An Intra-Bone Axial Load Transducer: Development and Validation in an In-Vitro Radius Model

Background Accurate measurement of forces through the proximal radius can assess the effects of some surgical procedures on radioulnar load sharing, but is difficult to achieve given the redundant loading nature of the musculoskeletal system. Previously reported devices have relied on indirect measurements that may alter articular joint location and function. An axial load transducer interposed in the diaphysis of the radius may accurately quantify unknown axial loads of the proximal radius, and maintain articular location. Methods An in-vitro radius model was developed by interposing an axial load transducer in the diaphysis of the proximal radius. Static loads of 20, 40, 60, 80, and 100 N were applied with a servo-hydraulic actuator to the native radial head at angles of 10°, 20°, 30°, and 40° in the anterior, posterior, medial and lateral directions. Findings Linear regression of five repeatability trials showed excellent agreement between the transducer and applied loads (R 2 = 1 for all trials). For off-axis net joint loads, the majority of measured loading errors were within the inter-quartile range for mean loads up to 80 N. Loads below 80 N and outside the inter-quartile range had errors of less than 1 N. Conclusions The repeatability and off-axis net joint load results of this study validate the effectiveness of the interposed axial load transducer to accurately quantify proximal radius loads. The surgical technique preserves the native articular location and soft-tissue constructs, like the annular ligament. The modular design allows for testing the effects of length-changing osteotomies in subsequent biomechanical studies

Quantitative Computed Tomography (QCT) derived Bone Mineral Density (BMD) in finite element studies: a review of the literature

© 2016, The Author(s). Background: Finite element modeling of human bone provides a powerful tool to evaluate a wide variety of outcomes in a highly repeatable and parametric manner. These models are most often derived from computed tomography data, with mechanical properties related to bone mineral density (BMD) from the x-ray energy attenuation provided from this data. To increase accuracy, many researchers report the use of quantitative computed tomography (QCT), in which a calibration phantom is used during image acquisition to improve the estimation of BMD. Since model accuracy is dependent on the methods used in the calculation of BMD and density-mechanical property relationships, it is important to use relationships developed for the same anatomical location and using the same scanner settings, as these may impact model accuracy. The purpose of this literature review is to report the relationships used in the conversion of QCT equivalent density measures to ash, apparent, and/or tissue densities in recent finite element (FE) studies used in common density-modulus relationships. For studies reporting experimental validation, the validation metrics and results are presented. Results: Of the studies reviewed, 29% reported the use of a dipotassium phosphate (K2HPO4) phantom, 47% a hydroxyapatite (HA) phantom, 13% did not report phantom type, 7% reported use of both K2HPO4 and HA phantoms, and 4% alternate phantom types. Scanner type and/or settings were omitted or partially reported in 31% of studies. The majority of studies used densitometric and/or density-modulus relationships derived from different anatomical locations scanned in different scanners with different scanner settings. The methods used to derive various densitometric relationships are reported and recommendations are provided toward the standardization of reporting metrics. Conclusions: This review assessed the current state of QCT-based FE modeling with use of clinical scanners. It was found that previously developed densitometric relationships vary by anatomical location, scanner type and settings. Reporting of all parameters used when referring to previously developed relationships, or in the development of new relationships, may increase the accuracy and repeatability of future FE models

Evidence of a high incidence of subclinically affected calves in a herd of cattle with fatal cases of Bovine Neonatal Pancytopenia (BNP).

BACKGROUND: Bovine Neonatal Pancytopenia (BNP) is a disease of calves characterised by bone marrow trilineage hypoplasia, mediated by ingestion of alloantibodies in colostrum. Suspected subclinical forms of BNP have been reported, suggesting that observed clinical cases may not represent the full extent of the disease. However to date there are no objective data available on the incidence of subclinical disease or its temporal distribution. This study aimed to 1) ascertain whether subclinical BNP occurs and, if so, to determine the incidence on an affected farm and 2) determine whether there is evidence of temporal clustering of BNP cases on this farm. To achieve these aims, haematological screening of calves born on the farm during one calving season was carried out, utilising blood samples collected at defined ages. These data were then analysed in comparison to data from both known BNP-free control animals and histopathologically confirmed BNP cases. An ordinal logistic regression model was used to create a composite haematology score to predict the probabilities of calves being normal, based on their haematology measurements at 10–14 days old. RESULTS: This study revealed that 15% (21 of 139) of the clinically normal calves on this farm had profoundly abnormal haematology (<5% chance of being normal) and could be defined as affected by subclinical BNP. Together with clinical BNP cases, this gave the study farm a BNP incidence of 18%. Calves with BNP were found to be distributed throughout the calving period, with no clustering, and no significant differences in the date of birth of cases or subclinical cases were found compared to the rest of the calves. This study did not find any evidence of increased mortality or increased time from birth to sale in subclinical BNP calves but, as the study only involved a single farm and adverse effects may be determined by other inter-current diseases it remains possible that subclinical BNP has a detrimental impact on the health and productivity of calves under certain circumstances. CONCLUSIONS: Subclinical BNP was found to occur at a high incidence in a herd of cattle with fatal cases of BNP

Bladder tumour-derived somatic TSC1 missense mutations cause loss of function via distinct mechanisms

More than 50% of transitional cell carcinomas of the bladder show loss of heterozygosity of a region spanning the TSC1 locus at 9q34 and mutations of TSC1 have been identified in 14.5% of tumours. These comprise nonsense mutations, splicing mutations, small deletions and missense mutations. Missense mutations are only rarely found in the germline in TSC disease. Therefore, we have examined six somatic missense mutations found in bladder cancer to determine whether these result in loss of function. We describe loss of function via distinct mechanisms. Five mutations caused mutually exclusive defects at mRNA and protein levels. Of these, two mutations caused pre-mRNA splicing errors that were predicted to result in premature protein truncation and three resulted in markedly reduced stability of exogenous TSC1 protein. Primary tumours with aberrant TSC1 pre-mRNA splicing were confirmed as negative for TSC1 expression by immunohistochemistry. Expression was also significantly reduced in a tumour with a TSC1 missense mutation resulting in diminished protein half-life. A single TSC1 missense mutation identified in a tumour with retained heterozygosity of the TSC1 region on chromosome 9 caused an apparently TSC2- and mTOR-independent localization defect of the mutant protein. We conclude that although TSC1 missense mutations do not play a major role in causation of TSC disease, they represent a significant proportion of somatic loss of function mutations in bladder cancer

The twilight of the Liberal Social Contract? On the Reception of Rawlsian Political Liberalism

This chapter discusses the Rawlsian project of public reason, or public justification-based 'political' liberalism, and its reception. After a brief philosophical rather than philological reconstruction of the project, the chapter revolves around a distinction between idealist and realist responses to it. Focusing on political liberalism’s critical reception illuminates an overarching question: was Rawls’s revival of a contractualist approach to liberal legitimacy a fruitful move for liberalism and/or the social contract tradition? The last section contains a largely negative answer to that question. Nonetheless the chapter's conclusion shows that the research programme of political liberalism provided and continues to provide illuminating insights into the limitations of liberal contractualism, especially under conditions of persistent and radical diversity. The programme is, however, less receptive to challenges to do with the relative decline of the power of modern states

Constitutivism

A brief explanation and overview of constitutivism

Novel Riboswitch Ligand Analogs as Selective Inhibitors of Guanine-Related Metabolic Pathways

Riboswitches are regulatory elements modulating gene expression in response to specific metabolite binding. It has been recently reported that riboswitch agonists may exhibit antimicrobial properties by binding to the riboswitch domain. Guanine riboswitches are involved in the regulation of transport and biosynthesis of purine metabolites, which are critical for the nucleotides cellular pool. Upon guanine binding, these riboswitches stabilize a 5′-untranslated mRNA structure that causes transcription attenuation of the downstream open reading frame. In principle, any agonistic compound targeting a guanine riboswitch could cause gene repression even when the cell is starved for guanine. Antibiotics binding to riboswitches provide novel antimicrobial compounds that can be rationally designed from riboswitch crystal structures. Using this, we have identified a pyrimidine compound (PC1) binding guanine riboswitches that shows bactericidal activity against a subgroup of bacterial species including well-known nosocomial pathogens. This selective bacterial killing is only achieved when guaA, a gene coding for a GMP synthetase, is under the control of the riboswitch. Among the bacterial strains tested, several clinical strains exhibiting multiple drug resistance were inhibited suggesting that PC1 targets a different metabolic pathway. As a proof of principle, we have used a mouse model to show a direct correlation between the administration of PC1 and the reduction of Staphylococcus aureus infection in mammary glands. This work establishes the possibility of using existing structural knowledge to design novel guanine riboswitch-targeting antibiotics as powerful and selective antimicrobial compounds. Particularly, the finding of this new guanine riboswitch target is crucial as community-acquired bacterial infections have recently started to emerge

ECRG4 is a candidate tumor suppressor gene frequently hypermethylated in colorectal carcinoma and glioma

<p>Abstract</p> <p>Background</p> <p>Cancer cells display widespread changes in DNA methylation that may lead to genetic instability by global hypomethylation and aberrant silencing of tumor suppressor genes by focal hypermethylation. In turn, altered DNA methylation patterns have been used to identify putative tumor suppressor genes.</p> <p>Methods</p> <p>In a methylation screening approach, we identified <it>ECRG4 </it>as a differentially methylated gene. We analyzed different cancer cells for <it>ECRG4 </it>promoter methylation by COBRA and bisulfite sequencing. Gene expression analysis was carried out by semi-quantitative RT-PCR. The <it>ECRG4 </it>coding region was cloned and transfected into colorectal carcinoma cells. Cell growth was assessed by MTT and BrdU assays. ECRG4 localization was analyzed by fluorescence microscopy and Western blotting after transfection of an <it>ECRG4-eGFP </it>fusion gene.</p> <p>Results</p> <p>We found a high frequency of <it>ECRG4 </it>promoter methylation in various cancer cell lines. Remarkably, aberrant methylation of <it>ECRG4 </it>was also found in primary human tumor tissues, including samples from colorectal carcinoma and from malignant gliomas. <it>ECRG4 </it>hypermethylation associated strongly with transcriptional silencing and its expression could be re-activated <it>in vitro </it>by demethylating treatment with 5-aza-2'-deoxycytidine. Overexpression of <it>ECRG4 </it>in colorectal carcinoma cells led to a significant decrease in cell growth. In transfected cells, ECRG4 protein was detectable within the Golgi secretion machinery as well as in the culture medium.</p> <p>Conclusions</p> <p><it>ECRG4 </it>is silenced via promoter hypermethylation in different types of human cancer cells. Its gene product may act as inhibitor of cell proliferation in colorectal carcinoma cells and may play a role as extracellular signaling molecule.</p

The national portfolio for postgraduate family medicine training in South Africa : a descriptive study of acceptability, educational impact, and usefulness for assessment

Background: Since 2007 a portfolio of learning has become a requirement for assessment of postgraduate family medicine training by the Colleges of Medicine of South Africa. A uniform portfolio of learning has been developed and content validity established among the eight postgraduate programmes. The aim of this study was to investigate the portfolio's acceptability, educational impact, and perceived usefulness for assessment of competence. Methods: Two structured questionnaires of 35 closed and open-ended questions were delivered to 53 family physician supervisors and 48 registrars who had used the portfolio. Categorical and nominal/ordinal data were analysed using simple descriptive statistics. The open-ended questions were analysed with ATLAS.ti software. Results: Half of registrars did not find the portfolio clear, practical or feasible. Workshops on portfolio use, learning, and supervision were supported, and brief dedicated time daily for reflection and writing. Most supervisors felt the portfolio reflected an accurate picture of learning, but just over half of registrars agreed. While the portfolio helped with reflection on learning, participants were less convinced about how it helped them plan further learning. Supervisors graded most rotations, suggesting understanding the summative aspect, while only 61% of registrars reflected on rotations, suggesting the formative aspects are not yet optimally utilised. Poor feedback, the need for protected academic time, and pressure of service delivery impacting negatively on learning. Conclusion: This first introduction of a national portfolio for postgraduate training in family medicine in South Africa faces challenges similar to those in other countries. Acceptability of the portfolio relates to a clear purpose and guide, flexible format with tools available in the workplace, and appreciating the changing educational environment from university-based to national assessments. The role of the supervisor in direct observations of the registrar and dedicated educational meetings, giving feedback and support, cannot be overemphasized