Bias in the physical examination of patients with lumbar radiculopathy

<p>Abstract</p> <p>Background</p> <p>No prior studies have examined systematic bias in the musculoskeletal physical examination. The objective of this study was to assess the effects of bias due to prior knowledge of lumbar spine magnetic resonance imaging findings (MRI) on perceived diagnostic accuracy of the physical examination for lumbar radiculopathy.</p> <p>Methods</p> <p>This was a cross-sectional comparison of the performance characteristics of the physical examination with blinding to MRI results (the 'independent group') with performance in the situation where the physical examination was not blinded to MRI results (the 'non-independent group'). The reference standard was the final diagnostic impression of nerve root impingement by the examining physician. Subjects were recruited from a hospital-based outpatient specialty spine clinic. All adults age 18 and older presenting with lower extremity radiating pain of duration ≤ 12 weeks were evaluated for participation. 154 consecutively recruited subjects with lumbar disk herniation confirmed by lumbar spine MRI were included in this study. Sensitivities and specificities with 95% confidence intervals were calculated in the independent and non-independent groups for the four components of the radiculopathy examination: 1) provocative testing, 2) motor strength testing, 3) pinprick sensory testing, and 4) deep tendon reflex testing.</p> <p>Results</p> <p>The perceived sensitivity of sensory testing was higher with prior knowledge of MRI results (20% vs. 36%; p = 0.05). Sensitivities and specificities for exam components otherwise showed no statistically significant differences between groups.</p> <p>Conclusions</p> <p>Prior knowledge of lumbar MRI results may introduce bias into the pinprick sensory testing component of the physical examination for lumbar radiculopathy. No statistically significant effect of bias was seen for other components of the physical examination. The effect of bias due to prior knowledge of lumbar MRI results should be considered when an isolated sensory deficit on examination is used in medical decision-making. Further studies of bias should include surgical clinic populations and other common diagnoses including shoulder, knee and hip pathology.</p

Identification of the first ATRIP-deficient patient and novel mutations in ATR define a clinical spectrum for ATR-ATRIP Seckel Syndrome

A homozygous mutational change in the Ataxia-Telangiectasia and RAD3 related (ATR) gene was previously reported in two related families displaying Seckel Syndrome (SS). Here, we provide the first identification of a Seckel Syndrome patient with mutations in ATRIP, the gene encoding ATR-Interacting Protein (ATRIP), the partner protein of ATR required for ATR stability and recruitment to the site of DNA damage. The patient has compound heterozygous mutations in ATRIP resulting in reduced ATRIP and ATR expression. A nonsense mutational change in one ATRIP allele results in a C-terminal truncated protein, which impairs ATR-ATRIP interaction; the other allele is abnormally spliced. We additionally describe two further unrelated patients native to the UK with the same novel, heterozygous mutations in ATR, which cause dramatically reduced ATR expression. All patient-derived cells showed defective DNA damage responses that can be attributed to impaired ATR-ATRIP function. Seckel Syndrome is characterised by microcephaly and growth delay, features also displayed by several related disorders including Majewski (microcephalic) osteodysplastic primordial dwarfism (MOPD) type II and Meier-Gorlin Syndrome (MGS). The identification of an ATRIP-deficient patient provides a novel genetic defect for Seckel Syndrome. Coupled with the identification of further ATR-deficient patients, our findings allow a spectrum of clinical features that can be ascribed to the ATR-ATRIP deficient sub-class of Seckel Syndrome. ATR-ATRIP patients are characterised by extremely severe microcephaly and growth delay, microtia (small ears), micrognathia (small and receding chin), and dental crowding. While aberrant bone development was mild in the original ATR-SS patient, some of the patients described here display skeletal abnormalities including, in one patient, small patellae, a feature characteristically observed in Meier-Gorlin Syndrome. Collectively, our analysis exposes an overlapping clinical manifestation between the disorders but allows an expanded spectrum of clinical features for ATR-ATRIP Seckel Syndrome to be define

Nash Social Welfare in Selfish and Online Load Balancing

In load balancing problems there is a set of clients, each wishing to select a resource from a set of permissible ones, in order to execute a certain task. Each resource has a latency function, which depends on its workload, and a client's cost is the completion time of her chosen resource. Two fundamental variants of load balancing problems are {\em selfish load balancing} (aka. {\em load balancing games}), where clients are non-cooperative selfish players aimed at minimizing their own cost solely, and {\em online load balancing}, where clients appear online and have to be irrevocably assigned to a resource without any knowledge about future requests. We revisit both selfish and online load balancing under the objective of minimizing the {\em Nash Social Welfare}, i.e., the geometric mean of the clients' costs. To the best of our knowledge, despite being a celebrated welfare estimator in many social contexts, the Nash Social Welfare has not been considered so far as a benchmarking quality measure in load balancing problems. We provide tight bounds on the price of anarchy of pure Nash equilibria and on the competitive ratio of the greedy algorithm under very general latency functions, including polynomial ones. For this particular class, we also prove that the greedy strategy is optimal as it matches the performance of any possible online algorithm

An experimental study of Quartets MaxCut and other supertree methods

<p>Abstract</p> <p>Background</p> <p>Supertree methods represent one of the major ways by which the Tree of Life can be estimated, but despite many recent algorithmic innovations, matrix representation with parsimony (MRP) remains the main algorithmic supertree method.</p> <p>Results</p> <p>We evaluated the performance of several supertree methods based upon the Quartets MaxCut (QMC) method of Snir and Rao and showed that two of these methods usually outperform MRP and five other supertree methods that we studied, under many realistic model conditions. However, the QMC-based methods have scalability issues that may limit their utility on large datasets. We also observed that taxon sampling impacted supertree accuracy, with poor results obtained when all of the source trees were only sparsely sampled. Finally, we showed that the popular optimality criterion of minimizing the total topological distance of the supertree to the source trees is only weakly correlated with supertree topological accuracy. Therefore evaluating supertree methods on biological datasets is problematic.</p> <p>Conclusions</p> <p>Our results show that supertree methods that improve upon MRP are possible, and that an effort should be made to produce scalable and robust implementations of the most accurate supertree methods. Also, because topological accuracy depends upon taxon sampling strategies, attempts to construct very large phylogenetic trees using supertree methods should consider the selection of source tree datasets, as well as supertree methods. Finally, since supertree topological error is only weakly correlated with the supertree's topological distance to its source trees, development and testing of supertree methods presents methodological challenges.</p

Automated Analysis of Craniofacial Morphology Using Magnetic Resonance Images

Quantitative analysis of craniofacial morphology is of interest to scholars working in a wide variety of disciplines, such as anthropology, developmental biology, and medicine. T1-weighted (anatomical) magnetic resonance images (MRI) provide excellent contrast between soft tissues. Given its three-dimensional nature, MRI represents an ideal imaging modality for the analysis of craniofacial structure in living individuals. Here we describe how T1-weighted MR images, acquired to examine brain anatomy, can also be used to analyze facial features. Using a sample of typically developing adolescents from the Saguenay Youth Study (N = 597; 292 male, 305 female, ages: 12 to 18 years), we quantified inter-individual variations in craniofacial structure in two ways. First, we adapted existing nonlinear registration-based morphological techniques to generate iteratively a group-wise population average of craniofacial features. The nonlinear transformations were used to map the craniofacial structure of each individual to the population average. Using voxel-wise measures of expansion and contraction, we then examined the effects of sex and age on inter-individual variations in facial features. Second, we employed a landmark-based approach to quantify variations in face surfaces. This approach involves: (a) placing 56 landmarks (forehead, nose, lips, jaw-line, cheekbones, and eyes) on a surface representation of the MRI-based group average; (b) warping the landmarks to the individual faces using the inverse nonlinear transformation estimated for each person; and (3) using a principal components analysis (PCA) of the warped landmarks to identify facial features (i.e. clusters of landmarks) that vary in our sample in a correlated fashion. As with the voxel-wise analysis of the deformation fields, we examined the effects of sex and age on the PCA-derived spatial relationships between facial features. Both methods demonstrated significant sexual dimorphism in craniofacial structure in areas such as the chin, mandible, lips, and nose

Immunotherapy of pediatric brain tumor patients should include an immunoprevention strategy: a medical hypothesis paper

Adults diagnosed with Glioblastoma multiforme (GBM) are frequently faced with a 7% chance of surviving 2 years compared with pediatric patients with GBM who have a 26% survival rate. Our recent screen of possible glioma-associated antigen precursor protein (TAPP) profiles displayed from different types of pediatric brain tumors showed that pediatric patients contained a subset of the tumor antigens displayed by adult GBM patients. Adult GBM possess at least 27 tumor antigens that can potentially stimulate T cell immune responses, suggesting that these tumors are quite antigenic. In contrast, pediatric brain tumors only expressed nine tumor antigens with mRNA levels that were equivalent to those displayed by adult GBM. These tumor-associated antigens could be used as possible targets of therapeutic immunization for pediatric brain cancer patients. Children have developing immune systems that peak at puberty. An immune response mounted by these pediatric patients might account for their extended life spans, even though the pediatric brain tumors express far fewer total tumor-associated antigens. Here we present a hypothesis that pediatric brain tumor patients might be the best patients to show that immunotherapy can be used to successfully treat established cancers. We speculate that immunotherapy should include a panel of tumor antigens that might prevent the out-growth of more malignant tumor cells and thereby prevent the brain tumor relapse. Thus, pediatric brain tumor patients might provide an opportunity to prove the concept of immunoprevention

Methamphetamine induces endoplasmic reticulum stress related gene CHOP/Gadd153/ddit3 in dopaminergic cells

We examined the toxicity of methamphetamine and dopamine in CATH.a cells, which were derived from mouse dopamine-producing neural cells in the central nervous system. Use of the quantitative real-time polymerase chain reaction revealed that transcripts of the endoplasmic reticulum stress related gene (CHOP/Gadd153/ddit3) were considerably induced at 24–48 h after methamphetamine administration (but only under apoptotic conditions), whereas dopamine slightly induced CHOP/Gadd153/ddit3 transcripts at an early stage. We also found that dopamine and methamphetamine weakly induced transcripts for the glucose-regulated protein 78 gene (Grp78/Bip) at the early stage. Analysis by immunofluorescence microscopy demonstrated an increase of　CHOP/Gadd153/ddit3 and Grp78/Bip proteins at 24 h after methamphetamine administration. Treatment of CATH.a cells with methamphetamine caused a re-distribution of dopamine inside the cells, which mimicked the presynaptic activity of neurons with cell bodies located in the ventral tegmental area or the substantia nigra. Thus, we have demonstrated the existence of endoplasmic reticulum stress in a model of presynaptic dopaminergic neurons for the first time. Together with the recent evidence suggesting the importance of presynaptic toxicity, our findings provide new insights into the mechanisms of dopamine toxicity, which might represent one of the most important mechanisms of methamphetamine toxicity and addiction

Perturbing Dynamin Reveals Potent Effects on the Drosophila Circadian Clock

BACKGROUND: Transcriptional feedback loops are central to circadian clock function. However, the role of neural activity and membrane events in molecular rhythms in the fruit fly Drosophila is unclear. To address this question, we expressed a temperature-sensitive, dominant negative allele of the fly homolog of dynamin called shibire(ts1) (shi(ts1)), an active component in membrane vesicle scission. PRINCIPAL FINDINGS: Broad expression in clock cells resulted in unexpectedly long, robust periods (>28 hours) comparable to perturbation of core clock components, suggesting an unappreciated role of membrane dynamics in setting period. Expression in the pacemaker lateral ventral neurons (LNv) was necessary and sufficient for this effect. Manipulation of other endocytic components exacerbated shi(ts1)'s behavioral effects, suggesting its mechanism is specific to endocytic regulation. PKA overexpression rescued period effects suggesting shi(ts1) may downregulate PKA pathways. Levels of the clock component PERIOD were reduced in the shi(ts1)-expressing pacemaker small LNv of flies held at a fully restrictive temperature (29 degrees C). Less restrictive conditions (25 degrees C) delayed cycling proportional to observed behavioral changes. Levels of the neuropeptide PIGMENT-DISPERSING FACTOR (PDF), the only known LNv neurotransmitter, were also reduced, but PERIOD cycling was still delayed in flies lacking PDF, implicating a PDF-independent process. Further, shi(ts1) expression in the eye also results in reduced PER protein and per and vri transcript levels, suggesting that shibire-dependent signaling extends to peripheral clocks. The level of nuclear CLK, transcriptional activator of many core clock genes, is also reduced in shi(ts1) flies, and Clk overexpression suppresses the period-altering effects of shi(ts1). CONCLUSIONS: We propose that membrane protein turnover through endocytic regulation of PKA pathways modulates the core clock by altering CLK levels and/or activity. These results suggest an important role for membrane scission in setting circadian period

CCN2/Connective Tissue Growth Factor Is Essential for Pericyte Adhesion and Endothelial Basement Membrane Formation during Angiogenesis

CCN2/Connective Tissue Growth Factor (CTGF) is a matricellular protein that regulates cell adhesion, migration, and survival. CCN2 is best known for its ability to promote fibrosis by mediating the ability of transforming growth factor β (TGFβ) to induce excess extracellular matrix production. In addition to its role in pathological processes, CCN2 is required for chondrogenesis. CCN2 is also highly expressed during development in endothelial cells, suggesting a role in angiogenesis. The potential role of CCN2 in angiogenesis is unclear, however, as both pro- and anti-angiogenic effects have been reported. Here, through analysis of Ccn2-deficient mice, we show that CCN2 is required for stable association and retention of pericytes by endothelial cells. PDGF signaling and the establishment of the endothelial basement membrane are required for pericytes recruitment and retention. CCN2 induced PDGF-B expression in endothelial cells, and potentiated PDGF-B-mediated Akt signaling in mural (vascular smooth muscle/pericyte) cells. In addition, CCN2 induced the production of endothelial basement membrane components in vitro, and was required for their expression in vivo. Overall, these results highlight CCN2 as an essential mediator of vascular remodeling by regulating endothelial-pericyte interactions. Although most studies of CCN2 function have focused on effects of CCN2 overexpression on the interstitial extracellular matrix, the results presented here show that CCN2 is required for the normal production of vascular basement membranes