Venous Thromboembolism in Cancer: Frequently Asked Questions When Guidelines are Inconclusive.

Management of Venous thromboembolism (VTE) in cancer patients is difficult when guidelines are inconclusive. To share a reasonable and homogeneous behavior in such circumstances, four issues, which are felt as problematic by oncologists and surgeons, have been selected; all were uncovered or only partially covered by current guidelines. Results from the literature and author's specific experience in the field were utilized to suggest reasonable solutions to the raised questions. The reported experience is the first to provide real-world management guidance for VTE in cancer patients. The effort of putting together literature review and author's experience brought to the adoption of a common behavior.

Are sputum eosinophil cationic protein and eosinophils differently associated with clinical and functional findings of asthma?

BACKGROUND: Sputum eosinophil counts and eosinophil cationic protein (ECP) levels are usually increased in asthmatic patients. The correlation between sputum eosinophils or ECP and clinical findings of asthma has been previously investigated but many of these studies have been performed on small samples of asthmatic patients, considering only few clinical indices and often including patients on oral or inhaled corticosteroids, which might be confounding when interpreting the relationship between disease activity and airway inflammation. OBJECTIVE: To assess whether sputum eosinophils and ECP were differently related to functional and clinical parameters of asthma in a large number of steroid-naïve asthmatic patients, taking into account several potential determinants of activity and chronicity of asthma. METHODS: One hundred and twenty-nine patients with mild-moderate asthma were studied. Sputum was induced by hypertonic saline inhalation and processed using the whole sample method. RESULTS: Sputum eosinophils and ECP significantly correlated with each other (r = 0.41, P < 0.001). When patients were grouped on the basis of high/low sputum eosinophils and high/low sputum ECP levels, significant differences were observed among groups, with patients with high sputum eosinophils and ECP showing the greatest asthma severity. In the overall sample, disease duration inversely correlated with sputum eosinophils, whereas FEV1 and peak expiratory flow (PEF) inversely correlated with sputum ECP. Rescue ß2 -agonist use and total symptom score positively correlated with both eosinophil counts and sputum ECP. Stepwise regression analysis showed that symptom score and disease duration accounted for 17.6% of sputum eosinophil variance, whereas symptom score and FEV1 accounted for 14.7% of sputum ECP variance. CONCLUSIONS AND CLINICAL RELEVANCE: Both sputum eosinophils and ECP are weakly related to clinical markers of asthma severity. However, ECP was more closely related to lung function parameters than eosinophil counts.

Synthetic gauge fields in synthetic dimensions.

We describe a simple technique for generating a cold-atom lattice pierced by a uniform magnetic field. Our method is to extend a one-dimensional optical lattice into the "dimension" provided by the internal atomic degrees of freedom, yielding a synthetic two-dimensional lattice. Suitable laser coupling between these internal states leads to a uniform magnetic flux within the two-dimensional lattice. We show that this setup reproduces the main features of magnetic lattice systems, such as the fractal Hofstadter-butterfly spectrum and the chiral edge states of the associated Chern insulating phases.

Tiotropium: a new therapeutic option in asthma.

Although bronchial hyperresponsiveness to cholinergic agents is a main feature of asthma, the role of anticholinergic drugs in chronic asthma management has been largely underestimated. Several single-dose studies comparing acute bronchodilation induced by ipratropium bromide with salbutamol have shown that salbutamol is more effective than ipratropium in treating asthma. Recently, tiotropium has been studied in asthma, when added to low-medium dose inhaled corticosteroids (ICS) in unselected moderate asthmatics or in patients with uncontrolled asthma, or with COPD and history of asthma. Later, studies on patients with Arg/Arg beta2-receptor polymorphism demonstrated a similar efficacy of tiotropium in comparison with salmeterol, when both were added to ICS. More recently, pivotal long-term studies have been performed on severe asthmatics uncontrolled under ICS/LABA combination, showing the efficacy of tiotropium in improving lung function and in increasing the time until the first severe asthma exacerbation. These data support the use of tiotropium on top of ICS/LABA combination in moderate-severe asthmatic patients. New studies are going to be published on the use of tiotropium in mild and moderate asthmatics, when added to low or medium dose ICS, in comparison with ICS alone or with ICS/LABA combination. These data might extend the indication for using tiotropium in asthma. Therefore, tiotropium represents now a valid therapeutic option, in addition to the current therapy available for severe asthmatics, and in alternative to LABA in selected asthma populations. The specific asthma phenotype which may be appropriate for tiotropium treatment should still be defined.

Quantum simulation of an extra dimension.

We present a general strategy to simulate a D+1-dimensional quantum system using a D-dimensional one. We analyze in detail a feasible implementation of our scheme using optical lattice technology. The simplest nontrivial realization of a fourth dimension corresponds to the creation of a bi-volume geometry. We also propose single- and many-particle experimental signatures to detect the effects of the extra dimension.

Role of NF-kappaB and PPAR-gamma in lung inflammation induced by monocyte-derived microparticles.

Microparticles (MP) are phospholipid vesicles shed by cells upon activation or apoptosis. Monocyte-derived MP upregulate the synthesis of proinflammatory mediators by lung epithelial cells; the molecular bases of such activity are unknown. Peroxisome proliferator-activated receptors (PPAR) have been demonstrated to be involved in the modulation of nuclear factor (NF)-κB transcriptional activity and inflammation. We investigated whether the upregulation of the synthesis of proinflammatory cytokines by human lung epithelial cells induced by monocyte/macrophage-derived MP involves NF-κB activation and is modulated by PPAR-γ. MP were generated by stimulation of human monocytes/macrophages with the calcium ionophore, A23187. MP were incubated with human lung epithelial cells. NF-κB translocation was assessed by electrophoretic mobility shift assay. Interleukin (IL)-8 and monocyte chemotactic protein (MCP)-1 synthesis was assessed by ELISA and RT-PCR. Stimulation of A549 alveolar cells with monocyte/macrophage-derived MP caused an increase in NF-κB activation and IL-8 and MCP-1 synthesis that was inhibited by pre-incubation with the PPAR-γ agonists, rosiglitazone and 15-deoxy-Δ12,14-prostaglandin-J2. Parallel experiments with normal human bronchial epithelial cells largely confirmed the results. The effects of PPAR-γ agonists were reversed by the specific antagonist, GW9662. Upregulation of the synthesis of proinflammatory mediators by human lung epithelial cells induced by monocyte/macrophage-derived MP is mediated by NF-κB activation through a PPAR-γ dependent pathway.

Tunable multiple layered Dirac cones in optical lattices.

We show that multiple layered Dirac cones can emerge in the band structure of properly addressed multicomponent cold fermionic gases in optical lattices. The layered Dirac cones contain multiple copies of massless spin-1/2 Dirac fermions at the same location in momentum space, whose different Fermi velocity can be tuned at will. On-site microwave Raman transitions can further be used to mix the different Dirac species, resulting in either splitting of or preserving the Dirac point (depending on the symmetry of the on-site term). The tunability of the multiple layered Dirac cones allows us to simulate a number of fundamental phenomena in modern physics, such as neutrino oscillations and exotic particle dispersions with E~p(N) for arbitrary integer N.

The diagnosis of pulmonary embolism.

The diagnosis of pulmonary embolism is challenging, and autoptic series have demonstrated that a high percentage of cases are not recognized ante-mortem. A number of predisposing factors, symptoms and signs associated with pulmonary embolism have been recognized, and should be used to raise the suspicion of the disease. These include immobilization, recent surgery, active cancer, previous thromboembolism, syncope, dyspnoea, chest pain, haemoptysis, signs of deep vein thrombosis, hypocarbic hypoxemia. Once pulmonary embolism is suspected, the clinical probability of the disease should be assessed; to this end, three clinical rules have been proposed and validated (the revised Geneva score, the Wells score and the PISA-PED score) while others await clinical validation. In case of low clinical probability, a negative a D-dimer test is sufficient to rule out the diagnosis, while if the clinical probability is high, or the D-dimer test is positive, further tests are necessary. Computer tomography angiography or perfusion lung scan are the imaging tests of choice, depending on local availability and experience. If the clinical probability and the results of the imaging test are concordant, a definitive diagnosis can be obtained; if the results are discordant, further testing is necessary. In particular, in the specific case of a small clot (i.e. segmental or subsegmental) incidentally recognized at a computer tomography obtained for other reasons in a patient without a clinical suspicion of pulmonary embolism, an occurrence whose frequency is rapidly increasing in clinical practice, a final diagnosis cannot be made without further confirmatory testing.

Transient subdiffusion from an Ising environment.

We introduce a model in which a particle performs a continuous-time random walk (CTRW) coupled to an environment with Ising dynamics. The particle shows locally varying diffusivity determined by the geometrical properties of the underlying Ising environment, that is, the diffusivity depends on the size of the connected area of spins pointing in the same direction. The model shows anomalous diffusion when the Ising environment is at critical temperature. We show that any finite scale introduced by a temperature different from the critical one, or a finite size of the environment, cause subdiffusion only during a transient time. The characteristic time, at which the system returns to normal diffusion after the subdiffusive plateau depends on the limiting scale and on how close the temperature is to criticality. The system also displays apparent ergodicity breaking at intermediate time, while ergodicity breaking at longer time occurs only under the idealized infinite environment at the critical temperature.

Nonergodic subdiffusion from transient interactions with heterogeneous partners.

Spatiotemporal disorder has been recently associated to the occurrence of anomalous nonergodic diffusion of molecular components in biological systems, but the underlying microscopic mechanism is still unclear. We introduce a model in which a particle performs continuous Brownian motion with changes of diffusion coefficients induced by transient molecular interactions with diffusive binding partners. In spite of the exponential distribution of waiting times, the model shows subdiffusion and nonergodicity similar to the heavy-tailed continuous time random walk. The dependence of these properties on the density of binding partners is analyzed and discussed. Our work provides an experimentally testable microscopic model to investigate the nature of nonergodicity in disordered media.

Serum antibodies to benzo(a)pyrene diol epoxide-DNA adducts in the general population: effects of air pollution, tobacco smoking, and family history of lung diseases.

Polycyclic aromatic hydrocarbons (PAHs) are almost ubiquitous pollutants that may interact with metabolic systems in human tissues and eventually cause cancer. PAH-adducted DNA becomes antigenic and antibodies anti-benzo(a)pyrene diol epoxide (BPDE)-DNA may be found in serum of PAH-exposed subjects. The presence of serum antibodies anti-BPDE-DNA adduct was investigated in 1345 individuals from family clusters of the general population of a small area in central Italy in whom information about smoking habits, site of residence, and personal and family history of lung diseases, including cancer, were obtained. Anti-BPDE-DNA antibodies in the sera were detected with a direct ELISA and the association of anti-BPDE-DNA antibodies with subjects' data from a standardized respiratory questionnaire including age, occupation, tobacco smoking habits, respiratory symptoms, and family history of respiratory diseases was subsequently tested by multivariate logistic regression analysis. The overall prevalence of subjects with anti-BPDE-DNA antibodies was 21.0% (n=283), with no differences between males and females. Anti-BPDE-DNA positivity was associated with living in the urban area [odds ratio (OR), 1.49; 95% confidence interval (CI), 1.16-1.92], with active tobacco smoking (OR, 1.25; 95% CI, 1.06-1.48), and with family history of lung cancer (OR, 1.30; 95% CI, 0.90-1.88), and positivity increased with the number of members in the family cluster positive to anti-BPDE-DNA antibodies (OR, 1.30; 95% CI, 1.03-1.65). This study on a large general population sample indicates that serum anti-BPDE-DNA antibodies may be considered as biomarkers of exposure to environmental carcinogens and of DNA damage. The genetic and familial components of their association with tobacco smoking lend further support to the argument about the familial predisposition to lung cancer.

Platelet-leukocyte-endothelial cell interaction on the blood vessel wall.

Leukocytes, platelets, and endothelial cells interact at sites of vascular injury and inflammation through adhesion receptors on the cell surface. On binding of ligand to receptor, these receptors initiate intracellular signaling that leads to the modulation of several biological properties of the cells involved. These finely regulated processes involve several classes of cell adhesion molecules: integrins, immunoglobulin-like proteins, selectins, and mucin-like proteins as well as an array of soluble mediators. Interaction of these cell adhesion molecules serves to recruit circulating cells to the blood vessel endothelium or to accumulated platelets on the vessel wall and to foster cell-cell communication. The importance of these interactions to inflammation, blood coagulation, and the immune response is outlined.

Detection of distinct isoform patterns of the beta-amyloid precursor protein in human platelets and lymphocytes.

Cerebral deposition of the amyloid beta-protein (A beta P), approximately 40 residue fragment of the integral membrane protein, beta-amyloid precursor protein (beta APP), has been implicated as the probable cause of some cases of familial Alzheimer's disease (AD). The parallels between A beta P deposition in AD and the deposition of certain plasma proteins in systemic amyloid diseases has heightened interest in the analysis of beta APP in circulating cells and plasma. Here, we describe distinct isoform patterns of beta APP in peripheral platelets and lymphocytes. PCR-mediated amplification of mRNA from purified platelets demonstrated the expression of all three major beta APP transcripts (beta APP770,751,695). The full-length, approximately 140 kDa form of beta APP751,770 was detected in membranes of resting and activated platelets but very little immature, approximately 122 kDa beta APP751,770 was found, suggesting a different processing of beta APP in platelets than that described in a variety of cultured cells and tissues. Platelets stimulated with thrombin, calcium ionophore, or collagen released the soluble, carboxyl-truncated form of beta APP (protease nexin-II), but no evidence for the shedding of full-length beta APP associated with platelet microparticles was found, in contrast to previous reports. As a positive control marker for microparticles, the fibrinogen receptor subunit, GPIIIa, was readily detected in platelet releasates. Resting and activated platelets contained similar amounts of the approximately 10 kDa carboxyl terminal beta APP fragment that is retained in platelet membranes following the constitutive cleavage of protease nexin-II. Nonstimulated peripheral B and T lymphocytes contained small amounts of membrane-associated mature and immature beta APP751,770. The potentially amyloidogenic full-length beta APP molecules present in circulating platelets and lymphocytes but not in microparticles could serve as a source of the microvascular A beta P deposited during aging and particularly in AD.

12-Hydroxyeicosatetraenoic acid upregulates P-selectin-induced tissue factor activity on monocytes.

12-Hydroxyeicosatetraenoic acid (12-HETE), a product of the platelet lipoxygenase pathway, amplifies tissue factor expression by P-selectin-stimulated monocytes in a time- and dose-dependent fashion. The same effect is observed when monocytes are incubated with Chinese hamster ovary cells transfected with the P-selectin cDNA. Both 5-HETE and leukotriene C4 are inactive in this system. Furthermore, the effect is not dependent on non-specific monocyte adhesion, since monocytes incubated with CHO cells expressing E-selectin do not express tissue factor, either in the presence or in the absence of 12-HETE. These results show that 12-HETE is a cofactor for the expression of tissue factor by monocytes.

Thrombus formation: direct real-time observation and digital analysis of thrombus assembly in a living mouse by confocal and widefield intravital microscopy.

We have developed novel instrumentation using confocal and widefield microscopy to image and analyze thrombus formation in real time in the microcirculation of a living mouse. This system provides high-speed, near-simultaneous acquisition of images of multiple fluorescent probes and a brightfield channel, and supports laser-induced injury through the microscope optics. Although this imaging facility requires interface of multiple hardware components, the primary challenge in vascular imaging is careful experimental design and interpretation. This system has been used to localize tissue factor during thrombus formation, to observe defects in thrombus assembly in genetically altered mice, to study the kinetics of platelet activation and P-selectin expression following vascular injury, to analyze leukocyte rolling on arterial thrombi, to generate three-dimensional models of thrombi, and to analyze the effect of antithrombotic agents in vivo.

Dynamic sodium chemical shift imaging for the study of aqueous humor flow.

Ocular images were obtained using sodium chemical shift imaging (CSI) and 1,4,7,10-tetraazacyclododecane-N,N'N",N"'-tetramethylenephospho nate thulium (III) [Tm(DOTP)5-], a paramagnetic chemical shift reagent. After injecting the shift reagent into the anterior chamber of rabbits, serial imaging was done, monitoring the change in chemical shift with time. Sodium CSI produced images of the eye in three dimensions, quantitatively depicting the spatial and temporal changes in the concentration of a paramagnetic tracer substance. The Tm(DOTP)5- is eliminated from the anterior chamber by first-order kinetics with a half-life of 49 min. These data suggest that this substance is eliminated from the anterior chamber at the same rate as aqueous humor is replaced. Sodium CSI shows promise as a valuable technique for monitoring fluid dynamics in the living eye.

Comparison of algorithms for determining the end-point of the forced vital capacity maneuver.

The criteria of the American Thoracic Society (ATS) for determining the end-point of the forced vital capacity (FVC) maneuver were compared with an algorithm employed by a computer system (Hewlett-Packard), which yields a later end-point. The 150 subjects tested were divided into five groups of 30 on the basis of the following spirometric diagnoses: normal; small airways' obstruction (SAO); mild airways' obstruction (MAO); severe chronic obstructive pulmonary disease (COPD); or restrictive disease. The subjects performed a minimum of three maneuvers according to ATS standards, and the flow-volume curves with the greatest sum of FVC and forced expiratory volume in one second (FEV) were chosen for analysis by the two algorithms. Hewlett-Packard (HP) values for FVC and FVC time were always higher than the corresponding ATS values, and the HP values for flows were always lower than the corresponding ATS values. The higher differences were observed in the SAO group. In the group with severe COPD, high FVC differences and low flow differences were observed; on the contrary, in the restrictive group, low FVC differences and high flow differences were present. These results, in addition to the different location of the FVC end point, may be explained by the different morphology of the flow-volume curves. In conclusion, the ATS algorithm caused a systematic underevaluation of FVC and a systematic overevaluation of flows, which cause practical consequences only in the SAO group. In fact, 28 percent (17/60) of the subjects with SAO characteristics were considered "normal" using ATS criteria for the end-point.

Prospective study of a standardized questionnaire to improve clinical estimate of pulmonary embolism.

A standardized questionnaire was administered to 100 patients suspected of having pulmonary embolism to investigate whether clinical data may be reliably used in the decision-making process of such patients. Questionnaire data were compared with lung scintigraphy outcome and 16 variables were selected as significantly associated with the scintigraphic diagnosis. Based on these variables, patients with abnormal scintigraphy compatible with pulmonary embolism and patients with scintigraphy not compatible with embolism were classified in accordance with the scintigraphic diagnosis. When these 16 variables were tested in an additional validation group, clinical and scintigraphic diagnosis matched in most cases. These results show that clinical data can be used to predict the outcome of lung perfusion scintigraphy in patients suspected of pulmonary embolism. Use of a standardized questionnaire can improve the accuracy of pretest assessment of such patients and positively influence the decisions to start heparin coverage or obtain pulmonary angiography.

Myocardial tissue characterization by autocorrelation of two-dimensional ultrasonic backscatter.

To evaluate a novel method for determining the spatial distribution of echocardiographic information based on the two-dimensional autocorrelation function, echocardiographic images were obtained from specific regions of interest from 10 healthy volunteers, seven patients with genetically defined hypertrophic cardiomyopathy, and nine patients with pressure-overload hypertrophy. The wavelength of distinct peaks from the two-dimensional autocorrelation of the images was compared between groups of patients and demonstrated a significant decrease in the mean length scale associated with distinct secondary correlation peaks in patients with hypertrophic cardiomyopathy or pressure-overload hypertrophy compared with healthy volunteers (p = 0.0009). With a discriminating wavelength of 3.3 mm, the sensitivity of this technique for detecting abnormal myocardium was 84% with a specificity of 89%. This study suggests that ultrasonic tissue characterization based on the two-dimensional autocorrelation function may have potential for distinguishing normal from abnormal myocardium and provides a rationale for textural approaches to ultrasonic tissue characterization.

Cell-cell interaction and tissue factor expression.

Following tissue injury, blood components come into contact with the subendothelial tissue, a thrombogenic surface. Tissue factor, found in the media and adventitia of the vascular wall, or available on the membrane of activated monocytes and endothelial cells, triggers blood coagulation. A complex interaction between soluble molecules and cells then takes place, a fibrin mesh is formed, and the resulting clot limits or stops the loss of blood. Platelets, monocytes, and endothelial cells co-localize and interact in the area of vascular injury. This close relationship, which is regulated by an array of cell-cell adhesion molecules, favours the modulation of the biochemical pathways of these cells. The aim of this review is to summarize the contribution of these cells and their interactions in tissue factor expression and its possible relevance in the pathogenesis of vascular diseases.