From caging to rouse dynamics in polymer melts with intramolecular barriers: a critical test of the mode coupling theory

By means of computer simulations and solution of the equations of the mode coupling theory (MCT),we investigate the role of the intramolecular barriers on several dynamic aspects of nonentangled polymers. The investigated dynamic range extends from the caging regime characteristic of glass-formers to the relaxation of the chain Rouse modes. We review our recent work on this question,provide new results, and critically discuss the limitations of the theory. Solutions of the MCT for the structural relaxation reproduce qualitative trends of simulations for weak and moderate barriers. However, a progressive discrepancy is revealed as the limit of stiff chains is approached. This dis-agreement does not seem related with dynamic heterogeneities, which indeed are not enhanced by increasing barrier strength. It is not connected either with the breakdown of the convolution approximation for three-point static correlations, which retains its validity for stiff chains. These findings suggest the need of an improvement of the MCT equations for polymer melts. Concerning the relaxation of the chain degrees of freedom, MCT provides a microscopic basis for time scales from chain reorientation down to the caging regime. It rationalizes, from first principles, the observed deviations from the Rouse model on increasing the barrier strength. These include anomalous scaling of relaxation times, long-time plateaux, and nonmonotonous wavelength dependence of the mode correlators.

Impact of physical activity on activity of daily living in moderate to severe dementia: a critical review

The objectives of this study were to describe the different modalities of physical activity programs designed for moderate to severe dementia and to identify their impact on functional independence in activities of daily living (ADL). A critical review of randomized controlled trials related to the impact of physical activity programs in moderately to severely demented persons on ADL performance and meta-analysis of the identified studies were performed. Among the 303 identified articles, five responded to the selection criteria. Four out of the five studies demonstrated limited methodological quality. In one high-quality study, physical activity programs significantly delayed deterioration of ADL performance. The program components and ADL assessment tools vary widely across studies. Although the proposed treatments have not proven their efficiency in improving the ADL status of the patients, they were able to limit the decline in ADL functioning. Future research is warranted in order to identify clinically relevant modalities for physical activity programs for people with moderate to severe dementia.

A critical role of autophagy in antileukemia/lymphoma effects of APO866, an inhibitor of NAD biosynthesis.

APO866, an inhibitor of NAD biosynthesis, exhibits potent antitumor properties in various malignancies. Recently, it has been shown that APO866 induces apoptosis and autophagy in human hematological cancer cells, but the role of autophagy in APO866-induced cell death remains unclear. Here, we report studies on the molecular mechanisms underlying APO866-induced cell death with emphasis on autophagy. Treatment of leukemia and lymphoma cells with APO866 induced both autophagy, as evidenced by an increase in autophagosome formation and in SQSTM1/p62 degradation, but also increased caspase activation as revealed by CASP3/caspase 3 cleavage. As an underlying mechanism, APO866-mediated autophagy was found to deplete CAT/catalase, a reactive oxygen species (ROS) scavenger, thus promoting ROS production and cell death. Inhibition of autophagy by ATG5 or ATG7 silencing prevented CAT degradation, ROS production, caspase activation, and APO866-induced cell death. Finally, supplementation with exogenous CAT also abolished APO866 cytotoxic activity. Altogether, our results indicated that autophagy is essential for APO866 cytotoxic activity on cells from hematological malignancies and also indicate an autophagy-dependent CAT degradation, a novel mechanism for APO866-mediated cell killing. Autophagy-modulating approaches could be a new way to enhance the antitumor activity of APO866 and related agents.

A critical evaluation of secondary cancer risk models applied to Monte Carlo dose distributions of 2-dimensional, 3-dimensional conformal and hybrid intensity-modulated radiation therapy for breast cancer.

The comparison of radiotherapy techniques regarding secondary cancer risk has yielded contradictory results possibly stemming from the many different approaches used to estimate risk. The purpose of this study was to make a comprehensive evaluation of different available risk models applied to detailed whole-body dose distributions computed by Monte Carlo for various breast radiotherapy techniques including conventional open tangents, 3D conformal wedged tangents and hybrid intensity modulated radiation therapy (IMRT). First, organ-specific linear risk models developed by the International Commission on Radiological Protection (ICRP) and the Biological Effects of Ionizing Radiation (BEIR) VII committee were applied to mean doses for remote organs only and all solid organs. Then, different general non-linear risk models were applied to the whole body dose distribution. Finally, organ-specific non-linear risk models for the lung and breast were used to assess the secondary cancer risk for these two specific organs. A total of 32 different calculated absolute risks resulted in a broad range of values (between 0.1% and 48.5%) underlying the large uncertainties in absolute risk calculation. The ratio of risk between two techniques has often been proposed as a more robust assessment of risk than the absolute risk. We found that the ratio of risk between two techniques could also vary substantially considering the different approaches to risk estimation. Sometimes the ratio of risk between two techniques would range between values smaller and larger than one, which then translates into inconsistent results on the potential higher risk of one technique compared to another. We found however that the hybrid IMRT technique resulted in a systematic reduction of risk compared to the other techniques investigated even though the magnitude of this reduction varied substantially with the different approaches investigated. Based on the epidemiological data available, a reasonable approach to risk estimation would be to use organ-specific non-linear risk models applied to the dose distributions of organs within or near the treatment fields (lungs and contralateral breast in the case of breast radiotherapy) as the majority of radiation-induced secondary cancers are found in the beam-bordering regions.

Phosphorylation of CARMA1 by HPK1 is critical for NF-kappaB activation in T cells.

Activation of the NF-kappaB pathway in T cells is required for induction of an adaptive immune response. Hematopoietic progenitor kinase (HPK1) is an important proximal mediator of T-cell receptor (TCR)-induced NF-kappaB activation. Knock-down of HPK1 abrogates TCR-induced IKKbeta and NF-kappaB activation, whereas active HPK1 leads to increased IKKbeta activity in T cells. Yet, the precise molecular mechanism of this process remains elusive. Here, we show that HPK1-mediated NF-kappaB activation is dependent on the adaptor protein CARMA1. HPK1 interacts with CARMA1 in a TCR stimulation-dependent manner and phosphorylates the linker region of CARMA1. Interestingly, the putative HPK1 phosphorylation sites in CARMA1 are different from known PKC consensus sites. Mutations of residues S549, S551, and S552 in CARMA1 abrogated phosphorylation of a CARMA1-linker construct by HPK1 in vitro. In addition, CARMA1 S551A or S5549A/S551A point mutants failed to restore HPK1-mediated and TCR-mediated NF-kappaB activation and IL-2 expression in CARMA1-deficient T cells. Thus, we identify HPK1 as a kinase specific for CARMA1 and suggest HPK1-mediated phosphorylation of CARMA1 as an additional regulatory mechanism tuning the NF-kappaB response upon TCR stimulation.

Development process and initial validation of the ethical conflict in nursing questionnaire-critical care version

Background: Ethical conflicts are arising as a result of the growing complexity of clinical care, coupled with technological advances. Most studies that have developed instruments for measuring ethical conflict base their measures on the variables"frequency" and"degree of conflict". In our view, however, these variables are insufficient for explaining the root of ethical conflicts. Consequently, the present study formulates a conceptual model that also includes the variable"exposure to conflict", as well as considering six"types of ethical conflict". An instrument was then designed to measure the ethical conflicts experienced by nurses who work with critical care patients. The paper describes the development process and validation of this instrument, the Ethical Conflict in Nursing Questionnaire Critical Care Version (ECNQ-CCV). Methods: The sample comprised 205 nursing professionals from the critical care units of two hospitals in Barcelona (Spain). The ECNQ-CCV presents 19 nursing scenarios with the potential to produce ethical conflict in the critical care setting. Exposure to ethical conflict was assessed by means of the Index of Exposure to Ethical Conflict (IEEC), a specific index developed to provide a reference value for each respondent by combining the intensity and frequency of occurrence of each scenario featured in the ECNQ-CCV. Following content validity, construct validity was assessed by means of Exploratory Factor Analysis (EFA), while Cronbach"s alpha was used to evaluate the instrument"s reliability. All analyses were performed using the statistical software PASW v19. Results: Cronbach"s alpha for the ECNQ-CCV as a whole was 0.882, which is higher than the values reported for certain other related instruments. The EFA suggested a unidimensional structure, with one component accounting for 33.41% of the explained variance. Conclusions: The ECNQ-CCV is shown to a valid and reliable instrument for use in critical care units. Its structure is such that the four variables on which our model of ethical conflict is based may be studied separately or in combination. The critical care nurses in this sample present moderate levels of exposure to ethical conflict. This study represents the first evaluation of the ECNQ-CCV.

Development process and initial validation of the ethical conflict in nursing questionnaire-critical care version

Background: Ethical conflicts are arising as a result of the growing complexity of clinical care, coupled with technological advances. Most studies that have developed instruments for measuring ethical conflict base their measures on the variables"frequency" and"degree of conflict". In our view, however, these variables are insufficient for explaining the root of ethical conflicts. Consequently, the present study formulates a conceptual model that also includes the variable"exposure to conflict", as well as considering six"types of ethical conflict". An instrument was then designed to measure the ethical conflicts experienced by nurses who work with critical care patients. The paper describes the development process and validation of this instrument, the Ethical Conflict in Nursing Questionnaire Critical Care Version (ECNQ-CCV). Methods: The sample comprised 205 nursing professionals from the critical care units of two hospitals in Barcelona (Spain). The ECNQ-CCV presents 19 nursing scenarios with the potential to produce ethical conflict in the critical care setting. Exposure to ethical conflict was assessed by means of the Index of Exposure to Ethical Conflict (IEEC), a specific index developed to provide a reference value for each respondent by combining the intensity and frequency of occurrence of each scenario featured in the ECNQ-CCV. Following content validity, construct validity was assessed by means of Exploratory Factor Analysis (EFA), while Cronbach"s alpha was used to evaluate the instrument"s reliability. All analyses were performed using the statistical software PASW v19. Results: Cronbach"s alpha for the ECNQ-CCV as a whole was 0.882, which is higher than the values reported for certain other related instruments. The EFA suggested a unidimensional structure, with one component accounting for 33.41% of the explained variance. Conclusions: The ECNQ-CCV is shown to a valid and reliable instrument for use in critical care units. Its structure is such that the four variables on which our model of ethical conflict is based may be studied separately or in combination. The critical care nurses in this sample present moderate levels of exposure to ethical conflict. This study represents the first evaluation of the ECNQ-CCV.

Evaluación de los factores de riesgo y los tipos de superficie para el desarrollo de las úlceras por presión en el enfermo crítico = Assessment of risk factors and the types of surface for the development of pressure ulcers on critical ill patients

The main objective of this article is to assess the risk factors and the types of surface for the development of pressure ulcers (PU) on critical ill patients in an Intensive Care Unit (ICU)

Interferon-gamma is a critical modulator of CB(2) cannabinoid receptor signaling during neuropathic pain

Nerve injuries often lead to neuropathic pain syndrome. The mechanisms contributing to this syndrome involve local inflammatory responses, activation of glia cells, and changes in the plasticity of neuronal nociceptive pathways. Cannabinoid CB(2) receptors contribute to the local containment of neuropathic pain by modulating glial activation in response to nerve injury. Thus, neuropathic pain spreads in mice lacking CB(2) receptors beyond the site of nerve injury. To further investigate the mechanisms leading to the enhanced manifestation of neuropathic pain, we have established expression profiles of spinal cord tissues from wild-type and CB(2)-deficient mice after nerve injury. An enhanced interferon-gamma (IFN-gamma) response was revealed in the absence of CB(2) signaling. Immunofluorescence stainings demonstrated an IFN-gamma production by astrocytes and neurons ispilateral to the nerve injury in wild-type animals. In contrast, CB(2)-deficient mice showed neuronal and astrocytic IFN-gamma immunoreactivity also in the contralateral region, thus matching the pattern of nociceptive hypersensitivity in these animals. Experiments in BV-2 microglia cells revealed that transcriptional changes induced by IFN-gamma in two key elements for neuropathic pain development, iNOS (inducible nitric oxide synthase) and CCR2, are modulated by CB(2) receptor signaling. The most direct support for a functional involvement of IFN-gamma as a mediator of CB(2) signaling was obtained with a double knock-out mouse strain deficient in CB(2) receptors and IFN-gamma. These animals no longer show the enhanced manifestations of neuropathic pain observed in CB(2) knock-outs. These data clearly demonstrate that the CB(2) receptor-mediated control of neuropathic pain is IFN-gamma dependent.

Stage-specific integration of maternal and embryonic peroxisome proliferator-activated receptor delta signaling is critical to pregnancy success.

Successful pregnancy depends on well coordinated developmental events involving both maternal and embryonic components. Although a host of signaling pathways participate in implantation, decidualization, and placentation, whether there is a common molecular link that coordinates these processes remains unknown. By exploiting genetic, molecular, pharmacological, and physiological approaches, we show here that the nuclear transcription factor peroxisome proliferator-activated receptor (PPAR) delta plays a central role at various stages of pregnancy, whereas maternal PPARdelta is critical to implantation and decidualization, and embryonic PPARdelta is vital for placentation. Using trophoblast stem cells, we further elucidate that a reciprocal relationship between PPARdelta-AKT and leukemia inhibitory factor-STAT3 signaling pathways serves as a cell lineage sensor to direct trophoblast cell fates during placentation. This novel finding of stage-specific integration of maternal and embryonic PPARdelta signaling provides evidence that PPARdelta is a molecular link that coordinates implantation, decidualization, and placentation crucial to pregnancy success. This study is clinically relevant because deferral of on time implantation leads to spontaneous pregnancy loss, and defective trophoblast invasion is one cause of preeclampsia in humans.

Ising critical behavior of a non-Halmiltonian lattice system

We study steady states in d-dimensional lattice systems that evolve in time by a probabilistic majority rule, which corresponds to the zero-temperature limit of a system with conflicting dynamics. The rule satisfies detailed balance for d=1 but not for d>1. We find numerically nonequilibrium critical points of the Ising class for d=2 and 3.

Palliative surgical procedures to restore shoulder function in obstetric brachial palsy. Critical analysis of Narakas' series.

Dr. Narakas intended to study a series of 61 cases of shoulder sequelae of obstetric palsy. His vast experience would have enriched our clinical knowledge of this ailment. The authors carry on with that study to clarify his therapeutic approach and share the benefit of his experience.

Tumor localization of radiolabeled antibodies against carcinoembryonic antigen in patients with carcinoma: a critical evaluation.

Purified, [131I]-labeled goat antibodies against carcinoembryonic antigen, which have been shown to localize in human carcinoma in nude mice, were injected into 27 patients with carcinoma. Patients were scanned with a scintillation camera at various intervals. In 11 patients, radioactivity was detectable in the tumor 48 hours after injection. Computerized subtraction of blood-pool radioactivity provided clearer pictures in positive cases, but in 16 patients the scans remained doubtful or negative. To study the specificity of [131I]-antibody localization, we gave some patients simultaneous injections of [125I]-labeled normal IgG. Both isotopes were measured by means of scintillation counting in tumors and normal tissues recovered after surgery. The results demonstrated that only the anti-CEA antibodies localized in tumors. However, the total antibody-derived radioactivity in the tumor was only about 0.001 of the injected dose. We conclude that, despite the present demonstration of specificity, this method of tumor detection is not yet clinically useful.