Clinical classification criteria for neurogenic claudication caused by lumbar spinal stenosis. The N-CLASS criteria

Background Context Since imaging findings of lumbar spinal stenosis (LSS) may not be associated with symptoms, clinical classification criteria based on patient symptoms and physical examination findings are needed. Purpose To develop clinical classification criteria that identify patients with neurogenic claudication (NC) caused by LSS. Study Design Two stage process. Phase 1: Delphi process; Phase 2: cross-sectional study. Patient Sample Outpatients recruited from spine clinics in 5 countries. Outcome Measure Items from history and physical examination. Methods Phase 1: A list of potential predictors of NC caused by LSS was based on the available literature and evaluated through a Delphi process involving seventeen spine specialists (surgeons and non-surgeons) from 8 countries. Phase 2: Nineteen different clinical spine specialists from 5 countries identified patients they classified as having: 1) NC caused by LSS 2) Radicular pain caused by lumbar disc herniation (LDH), or 3) non-specific low back pain (NSLBP) with radiating leg pain. Patients completed survey items and specialists documented examination signs. Coefficients from General Estimating Equation models were used to select predictors, generate a clinical classification score and obtain a receiver operating characteristic (ROC) curve. Conduction of the Delphi process, data management and statistical analysis were partially supported by an unrestricted grant of less than 15000 US dollars from Merck Sharp and Dohme. No fees were allocated to participating spine specialists. Results Phase 1 generated a final list of 46 items related to LSS. In phase 2, 209 patients with leg pain caused by LSS (n=63), LDH (n=89) or NSLBP (n=57) were included. Criteria which independently predicted NC (p<0.05) were: age over 60; positive 30 second extension test; negative straight leg test; pain in both legs; leg pain relieved by sitting, and leg pain decreased by leaning forward or flexing the spine. A classification score using a weighted set of these criteria was developed. The proposed N-CLASS score ranged from 0 to 19, had an area under the curve of 0.92, and the cutoff (>10/19) to obtain a specificity of >90.0% resulted in a sensitivity of 82.0%. Conclusion Clinical criteria independently associated with neurogenic claudication due to LSS were identified. Use of these symptom and physical variables as a classification score for clinical research could improve homogeneity among enrolled patients

Effect of Global Cardiac Ischemia on Human Ventricular Fibrillation: Insights from a Multi-scale Mechanistic Model of the Human Heart

Acute regional ischemia in the heart can lead to cardiac arrhythmias such as ventricular fibrillation (VF), which in turn compromise cardiac output and result in secondary global cardiac ischemia. The secondary ischemia may influence the underlying arrhythmia mechanism. A recent clinical study documents the effect of global cardiac ischaemia on the mechanisms of VF. During 150 seconds of global ischemia the dominant frequency of activation decreased, while after reperfusion it increased rapidly. At the same time the complexity of epicardial excitation, measured as the number of epicardical phase singularity points, remained approximately constant during ischemia. Here we perform numerical studies based on these clinical data and propose explanations for the observed dynamics of the period and complexity of activation patterns. In particular, we study the effects on ischemia in pseudo-1D and 2D cardiac tissue models as well as in an anatomically accurate model of human heart ventricles. We demonstrate that the fall of dominant frequency in VF during secondary ischemia can be explained by an increase in extracellular potassium, while the increase during reperfusion is consistent with washout of potassium and continued activation of the ATP-dependent potassium channels. We also suggest that memory effects are responsible for the observed complexity dynamics. In addition, we present unpublished clinical results of individual patient recordings and propose a way of estimating extracellular potassium and activation of ATP-dependent potassium channels from these measurements

Characteristics of the Alternative Phenotype of Microglia/Macrophages and its Modulation in Experimental Gliomas

Microglia (brain resident macrophages) accumulate in malignant gliomas and instead of initiating the anti-tumor response, they switch to a pro-invasive phenotype, support tumor growth, invasion, angiogenesis and immunosuppression by release of cytokines/chemokines and extracellular matrix proteases. Using immunofluorescence and flow cytometry, we demonstrate an early accumulation of activated microglia followed by accumulation of macrophages in experimental murine EGFP-GL261 gliomas. Those cells acquire the alternative phenotype, as evidenced by evaluation of the production of ten pro/anti-inflammatory cytokines and expression profiling of 28 genes in magnetically-sorted CD11b+ cells from tumor tissues. Furthermore, we show that infiltration of implanted gliomas by amoeboid, Iba1-positive cells can be reduced by a systematically injected cyclosporine A (CsA) two or eight days after cell inoculation. The up-regulated levels of IL-10 and GM-CSF, increased expression of genes characteristic for the alternative and pro-invasive phenotype (arg-1, mt1-mmp, cxcl14) in glioma-derived CD11b+ cells as well as enhanced angiogenesis and tumor growth were reduced in CsA-treated mice. Our findings define for the first time kinetics and biochemical characteristics of glioma-infiltrating microglia/macrophages. Inhibition of the alternative activation of tumor-infiltrating macrophages significantly reduced tumor growth. Thus, blockade of microglia/macrophage infiltration and their pro-invasive functions could be a novel therapeutic strategy in malignant gliomas

Genetic variation and evolutionary demography of Fenneropenaeus chinensis populations, as revealed by the analysis of mitochondrial control region sequences

Genetic variation and evolutionary demography of the shrimp Fenneropenaeus chinensis were investigated using sequence data of the complete mitochondrial control region (CR). Fragments of 993 bp of the CR were sequenced for 93 individuals from five localities over most of the species' range in the Yellow Sea and the Bohai Sea. There were 84 variable sites defining 68 haplotypes. Haplotype diversity levels were very high (0.95 ± 0.03-0.99 ± 0.02) in F. chinensis populations, whereas those of nucleotide diversity were moderate to low (0.66 ± 0.36%-0.84 ± 0.46%). Analysis of molecular variance and conventional population statistics (FST ) revealed no significant genetic structure throughout the range of F. chinensis. Mismatch distribution, estimates of population parameters and neutrality tests revealed that the significant fluctuations and shallow coalescence of mtDNA genealogies observed were coincident with estimated demographic parameters and neutrality tests, in implying important past-population size fluctuations or range expansion. Isolation with Migration (IM) coalescence results suggest that F. chinensis, distributed along the coasts of northern China and the Korean Peninsula (about 1000 km apart), diverged recently, the estimated time-split being 12,800 (7,400-18,600) years ago

Incidental occult gunshot wound detected by postmortem computed tomography

The body of a 59 year old woman underwent postmortem computed tomography (PMCT) examination prior to forensic autopsy, using a 256 slice multidetector row computed tomography scanner. A large left tension pneumothorax detected on the PMCT was considered to be a likely cause of death and this was confirmed at autopsy. In addition there was an unsuspected PMCT finding of a probable gunshot injury traversing the right orbit, facial bones and frontal sinus. The autopsy technique was adjusted accordingly and PMCT findings confirmed. PMCT in this case was not only diagnostic of cause of death, but also revealed retained projectile fragments of an old gunshot wound to the face. Without prior imaging such findings would have been undetected at autopsy. This case further underscores the contribution of routine PMCT examination to forensic autopsy practice

Chronic p53-independent p21 expression causes genomic instability by deregulating replication licensing

The cyclin-dependent kinase inhibitor p21WAF1/CIP1 (p21) is a cell-cycle checkpoint effector and inducer of senescence, regulated by p53. Yet, evidence suggests that p21 could also be oncogenic, through a mechanism that has so far remained obscure. We report that a subset of atypical cancerous cells strongly expressing p21 showed proliferation features. This occurred predominantly in p53-mutant human cancers, suggesting p53-independent upregulation of p21 selectively in more aggressive tumour cells. Multifaceted phenotypic and genomic analyses of p21-inducible, p53-null, cancerous and near-normal cellular models showed that after an initial senescence-like phase, a subpopulation of p21-expressing proliferating cells emerged, featuring increased genomic instability, aggressiveness and chemoresistance. Mechanistically, sustained p21 accumulation inhibited mainly the CRL4–CDT2 ubiquitin ligase, leading to deregulated origin licensing and replication stress. Collectively, our data reveal the tumour-promoting ability of p21 through deregulation of DNA replication licensing machinery—an unorthodox role to be considered in cancer treatment, since p21 responds to various stimuli including some chemotherapy drugs

Proteomic and Physiological Responses of Kineococcus radiotolerans to Copper

Copper is a highly reactive, toxic metal; consequently, transport of this metal within the cell is tightly regulated. Intriguingly, the actinobacterium Kineococcus radiotolerans has been shown to not only accumulate soluble copper to high levels within the cytoplasm, but the phenotype also correlated with enhanced cell growth during chronic exposure to ionizing radiation. This study offers a first glimpse into the physiological and proteomic responses of K. radiotolerans to copper at increasing concentration and distinct growth phases. Aerobic growth rates and biomass yields were similar over a range of Cu(II) concentrations (0–1.5 mM) in complex medium. Copper uptake coincided with active cell growth and intracellular accumulation was positively correlated with Cu(II) concentration in the growth medium (R2 = 0.7). Approximately 40% of protein coding ORFs on the K. radiotolerans genome were differentially expressed in response to the copper treatments imposed. Copper accumulation coincided with increased abundance of proteins involved in oxidative stress and defense, DNA stabilization and repair, and protein turnover. Interestingly, the specific activity of superoxide dismutase was repressed by low to moderate concentrations of copper during exponential growth, and activity was unresponsive to perturbation with paraquot. The biochemical response pathways invoked by sub-lethal copper concentrations are exceptionally complex; though integral cellular functions are preserved, in part, through the coordination of defense enzymes, chaperones, antioxidants and protective osmolytes that likely help maintain cellular redox. This study extends our understanding of the ecology and physiology of this unique actinobacterium that could potentially inspire new biotechnologies in metal recovery and sequestration, and environmental restoration

Follicular fluid content and oocyte quality: from single biochemical markers to metabolomics

The assessment of oocyte quality in human in vitro fertilization (IVF) is getting increasing attention from embryologists. Oocyte selection and the identification of the best oocytes, in fact, would help to limit embryo overproduction and to improve the results of oocyte cryostorage programs. Follicular fluid (FF) is easily available during oocyte pick-up and theorically represents an optimal source on non-invasive biochemical predictors of oocyte quality. Unfortunately, however, the studies aiming to find a good molecular predictor of oocyte quality in FF were not able to identify substances that could be used as reliable markers of oocyte competence to fertilization, embryo development and pregnancy. In the last years, a well definite trend toward passing from the research of single molecular markers to more complex techniques that study all metabolites of FF has been observed. The metabolomic approach is a powerful tool to study biochemical predictors of oocyte quality in FF, but its application in this area is still at the beginning. This review provides an overview of the current knowledge about the biochemical predictors of oocyte quality in FF, describing both the results coming from studies on single biochemical markers and those deriving from the most recent studies of metabolomic

Flexible working and unpaid overtime in the UK: The role of gender, parental and occupational status

Recent studies have shown that flexible boundaries between work and family may make employees work harder and longer. Yet most studies were not able to show whether there are differences across different types of flexible working arrangements, and whether this relationship may only hold for certain groups of workers. We examine how three different types of flexible working arrangements, that is schedule control, flexitime, and teleworking, are associated with an increase in unpaid overtime hours of workers in the UK using the Understanding Society data from 2010-2015 and fixed effects panel regression models. Results show that the flexible arrangements that were introduced primarily for work-life balance purposes, i.e., flexitime and teleworking, do not necessarily increase unpaid overtime hours significantly. On the other hand, workers’ control over their schedule, mainly introduced as a part of high-performance strategies, leads to increased unpaid overtime hours. This is especially true for professional men, and women without children, especially those working full-time, and surprisingly part-time working mothers. The results of this study point to the importance of distinguishing between different groups of workers as well as between different types of arrangements when examining outcomes of flexible working. Furthermore, the results of the study contribute to the argument that performance enhancing flexible working arrangements can potentially exacerbate gender inequalities in the labour market by enabling men to commit more time to their jobs, while for women, especially full-time working mothers, this may be less possible

Status and Prospects of ZnO-Based Resistive Switching Memory Devices

In the advancement of the semiconductor device technology, ZnO could be a prospective alternative than the other metal oxides for its versatility and huge applications in different aspects. In this review, a thorough overview on ZnO for the application of resistive switching memory (RRAM) devices has been conducted. Various efforts that have been made to investigate and modulate the switching characteristics of ZnO-based switching memory devices are discussed. The use of ZnO layer in different structure, the different types of filament formation, and the different types of switching including complementary switching are reported. By considering the huge interest of transparent devices, this review gives the concrete overview of the present status and prospects of transparent RRAM devices based on ZnO. ZnO-based RRAM can be used for flexible memory devices, which is also covered here. Another challenge in ZnO-based RRAM is that the realization of ultra-thin and low power devices. Nevertheless, ZnO not only offers decent memory properties but also has a unique potential to be used as multifunctional nonvolatile memory devices. The impact of electrode materials, metal doping, stack structures, transparency, and flexibility on resistive switching properties and switching parameters of ZnO-based resistive switching memory devices are briefly compared. This review also covers the different nanostructured-based emerging resistive switching memory devices for low power scalable devices. It may give a valuable insight on developing ZnO-based RRAM and also should encourage researchers to overcome the challenges