale - a valid and reliable, self-report measure of attitudes - was administered to students along with a brief demographic form. Mean scores, t-tests, and ANOVA were used to analyse student attitudes. Ethics approval was granted.
Results
548 students participated. Statistically significant differences were found between the courses (p = 0.05), year of the course (p = 0.09), and gender (p = 0.04) for the medical condition of intellectual disability. There was no statistically significant difference between the courses, year of the course, gender, and age group for substance abuse or acute mental illness conditions.
Conclusion
The findings suggest that students in undergraduate health-related courses, as a group, have a strong regard for patients with intellectual disability and some regard for patients with acute mental illness, but not for patients presenting with substance abuse problems.
doi:10.1186/1472-6920-10-71
PMCID: PMC2972293  PMID: 20964840
3.  Myocarditis as a prognostic indicator in systemic lupus erythematosus 
Postgraduate Medical Journal  2004;80(944):366-367.
Lupus myocarditis is a life threatening complication of systemic lupus erythematosus (SLE). A case of left ventricular failure secondary to myocarditis occurring in a patient with SLE is reported. Despite resolution of the cardiac failure with pulsed cyclophosphamide and steroids, she eventually died of non-cardiac complications 18 months later. The literature is also reviewed.
doi:10.1136/pgmj.2003.012450
PMCID: PMC1743021  PMID: 15192176
4.  Utility of an optically-based, micromechanical system for printing collagen fibers 
Biomaterials  2013;34(11):2577-2587.
Collagen's success as the principal structural element in load-bearing, connective tissue has motivated the development of numerous engineering approaches designed to recapitulate native fibril morphology and strength. It has been shown recently that collagen fibers can be drawn from monomeric solution through a fiber forming buffer (FFB), followed by numerous additional treatments in a complex serial process. However, internal fibril alignment, packing and resultant mechanical behavior of the fibers have not been optimized and remain inferior to native tissue. Further, no system has been developed which permits simultaneous application of molecular crowding, measurement of applied load, and direct observation of polymerization dynamics during fiber printing. The ability to perform well-controlled investigations early in the process of fiber formation, which vary single input parameters (i.e. collagen concentration, crowding agent concentration, draw rate, flow rate, temperature, pH, etc.) should substantially improve fiber morphology and strength. We have thus designed, built, and tested a versatile, in situ, optically-based, micromechanical assay and fiber printing system which permits the correlation of parameter changes with mechanical properties of fibers immediately after deposition into an FFB. We demonstrate the sensitivity of the assay by detecting changes in the fiber mechanics in response to draw rate, collagen type, small changes in the molecular crowding agent concentration and to variations in pH. In addition we found the ability to observe fiber polymerization dynamics leads to intriguing new insights into collagen assembly behavior.
doi:10.1016/j.biomaterials.2012.12.028
PMCID: PMC3789386  PMID: 23352045
Collagen; Polyethylene glycol; Tissue engineering; Fiber extrusion; Biomimetic
5.  Experimental Transmission of Infectious Pancreatic Necrosis Virus from the Blue Mussel, Mytilus edulis, to Cohabitating Atlantic Salmon (Salmo salar) Smolts 
Applied and Environmental Microbiology  2013;79(19):5882-5890.
Integrated multitrophic aquaculture (IMTA) reduces the environmental impacts of commercial aquaculture systems by combining the cultivation of fed species with extractive species. Shellfish play a critical role in IMTA systems by filter-feeding particulate-bound organic nutrients. As bioaccumulating organisms, shellfish may also increase disease risk on farms by serving as reservoirs for important finfish pathogens such as infectious pancreatic necrosis virus (IPNV). The ability of the blue mussel (Mytilus edulis) to bioaccumulate and transmit IPNV to naive Atlantic salmon (Salmo salar) smolts was investigated. To determine the ability of mussels to filter and accumulate viable IPNV, mussels were held in water containing log 4.6 50% tissue culture infective dose(s) (TCID50) of the West Buxton strain of IPNV ml−1. Viable IPNV was detected in the digestive glands (DGs) of IPNV-exposed mussels as early as 2 h postexposure. The viral load in mussel DG tissue significantly increased with time and reached log 5.35 ± 0.25 TCID50 g of DG tissue−1 after 120 h of exposure. IPNV titers never reached levels that were significantly greater than that in the water. Viable IPNV was detected in mussel feces out to 7 days postdepuration, and the virus persisted in DG tissues for at least 18 days of depuration. To determine whether IPNV can be transmitted from mussels to Atlantic salmon, IPNV-exposed mussels were cohabitated with naive Atlantic salmon smolts. Transmission of IPNV did occur from mussels to smolts at a low frequency. The results demonstrate that a nonenveloped virus, such as IPNV, can accumulate in mussels and be transferred to naive fish.
doi:10.1128/AEM.01142-13
PMCID: PMC3811390  PMID: 23872575
6.  Neural Correlates of Impaired Vision in Adolescents Born Extremely Preterm and/or Extremely Low Birthweight 
PLoS ONE  2014;9(3):e93188.
Background
Adolescents born extremely preterm (EP; <28 weeks' gestation) and/or extremely low birthweight (ELBW; <1000 g) experience high rates of visual impairments, however the potential neural correlates of visual impairments in EP/ELBW adolescents require further investigation. This study aimed to: 1) compare optic radiation and primary visual cortical structure between EP/ELBW adolescents and normal birthweight controls; 2) investigate associations between perinatal factors and optic radiation and primary visual cortical structure in EP/ELBW adolescents; 3) investigate associations between optic radiation and primary visual cortical structure in EP/ELBW adolescents and the odds of impaired vision.
Methods
196 EP/ELBW adolescents and 143 controls underwent magnetic resonance imaging at a mean age of 18 years. Optic radiations were delineated using constrained spherical deconvolution based probabilistic tractography. Primary visual cortices were segmented using FreeSurfer software. Diffusion tensor variables and tract volume of the optic radiations, as well as volume, surface area and thickness of the primary visual cortices, were estimated.
Results
Axial, radial and mean diffusivities within the optic radiations, and primary visual cortical thickness, were higher in the EP/ELBW adolescents than controls. Within EP/ELBW adolescents, postnatal corticosteroid exposure was associated with altered optic radiation diffusion values and lower tract volume, while decreasing gestational age at birth was associated with increased primary visual cortical volume, area and thickness. Furthermore, decreasing optic radiation fractional anisotropy and tract volume, and increasing optic radiation diffusivity in EP/ELBW adolescents were associated with increased odds of impaired vision, whereas primary visual cortical measures were not associated with the odds of impaired vision.
Conclusions
Optic radiation and primary visual cortical structure are altered in EP/ELBW adolescents compared with controls, with the greatest alterations seen in those exposed to postnatal corticosteroids and those born earliest. Structural alterations to the optic radiations may increase the risk of impaired vision in EP/ELBW adolescents.
doi:10.1371/journal.pone.0093188
PMCID: PMC3964000  PMID: 24663006
7.  The nuclear basket proteins Mlp1p and Mlp2p are part of a dynamic interactome including Esc1p and the proteasome 
Molecular Biology of the Cell  2013;24(24):3920-3938.
Mlp1p and Mlp2p form the basket of the yeast nuclear pore complex (NPC) and contribute to NPC positioning, nuclear stability, and nuclear envelope morphology. The Mlps also embed the NPC within an extended interactome, which includes protein complexes involved in mRNP biogenesis, silencing, spindle organization, and protein degradation.
The basket of the nuclear pore complex (NPC) is generally depicted as a discrete structure of eight protein filaments that protrude into the nucleoplasm and converge in a ring distal to the NPC. We show that the yeast proteins Mlp1p and Mlp2p are necessary components of the nuclear basket and that they also embed the NPC within a dynamic protein network, whose extended interactome includes the spindle organizer, silencing factors, the proteasome, and key components of messenger ribonucleoproteins (mRNPs). Ultrastructural observations indicate that the basket reduces chromatin crowding around the central transporter of the NPC and might function as a docking site for mRNP during nuclear export. In addition, we show that the Mlps contribute to NPC positioning, nuclear stability, and nuclear envelope morphology. Our results suggest that the Mlps are multifunctional proteins linking the nuclear transport channel to multiple macromolecular complexes involved in the regulation of gene expression and chromatin maintenance.
doi:10.1091/mbc.E13-07-0412
PMCID: PMC3861087  PMID: 24152732
8.  An analysis of reported motivational orientation in students undertaking doctoral studies in the biomedical sciences 
BMC Medical Education  2014;14:38.
Background
As the source of a sizeable percentage of research output and the future arbiters of science policy, practice and direction, doctoral (Ph.D.) students represent a key demographic in the biomedical research community. Despite this, doctoral learning in the biomedical sciences has, to date, received little research attention.
Methods
In the present study we aimed to qualitatively describe the motivational orientations present in semi-structured interview transcripts from a cohort of seventeen biomedical Ph.D. students drawn from two research intensive Australian Group of Eight universities.
Results
Applying elements of self-determination theory, external and introjected control loci (both strongly associated with alienation, disengagement and poor learning outcomes) were identified as common motivational determinants in this cohort.
Conclusions
The importance of these findings to doctoral learning is discussed in light of previous research undertaken in higher education settings in the United States and the European Union. With motivation accepted as a malleable, context-sensitive factor, these data provide for both a better understanding of doctoral learning and highlight a potential avenue for future research aimed at improving outcomes and promoting meaningful learning processes in the biomedical doctorate.
doi:10.1186/1472-6920-14-38
PMCID: PMC3974041  PMID: 24571918
Ph.D.; Biomedical; Self-determination theory; Motivation; Doctorate; Control
9.  Streptolysin S-like virulence factors: the continuing sagA 
Nature reviews. Microbiology  2011;9(9):670-681.
Streptolysin S (SLS) is a potent cytolytic toxin and virulence factor produced by nearly all Streptococcus pyogenes strains. Despite a 100-year history of research on this toxin, it has only recently been established that SLS represents the archetypal example of an extended family of post-translationally modified virulence factors also produced by some other streptococci and Gram-positive pathogens, such as Listeria monocytogenes and Clostridium botulinum. In this Review we describe the identification, genetics, biochemistry and various functions of SLS. We also discuss the shared features of the virulence-associated SLS-like peptides, as well as their place within the rapidly expanding family of thiazole/oxazole-modified microcins (TOMMs).
doi:10.1038/nrmicro2624
PMCID: PMC3928602  PMID: 21822292
10.  Serotonergic mechanisms responsible for levodopa-induced dyskinesias in Parkinson’s disease patients 
The Journal of Clinical Investigation  2014;124(3):1340-1349.
Levodopa-induced dyskinesias (LIDs) are the most common and disabling adverse motor effect of therapy in Parkinson’s disease (PD) patients. In this study, we investigated serotonergic mechanisms in LIDs development in PD patients using 11C-DASB PET to evaluate serotonin terminal function and 11C-raclopride PET to evaluate dopamine release. PD patients with LIDs showed relative preservation of serotonergic terminals throughout their disease. Identical levodopa doses induced markedly higher striatal synaptic dopamine concentrations in PD patients with LIDs compared with PD patients with stable responses to levodopa. Oral administration of the serotonin receptor type 1A agonist buspirone prior to levodopa reduced levodopa-evoked striatal synaptic dopamine increases and attenuated LIDs. PD patients with LIDs that exhibited greater decreases in synaptic dopamine after buspirone pretreatment had higher levels of serotonergic terminal functional integrity. Buspirone-associated modulation of dopamine levels was greater in PD patients with mild LIDs compared with those with more severe LIDs. These findings indicate that striatal serotonergic terminals contribute to LIDs pathophysiology via aberrant processing of exogenous levodopa and release of dopamine as false neurotransmitter in the denervated striatum of PD patients with LIDs. Our results also support the development of selective serotonin receptor type 1A agonists for use as antidyskinetic agents in PD.
doi:10.1172/JCI71640
PMCID: PMC3934188  PMID: 24531549
11.  Do Nurse-Led Skill Training Interventions Affect Informal Caregivers’ Out-of-Pocket Expenditures? 
The Gerontologist  2012;53(1):60-70.
Purpose of the Study:
This paper is a report of a study of the Assistance, Support, and Self-health Initiated through Skill Training (ASSIST) randomized control trial. The aim of this paper is to understand whether participating in ASSIST significantly changed the out-of-pocket (OOP) costs for family caregivers of Alzheimer’s disease (AD) or Parkinson's disease (PD) patients.
Design and Methods:
Secondary analysis of randomized control trial data, calculating average treatment effects of the intervention on OOP costs. Enrollment in the ASSIST trial occurred between 2002 and 2007 at 2 sites: Durham, North Carolina, and Birmingham, Alabama. We profile OOP costs for caregivers who participated in the ASSIST study and use 2-part expenditure models to examine the average treatment effect of the intervention on caregiver OOP expenditures.
Results:
ASSIST-trained AD and PD caregivers reported monthly OOP expenditures that averaged $500–$600. The intervention increased the likelihood of caregivers spending any money OOP by 26 percentage points over usual care, but the intervention did not significantly increase overall OOP costs.
Implications:
The ASSIST intervention was effective and inexpensive to the caregiver in direct monetary outlays; thus, there are minimal unintended consequences of the trial on caregiver financial well-being.
doi:10.1093/geront/gns045
PMCID: PMC3551205  PMID: 22459694
Cost analysis; Intervention study; Nurses/midwives/nursing; Alzheimer’s disease; Parkinson's disease; Average treatment effect
12.  A panel of genes methylated with high frequency in colorectal cancer 
BMC Cancer  2014;14:54.
Background
The development of colorectal cancer (CRC) is accompanied by extensive epigenetic changes, including frequent regional hypermethylation particularly of gene promoter regions. Specific genes, including SEPT9, VIM1 and TMEFF2 become methylated in a high fraction of cancers and diagnostic assays for detection of cancer-derived methylated DNA sequences in blood and/or fecal samples are being developed. There is considerable potential for the development of new DNA methylation biomarkers or panels to improve the sensitivity and specificity of current cancer detection tests.
Methods
Combined epigenomic methods – activation of gene expression in CRC cell lines following DNA demethylating treatment, and two novel methods of genome-wide methylation assessment – were used to identify candidate genes methylated in a high fraction of CRCs. Multiplexed amplicon sequencing of PCR products from bisulfite-treated DNA of matched CRC and non-neoplastic tissue as well as healthy donor peripheral blood was performed using Roche 454 sequencing. Levels of DNA methylation in colorectal tissues and blood were determined by quantitative methylation specific PCR (qMSP).
Results
Combined analyses identified 42 candidate genes for evaluation as DNA methylation biomarkers. DNA methylation profiles of 24 of these genes were characterised by multiplexed bisulfite-sequencing in ten matched tumor/normal tissue samples; differential methylation in CRC was confirmed for 23 of these genes. qMSP assays were developed for 32 genes, including 15 of the sequenced genes, and used to quantify methylation in tumor, adenoma and non-neoplastic colorectal tissue and from healthy donor peripheral blood. 24 of the 32 genes were methylated in >50% of neoplastic samples, including 11 genes that were methylated in 80% or more CRCs and a similar fraction of adenomas.
Conclusions
This study has characterised a panel of 23 genes that show elevated DNA methylation in >50% of CRC tissue relative to non-neoplastic tissue. Six of these genes (SOX21, SLC6A15, NPY, GRASP, ST8SIA1 and ZSCAN18) show very low methylation in non-neoplastic colorectal tissue and are candidate biomarkers for stool-based assays, while 11 genes (BCAT1, COL4A2, DLX5, FGF5, FOXF1, FOXI2, GRASP, IKZF1, IRF4, SDC2 and SOX21) have very low methylation in peripheral blood DNA and are suitable for further evaluation as blood-based diagnostic markers.
doi:10.1186/1471-2407-14-54
PMCID: PMC3924905  PMID: 24485021
Colorectal cancer; DNA methylation; Biomarker
13.  Smoking Initiation and the Iron Law of Demand * 
Journal of health economics  2012;32(1):114-127.
We show, with three longitudinal datasets, that cigarette taxes and prices affect smoking initiation decisions. Previous longitudinal studies have found somewhat mixed results, but generally have not found initiation to be sensitive to increases in price or tax. We show that the lack of statistical significance in previous studies may be at least partially attributed to a lack of policy variation in the time periods studied, truncated behavioral windows, or mis-assignment of price and tax rates in retrospective data (which occurs when one has no information about respondents’ prior state or region of residence in retrospective data). We show how each factor may affect the estimation of initiation models. Our findings suggest several problems that are applicable to initiation behavior generally, particularly those for which individuals’ responses to policy changes may be noisy or small in magnitude.
doi:10.1016/j.jhealeco.2012.08.006
PMCID: PMC3538930  PMID: 23220458
Smoking initiation; Cigarette price elasticity; cigarette tax elasticity; chronological behavioral windows; measurement error
14.  B cells use mechanical energy to discriminate antigen affinities 
Science (New York, N.Y.)  2013;340(6140):1587-1590.
The generation of high-affinity antibodies depends on the ability of B cells to extract antigens from the surfaces of antigen-presenting cells. B cells that express high-affinity B cell receptors (BCRs) acquire more antigen and obtain better T cell help. However, the mechanisms by which B cells extract antigen remain unclear. Using fluid and flexible membrane substrates to mimic antigen-presenting cells, we show that B cells acquire antigen by dynamic myosin IIa-mediated contractions that pull-out and invaginate the presenting membranes. The forces generated by myosin IIa contractions ruptured most individual BCR-antigen bonds and promoted internalization of only high-affinity, multivalent BCR microclusters. Thus, B cell contractility contributes to affinity discrimination by mechanically testing the strength of antigen binding.
doi:10.1126/science.1237572
PMCID: PMC3713314  PMID: 23686338
15.  Comparison of remission criteria in a tumour necrosis factor inhibitor treated rheumatoid arthritis longitudinal cohort: patient global health is a confounder 
Arthritis Research & Therapy  2013;15(6):R221.
Introduction
Our objectives were to assess the frequency and sustainability of American College of Rheumatology (ACR)/European League against Rheumatism (EULAR) and Disease Activity Score (DAS)28(4v)–C-reactive protein (CRP) remission 12 months after the initiation of tumour necrosis factor inhibitor (TNFi) therapy in a rheumatoid arthritis (RA) cohort.
Methods
Data were collected of 273 biologic naive RA patients at baseline, then 3, 6 and 12 months post-TNFi therapy. Remission status was calculated using DAS28(4v)-CRP <2.6 and ACR/EULAR Boolean criteria. Response was scored using EULAR criteria.
Results
Mean (range) patient age was 59.9 (7.2-85.4) years with disease duration of 13.4 (1.0-52.0) years. Responder status maintained from 3–12 months (86%, 82.4%), laboratory/clinical parameters (erythrocyte sedimentation rate (ESR), CRP, patient global health (PGH), DAS28(4v)-CRP) also showed sustained improvement (P < 0.05). DAS28 remission was reached by 102 subjects at 1 year, 27 patients were in Boolean remission, but 75 missed it from the DAS28 remission group. Patients in remission were younger (P = 0.041) with lower baseline tender joint count (TJC)28 and PGH than those not in remission (P = 0.001, P = 0.047). DAS28 remission patients were older (P = 0.026) with higher 12 months PGH and subsequently higher DAS28 than Boolean remission patients (P < 0.0001). Patients not achieving Boolean remission due to missing one subcriteria most frequently missed PGH ≤1 criteria (79.8%).
Conclusions
Only 10% of this TNFi treated cohort achieved remission according to the new ACR/EULAR criteria, which requires lower disease activity. More stringent criteria may ensure further resolution of disease activity and better longterm radiographic outcome, which supports earlier intervention with biologic therapy in RA.
doi:10.1186/ar4421
PMCID: PMC3978469  PMID: 24365061
16.  Suppressive CD8+ T Cells Arise in the Absence of CD4 Help and Compromise Control of Persistent Virus 
Journal of immunology (Baltimore, Md. : 1950)  2011;186(11):10.4049/jimmunol.1003812.
There is an urgent need to develop novel therapies for controlling chronic virus infections in immunocompromised patients. Disease associated with persistent γ-herpesvirus infection (EBV, human herpesvirus 8) is a significant problem in AIDS patients and transplant recipients, and clinical management of these conditions is difficult. Immune surveillance failure followed by γ-herpes-virus recrudescence can be modeled using murine γ-herpesvirus (MHV)-68 in mice lacking CD4+ T cells. In contrast with other chronic infections, no obvious defect in the functional capacity of the viral-specific CD8+ T cell response was detected. We show in this article that adoptive transfer of MHV-68–specific CD8+ T cells was ineffective at reducing the viral burden. Together, these indicate the potential presence of T cell extrinsic suppressive factors. Indeed, CD4-depleted mice infected with MHV-68 express increased levels of IL-10, a cytokine capable of suppressing the function of both APCs and T cells. CD4-depleted mice developed a population of CD8+ T cells capable of producing IL-10 that suppressed viral control. Although exhibiting cell surface markers indicative of activation, the IL-10–producing cells expressed increased levels of programmed death-1 but were not enriched in the MHV-68–specific compartment, nor were they uniformly CD44hi. Therapeutic administration of an IL-10R blocking Ab enhanced control of the recrudescent virus. These data implicate IL-10 as a promising target for the restoration of immune surveillance against chronic γ-herpesvirus infection in immunosuppressed individuals.
doi:10.4049/jimmunol.1003812
PMCID: PMC3854932  PMID: 21531895
17.  VGKC positive autoimmune encephalopathy mimicking dementia 
BMJ Case Reports  2011;2011:bcr0820114642.
Voltage gated potassium channel antibodies (VGKC Abs) are known to cause three rare neurological syndromes- neuromyotonia, Morvan’s syndrome and limbic encephalitis although an increasing array of other associated neurological symptoms are becoming recognised. The authors describe the case of a 60-year-old female who presented to the neurology clinic with an apparent early onset dementing process. She was noted to have both extrapyramidal and frontal release signs on examination and was admitted for further evaluation. Her dementia investigation including a neoplastic screen was negative except for VGKC antibody positivity. Her symptoms dramatically improved with commencement of immunosuppression. A non-paraneoplastic VGKC antibody associated dementia-like syndrome has rarely been described. The authors add to the few existing reports of what represents an important reversible cause of cognitive impairment.
doi:10.1136/bcr.08.2011.4642
PMCID: PMC3229339  PMID: 22674939
18.  Different affinity windows for virus and cancer-specific T-cell receptors – implications for therapeutic strategies 
European journal of immunology  2012;42(12):3174-3179.
Summary
T-cell destiny during thymic selection depends on the affinity of the T-cell receptor (TCR) for autologous peptide ligands presented in the context of MHC molecules. This is a delicately balanced process; robust binding leads to negative selection, yet some affinity for the antigen complex is required for positive selection. All TCRs of the resulting repertoire thus have some intrinsic affinity for an MHC type presenting an assortment of peptides. Generally, TCR affinities of peripheral T cells will be low towards self-derived peptides, as these would have been presented during thymic selection, whereas, by serendipity, binding to pathogen-derived peptides which are encountered de novo could be stronger. A crucial question in assessing immunotherapeutic strategies for cancer is whether natural TCR repertoires have the capacity for efficiently recognizing tumor associated peptide antigens (TAPAs). Here, we report a comprehensive comparison of TCR affinities to a range of HLA-A2 presented antigens. TCRs which bind viral antigens (VAs) fall within a strikingly higher affinity range than those which bind cancer-related antigens. This difference may be one of the key explanations for tumor immune escape and for the deficiencies of T-cell vaccines against cancer.
doi:10.1002/eji.201242606
PMCID: PMC3776049  PMID: 22949370
Thymic selection; TCR; T-cell; Immunotherapy; Tumor immunology
19.  The Potential Link between Gut Microbiota and IgE-Mediated Food Allergy in Early Life 
There has been a dramatic rise in the prevalence of IgE-mediated food allergy over recent decades, particularly among infants and young children. The cause of this increase is unknown but one putative factor is a change in the composition, richness and balance of the microbiota that colonize the human gut during early infancy. The coevolution of the human gastrointestinal tract and commensal microbiota has resulted in a symbiotic relationship in which gut microbiota play a vital role in early life immune development and function, as well as maintenance of gut wall epithelial integrity. Since IgE mediated food allergy is associated with immune dysregulation and impaired gut epithelial integrity there is substantial interest in the potential link between gut microbiota and food allergy. Although the exact link between gut microbiota and food allergy is yet to be established in humans, recent experimental evidence suggests that specific patterns of gut microbiota colonization may influence the risk and manifestations of food allergy. An understanding of the relationship between gut microbiota and food allergy has the potential to inform both the prevention and treatment of food allergy. In this paper we review the theory and evidence linking gut microbiota and IgE-mediated food allergy in early life. We then consider the implications and challenges for future research, including the techniques of measuring and analyzing gut microbiota, and the types of studies required to advance knowledge in the field.
doi:10.3390/ijerph10127235
PMCID: PMC3881164  PMID: 24351744
gut microbiota; immune development; food allergy
20.  THE NATURE AND SCOPE OF STRESSFUL SPOUSAL CAREGIVING RELATIONSHIPS 
Journal of family nursing  2011;17(2):10.1177/1074840711405666.
The caregiving literature provides compelling evidence that caregiving burden and depressive symptoms are linked with stressful care relationships however relational difficulties around caregiving are seldom described in the literature. This paper presents findings from content analysis of baseline interviews with 40 Alzheimer’s disease and Parkinson’s disease spousal caregivers enrolled in a home care skill training trial who identified their care relationship as a source of care burden. Disappointment and sadness about the loss of the relationship; tension within the relationship; and care decision conflicts within the relationship were recurrent themes of relational stress in caregiving. These spousal caregivers had relationship quality scores below the mean and burden and depressive symptom scores above the means of the other caregivers in the study. These findings provide support for developing dyadic interventions that help spouses manage relational losses, care-related tensions and care decision making conflicts.
doi:10.1177/1074840711405666
PMCID: PMC3839348  PMID: 21531858
Spousal caregivers; spousal relationships; relationship quality; relational stress; caregiving burden; Alzheimer’s disease; Parkinson’s disease
21.  Elucidating the ensemble of functionally-relevant transitions in protein systems with a robotics-inspired method 
BMC Structural Biology  2013;13(Suppl 1):S8.
Background
Many proteins tune their biological function by transitioning between different functional states, effectively acting as dynamic molecular machines. Detailed structural characterization of transition trajectories is central to understanding the relationship between protein dynamics and function. Computational approaches that build on the Molecular Dynamics framework are in principle able to model transition trajectories at great detail but also at considerable computational cost. Methods that delay consideration of dynamics and focus instead on elucidating energetically-credible conformational paths connecting two functionally-relevant structures provide a complementary approach. Effective sampling-based path planning methods originating in robotics have been recently proposed to produce conformational paths. These methods largely model short peptides or address large proteins by simplifying conformational space.
Methods
We propose a robotics-inspired method that connects two given structures of a protein by sampling conformational paths. The method focuses on small- to medium-size proteins, efficiently modeling structural deformations through the use of the molecular fragment replacement technique. In particular, the method grows a tree in conformational space rooted at the start structure, steering the tree to a goal region defined around the goal structure. We investigate various bias schemes over a progress coordinate for balance between coverage of conformational space and progress towards the goal. A geometric projection layer promotes path diversity. A reactive temperature scheme allows sampling of rare paths that cross energy barriers.
Results and conclusions
Experiments are conducted on small- to medium-size proteins of length up to 214 amino acids and with multiple known functionally-relevant states, some of which are more than 13Å apart of each-other. Analysis reveals that the method effectively obtains conformational paths connecting structural states that are significantly different. A detailed analysis on the depth and breadth of the tree suggests that a soft global bias over the progress coordinate enhances sampling and results in higher path diversity. The explicit geometric projection layer that biases the exploration away from over-sampled regions further increases coverage, often improving proximity to the goal by forcing the exploration to find new paths. The reactive temperature scheme is shown effective in increasing path diversity, particularly in difficult structural transitions with known high-energy barriers.
doi:10.1186/1472-6807-13-S1-S8
PMCID: PMC3952944  PMID: 24565158
22.  Contribution of Brain Size to IQ and Educational Underperformance in Extremely Preterm Adolescents 
PLoS ONE  2013;8(10):e77475.
Objectives
Extremely preterm (EP) survivors have smaller brains, lower IQ, and worse educational achievement than their term-born peers. The contribution of smaller brain size to the IQ and educational disadvantages of EP is unknown. This study aimed (i) to compare brain volumes from multiple brain tissues and structures between EP-born (<28weeks) and term-born (≥37weeks) control adolescents, (ii) to explore the relationships of brain tissue volumes with IQ and basic educational skills and whether this differed by group, and (iii) to explore how much total brain tissue volume explains the underperformance of EP adolescents compared with controls.
Methods
Longitudinal cohort study of 148 EP and 132 term controls born in Victoria, Australia in 1991-92. At age 18, magnetic resonance imaging-determined brain volumes of multiple tissues and structures were calculated. IQ and educational skills were measured using the Wechsler Abbreviated Scale of Intelligence (WASI) and the Wide Range Achievement Test(WRAT-4), respectively.
Results
Brain volumes were smaller in EP adolescents compared with controls (mean difference [95% confidence interval] of -5.9% [-8.0, -3.7%] for total brain tissue volume). The largest relative differences were noted in the thalamus and hippocampus. The EP group had lower IQs(-11.9 [-15.4, -8.5]), spelling(-8.0 [-11.5, -4.6]), math computation(-10.3 [-13.7, -6.9]) and word reading(-5.6 [-8.8, -2.4]) scores than controls; all p-values<0.001. Volumes of total brain tissue and other brain tissues and structures correlated positively with IQ and educational skills, a relationship that was similar for both the EP and controls. Total brain tissue volume explained between 20-40% of the IQ and educational outcome differences between EP and controls.
Conclusions
EP adolescents had smaller brain volumes, lower IQs and poorer educational performance than controls. Brain volumes of multiple tissues and structures are related to IQ and educational outcomes. Smaller total brain tissue volume is an important contributor to the cognitive and educational underperformance of adolescents born EP.
doi:10.1371/journal.pone.0077475
PMCID: PMC3793949  PMID: 24130887
23.  A Mid-Term Analysis Suggests Ceramic on Ceramic Hip Arthroplasty Is Durable with Minimal Wear and Low Risk of Squeak 
HSS Journal  2012;8(3):291-294.
Background
The incidence of hip replacements in the younger patient is ever increasing. With this in mind, improving the longevity of hip arthroplasties is paramount. Alumina ceramic is a promising bearing surface due to its low wear rate and biological inertness.
Purpose
This study aims to review our experience with ceramic-on-ceramic total hip arthroplasty, reporting on the need for revision as well as the cause of failure. Our secondary purpose is to review our experience with the phenomenon of squeaking analysing and its effect on clinical outcome with specific emphasis on component positioning. Also reported are the results of our retrieval analysis of explanted components documenting the wear rate and our analysis of strip wear.
Methods
A consecutive series of 301 primary cementless alumina-on-alumina total hip arthroplasties at a minimum of 10 years follow-up was reviewed. These arthroplasties all had third-generation ceramic-on-ceramic bearings performed through a posterior approach with repair of capsule and external rotators to bone. We analysed hips both clinically and radiographically. Analysis of wear in 62 ceramic bearings was performed using a Roundtest RA300 machine (Mitutoyo; Andover, UK), which has an accuracy of 0.01 μm.
Results
Overall, the survival rate of the implants was 98% at 10 years. No ceramic fractures were encountered in this study. Seventy-four patients reported squeaking hips, and two cases were revised due to squeaking (0.6%). No failures were related to bearing wear.
Conclusions
We believe that ceramic-on-ceramic is a safe bearing coupling with excellent survivorship at 10 years.
doi:10.1007/s11420-012-9291-y
PMCID: PMC3470676  PMID: 24082875
ceramic-on-ceramic; alumina; review; squeaking; alumina fracture
24.  Acute Gastrointestinal Infection Induces Long-Lived Microbiota-Specific T Cell Responses* 
Science (New York, N.Y.)  2012;337(6101):1553-1556.
The mammalian gastrointestinal tract contains a large and diverse population of commensal bacteria and is also one of the primary sites of exposure to pathogens. How the immune system perceives commensals in the context of mucosal infection is unclear. Here we show that during a gastrointestinal infection, tolerance to commensals is lost and microbiota-specific T cells are activated and differentiate to inflammatory effector cells. Furthermore, these T cells go on to form memory cells that are phenotypically and functionally consistent with pathogen-specific T cells. Our results suggest that during a gastrointestinal infection, the immune response to commensals parallels the immune response against pathogenic microbes and that adaptive responses against commensals are an integral component of mucosal immunity.
doi:10.1126/science.1220961
PMCID: PMC3784339  PMID: 22923434
25.  Detection and Correction of Interference in SRM Analysis 
Methods (San Diego, Calif.)  2013;61(3):299-303.
Selected Reaction Monitoring (SRM) is a method of choice for accurate quantitation of low-abundance proteins in complex backgrounds. This strategy is, however, sensitive to interference from other components in the sample that have the same precursor and fragment masses as the monitored transitions. We present here an approach to detect interference by using the expected relative intensity of SRM transitions. We also designed an algorithm to automatically detect the linear range of calibration curves. These approaches were applied to the experimental data of Clinical Proteomic Tumor Analysis Consortium (CPTAC) Verification Work Group Study 7 and show that the corrected measurements provide more accurate quantitation than the uncorrected data.
doi:10.1016/j.ymeth.2013.05.008
PMCID: PMC3771650  PMID: 23707623

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