Effect of pathology type and severity on the distribution of MRI signal intensities within the degenerated nucleus pulposus: application to idiopathic scoliosis and spondylolisthesis

<p>Abstract</p> <p>Background</p> <p>Disc degeneration is characterized by a loss of cellularity, degradation of the extracellular matrix, and, as a result, morphological changes and biomechanical alterations. We hypothesized that the distribution of the MR signal intensity within the nucleus zone of the intervertebral disc was modified according to the pathology and the severity of the pathology. The objective of this study was to propose new parameters characterizing the distribution of the signal intensity within the nucleus zone of lumbar intervertebral discs, and to quantify these changes in patients suffering from spondylolisthesis or idiopathic scoliosis.</p> <p>Methods</p> <p>A retrospective study had been performed on T2-weighted MR images of twenty nine patients suffering from spondylolisthesis and/or scoliosis. The high intensity zone of the nucleus pulposus was semi-automatically detected. The distance "DX" between the center weighted by the signal intensity and the geometrical center was quantified. The sum of the signal intensity on the axis perpendicular to the longitudinal axis of the disc was plotted for each position of the longitudinal axis allowing defining the maximum sum "SM" and its position "PSM".</p> <p>Results</p> <p>"SM" was clearly higher and "PSM" was more shifted for scoliosis than for spondylolisthesis. A two-way analysis of variance showed that the differences observed on "DX" were not attributed to the pathology nor its severity, the differences observed on "SM" were attributed to the pathology but not to its severity, and the differences observed on "PSM" were attributed to both the pathology and its severity.</p> <p>Conclusions</p> <p>The technique proposed in this study showed significant differences in the distribution of the MR signal intensity within the nucleus zone of intervertebral discs due to the pathology and its severity. The dependence of the "PSM" parameter to the severity of the pathology suggests this parameter as a predictive factor of the pathology progression. This new technique should be useful for the early diagnosis of intervertebral disc pathologies as it highlights abnormal patterns in the MRI signal for low severity of the pathology.</p

How does study quality affect the results of a diagnostic meta-analysis?

Background: The use of systematic literature review to inform evidence based practice in diagnostics is rapidly expanding. Although the primary diagnostic literature is extensive, studies are often of low methodological quality or poorly reported. There has been no rigorously evaluated, evidence based tool to assess the methodological quality of diagnostic studies. The primary objective of this study was to determine the extent to which variations in the quality of primary studies impact the results of a diagnostic meta-analysis and whether this differs with diagnostic test type. A secondary objective was to contribute to the evaluation of QUADAS, an evidence-based tool for the assessment of quality in diagnostic accuracy studies. Methods: This study was conducted as part of large systematic review of tests used in the diagnosis and further investigation of urinary tract infection (UTI) in children. All studies included in this review were assessed using QUADAS, an evidence-based tool for the assessment of quality in systematic reviews of diagnostic accuracy studies. The impact of individual components of QUADAS on a summary measure of diagnostic accuracy was investigated using regression analysis. The review divided the diagnosis and further investigation of UTI into the following three clinical stages: diagnosis of UTI, localisation of infection, and further investigation of the UTI. Each stage used different types of diagnostic test, which were considered to involve different quality concerns. Results: Many of the studies included in our review were poorly reported. The proportion of QUADAS items fulfilled was similar for studies in different sections of the review. However, as might be expected, the individual items fulfilled differed between the three clinical stages. Regression analysis found that different items showed a strong association with test performance for the different tests evaluated. These differences were observed both within and between the three clinical stages assessed by the review. The results of regression analyses were also affected by whether or not a weighting (by sample size) was applied. Our analysis was severely limited by the completeness of reporting and the differences between the index tests evaluated and the reference standards used to confirm diagnoses in the primary studies. Few tests were evaluated by sufficient studies to allow meaningful use of meta-analytic pooling and investigation of heterogeneity. This meant that further analysis to investigate heterogeneity could only be undertaken using a subset of studies, and that the findings are open to various interpretations. Conclusion: Further work is needed to investigate the influence of methodological quality on the results of diagnostic meta-analyses. Large data sets of well-reported primary studies are needed to address this question. Without significant improvements in the completeness of reporting of primary studies, progress in this area will be limited

CHEK2 1100delC is prevalent in Swedish early onset familial breast cancer

<p>Abstract</p> <p>Background</p> <p>A truncating variant, 1100delC, in check point-kinase CHEK2, has been identified as a risk factor for familial and sporadic breast cancer. The prevalence in healthy non-breast cancer cases is low and varies between populations.</p> <p>Methods</p> <p>We analyzed the prevalence of <it>CHEK2 </it>1100delC in 763 breast cancer patients with a defined family history and 760 controls from the Stockholm region. The breast cancer patients originated from; a population-based cohort (n = 452) and from a familial cancer clinic (n = 311), the detailed family history was known in both groups.</p> <p>Results</p> <p>The variant was found in 2.9% of the familial cases from the population-based cohort and in 1.9% from the familial cancer clinic. In total 2.2% of the patients with a family history of breast cancer carried the variant compared to 0.7% of the controls (p = 0.03). There was no increased prevalence in sporadic patients (0.3%). The variant was most frequent in young familial patients (5.1% of cases ≤45 years, p = 0.003). The mean age at diagnosis of variant carriers was 12 years lower than in non-carriers (p = 0.001).</p> <p>Conclusion</p> <p>In conclusion, <it>CHEK2 </it>1100delC exists in the Swedish population. The prevalence is increased in familial breast cancer and the variant seems to influence age at onset.</p

Arrhythmia Caused by a Drosophila Tropomyosin Mutation Is Revealed Using a Novel Optical Coherence Tomography Instrument

Background: Dilated cardiomyopathy (DCM) is a severe cardiac condition that causes high mortality. Many genes have been confirmed to be involved in this disease. An ideal system with which to uncover disease mechanisms would be one that can measure the changes in a wide range of cardiac activities associated with mutations in specific, diversely functional cardiac genes. Such a system needs a genetically manipulable model organism that allows in vivo measurement of cardiac phenotypes and a detecting instrument capable of recording multiple phenotype parameters. Methodology and Principal Findings: With a simple heart, a transparent body surface at larval stages and available genetic tools we chose Drosophila melanogaster as our model organism and developed for it a dual en-face/Doppler optical coherence tomography (OCT) instrument capable of recording multiple aspects of heart activity, including heart contraction cycle dynamics, ostia dynamics, heartbeat rate and rhythm, speed of heart wall movement and light reflectivity of cardiomyocytes in situ. We applied this OCT instrument to a model of Tropomyosin-associated DCM established in adult Drosophila. We show that DCM pre-exists in the larval stage and is accompanied by an arrhythmia previously unidentified in this model. We also detect reduced mobility and light reflectivity of cardiomyocytes in mutants. Conclusion: These results demonstrate the capability of our OCT instrument to characterize in detail cardiac activity i

Effectiveness of interventions aimed at improving physical and psychological outcomes of fall-related injuries in people with dementia: a narrative systematic review

Background: The annual prevalence of falls in people with dementia ranges from 47 to 90%. Falls are a common reason for hospital admission in people with dementia, and there is limited research evidence regarding the care pathways experienced by this population. In addition to immediate management of an injury, prevention of further falls is likely to be an important part of any successful intervention. This review aims to assess the effectiveness of interventions for improving the physical and psychological wellbeing of people with dementia who have sustained a fall-related injury. Methods: Systematic review methodologies were employed utilising searches across multiple databases (MEDLINE, CENTRAL, Health Management Information Consortium, EMBASE, CINAHL, Web of Science, Allied and Complementary Medicine Database, and Physiotherapy Evidence Database (PEDro)) and citation chaining. Studies including people with a known diagnosis of dementia living in the community and who present at health services with a fall, with or without injury, were included. Outcomes of interest included mobility, recurrent falls, activities of daily living, length of hospital stay, and post-discharge residence. Results were independently reviewed and quality assessed by two researchers, and data extracted using a customised form. A narrative synthesis was performed due to heterogeneity of the included studies. Results: Seven studies were included. Interventions clustered into three broad categories: multidisciplinary in-hospital post-surgical geriatric assessment; pharmaceuticals; and multifactorial assessment. Multidisciplinary care and early mobilisation showed short-term improvements for some outcomes. Only an annual administration of zoledronic acid showed long-term reduction in recurrent falls. Conclusions: Due to high heterogeneity across the studies, definitive conclusions could not be reached. Most post-fall interventions were not aimed at patients with dementia and have shown little efficacy regardless of cognitive status. Minor improvements to some quality of life indicators were shown, but these were generally not statistically significant. Conclusions were also limited due to most studies addressing hip fracture; the interventions provided for this type of injury may not be suitable for other types of fractures or soft tissue injuries, or for use in primary care

Mitochondrial haplogroup N1a phylogeography, with implication to the origin of European farmers

<p>Abstract</p> <p>Background</p> <p>Tracing the genetic origin of central European farmer N1a lineages can provide a unique opportunity to assess the patterns of the farming technology spread into central Europe in the human prehistory. Here, we have chosen twelve N1a samples from modern populations which are most similar with the farmer N1a types and performed the complete mitochondrial DNA genome sequencing analysis. To assess the genetic and phylogeographic relationship, we performed a detailed survey of modern published N1a types from Eurasian and African populations.</p> <p>Results</p> <p>The geographic origin and expansion of farmer lineages related N1a subclades have been deduced from combined analysis of 19 complete sequences with 166 N1a haplotypes. The phylogeographic analysis revealed that the central European farmer lineages have originated from different sources: from eastern Europe, local central Europe, and from the Near East via southern Europe.</p> <p>Conclusions</p> <p>The results obtained emphasize that the arrival of central European farmer lineages did not occur via a single demic diffusion event from the Near East at the onset of the Neolithic spread of agriculture into Europe. Indeed these results indicate that the Neolithic transition process was more complex in central Europe and possibly the farmer N1a lineages were a result of a 'leapfrog' colonization process.</p

Interaction of microtubules and actin during the post-fusion phase of exocytosis

Exocytosis is the intracellular trafficking step where a secretory vesicle fuses with the plasma membrane to release vesicle content. Actin and microtubules both play a role in exocytosis; however, their interplay is not understood. Here we study the interaction of actin and microtubules during exocytosis in lung alveolar type II (ATII) cells that secrete surfactant from large secretory vesicles. Surfactant extrusion is facilitated by an actin coat that forms on the vesicle shortly after fusion pore opening. Actin coat compression allows hydrophobic surfactant to be released from the vesicle. We show that microtubules are localized close to actin coats and stay close to the coats during their compression. Inhibition of microtubule polymerization by colchicine and nocodazole affected the kinetics of actin coat formation and the extent of actin polymerisation on fused vesicles. In addition, microtubule and actin cross-linking protein IQGAP1 localized to fused secretory vesicles and IQGAP1 silencing influenced actin polymerisation after vesicle fusion. This study demonstrates that microtubules can influence actin coat formation and actin polymerization on secretory vesicles during exocytosis

More Than 1,001 Problems with Protein Domain Databases: Transmembrane Regions, Signal Peptides and the Issue of Sequence Homology

Large-scale genome sequencing gained general importance for life science because functional annotation of otherwise experimentally uncharacterized sequences is made possible by the theory of biomolecular sequence homology. Historically, the paradigm of similarity of protein sequences implying common structure, function and ancestry was generalized based on studies of globular domains. Having the same fold imposes strict conditions over the packing in the hydrophobic core requiring similarity of hydrophobic patterns. The implications of sequence similarity among non-globular protein segments have not been studied to the same extent; nevertheless, homology considerations are silently extended for them. This appears especially detrimental in the case of transmembrane helices (TMs) and signal peptides (SPs) where sequence similarity is necessarily a consequence of physical requirements rather than common ancestry. Thus, matching of SPs/TMs creates the illusion of matching hydrophobic cores. Therefore, inclusion of SPs/TMs into domain models can give rise to wrong annotations. More than 1001 domains among the 10,340 models of Pfam release 23 and 18 domains of SMART version 6 (out of 809) contain SP/TM regions. As expected, fragment-mode HMM searches generate promiscuous hits limited to solely the SP/TM part among clearly unrelated proteins. More worryingly, we show explicit examples that the scores of clearly false-positive hits, even in global-mode searches, can be elevated into the significance range just by matching the hydrophobic runs. In the PIR iProClass database v3.74 using conservative criteria, we find that at least between 2.1% and 13.6% of its annotated Pfam hits appear unjustified for a set of validated domain models. Thus, false-positive domain hits enforced by SP/TM regions can lead to dramatic annotation errors where the hit has nothing in common with the problematic domain model except the SP/TM region itself. We suggest a workflow of flagging problematic hits arising from SP/TM-containing models for critical reconsideration by annotation users