Heparin as a risk factor for perigraft seroma complicating the modified Blalock-Taussig shunt

OBJECTIVE: The purpose of this study was to determine the risk factors associated with the occurrence of perigraft seromas complicating systemic-to-pulmonary polytetrafluoroethylene grafts. METHODS: Clinical and perioperative variables were reexamined, blinded for the outcome variable perigraft seroma, in 60 patients undergoing 67 consecutive graft procedures in a 3.5-year period. RESULTS: Eight cases of perigraft seroma were diagnosed in six patients. Univariate analysis revealed age (p = 0.02), a diagnosis of pulmonary atresia with ventricular septal defect and systemic-pulmonary collaterals (p = 0.001), reimplantation of collaterals during the procedure (p < 0.001), and intravenous heparin administered after operation (p < 0.0001) as risk factors for symptomatic perigraft seroma. Multivariable analysis defined heparin as the only significant factor associated with symptomatic perigraft seroma. Consolidation of the upper lobe on chest radiograph, ipsilateral to the shunt, directly after operation (p = 0.01), but especially 8 to 10 days after operation (p < 0.0001), or the need for prolonged drainage of pleural fluid (p < 0.0001) were correlated with the occurrence of perigraft seroma. Perigraft seroma led to four early rethoracotomies in three patients and to accelerated corrective surgery in three cases. Consolidation and absent perfusion of lung segments persisted in two patients. CONCLUSIONS: Our data suggest that the use of heparin leads to an increased risk of perigraft seroma, complicating systemic-pulmonary polytetrafluoroethylene grafts. Prolonged pleural drainage and/or postoperative consolidation of the upper lobe indicate the development of symptomatic perigraft seroma. Treatment is controversial and results are unpredictable. Expectative management seems to be justified so long as permitted by the clinical condition

Nuclear DDX3 expression predicts poor outcome in colorectal and breast cancer

Purpose: DEAD box protein 3 (DDX3) is an RNA helicase with oncogenic properties that shuttles between the cytoplasm and nucleus. The majority of DDX3 is found in the cytoplasm, but a subset of tumors has distinct nuclear DDX3 localization of yet unknown biological significance. This study aimed to evaluate the significance of and mechanisms behind nuclear DDX3 expression in colorectal and breast cancer. Methods: Expression of nuclear DDX3 and the nuclear exporter chromosome region maintenance 1 (CRM1) was evaluated by immunohistochemistry in 304 colorectal and 292 breast cancer patient samples. Correlations between the subcellular localization of DDX3 and CRM1 and the difference in overall survival between patients with and without nuclear DDX3 were studied. In addition, DDX3 mutants were created for in vitro evaluation of the mechanism behind nuclear retention of DDX3. Results: DDX3 was present in the nucleus of 35% of colorectal and 48% of breast cancer patient samples and was particularly strong in the nucleolus. Nuclear DDX3 correlated with worse overall survival in both colorectal (hazard ratio [HR] 2.34, P&#60;0.001) and breast cancer (HR 2.39, P=0.004) patients. Colorectal cancers with nuclear DDX3 expression more often had cytoplasmic expression of the nuclear exporter CRM1 (relative risk 1.67, P=0.04). In vitro analysis of DDX3 deletion mutants demonstrated that CRM1-mediated export was most dependent on the N-terminal nuclear export signal. Conclusion: Overall, we conclude that nuclear DDX3 is partially CRM1-mediated and predicts worse survival in colorectal and breast cancer patients, putting it forward as a target for therapeutic intervention with DDX3 inhibitors under development in these cancer types

Astrocyte-derived tissue Transglutaminase affects fibronectin deposition, but not aggregation, during cuprizone-induced demyelination

Astrogliosis as seen in Multiple Sclerosis (MS) develops into astroglial scarring, which is beneficial because it seals off the site of central nervous system (CNS) damage. However, astroglial scarring also forms an obstacle that inhibits axon outgrowth and (re) myelination in brain lesions. This is possibly an important cause for incomplete remyelination in the CNS of early stage MS patients and for failure in remyelination when the disease progresses. In this study we address whether under demyelinating conditions in vivo, tissue Transglutaminase (TG2), a Ca2+-dependent enzyme that catalyses posttranslational modification of proteins, contributes to extracellular matrix (ECM) deposition and/or aggregation. We used the cuprizone model for de- and remyelination. TG2 immunoreactivity and enzymatic activity time-dependently appeared in astrocytes and ECM, respectively, in the corpus callosum of cuprizone-treated mice. Enhanced presence of soluble monomeric and multimeric fibronectin was detected during demyelination, and fibronectin immunoreactivity was slightly decreased in cuprizone-treated TG2(-/-) mice. In vitro TG2 overexpression in astrocytes coincided with more, while knock-down of TG2 with less fibronectin production. TG2 contributes, at least partly, to fibronectin production, and may play a role in fibronectin deposition during cuprizone-induced demyelination. Our observations are of interest in understanding the functional implications of TG2 during astrogliosis

Monocyte behaviour and tissue transglutaminase expression during experimental autoimmune encephalomyelitis in transgenic CX3CR1gfp/gfp mice

Leukocyte infiltration into the central nervous system (CNS) is a key pathological feature in multiple sclerosis (MS) and the MS animal model experimental autoimmune encephalomyelitis (EAE). Recently, preventing leukocyte influx into the CNS of MS patients is the main target of MS therapies and insight into cell behaviour in the circulation is needed for further elucidation of such therapies. In this study, we aimed at in vivo visualization of monocytes in a time-dependent manner during EAE. Using intravital two-photon microscopy (IVM), we imaged CX3CR1gfp/gfp mice during EAE, visualizing CX3CR1-GFP+ monocytes and their dynamics in the spinal cord vasculature. Our observations showed that intraluminal crawling of CX3CR1-GFP+ monocytes increased even before the clinical onset of EAE due to immunization of the animals. Furthermore, intraluminal crawling remained elevated during ongoing clinical disease. Besides, the displacement of these cells was larger during the peak of EAE compared to the control animals. In addition, we showed that the enzyme tissue transglutaminase (TG2), which is present in CNS-infiltrated cells in MS patients, is likewise found in CX3CR1-GFP+ monocytes in the spinal cord lesions and at the luminal side of the vasculature during EAE. It might thereby contribute to adhesion and crawling of monocytes, facilitating extravasation into the CNS. Thus, we put forward that interference with monocyte adhesion, by e.g. inhibition of TG2, should be applied at a very early stage of EAE and possibly MS, to effectively combat subsequent pathology

Homeomorphic Embedding for Online Termination of Symbolic Methods

Well-quasi orders in general, and homeomorphic embedding in particular, have gained popularity to ensure the termination of techniques for program analysis, specialisation, transformation, and verification. In this paper we survey and discuss this use of homeomorphic embedding and clarify the advantages of such an approach over one using well-founded orders. We also discuss various extensions of the homeomorphic embedding relation. We conclude with a study of homeomorphic embedding in the context of metaprogramming, presenting some new (positive and negative) results and open problems

Signaling in Secret: Pay-for-Performance and the Incentive and Sorting Effects of Pay Secrecy

Key Findings: Pay secrecy adversely impacts individual task performance because it weakens the perception that an increase in performance will be accompanied by increase in pay; Pay secrecy is associated with a decrease in employee performance and retention in pay-for-performance systems, which measure performance using relative (i.e., peer-ranked) criteria rather than an absolute scale (see Figure 2 on page 5); High performing employees tend to be most sensitive to negative pay-for- performance perceptions; There are many signals embedded within HR policies and practices, which can influence employees’ perception of workplace uncertainty/inequity and impact their performance and turnover intentions; and When pay transparency is impractical, organizations may benefit from introducing partial pay openness to mitigate these effects on employee performance and retention

Quantification of pharmacodynamic interactions between dexmedetomidine and midazolam in the rat

ABSTRACT The pharmacodynamic (PD) interaction between the benzodiazepine agonist midazolam and the ␣ 2 -adrenergic agonist dexmedetomidine was characterized for defined measures of anesthetic action and cardiovascular and ventilatory side effects in 33 rats. For various combinations of constant plasma concentrations of midazolam (0.1-20 g/ml) and dexmedetomidine (0.3-19 ng/ml) obtained by target-controlled infusion, the whisker reflex (WR), righting reflex (RR), startle reflex to noise (SR), tail clamp response (TC), and corneal reflex (CR) were assessed. EEG (power in 0.5-3.5-Hz frequency band), mean arterial pressure, and heart rate were recorded continuously. Blood gas values and arterial drug concentrations were determined regularly. The nature and extent of PD interaction was quantified by the model parameter synergy (SYN Ͻ 0, antagonism; SYN ϭ 0, additivity; and SYN Ͼ 0, synergy). With increasing drug concentrations WR was lost first, followed by RR, SR, TC, and CR. These effects were accompanied by an increase of the EEG measure. The drug interaction was synergistic for all stimulus-response measures and the degree of synergy increased with deeper levels of central nervous system depression (SYN was 7.3, 145, 560, 374, and 1490 for WR, RR, SR, TC, and CR, respectively). The cardiovascular side effects of dexmedetomidine, evaluated at similar PD endpoints, were reduced in the presence of midazolam. Ventilatory side effects were minor for all drug combinations. The nature and extent of the PD interactions were not reflected in the EEG measure. In clinical anesthetic practice adequate general anesthesia requires a minimum of two different classes of anesthetic drugs. A hypnotic (inhalational anesthetic, i.v. anesthetic) and an analgesic (opiate) drug are titrated to achieve adequate CNS depression. A muscle relaxant can be used to facilitate surgical procedures. This anesthetic combination is termed &quot;balanced anesthesia&quot; (Hug, 1990; Many variables influence the complex relationship between dosage, plasma concentration, and drug effect. To optimize the delivery of anesthetic drugs to individual patients, it is important to distinguish between pharmacokinetic (PK) and pharmacodynamic (PD) interactions. For example, Dexmedetomidine, a selective ␣ 2 -adrenergic agonist, is being studied for potential use in anesthetic practice because of its combined analgesic, sedative, hypnotic, and anxiolytic effect

Macroscopic quantum phenomena in Josephson structures

The Josephson effect is a probe with unparalleled capabilities for the study of a variety of macroscopic quantum phenomena. This is a survey of important achievements and challenging trends, in particular macroscopic quantum tunneling and energy level quantization. We focus on high-T-C superconducting structures and recent research on nanostructures