A biomechanical analysis of growing rods used in the management of early onset scoliosis

INTRODUCTION Managing spinal deformities in young children is challenging, particularly early onset scoliosis (EOS). Surgical intervention is often required if EOS has been unresponsive to conservative treatment particularly with rapidly progressive curves. An emerging treatment option for EOS is fusionless scoliosis surgery. Similar to bracing, this surgical option potentially harnesses growth, motion and function of the spine along with correcting spinal deformity. Dual growing rods are one such fusionless treatment, which aims to modulate growth of the vertebrae. The aim of this study was to ascertain the extent to which semiconstrained growing rods (Medtronic, Sofamor, Danek, Memphis, TN) with a telescopic sleeve component, reduce rotational constraint on the spine compared with standard "constrained / rigid" rods and hence potentially provide a more physiological mechanical environment for the growing spine. METHODS Six 40-60kg English Large White porcine spines served as a model for the paediatric human spine. Each spine was dissected into a 7 level thoracolumbar multi-segment unit (MSU), removing all non-ligamentous soft tissues and leaving 3cm of ribs either side. Pure nondestructive axial rotation moments of ±4Nm at a constant rotation rate of 8deg.s-1 were applied to the mounted MSU spines using a biaxial Instron testing machine. Displacement of each vertebral level was captured using a 3D motion tracking system (Optotrak 3020, Northern Digital Inc, Waterloo, ON). Each spine was tested in an un-instrumented state first and then with appropriately sized semi-constrained growing rods and rigid rods in alternating sequence. The rods were secured by multi-axial pedicle screws (Medtronic CD Horizon) at levels 2 and 6 of the construct. The range of motion (ROM), neutral zone (NZ) size and stiffness (Nm.deg-1) were calculated from the Instron load-displacement data and intervertebral ROM was calculated through a MATLAB algorithm from Optotrak data. RESULTS Irrespective of the order of testing, rigid rods significantly reduced the total ROM compared with semi-constrained rods (p<0.05) with in a significantly stiffer spine for both left and right axial rotation (p<0.05). Analysing the intervertebral motion within the instrumented levels 2-6, rigid rods showed reduced ROM compared with semi-constrained growing rods and compared with un-instrumented motion segments. CONCLUSION Semi-constrained growing rods maintain similar stiffness in axial rotation to un-instrumented spines, while dual rigid rods significantly reduce axial rotation. Clinically the effect of semi-constrained growing rods as observed in this study is that they would be expected to allow growth via the telescopic rod components while maintaining the axial flexibility of the spine, which may reduce occurrence of the crankshaft phenomenon.

Religion, Charity and Human Rights

For the first time in 400 years a number of leading common law nations have, fairly simultaneously, embarked on charity law reform leading to an encoding of key definitional matters in charity legislation. This book provides an analysis of international case law developments on the ever growing range of issues now being generated by clashes between human rights, religion and charity law. Kerry O'Halloran identifies and assesses the agenda of 'moral imperatives', such as abortion and gay marriage that delineate the legal interface and considers their significance for those with and those without religious belief. By assessing jurisdictional differences in the law relating to religion/human rights/charity the author provides a picture of the evolving 'culture wars' that now typify and differentiates societies in western nations including the USA, England and Wales, Ireland, Australia, Canada and New Zealand.

Molecular network analysis using reverse phase protein microarrays for patient tailored therapy.

The practice of medicine has always aimed at individualized treatment of disease. The relationship between patient and physician has always been a personal one, and the physician's choice of treatment has been intended to be the best fit for the patient's needs. The necessary pooling/grouping of disease families and their assignment to a number of drugs or treatment methods has, consequently, led to an increase in the number of effective therapies. However, given the heterogeneity of most human diseases, and cancer specifically, it is currently impossible for the treating clinician to effectively predict a patient's response and outcome based on current technologies, much less the idiosyncratic resistances and adverse effects associated with the limited therapeutic options.

Analysis of albumin-associated peptides and proteins from ovarian cancer patients

Albumin binds low–molecular-weight molecules, including proteins and peptides, which then acquire its longer half-life, thereby protecting the bound species from kidney clearance. We developed an experimental method to isolate albumin in its native state and to then identify [mass spectrometry (MS) sequencing] the corresponding bound low–molecular-weight molecules. We used this method to analyze pooled sera from a human disease study set (high-risk persons without cancer, n= 40; stage I ovarian cancer, n = 30; stage III ovarian cancer, n = 40) to demonstrate the feasibility of this approach as a discovery method. Methods Albumin was isolated by solid-phase affinity capture under native binding and washing conditions. Captured albumin-associated proteins and peptides were separated by gel electrophoresis and subjected to iterative MS sequencing by microcapillary reversed-phase tandem MS. Selected albumin-bound protein fragments were confirmed in human sera by Western blotting and immunocompetition. Results In total, 1208 individual protein sequences were predicted from all 3 pools. The predicted sequences were largely fragments derived from proteins with diverse biological functions. More than one third of these fragments were identified by multiple peptide sequences, and more than one half of the identified species were in vivo cleavage products of parent proteins. An estimated 700 serum peptides or proteins were predicted that had not been reported in previous serum databases. Several proteolytic fragments of larger molecules that may be cancer-related were confirmed immunologically in blood by Western blotting and peptide immunocompetition. BRCA2, a 390-kDa low-abundance nuclear protein linked to cancer susceptibility, was represented in sera as a series of specific fragments bound to albumin. Conclusion Carrier-protein harvesting provides a rich source of candidate peptides and proteins with potential diverse tissue and cellular origins that may reflect important disease-related information.

A biomechanical analysis of growing rods used in the management of early onset scoliosis

INTRODUCTION Managing spinal deformities in young children is challenging, particularly early-onset scoliosis (EOS). Any progressive spinal deformity particularly in early life presents significant health risks for the child and a challenge for the treating surgeon. Surgical intervention is often required if EOS has been unresponsive to conservative treatment particularly with rapidly progressive curves. An emerging treatment option particularly for EOS is fusionless scoliosis surgery. Similar to bracing this surgical option potentially harnesses growth, motion and function of the spine along with correcting spinal deformity. Dual growing rods is one such fusionless treatment, which aims to modulate growth of the vertebrae. The aim of this study was to ascertain the extent to which semi-constrained growing rods (Medtronic, Memphis, TN) with a telescopic sleeve component, reduce rotational constraint on the spine compared with standard rigid rods and hence potentially provide a more physiological mechanical environment for the growing spine. METHODS Six 40-60kg English Large White porcine spines served as a model for the paediatric human spine. Each spine was dissected into 7 level thoracolumbar multi-segment unit (MSU) spines, removing all non-ligamentous soft tissues. Appropriately sized semi-constrained growing rods and rigid rods were secured by multi-axial screws (Medtronic) prior to testing in alternating sequences for each spine. Pure nondestructive moments of +/4Nm at a constant rotation rate of 8deg/s was applied to the mounted MSU spines. Displacement of each level was captured using an Optotrak (Northern Digital Inc, Waterloo, ON). The range of motion (ROM), neutral zone (NZ) size and stiffness (Nm/deg) were calculated from the Instron load-displacement data and intervertebral ROM was calculated through a MATLAB algorithm from Optotrak data. RESULTS Irrespective of sequence order rigid rods significantly reduced the total ROM (deg) than compared to semi-constrained rods (p<0.05) and resulted in a significantly stiffer (Nm/deg) spine for both left and right axial rotation testing (p<0.05). Analysing the intervertebral motion within the instrumented levels, rigid rods showed reduced ROM (Deg) than compared to semi-constrained growing rods and the un-instrumented (UN-IN) test sequences. CONCLUSION The semi-constrained growing rods maintained rotation similar to UN-IN spines while the rigid rods showed significantly reduced axial rotation across all instrumented levels. Clinically the effect of semi-constrained growing rods evaluated in this study is that they will allow growth via the telescopic rod components while maintaining the axial rotation ability of the spine, which may also reduce the occurrence of the crankshaft phenomenon.

Clinicopathological relevance of BRAF mutations in human cancer

BRAF represents one of the most frequently mutated protein kinase genes in human tumours. The mutation is commonly tested in pathology practice. BRAF mutation is seen in melanoma, papillary thyroid carcinoma (including papillary thyroid carcinoma arising from ovarian teratoma), ovarian serous tumours, colorectal carcinoma, gliomas, hepatobiliary carcinomas and hairy cell leukaemia. In these cancers, various genetic aberrations of the BRAF proto-oncogene, such as different point mutations and chromosomal rearrangements, have been reported. The most common mutation, BRAF V600E, can be detected by DNA sequencing and immunohistochemistry on formalin fixed, paraffin embedded tumour tissue. Detection of BRAF V600E mutation has the potential for clinical use as a diagnostic and prognostic marker. In addition, a great deal of research effort has been spent in strategies inhibiting its activity. Indeed, recent clinical trials involving BRAF selective inhibitors exhibited promising response rates in metastatic melanoma patients. Clinical trials are underway for other cancers. However, cutaneous side effects of treatment have been reported and therapeutic response to cancer is short-lived due to the emergence of several resistance mechanisms. In this review, we give an update on the clinical pathological relevance of BRAF mutation in cancer. It is hoped that the review will enhance the direction of future research and assist in more effective use of the knowledge of BRAF mutation in clinical practice.

Quantitative analysis of survivin in colorectal adenocarcinoma : increased expression and correlation with telomerase activity

The aims of the present study are to quantitatively analyze survivin expression, its clinicopathologic roles, and correlation with telomerase activity in a large cohort of patients with colorectal adenocarcinoma. Real-time polymerase chain reaction was used to quantitate expression level of survivin messenger RNA and human telomerase reverse transcriptase messenger RNA (telomerase activity) in 51 patients with colorectal adenocarcinomas. The findings were correlated with the clinicopathologic features of patients, which were prospectively collected into a computerized database. Survivin messenger RNA was expressed in all tumor samples. The level of expression in tumor tissues was increased in comparison with matched nontumor mucosa in the same patient (P = .01). The level of expression of survivin was significantly correlated with the level of human telomerase reverse transcriptase expression (P = .008) and size of the colorectal adenocarcinomas (P = .004). Survival of the patients with colorectal adenocarcinoma was associated with the TNM stages (P = .001) and not with the level of expression of survivin. Thus, survivin activity was altered in colorectal adenocarcinoma. The high prevalence of survivin expression and correlation with telomerase activity are important factors for consideration in gene targeting therapy for colorectal adenocarcinoma.

Geographical distribution of human Schistosoma japonicum infection in the Philippines : tools to support disease control and further elimination

S. japonicum infection is believed to be endemic in 28 of the 80 provinces of the Philippines and the most recent data on schistosomiasis prevalence have shown considerable variability between provinces. In order to increase the efficient allocation of parasitic disease control resources in the country, we aimed to describe the small scale spatial variation in S. japonicum prevalence across the Philippines, quantify the role of the physical environment in driving the spatial variation of S. japonicum, and develop a predictive risk map of S. japonicum infection. Data on S. japonicum infection from 35,754 individuals across the country were geo-located at the barangay level and included in the analysis. The analysis was then stratified geographically for Luzon, the Visayas and Mindanao. Zero-inflated binomial Bayesian geostatistical models of S. japonicum prevalence were developed and diagnostic uncertainty was incorporated. Results of the analysis show that in the three regions, males and individuals aged ≥ 20 years had significantly higher prevalence of S. japonicum compared with females and children <5 years. The role of the environmental variables differed between regions of the Philippines. S. japonicum infection was widespread in the Visayas whereas it was much more focal in Luzon and Mindanao. This analysis revealed significant spatial variation in prevalence of S. japonicum infection in the Philippines. This suggests that a spatially targeted approach to schistosomiasis interventions, including mass drug administration, is warranted. When financially possible, additional schistosomiasis surveys should be prioritized to areas identified to be at high risk, but which were underrepresented in our dataset.

Human CD141(+) (BDCA-3)(+) dendritic cells (DCs) represent a unique myeloid DC subset that cross-presents necrotic cell antigens

The characterization of human dendritic cell (DC) subsets is essential for the design of new vaccines. We report the first detailed functional analysis of the human CD141(+) DC subset. CD141(+) DCs are found in human lymph nodes, bone marrow, tonsil, and blood, and the latter proved to be the best source of highly purified cells for functional analysis. They are characterized by high expression of toll-like receptor 3, production of IL-12p70 and IFN-beta, and superior capacity to induce T helper 1 cell responses, when compared with the more commonly studied CD1c(+) DC subset. Polyinosine-polycytidylic acid (poly I:C)-activated CD141(+) DCs have a superior capacity to cross-present soluble protein antigen (Ag) to CD8(+) cytotoxic T lymphocytes than poly I:C-activated CD1c(+) DCs. Importantly, CD141(+) DCs, but not CD1c(+) DCs, were endowed with the capacity to cross-present viral Ag after their uptake of necrotic virus-infected cells. These findings establish the CD141(+) DC subset as an important functionally distinct human DC subtype with characteristics similar to those of the mouse CD8 alpha(+) DC subset. The data demonstrate a role for CD141(+) DCs in the induction of cytotoxic T lymphocyte responses and suggest that they may be the most relevant targets for vaccination against cancers, viruses, and other pathogens.

A time series analysis of presentations to Queensland health facilities for alcohol-related conditions, following the increase in 'alcopops' tax

Objective: In response to concerns about the health consequences of high-risk drinking by young people, the Australian Government increased the tax on pre-mixed alcoholic beverages ('alcopops') favoured by this demographic. We measured changes in admissions for alcohol-related harm to health throughout Queensland, before and after the tax increase in April 2008. Methods: We used data from the Queensland Trauma Register, Hospitals Admitted Patients Data Collection, and the Emergency Department Information System to calculate alcohol-related admission rates per 100,000 people, for 15 - 29 year-olds. We analysed data over 3 years (April 2006 - April 2009), using interrupted time-series analyses. This covered 2 years before, and 1 year after, the tax increase. We investigated both mental and behavioural consequences (via F10 codes), and intentional/unintentional injuries (S and T codes). Results: We fitted an auto-regressive integrated moving average (ARIMA) model, to test for any changes following the increased tax. There was no decrease in alcohol-related admissions in 15 - 29 year-olds. We found similar results for males and females, as well as definitions of alcohol-related harms that were narrow (F10 codes only) and broad (F10, S and T codes). Conclusions: The increased tax on 'alcopops' was not associated with any reduction in hospital admissions for alcohol-related harms in Queensland 15 - 29 year-olds.

How does Nepal Television (NTV) frame natural disasters? A qualitative content analysis of news scripts using news frames and PPRR cycle

Introduction- This study investigates the prevailing status of Nepalese media portrayal of natural disasters. It is contributing to the development of a disaster management model to improve the effectiveness and efficiency of news production throughout the continuum of prevention, preparedness, response and recovery (PPRR) phases of disaster management. Theoretical framework- Studies of media content often rely on framing as the theoretical underpinning of the study, as it describes how the press crafts the message. However there are additional theoretical perspectives that underline an understanding of the role of the media. This article outlines a conceptual understanding of the role of the media in modern society, the way that this conceptual understanding is used in the crafting of media messages and how those theoretical considerations are applied to the concepts that underpin effective disaster management. (R.M. Entman, 2003; Liu, 2007; Meng & Berger, 2008). Methodology- A qualitative descriptive design is used to analyse the disaster news of Nepal Television (NTV). However, this paper presents the preliminary findings of Nepal Television (a government owned Television station) using qualitative content analysis of 105 natural disaster related news scripts (June 2012-March 2013) based on the framing theory and PPRR cycle. Results- The preliminary results indicate that the media focus while framing natural disasters is dominated by human interest frame followed by responsibility frame. News about response phase was found to be most prominent in terms of PPRR cycle. Limited disaster reporting by NTV has impacted the national disaster management programs and strategies. The findings describe natural disasters are being reported within the limited understanding of the important principles of disaster management and PPRR cycle. Conclusion- This paper describes the current status of the coverage of natural disasters by Nepal Television to identify the frames used in the news content. It contributes to determining the characteristics of effective media reporting of natural disasters in the government owned media outlets, and also leads to including communities and agencies involved in disasters. It suggests the frames which are best suited for news making and how media responds to the different phases of the disaster cycle.

Insights into a multidrug resistant Escherichia coli pathogen of the globally disseminated ST131 lineage : genome analysis and virulence mechanisms

Escherichia coli strains causing urinary tract infection (UTI) are increasingly recognized as belonging to specific clones. E. coli clone O25b:H4-ST131 has recently emerged globally as a leading multi-drug resistant pathogen causing urinary tract and bloodstream infections in hospitals and the community. While most molecular studies to date examine the mechanisms conferring multi-drug resistance in E. coli ST131, relatively little is known about their virulence potential. Here we examined E. coli ST131 clinical isolates from two geographically diverse collections, one representing the major pathogenic lineages causing UTI across the United Kingdom and a second representing UTI isolates from patients presenting at two large hospitals in Australia. We determined a draft genome sequence for one representative isolate, E. coli EC958, which produced CTX-M-15 extended-spectrum β-lactamase, CMY-23 type AmpC cephalosporinase and was resistant to ciprofloxacin. Comparative genome analysis indicated that EC958 encodes virulence genes commonly associated with uropathogenic E. coli (UPEC). The genome sequence of EC958 revealed a transposon insertion in the fimB gene encoding the activator of type 1 fimbriae, an important UPEC bladder colonization factor. We identified the same fimB transposon insertion in 59% of the ST131 UK isolates, as well as 71% of ST131 isolates from Australia, suggesting this mutation is common among E. coli ST131 strains. Insertional inactivation of fimB resulted in a phenotype resembling a slower off-to-on switching for type 1 fimbriae. Type 1 fimbriae expression could still be induced in fimB-null isolates; this correlated strongly with adherence to and invasion of human bladder cells and bladder colonisation in a mouse UTI model. We conclude that E. coli ST131 is a geographically widespread, antibiotic resistant clone that has the capacity to produce numerous virulence factors associated with UTI.

Molecular analysis of type 3 fimbrial genes from Escherichia coli, Klebsiella and Citrobacter species

Background Catheter-associated urinary tract infection (CAUTI) is the most common nosocomial infection in the United States and is caused by a range of uropathogens. Biofilm formation by uropathogens that cause CAUTI is often mediated by cell surface structures such as fimbriae. In this study, we characterised the genes encoding type 3 fimbriae from CAUTI strains of Escherichia coli, Klebsiella pneumoniae, Klebsiella oxytoca, Citrobacter koseri and Citrobacter freundii. Results Phylogenetic analysis of the type 3 fimbrial genes (mrkABCD) from 39 strains revealed they clustered into five distinct clades (A-E) ranging from one to twenty-three members. The majority of sequences grouped in clade A, which was represented by the mrk gene cluster from the genome sequenced K. pneumoniae MGH78578. The E. coli and K. pneumoniae mrkABCD gene sequences clustered together in two distinct clades, supporting previous evidence for the occurrence of inter-genera lateral gene transfer. All of the strains examined caused type 3 fimbriae mediated agglutination of tannic acid treated human erythrocytes despite sequence variation in the mrkD-encoding adhesin gene. Type 3 fimbriae deletion mutants were constructed in 13 representative strains and were used to demonstrate a direct role for type 3 fimbriae in biofilm formation. Conclusions The expression of functional type 3 fimbriae is common to many Gram-negative pathogens that cause CAUTI and is strongly associated with biofilm growth. Our data provides additional evidence for the spread of type 3 fimbrial genes by lateral gene transfer. Further work is now required to substantiate the clade structure reported here by examining more strains as well as other bacterial genera that make type 3 fimbriae and cause CAUTI.

Rapid analysis of GSTM1, GSTT1 and GSTP1 polymorphisms using real-time polymerase chain reaction

Polymorphisms of glutathione transferases (GST) are important genetic determinants of susceptibility to environmental carcinogens (Rebbeck, 1997). The GSTs are a multigene family of dimeric enzymes involved in detoxification, and, in a few cases, the bioactivation of a variety of xenobiotics (Hayes et al., 1995). The cytosolic GST enzyme family consists of four major classes of enzymes, referred to as alpha, mu, pi and theta. Several members of this family (for example, GSTM1, GSTT1 and GSTP1) are polymorphic in human populations (Wormhoudt et al., 1999). Molecular epidemiology studies have examined the role of GST polymorphisms as susceptibility factors for environmentally and/or occupationally induced cancers (Wormhoudt et al., 1999). In particular, case-control studies showed a relationship between the GSTM1 null genotype and the development of cancer in association with smoking habits, which has been shown for cancers of the respiratory and gastrointestinal tracts as well as other cancer types (Miller et al., 1997). Only a few molecular epidemiological studies addressed the role of GSTT1 and GSTP1 polymorphisms in cancer susceptibility. Since GSTP1 is a key player in biotransformation/bioactivation of benzo(a)pyrene, GSTP1 may be even more important than GSTM1 in the prevention of tobacco-induced cancers (Harries et al., 1997; Harris et al., 1998). To date, this relationship has not been sufficiently addressed in humans. Comprehensive molecular epidemiological studies may add to the current knowledge of the role of GST polymorphisms in cancer susceptibility and extent of the knowledge gained from approaches that used phenotyping, such as GSTM1 activity as it relates to trans-stilbene oxide, or polymerase chain reaction (PCR) based genotyping of polymorphic isoenzymes (Bell et al., 1993; Pemble et al., 1994; Harries et al., 1997).