Serial optical coherence microscopy for label-free volumetric histopathology

The observation of histopathology using optical microscope is an essential procedure for examination of tissue biopsies or surgically excised specimens in biological and clinical laboratories. However, slide-based microscopic pathology is not suitable for visualizing the large-scale tissue and native 3D organ structure due to its sampling limitation and shallow imaging depth. Here, we demonstrate serial optical coherence microscopy (SOCM) technique that offers label-free, high-throughput, and large-volume imaging of ex vivo mouse organs. A 3D histopathology of whole mouse brain and kidney including blood vessel structure is reconstructed by deep tissue optical imaging in serial sectioning techniques. Our results demonstrate that SOCM has unique advantages as it can visualize both native 3D structures and quantitative regional volume without introduction of any contrast agents

Evaluation of metals that are potentially toxic to agricultural surface soils, using statistical analysis, in northwestern Saudi Arabia

© 2015, Springer-Verlag Berlin Heidelberg. Heavy metals in agricultural soils enter the food chain when taken up by plants. The main purpose of this work is to determine metal contamination in agricultural farms in northwestern Saudi Arabia. Fifty surface soil samples were collected from agricultural areas. The study focuses on the geochemical behavior of As, Cd, Co, Cr, Cu, Hg, Pb and Zn, and determines the enrichment factor and geoaccumulation index. Multivariate statistical analysis, including principle component analysis and cluster analysis, is also applied to the acquired data. The study shows considerable variation in the concentrations of the analyzed metals in the studied soil samples. This variation in concentration is attributed to the intensity of agricultural activities and, possibly, to nearby fossil fuel combustion activities, as well as to traffic flows from highways and local roads. Multivariate analysis suggests that As, Cd, Hg and Pb are associated with anthropogenic activities, whereas Co, Cr, Cu and Zn are mainly controlled by geogenic activities. Hg and Pb show the maximum concentration in the analyzed samples as compared to the background concentration

Hyperresponsiveness to inhaled but not intravenous methacholine during acute respiratory syncytial virus infection in mice

BACKGROUND: To characterise the acute physiological and inflammatory changes induced by low-dose RSV infection in mice. METHODS: BALB/c mice were infected as adults (8 wk) or weanlings (3 wk) with 1 × 10(5 )pfu of RSV A2 or vehicle (intranasal, 30 μl). Inflammation, cytokines and inflammatory markers in bronchoalveolar lavage fluid (BALF) and airway and tissue responses to inhaled methacholine (MCh; 0.001 – 30 mg/ml) were measured 5, 7, 10 and 21 days post infection. Responsiveness to iv MCh (6 – 96 μg/min/kg) in vivo and to electrical field stimulation (EFS) and MCh in vitro were measured at 7 d. Epithelial permeability was measured by Evans Blue dye leakage into BALF at 7 d. Respiratory mechanics were measured using low frequency forced oscillation in tracheostomised and ventilated (450 bpm, flexiVent) mice. Low frequency impedance spectra were calculated (0.5 – 20 Hz) and a model, consisting of an airway compartment [airway resistance (Raw) and inertance (Iaw)] and a constant-phase tissue compartment [coefficients of tissue damping (G) and elastance (H)] was fitted to the data. RESULTS: Inflammation in adult mouse BALF peaked at 7 d (RSV 15.6 (4.7 SE) vs. control 3.7 (0.7) × 10(4 )cells/ml; p < 0.001), resolving by 21 d, with no increase in weanlings at any timepoint. RSV-infected mice were hyperresponsive to aerosolised MCh at 5 and 7 d (PC(200 )Raw adults: RSV 0.02 (0.005) vs. control 1.1 (0.41) mg/ml; p = 0.003) (PC(200 )Raw weanlings: RSV 0.19 (0.12) vs. control 10.2 (6.0) mg/ml MCh; p = 0.001). Increased responsiveness to aerosolised MCh was matched by elevated levels of cysLT at 5 d and elevated VEGF and PGE(2 )at 7 d in BALF from both adult and weanling mice. Responsiveness was not increased in response to iv MCh in vivo or EFS or MCh challenge in vitro. Increased epithelial permeability was not detected at 7 d. CONCLUSION: Infection with 1 × 10(5 )pfu RSV induced extreme hyperresponsiveness to aerosolised MCh during the acute phase of infection in adult and weanling mice. The route-specificity of hyperresponsiveness suggests that epithelial mechanisms were important in determining the physiological effects. Inflammatory changes were dissociated from physiological changes, particularly in weanling mice

Numerical Analysis of Ca2+ Signaling in Rat Ventricular Myocytes with Realistic Transverse-Axial Tubular Geometry and Inhibited Sarcoplasmic Reticulum

The t-tubules of mammalian ventricular myocytes are invaginations of the cell membrane that occur at each Z-line. These invaginations branch within the cell to form a complex network that allows rapid propagation of the electrical signal, and hence synchronous rise of intracellular calcium (Ca2+). To investigate how the t-tubule microanatomy and the distribution of membrane Ca2+ flux affect cardiac excitation-contraction coupling we developed a 3-D continuum model of Ca2+ signaling, buffering and diffusion in rat ventricular myocytes. The transverse-axial t-tubule geometry was derived from light microscopy structural data. To solve the nonlinear reaction-diffusion system we extended SMOL software tool (http://mccammon.ucsd.edu/smol/). The analysis suggests that the quantitative understanding of the Ca2+ signaling requires more accurate knowledge of the t-tubule ultra-structure and Ca2+ flux distribution along the sarcolemma. The results reveal the important role for mobile and stationary Ca2+ buffers, including the Ca2+ indicator dye. In agreement with experiment, in the presence of fluorescence dye and inhibited sarcoplasmic reticulum, the lack of detectible differences in the depolarization-evoked Ca2+ transients was found when the Ca2+ flux was heterogeneously distributed along the sarcolemma. In the absence of fluorescence dye, strongly non-uniform Ca2+ signals are predicted. Even at modest elevation of Ca2+, reached during Ca2+ influx, large and steep Ca2+ gradients are found in the narrow sub-sarcolemmal space. The model predicts that the branched t-tubule structure and changes in the normal Ca2+ flux density along the cell membrane support initiation and propagation of Ca2+ waves in rat myocytes

Climate Change and the Potential Distribution of an Invasive Shrub, Lantana camara L

The threat posed by invasive species, in particular weeds, to biodiversity may be exacerbated by climate change. Lantana camara L. (lantana) is a woody shrub that is highly invasive in many countries of the world. It has a profound economic and environmental impact worldwide, including Australia. Knowledge of the likely potential distribution of this invasive species under current and future climate will be useful in planning better strategies to manage the invasion. A process-oriented niche model of L. camara was developed using CLIMEX to estimate its potential distribution under current and future climate scenarios. The model was calibrated using data from several knowledge domains, including phenological observations and geographic distribution records. The potential distribution of lantana under historical climate exceeded the current distribution in some areas of the world, notably Africa and Asia. Under future scenarios, the climatically suitable areas for L. camara globally were projected to contract. However, some areas were identified in North Africa, Europe and Australia that may become climatically suitable under future climates. In South Africa and China, its potential distribution could expand further inland. These results can inform strategic planning by biosecurity agencies, identifying areas to target for eradication or containment. Distribution maps of risk of potential invasion can be useful tools in public awareness campaigns, especially in countries that have been identified as becoming climatically suitable for L. camara under the future climate scenarios

Mechanisms of human telomerase reverse transcriptase (hTERT) regulation: clinical impacts in cancer

Background Limitless self-renewal is one of the hallmarks of cancer and is attained by telomere maintenance, essentially through telomerase (hTERT) activation. Transcriptional regulation of hTERT is believed to play a major role in telomerase activation in human cancers. Main body The dominant interest in telomerase results from its role in cancer. The role of telomeres and telomere maintenance mechanisms is well established as a major driving force in generating chromosomal and genomic instability. Cancer cells have acquired the ability to overcome their fate of senescence via telomere length maintenance mechanisms, mainly by telomerase activation. hTERT expression is up-regulated in tumors via multiple genetic and epigenetic mechanisms including hTERT amplifications, hTERT structural variants, hTERT promoter mutations and epigenetic modifications through hTERT promoter methylation. Genetic (hTERT promoter mutations) and epigenetic (hTERT promoter methylation and miRNAs) events were shown to have clinical implications in cancers that depend on hTERT activation. Knowing that telomeres are crucial for cellular self-renewal, the mechanisms responsible for telomere maintenance have a crucial role in cancer diseases and might be important oncological biomarkers. Thus, rather than quantifying TERT expression and its correlation with telomerase activation, the discovery and the assessment of the mechanisms responsible for TERT upregulation offers important information that may be used for diagnosis, prognosis, and treatment monitoring in oncology. Furthermore, a better understanding of these mechanisms may promote their translation into effective targeted cancer therapies. Conclusion Herein, we reviewed the underlying mechanisms of hTERT regulation, their role in oncogenesis, and the potential clinical applications in telomerase-dependent cancers.info:eu-repo/semantics/publishedVersio

Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease

Background: Experimental and clinical data suggest that reducing inflammation without affecting lipid levels may reduce the risk of cardiovascular disease. Yet, the inflammatory hypothesis of atherothrombosis has remained unproved. Methods: We conducted a randomized, double-blind trial of canakinumab, a therapeutic monoclonal antibody targeting interleukin-1β, involving 10,061 patients with previous myocardial infarction and a high-sensitivity C-reactive protein level of 2 mg or more per liter. The trial compared three doses of canakinumab (50 mg, 150 mg, and 300 mg, administered subcutaneously every 3 months) with placebo. The primary efficacy end point was nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. RESULTS: At 48 months, the median reduction from baseline in the high-sensitivity C-reactive protein level was 26 percentage points greater in the group that received the 50-mg dose of canakinumab, 37 percentage points greater in the 150-mg group, and 41 percentage points greater in the 300-mg group than in the placebo group. Canakinumab did not reduce lipid levels from baseline. At a median follow-up of 3.7 years, the incidence rate for the primary end point was 4.50 events per 100 person-years in the placebo group, 4.11 events per 100 person-years in the 50-mg group, 3.86 events per 100 person-years in the 150-mg group, and 3.90 events per 100 person-years in the 300-mg group. The hazard ratios as compared with placebo were as follows: in the 50-mg group, 0.93 (95% confidence interval [CI], 0.80 to 1.07; P = 0.30); in the 150-mg group, 0.85 (95% CI, 0.74 to 0.98; P = 0.021); and in the 300-mg group, 0.86 (95% CI, 0.75 to 0.99; P = 0.031). The 150-mg dose, but not the other doses, met the prespecified multiplicity-adjusted threshold for statistical significance for the primary end point and the secondary end point that additionally included hospitalization for unstable angina that led to urgent revascularization (hazard ratio vs. placebo, 0.83; 95% CI, 0.73 to 0.95; P = 0.005). Canakinumab was associated with a higher incidence of fatal infection than was placebo. There was no significant difference in all-cause mortality (hazard ratio for all canakinumab doses vs. placebo, 0.94; 95% CI, 0.83 to 1.06; P = 0.31). Conclusions: Antiinflammatory therapy targeting the interleukin-1β innate immunity pathway with canakinumab at a dose of 150 mg every 3 months led to a significantly lower rate of recurrent cardiovascular events than placebo, independent of lipid-level lowering. (Funded by Novartis; CANTOS ClinicalTrials.gov number, NCT01327846.