Oxidative Mechanisms of Monocyte-Mediated Cytotoxicity

Science.gov (United States)

Weiss, Stephen J.; Lobuglio, Albert F.; Kessler, Howard B.

1980-01-01

Human monocytes stimulated with phorbol myristate acetate were able to rapidly destroy autologous erythrocyte targets. Monocyte-mediated cytotoxicity was related to phorbol myristate acetate concentration and monocyte number. Purified preparations of lymphocytes were incapable of mediating erythrocyte lysis in this system. The ability of phorbol myristate acetate-stimulated monocytes to lyse erythrocyte targets was markedly impaired by catalase or superoxide dismutase but not by heat-inactivated enzymes or albumin. Despite a simultaneous requirement for superoxide anion and hydrogen peroxide in the cytotoxic event, a variety of hydroxyl radical and singlet oxygen scavengers did not effect cytolysis. However, tryptophan significantly inhibited cytotoxicity. The myeloperoxidase inhibitor cyanide enhanced erythrocyte destruction, whereas azide reduced it modestly. The inability of cyanide to reduce cytotoxicity coupled with the protective effect of superoxide dismutase suggests that cytotoxicity is independent of the classic myeloperoxidase system. We conclude that monocytes, stimulated with phorbol myristate acetate, generate superoxide anion and hydrogen peroxide, which together play an integral role in this cytotoxic mechanism.

Rheological and mechanical properties of polyamide 6 modified by electron-beam initiated mediation process

International Nuclear Information System (INIS)

Shin, Boo Young; Kim, Jae Hong

2015-01-01

Polyamide (PA6) has been modified by electron-beam initiated mediator process to improve drawbacks of PA6. Glycidyl methacrylate (GMA) was chosen as a reactive mediator for modification process of PA6. The mixture of the PA6 and GMA was prepared by using a twin-screw extruder, and then the mixture was exposed to electron-beam irradiation at various doses at room temperature. The modified PA6 were characterized by observing rheological and mechanical properties and compared virgin PA6. Thermal properties, water absorption, and gel fraction were also investigated. Tight gel was not found even when PA6 was irradiated at 200 kGy. Complex viscosity and storage modulus of PA6 were remarkably increased by electron-beam irradiation with medium of GMA. Maximum increase in complex viscosity was 75 times higher than virgin PA6 at 0.1 rad/s when it was irradiated at 200 kGy with the GMA. Mechanical properties were also improved without scarifying of processability. The reaction mechanisms for the mediation process with the reactive mediator of GMA were estimated to elucidate the cause of significantly enhanced rheological and mechanical properties without loss of thermoplasticity. - Highlights: • PA6 was modified by the electron-beam initiated mediation process. • Maximum increase in complex viscosity of modified PA6 was 75 times higher than virgin PA6 at 0.1 rad/s. • Mechanical properties were improved without scarifying of processability. • The GMA as a mediator played a key role in the electron-beam initiated mediation process

Clozapine-induced agranulocytosis: Evidence for an immune-mediated mechanism from a patient-specific in-vitro approach

Energy Technology Data Exchange (ETDEWEB)

Regen, Francesca; Herzog, Irmelin; Hahn, Eric; Ruehl, Claudia; Le Bret, Nathalie; Dettling, Michael; Heuser, Isabella [Dept. of Psychiatry, Campus Benjamin Franklin, Charité, University Medicine Berlin (Germany); Hellmann-Regen, Julian, E-mail: julian.hellmann@charite.de [Dept. of Psychiatry, Campus Benjamin Franklin, Charité, University Medicine Berlin (Germany); Berlin Institute of Health (BIH), Berlin (Germany)

2017-02-01

Use of the atypical antipsychotic clozapine (CZP) is compromised by the risk of potentially fatal agranulocytosis/granulocytopenia (CIAG). To address this, we have established a simple, personalized cell culture-based strategy to identify CIAG-susceptible patients, hypothesizing that an immunogenic and possibly haptene-based mechanism underlies CIAG pathophysiology. To detect a putative haptene-induced response to CZP in vitro exposure, a traditional lymphocyte stimulation assay was adapted and applied to patient-specific peripheral blood-derived mononuclear cells (PBMC). 6 patients with a history of CIAG, 6 patients under CZP treatment (without CIAG) and 12 matched healthy controls were studied. In vitro CZP exposure, even at strikingly low levels, resulted in significantly increased proliferation rates only in CIAG patients' PBMC. Other parameters including cell viability and mitogen-induced proliferation were also affected by in vitro CZP exposure, yet there was no significant difference between the groups. This personalized approach is a starting point for further investigations into a putative haptene-based mechanism underlying CIAG development, and may facilitate the future development of predictive testing. - Highlights: • Clozapine induces proliferation in PBMCs from patients with a history of CIAG. • Simple, PBMC-based assay results in robust effects of physiological clozapine levels. • Haptene-based mechanisms discussed to underlie clozapine-induced proliferation.

Reaction mechanisms of ruthenium tetroxide mediated oxidations of organic compounds

Energy Technology Data Exchange (ETDEWEB)

Froehaug, Astrid Elisabeth

1995-12-31

This thesis reports a study of the mechanism of ruthenium tetroxide mediated oxidations of saturated hydrocarbons, ethers, alkenes and alcohols. Several methods were used. The RuO{sub 4}-mediated oxidations of adamantane and cis-decalin were studied in CCl{sub 4}-CH{sub 3}CN-H{sub 2}O and in acetone-water. The rate of reaction was found to be moderately influenced by the polarity of the solvent. Solvent properties other than the polarity were also found to influence the reaction rates. From the oxidations of adamantane and adamantane-1,3,5,7-d{sub 4} two primary kinetic deuterium isotope effects were found. These were comparable with the deuterium isotope effects found for the analogous oxidations of cis-decalin and cis-decalin-d{sub 18}. The results seem to exclude both a one step hydride abstraction reaction mechanism and a one step concerted mechanism, as well as a scheme where two such mechanisms compete. The observations may be explained by a two step reaction mechanism consisting of a pre-equilibrium with formation of a substrate-RuO{sub 4} complex followed by a concerted rate determining reaction. The RuO{sub 4}-mediated oxidation of ethers was of kinetic second order with a small enthalpy of activation and a large negative entropy of activation. Oxidation of cyclopropylmethyl methyl ether gave methyl cyclopropanecarboxylate, no rearranged products were observed. On RuO{sub 4} oxidations in CCl{sub 4} with NaIO{sub 4} as stoichiometric oxidant, no chlorinated products were observed. Several observations not in agreement with a hydride or a hydrogen abstraction mechanism may be explained by assuming that the reaction proceeds by either a concerted reaction or by a reversible oxidative addition of the ether to RuO{sub 4} followed by a slow concerted step. 228 refs., 9 figs., 27 tabs.

Examination of Mechanisms Responsible for Organic Dust-related Diseases: Mediator Release induced by Microorgansims. A review

DEFF Research Database (Denmark)

Norn, Svend; Clementsen, Paul; Kristensen, K.S.

1994-01-01

Farmakologi, org. dust-related diseases, bacteria, pathogenic mechanisms, mediator release, entoxins - fungal spores......Farmakologi, org. dust-related diseases, bacteria, pathogenic mechanisms, mediator release, entoxins - fungal spores...

CD4 T cell-mediated protection from lethal influenza: perforin and antibody-mediated mechanisms give a one-two punch.

Science.gov (United States)

Brown, Deborah M; Dilzer, Allison M; Meents, Dana L; Swain, Susan L

2006-09-01

The mechanisms whereby CD4 T cells contribute to the protective response against lethal influenza infection remain poorly characterized. To define the role of CD4 cells in protection against a highly pathogenic strain of influenza, virus-specific TCR transgenic CD4 effectors were generated in vitro and transferred into mice given lethal influenza infection. Primed CD4 effectors conferred protection against lethal infection over a broad range of viral dose. The protection mediated by CD4 effectors did not require IFN-gamma or host T cells, but did result in increased anti-influenza Ab titers compared with untreated controls. Further studies indicated that CD4-mediated protection at high doses of influenza required B cells, and that passive transfer of anti-influenza immune serum was therapeutic in B cell-deficient mice, but only when CD4 effectors were present. Primed CD4 cells also acquired perforin (Pfn)-mediated cytolytic activity during effector generation, suggesting a second mechanism used by CD4 cells to confer protection. Pfn-deficient CD4 effectors were less able to promote survival in intact BALB/c mice and were unable to provide protection in B cell-deficient mice, indicating that Ab-independent protection by CD4 effectors requires Pfn. Therefore, CD4 effectors mediate protection to lethal influenza through at least two mechanisms: Pfn-mediated cytotoxicity early in the response promoted survival independently of Ab production, whereas CD4-driven B cell responses resulted in high titer Abs that neutralized remaining virus.

Mediating mechanisms of a military Web-based alcohol intervention.

Science.gov (United States)

Williams, Jason; Herman-Stahl, Mindy; Calvin, Sara L; Pemberton, Michael; Bradshaw, Michael

2009-03-01

This study explored the mediating mechanisms of two Web-based alcohol interventions in a sample of active duty United States military personnel. Personnel were recruited from eight bases and received the Drinker's Check-Up (N=1483), Alcohol Savvy (N=688), or served as controls (N=919). The interventions drew on motivational interviewing and social learning theory and targeted multiple mediators including social norms, perceived risks and benefits, readiness to change, and coping strategies. Baseline data were collected prior to the intervention and follow-up data on alcohol consumption were gathered 1 month and 6 months after program completion. Two mediation models were examined: (1) a longitudinal two-wave model with outcomes and mediators assessed concurrently at the 1-month follow-up; and (2) a three-wave model in which the causal chain was fully lagged. Results indicated strong support for the role of perceived descriptive norms in transmitting the effects of the Drinker's Check-Up, with consistent mediation across the majority of alcohol outcome measures for both the concurrent and fully lagged mediation models. These results suggest that web-based interventions that are effective in lowering perceived norms about the frequency and quantity of drinking may be a viable strategy for reducing alcohol consumption in military populations. The results did not support program mediation by the other targeted variables, indicating the need for future research on the effective components of alcohol interventions. The mediation models also suggest reasons why program effects were not found for some outcomes or were different across programs.

Mechanisms of bile acid mediated inflammation in the liver.

Science.gov (United States)

Li, Man; Cai, Shi-Ying; Boyer, James L

2017-08-01

Bile acids are synthesized in the liver and are the major component in bile. Impaired bile flow leads to cholestasis that is characterized by elevated levels of bile acid in the liver and serum, followed by hepatocyte and biliary injury. Although the causes of cholestasis have been extensively studied, the molecular mechanisms as to how bile acids initiate liver injury remain controversial. In this chapter, we summarize recent advances in the pathogenesis of bile acid induced liver injury. These include bile acid signaling pathways in hepatocytes as well as the response of cholangiocytes and innate immune cells in the liver in both patients with cholestasis and cholestatic animal models. We focus on how bile acids trigger the production of molecular mediators of neutrophil recruitment and the role of the inflammatory response in this pathological process. These advances point to a number of novel targets where drugs might be judged to be effective therapies for cholestatic liver injury. Copyright © 2017 Elsevier Ltd. All rights reserved.

A Longitudinal Study of Association between Heavy Metals and Itchy Eyes, Coughing in Chronic Cough Patients: Related with Non-Immunoglobulin E Mediated Mechanism

Directory of Open Access Journals (Sweden)

Thao Thi Thu Nguyen

2016-01-01

Full Text Available The association between heavy metals exposure and respiratory diseases or allergic sensitization showing high serum immunoglobulin E (IgE has been suggested. However, previous findings have been inconsistent and the mechanisms responsible remain unclear. We evaluated heavy metal exposure and its association with coughing, itchy eyes in chronic cough patients with different IgE levels. Ninety outpatients in Kanazawa University Hospital were recruited between January–June 2011. Subjects whose total IgE measured by radioimmunosorbent test were asked to record their daily symptoms. We collected daily total suspended particles (TSP from which concentrations of calcium (Ca, cadmium (Cd, chromium (Cr, iron (Fe, manganese (Mn, nickel (Ni, and lead (Pb were determined then divided into high and low level groups. Generalized estimating equations were applied to compute the relationship between concentrations of these metals and symptoms. All metals at high levels were significantly associated with itchy eyes compared with low levels, with exception of Ca, the six others were significant in patients with IgE < 250 IU/mL. Cd, Fe, Mn had association with coughing (odds ratio-OR (95% confidence interval-CI: 1.13 (1.03, 1.24, 1.22 (1.05, 1.42, and 1.13 (1.01, 1.27, respectively, this relationship remained significant for Cd (OR (95% CI: 1.14 (1.03, 1.27 and Mn (OR (95% CI: 1.15 (1.00, 1.31 in patients with lower IgE. Our findings demonstrate the relationship between aerial heavy metals and itchy eyes, coughing in chronic cough patients, suggesting these symptoms may be due to a non-IgE mediated mechanism.

Types of prayer and depressive symptoms among cancer patients: the mediating role of rumination and social support.

Science.gov (United States)

Pérez, John E; Rex Smith, Amy; Norris, Rebecca L; Canenguez, Katia M; Tracey, Elizabeth F; Decristofaro, Susan B

2011-12-01

We examined the association between different types of prayer and depressive symptoms--with rumination and social support as potential mediators--in a sample of predominantly White, Christian, and female ambulatory cancer patients. In a cross-sectional design, 179 adult cancer outpatients completed measures of prayer, rumination, social support, depressive symptoms, and demographic variables. Type and stage of cancer were collected from electronic medical charts. Depressive symptoms were negatively correlated with adoration prayer (r = -.15), reception prayer (r = -.17), thanksgiving prayer (r = -.29), and prayer for the well-being of others (r = -.26). In the path analysis, rumination fully mediated the link between thanksgiving prayer and depressive symptoms (β for indirect effect = -.05), whereas social support partially mediated the link between prayer for others and depressive symptoms (β for indirect effect = -.05). These findings suggest that unique mechanisms may link different prayer types to lower depressive symptoms among cancer patients.

Mechanism of feline immunodeficiency virus envelope glycoprotein-mediated fusion

International Nuclear Information System (INIS)

Garg, Himanshu; Fuller, Frederick J.; Tompkins, Wayne A.F.

2004-01-01

Feline immunodeficiency virus (FIV) shares remarkable homology to primate lentiviruses, human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV). The process of lentiviral env glycoprotein-mediated fusion of membranes is essential for viral entry and syncytia formation. A detailed understanding of this phenomenon has helped identify new targets for antiviral drug development. Using a model based on syncytia formation between FIV env-expressing cells and a feline CD4+ T cell line we have studied the mechanism of FIV env-mediated fusion. Using this model we show that FIV env-mediated fusion mechanism and kinetics are similar to HIV env. Syncytia formation could be blocked by CXCR4 antagonist AMD3100, establishing the importance of this receptor in FIV gp120 binding. Interestingly, CXCR4 alone was not sufficient to allow fusion by a primary isolate of FIV, as env glycoprotein from FIV-NCSU 1 failed to induce syncytia in several feline cell lines expressing CXCR4. Syncytia formation could be inhibited at a post-CXCR4 binding step by synthetic peptide T1971, which inhibits interaction of heptad repeat regions of gp41 and formation of the hairpin structure. Finally, using site-directed mutagenesis, we also show that a conserved tryptophan-rich region in the membrane proximal ectodomain of gp41 is critical for fusion, possibly at steps post hairpin structure formation

Involvement of midbrain tectum neurokinin-mediated mechanisms in fear and anxiety

International Nuclear Information System (INIS)

Brenes, J.C.; Broiz, A.C.; Bassi, G.S.; Schwarting, R.K.W.; Brandão, M.L.

2012-01-01

Electrical stimulation of midbrain tectum structures, particularly the dorsal periaqueductal gray (dPAG) and inferior colliculus (IC), produces defensive responses, such as freezing and escape behavior. Freezing also ensues after termination of dPAG stimulation (post-stimulation freezing). These defensive reaction responses are critically mediated by Y -aminobutyric acid and 5-hydroxytryptamine mechanisms in the midbrain tectum. Neurokinins (NKs) also play a role in the mediation of dPAG stimulation-evoked fear, but how NK receptors are involved in the global processing and expression of fear at the level of the midbrain tectum is yet unclear. The present study investigated the role of NK-1 receptors in unconditioned defensive behavior induced by electrical stimulation of the dPAG and IC of male Wistar rats. Spantide (100 pmol/0.2 µL), a selective NK-1 antagonist, injected into these midbrain structures had anti-aversive effects on defensive responses and distress ultrasonic vocalizations induced by stimulation of the dPAG but not of the IC. Moreover, intra-dPAG injections of spantide did not influence post-stimulation freezing or alter exploratory behavior in rats subjected to the elevated plus maze. These results suggest that NK-1 receptors are mainly involved in the mediation of defensive behavior organized in the dPAG. Dorsal periaqueductal gray-evoked post-stimulation freezing was not affected by intra-dPAG injections of spantide, suggesting that NK-1-mediated mechanisms are only involved in the output mechanisms of defensive behavior and not involved in the processing of ascending aversive information from the dPAG

Involvement of midbrain tectum neurokinin-mediated mechanisms in fear and anxiety

Energy Technology Data Exchange (ETDEWEB)

Brenes, J.C. [Experimental and Physiological Psychology, Philipps-University of Marburg, Marburg (Germany); Broiz, A.C.; Bassi, G.S. [Instituto de Neurociências e Comportamento, Campus USP, Ribeirão Preto, SP (Brazil); Laboratório de Psicobiologia, Faculdade de Filosofia, Ciências e Letras de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP (Brazil); Schwarting, R.K.W. [Experimental and Physiological Psychology, Philipps-University of Marburg, Marburg (Germany); Brandão, M.L. [Instituto de Neurociências e Comportamento, Campus USP, Ribeirão Preto, SP (Brazil); Laboratório de Psicobiologia, Faculdade de Filosofia, Ciências e Letras de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP (Brazil)

2012-03-09

Electrical stimulation of midbrain tectum structures, particularly the dorsal periaqueductal gray (dPAG) and inferior colliculus (IC), produces defensive responses, such as freezing and escape behavior. Freezing also ensues after termination of dPAG stimulation (post-stimulation freezing). These defensive reaction responses are critically mediated by {sub Y}-aminobutyric acid and 5-hydroxytryptamine mechanisms in the midbrain tectum. Neurokinins (NKs) also play a role in the mediation of dPAG stimulation-evoked fear, but how NK receptors are involved in the global processing and expression of fear at the level of the midbrain tectum is yet unclear. The present study investigated the role of NK-1 receptors in unconditioned defensive behavior induced by electrical stimulation of the dPAG and IC of male Wistar rats. Spantide (100 pmol/0.2 µL), a selective NK-1 antagonist, injected into these midbrain structures had anti-aversive effects on defensive responses and distress ultrasonic vocalizations induced by stimulation of the dPAG but not of the IC. Moreover, intra-dPAG injections of spantide did not influence post-stimulation freezing or alter exploratory behavior in rats subjected to the elevated plus maze. These results suggest that NK-1 receptors are mainly involved in the mediation of defensive behavior organized in the dPAG. Dorsal periaqueductal gray-evoked post-stimulation freezing was not affected by intra-dPAG injections of spantide, suggesting that NK-1-mediated mechanisms are only involved in the output mechanisms of defensive behavior and not involved in the processing of ascending aversive information from the dPAG.

MicroRNA-133 mediates cardiac diseases: Mechanisms and clinical implications

Energy Technology Data Exchange (ETDEWEB)

Liu, Yi; Liang, Yan [Guangdong Key Laboratory for Research and Development of Natural Drugs, Guangdong Medical University, Zhanjiang 524023, Guangdong (China); Zhang, Jin-fang [Department of Orthopaedics and Traumatology, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong (China); Fu, Wei-ming, E-mail: fuweiming76@smu.edu.cn [School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515 (China)

2017-05-15

MicroRNAs (miRNAs) belong to the family of small non-coding RNAs that mediate gene expression by post-transcriptional regulation. Increasing evidence have demonstrated that miR-133 is enriched in muscle tissues and myogenic cells, and its aberrant expression could induce the occurrence and development of cardiac disorders, such as cardiac hypertrophy, heart failure, etc. In this review, we summarized the regulatory roles of miR-133 in cardiac disorders and the underlying mechanisms, which suggest that miR-133 may be a potential diagnostic and therapeutic tool for cardiac disorders. - Highlights: • miR-218 is frequently downregulated in multiple cancers. • miR-218 plays pivotal roles in carcinogenesis. • miR-218 mediates proliferation, apoptosis, metastasis, invasion, etc. • miR-218 mediates tumorigenesis and metastasis via multiple pathways.

MicroRNA-133 mediates cardiac diseases: Mechanisms and clinical implications

International Nuclear Information System (INIS)

Liu, Yi; Liang, Yan; Zhang, Jin-fang; Fu, Wei-ming

2017-01-01

MicroRNAs (miRNAs) belong to the family of small non-coding RNAs that mediate gene expression by post-transcriptional regulation. Increasing evidence have demonstrated that miR-133 is enriched in muscle tissues and myogenic cells, and its aberrant expression could induce the occurrence and development of cardiac disorders, such as cardiac hypertrophy, heart failure, etc. In this review, we summarized the regulatory roles of miR-133 in cardiac disorders and the underlying mechanisms, which suggest that miR-133 may be a potential diagnostic and therapeutic tool for cardiac disorders. - Highlights: • miR-218 is frequently downregulated in multiple cancers. • miR-218 plays pivotal roles in carcinogenesis. • miR-218 mediates proliferation, apoptosis, metastasis, invasion, etc. • miR-218 mediates tumorigenesis and metastasis via multiple pathways.

Separating monocular and binocular neural mechanisms mediating chromatic contextual interactions.

Science.gov (United States)

D'Antona, Anthony D; Christiansen, Jens H; Shevell, Steven K

2014-04-17

When seen in isolation, a light that varies in chromaticity over time is perceived to oscillate in color. Perception of that same time-varying light may be altered by a surrounding light that is also temporally varying in chromaticity. The neural mechanisms that mediate these contextual interactions are the focus of this article. Observers viewed a central test stimulus that varied in chromaticity over time within a larger surround that also varied in chromaticity at the same temporal frequency. Center and surround were presented either to the same eye (monocular condition) or to opposite eyes (dichoptic condition) at the same frequency (3.125, 6.25, or 9.375 Hz). Relative phase between center and surround modulation was varied. In both the monocular and dichoptic conditions, the perceived modulation depth of the central light depended on the relative phase of the surround. A simple model implementing a linear combination of center and surround modulation fit the measurements well. At the lowest temporal frequency (3.125 Hz), the surround's influence was virtually identical for monocular and dichoptic conditions, suggesting that at this frequency, the surround's influence is mediated primarily by a binocular neural mechanism. At higher frequencies, the surround's influence was greater for the monocular condition than for the dichoptic condition, and this difference increased with temporal frequency. Our findings show that two separate neural mechanisms mediate chromatic contextual interactions: one binocular and dominant at lower temporal frequencies and the other monocular and dominant at higher frequencies (6-10 Hz).

Cell mediated immunity in patients with osteosarcoma

International Nuclear Information System (INIS)

Lloyd, E.L.; Henning, C.B.

1975-01-01

Because of the difficulty of obtaining suitable material, earlier studies on cell mediated immunity in the radium patients failed to include positive controls. Recently we were fortunate in obtaining samples of lymphocytes from two suitable patients who had had amputations for spontaneous osteosarcoma six months previously. Lymphocytes from both of these patients showed cytotoxicity to cultured cells derived from a human osteogenic sarcoma but not to normal fibroblasts. These results help to validate our test for early detection of osteosarcoma in the radium patients using measurements of cytotoxicity

The mediation effect of health literacy between subjective social status and depressive symptoms in patients with heart failure.

Science.gov (United States)

Zou, Huijing; Chen, Yuxia; Fang, Wenjie; Zhang, Yanting; Fan, Xiuzhen

2016-12-01

Depressive symptoms are prevalent and cause adverse outcomes in heart failure. Previous studies have linked depressive symptoms with socioeconomic status. However, little is known about the mechanisms underlying this relationship. This study aimed to evaluate the association between socioeconomic status and depressive symptoms, and to examine whether access to healthcare, health literacy and social support mediated this relationship in patients with heart failure. Cross-sectional design was used to study 321 patients with heart failure recruited from a general hospital. Demographics, clinical data, depressive symptoms, socioeconomic status (i.e., education, employment, income, and subjective social status), access to healthcare, health literacy, and social support were collected by patient interview, medical record review or questionnaires. A series of logistic regressions and linear regressions were conducted to examine mediation. The mean age of patients with heart failure was 63.6±10.6years. Fifty-eight patients (18%) had depressive symptoms. Lower subjective social status (OR=1.321, p=0.012) and lower health literacy (OR=1.065, psubjective social status and health literacy were entered simultaneously, the relationship between subjective social status and depressive symptoms became non-significant (OR=1.208, p=0.113), demonstrating mediation. Additionally, lower social support was associated with depressive symptoms (OR=1.062, p=0.007). In patients with heart failure, health literacy mediated the relationship between subjective social status and depressive symptoms. Lower social support was associated with depressive symptoms. Interventions should take these factors into account. Copyright © 2016 Elsevier Inc. All rights reserved.

Distinct Neural Mechanisms Mediate Olfactory Memory Formation at Different Timescales

Science.gov (United States)

McNamara, Ann Marie; Magidson, Phillip D.; Linster, Christiane; Wilson, Donald A.; Cleland, Thomas A.

2008-01-01

Habituation is one of the oldest forms of learning, broadly expressed across sensory systems and taxa. Here, we demonstrate that olfactory habituation induced at different timescales (comprising different odor exposure and intertrial interval durations) is mediated by different neural mechanisms. First, the persistence of habituation memory is…

Exercise mediates the association between positive affect and 5-year mortality in patients with ischemic heart disease

DEFF Research Database (Denmark)

Hoogwegt, Madelein T; Versteeg, Henneke; Hansen, Tina B

2013-01-01

Background- Positive affect has been associated with better prognosis in patients with ischemic heart disease, but the underlying mechanisms remain unclear. We examined whether positive affect predicted time to first cardiac-related hospitalization and all-cause mortality, and whether exercise me...... between positive affect and mortality. Interventions aimed at increasing both positive affect and exercise may have better results with respect to patients' prognosis and psychological well-being than interventions focusing on 1 of these factors alone.......Background- Positive affect has been associated with better prognosis in patients with ischemic heart disease, but the underlying mechanisms remain unclear. We examined whether positive affect predicted time to first cardiac-related hospitalization and all-cause mortality, and whether exercise...... mediated this relationship in patients with established ischemic heart disease. Methods and Results- The sample comprised 607 patients with ischemic heart disease from Holbæk Hospital, Denmark. In 2005, patients completed the Global Mood Scale (GMS) to assess positive affect and a purpose-designed question...

Calcitriol-mediated hypercalcemia in a patient with bilateral adrenal non-Hodgkin's B-cell lymphoma case report

Directory of Open Access Journals (Sweden)

Ana Abaroa-Salvatierra

2016-04-01

Full Text Available Calcitriol-mediated hypercalcemia is a frequent manifestation of hematological malignancies. However, there are a few reports of cases presenting with increased angiotensin-converting enzyme (ACE level, which suggests a possible mechanism similar to that of granulomatous diseases. We present a patient with hypercalcemia, normal parathyroid hormone, and parathyroid hormone-related protein levels but high calcitriol and ACE levels that, after further investigation, was diagnosed with bilateral adrenal non-Hodgkin's B-cell lymphoma. Primary adrenal lymphoma represents only 1% of all non-Hodgkin's lymphomas and is usually asymptomatic but should be considered by clinicians among the malignancies that cause calcitriol-mediated hypercalcemia.

Lung-Derived Mediators Induce Cytokine Production in Downstream Organs via an NF-κB-Dependent Mechanism

Directory of Open Access Journals (Sweden)

E. K. Patterson

2013-01-01

Full Text Available In the setting of acute lung injury, levels of circulating inflammatory mediators have been correlated with adverse outcomes. Previous studies have demonstrated that injured, mechanically ventilated lungs represent the origin of the host inflammatory response; however, mechanisms which perpetuate systemic inflammation remain uncharacterized. We hypothesized that lung-derived mediators generated by mechanical ventilation (MV are amplified by peripheral organs in a “feed forward” mechanism of systemic inflammation. Herein, lung-derived mediators were collected from 129X1/SVJ mice after 2 hours of MV while connected to the isolated perfused mouse lung model setup. Exposure of liver endothelial cells to lung-derived mediators resulted in a significant increase in G-CSF, IL-6, CXCL-1, CXCL-2, and MCP-1 production compared to noncirculated control perfusate media (P<0.05. Furthermore, inhibition of the NF-κB pathway significantly mitigated this response. Changes in gene transcription were confirmed using qPCR for IL-6, CXCL-1, and CXCL-2. Additionally, liver tissue obtained from mice subjected to 2 hours of in vivo MV demonstrated significant increases in hepatic gene transcription of IL-6, CXCL-1, and CXCL-2 compared to nonventilated controls. Collectively, this data demonstrates that lung-derived mediators, generated in the setting of MV, are amplified by downstream organs in a feed forward mechanism of systemic inflammation.

Testing of mechanisms of action of rituximab and clinical results in high-risk patients with aggressive CD20+ lymphoma

International Nuclear Information System (INIS)

Jezersek Novakovic, B.; Juznic Setina, T.; Vovk, M.; Kotnik, V.; Novakovic, S.

2007-01-01

Rituximab has been applied successfully in the treatment of indolent and aggressive CD20 positive B cell lymphomas, yet the exact in vivo mechanisms of its action have not been unambiguously explained. This study was therefore aimed to confirm the presumed major mechanisms of action of rituximab and concomitantly to assess the effectiveness of first-line chemo immunotherapy in high-risk patients with aggressive CD20 lymphomas. The activity of rituximab was tested in vitro on Raji and SU-DHL-4 cells using the cell proliferation assay and flow cytometry. In the clinical part of the study, 20 high-risk patients with aggressive CD 20 lymphomas were treated with R-CHOP. Only complement-mediated cytotoxicity was observed under the in vitro applied experimental conditions. Neither the direct apoptotic effect nor the antibody-dependent cell-mediated cytotoxicity was detected probably due to a too low concentration of rituximab and a too low ratio of cytotoxic lymphocytes to tumor cells. The treatment outcome in patients was excellent since complete remissions were achieved in 90% of poor-risk patients at the end of primary treatment and 80% of patients were disease-free at 18.5 months median observation period. According to our results, the complement-dependent cytotoxicity is an important mechanism of rituximab action in vitro. To achieve direct apoptosis, higher concentrations than 20 μg/ml of rituximab should be used, while for an effective antibody-dependent cell-mediated cytotoxicity, the ratio of cytotoxic lymphocytes to tumor cells should be higher than 1:1. In the high-risk patients with aggressive CD20 lymphomas, the addition of rituximab to CHOP substantially improves the therapeutic results. (author)

Psychosocial factors partially mediate the relationship between mechanical hyperalgesia and self-reported pain.

Science.gov (United States)

Mason, Kayleigh J; O'Neill, Terence W; Lunt, Mark; Jones, Anthony K P; McBeth, John

2018-01-26

Amplification of sensory signalling within the nervous system along with psychosocial factors contributes to the variation and severity of knee pain. Quantitative sensory testing (QST) is a non-invasive test battery that assesses sensory perception of thermal, pressure, mechanical and vibration stimuli used in the assessment of pain. Psychosocial factors also have an important role in explaining the occurrence of pain. The aim was to determine whether QST measures were associated with self-reported pain, and whether those associations were mediated by psychosocial factors. Participants with knee pain identified from a population-based cohort completed a tender point count and a reduced QST battery of thermal, mechanical and pressure pain thresholds, temporal summation, mechanical pain sensitivity (MPS), dynamic mechanical allodynia (DMA) and vibration detection threshold performed following the protocol by the German Research Network on Neuropathic Pain. QST assessments were performed at the most painful knee and opposite forearm (if pain-free). Participants were asked to score for their global and knee pain intensities within the past month (range 0-10), and complete questionnaire items investigating anxiety, depression, illness perceptions, pain catastrophising, and physical functioning. QST measures (independent variable) significantly correlated (Spearman's rho) with self-reported pain intensity (dependent variable) were included in structural equation models with psychosocial factors (latent mediators). Seventy-two participants were recruited with 61 participants (36 women; median age 64 years) with complete data included in subsequent analyses. Tender point count was significantly correlated with global pain intensity. DMA at the knee and MPS at the most painful knee and opposite pain-free forearm were significantly correlated with both global pain and knee pain intensities. Psychosocial factors including pain catastrophising sub-scales (rumination and

Patient-provider relationship as mediator between adult attachment and self-management in primary care patients with multiple chronic conditions.

Science.gov (United States)

Brenk-Franz, Katja; Strauß, Bernhard; Tiesler, Fabian; Fleischhauer, Christian; Schneider, Nico; Gensichen, Jochen

2017-06-01

The conceptual model of attachment theory has been applied to understand the predispositions of patients in medical care and the patient-provider relationship. In patients with chronic conditions insecure attachment was connected to poorer self-management. The patient-provider relationship is associated with a range of health related outcomes and self-management skills. We determined whether the quality of the patient-provider relationship mediates the link between adult attachment and self-management among primary care patients with multiple chronic diseases. 209 patients with a minimum of three chronic diseases (including type II diabetes, hypertension and at least one other chronic condition) between the ages of 50 and 85 from eight general practices were included in the APRICARE cohort study. Adult attachment was measured via self-report (ECR-RD), self-management skills by the FERUS and the patient-provider relationship by the PRA-D. The health status and chronicity were assessed by the GP. Multiple mediation analyses were used to examine whether aspects of the patient-provider relationship (communication, information, affectivity) are a mediators of associations between adult attachment and self-management. The analysis revealed that the quality of the patient-provider relationship mediated the effect of attachment on self-management in patients with multiple chronic conditions. Particularly the quality of communication and information over the course of treatment has a significant mediating influence. A personalized, attachment-related approach that promotes active patient-provider communication and gives information about the treatment to the patient may improve self-management skills in patients. Copyright © 2017 Elsevier Inc. All rights reserved.

The impact of patient and physician computer mediated communication skill training on reported communication and patient satisfaction.

Science.gov (United States)

Roter, Debra L; Wexler, Randy; Naragon, Phyllis; Forrest, Brian; Dees, Jason; Almodovar, Astrid; Wood, Julie

2012-09-01

The objective was to evaluate parallel patient and physician computer-mediated communication skill training on participants' report of skill use and patient satisfaction. Separate patient and clinician web-tools comprised of over 500, 10-s video clips demonstrating patient-centered skills in various ways. Four clinician members of the American Academy of Family Physicians National Research Network participated by enrolling 194 patients into a randomized patient trial and 29 physicians into a non-randomized clinician trial of respective interventions. All participants completed baseline and follow-up self-report measures of visit communication and satisfaction. Intervention patients reported using more skills than controls in five of six skill areas, including identification of problems/concerns, information exchange, treatment adherence, shared decision-making and interpersonal rapport (all ppost intervention, physicians reported using more skills in the same 5 areas (all pCommunication skill training delivered in a computer mediated format had a positive and parallel impact on both patient and clinician reported use of patient-centered communication and in patient satisfaction. Computer-mediated interventions are cost and time effective thereby increasing patient and clinician willingness to undertake training. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Improving quality-of-life outcomes for patients with cancer through mediating effects of depressive symptoms and functional status: a three-path mediation model.

Science.gov (United States)

Hsu, Mei-Chi; Tu, Chun-Hsien

2014-09-01

To test a hypothetical three-path mediation model evaluating the effects of functional status and depressive symptoms on the relationship between fatigue and quality of life in patients with cancer on the basis of the Theory of Unpleasant Symptoms. Patients with cancer often experience two or more concurrent, interrelated, mutually influential symptoms. Multiple unpleasant symptoms that have been proposed as mediating variables affecting quality of life in a model proposed in recent cancer studies are scanty. This study was a cross-sectional, descriptive, correlational design. Three hundred and twenty-six patients with cancer from oncology clinics were recruited in Taiwan between 2010-2011. Mediation models were tested and confirmed by applying structural modelling using Analysis of Moment Structures and the joint significance test. Fatigue affects patient quality of life directly or indirectly through functional status and depressive symptoms. These two mediating variables exhibited direct effects on quality of life. A path analysis approach revealed that 47·28 and 67·70% of the total effects of functional status and depressive symptoms, respectively, on the quality-of-life mediation models are attributable to 29·6 and 44·7% of the total effects between fatigue and quality of life, which mediated through two mediators, respectively. Quality of life may be enhanced by simultaneously improving physiological and psychological factors. An understanding of mediating effects is valuable in nursing care of patients with cancer, particularly in the early phase of treatment or in newly diagnosed stages I-III or recently treated patients with cancer in different disease stages. © 2013 John Wiley & Sons Ltd.

New mechanisms of gauge-mediated supersymmetry breaking

International Nuclear Information System (INIS)

Randall, L.

1997-01-01

New mechanisms for the communication of supersymmetry breaking via gauge interactions are introduced. These models do not require complicated dynamics to induce a non-vanishing F term for a singlet. The first class of models communicates supersymmetry breaking to the visible sector through a ''mediator'' field that transforms under both a messenger gauge group of the dynamical supersymmetry breaking sector and the standard model gauge group. This model has a distinctive phenomenology; in particular, the scalar superpartners should be heavier than the gaugino superpartners by at least an order of magnitude. The second class of models has a phenomenology more similar to the ''standard'' messenger sectors. A singlet is incorporated, but the model does not require complicated mechanisms to generate a singlet F term. The role of the singlet is to couple fields from the dynamical symmetry breaking sector to fields transforming under the standard model gauge group. We also mention a potential solution to the μ problem. (orig.)

Different Mechanisms of Inflammation Induced in Virus and Autoimmune-Mediated Models of Multiple Sclerosis in C57BL6 Mice

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Abhinoy Kishore

2013-01-01

Full Text Available Multiple sclerosis (MS is an inflammatory demyelinating disease of the human central nervous system (CNS. Neurotropic demyelinating strain of MHV (MHV-A59 or its isogenic recombinant strain RSA59 induces MS-like disease in mice mediated by microglia, along with a small population of T cells. The mechanism of demyelination is at least in part due to microglia-mediated myelin stripping, with some direct axonal injury. Immunization with myelin oligodendrocyte glycoprotein (MOG induces experimental autoimmune encephalomyelitis (EAE, a mainly CD4+ T-cell-mediated disease, although CD8+ T cells may play a significant role in demyelination. It is possible that both autoimmune and nonimmune mechanisms such as direct viral toxicity may induce MS. Our study directly compares CNS pathology in autoimmune and viral-induced MS models. Mice with viral-induced and EAE demyelinating diseases demonstrated similar patterns and distributions of demyelination that accumulated over the course of the disease. However, significant differences in acute inflammation were noted. Inflammation was restricted mainly to white matter at all times in EAE, whereas inflammation initially largely involved gray matter in acute MHV-induced disease and then is subsequently localized only in white matter in the chronic disease phase. The presence of dual mechanisms of demyelination may be responsible for the failure of immunosuppression to promote long-term remission in many MS patients.

Radiation and the lung: a reevaluation of the mechanisms mediating pulmonary injury

International Nuclear Information System (INIS)

Morgan, Graeme W.; Breit, Samuel N.

1995-01-01

Recent data from several investigators, including our unit, have provided additional information on the etiology of radiation-induced lung damage. These data suggest that there are two quite separate and distinct mechanisms involved: (a) classical radiation pneumonitis, which ultimately leads to pulmonary fibrosis is primarily due to radiation-induced local cytokine production confined to the field of irradiation; and (b) sporadic radiation pneumonitis, which is an immunologically mediated process resulting in a bilateral lymphocytic alveolitis that results in an 'out-of-field' response to localized pulmonary irradiation. Both animal experiments and human studies show that classical radiation pneumonitis has a threshold dose and a narrow sigmoid dose-response curve with increasing morbidity and mortality over a very small dose range. Clinical pneumonitis rarely causes death, whereas in the animal and human studies of classical radiation pneumonitis, all subjects will eventually suffer irreversible pulmonary damage and death. The description of classical radiation pneumonitis is that of an acute inflammatory response to lung irradiation, which is confined to the area of irradiation. Recent studies have also shown that irradiation induces gene transcription and results in the induction and release of proinflammatory cytokines and fibroblast mitogens in a similar fashion to other chronic inflammatory states, and which ultimately results in pulmonary fibrosis. The description of classical radiation pneumonitis does not adequately explain the following observed clinical characteristics: (a) the unpredictable and sporadic onset; (b) the occurrence in only a minority of patients; (c) the dyspnoea experienced, which is out of proportion to the volume of lung irradiated; and (d) the resolution of symptoms without sequelae in the majority of patients. We have demonstrated a bilateral lymphocytic alveolitis of activated T lymphocytes and a diffuse increase in gallium lung

Pathways from Religion to Health: Mediation by Psychosocial and Lifestyle Mechanisms.

Science.gov (United States)

Morton, Kelly R; Lee, Jerry W; Martin, Leslie R

2017-02-01

Religiosity, often measured as attendance at religious services, is linked to better physical health and longevity though the mechanisms linking the two are debated. Potential explanations include: a healthier lifestyle, increased social support from congregational members, and/or more positive emotions. Thus far, these mechanisms have not been tested simultaneously in a single model though they likely operate synergistically. We test this model predicting all-cause mortality in Seventh-day Adventists, a denomination that explicitly promotes a healthy lifestyle. This allows the more explicit health behaviors linked to the religious doctrine (e.g., healthy diet) to be compared with other mechanisms not specific to religious doctrine (e.g., social support and positive emotions). Finally, this study examines both Church Activity (including worship attendance and church responsibilities) and Religious Engagement (coping, importance, and intrinsic beliefs). Religious Engagement is more is more inner-process focused (vs. activity-based) and less likely to be confounded with age and its associated functional status limitations, although it should be noted that age is controlled in the present study. The findings suggest that Religious Engagement and Church Activity operate through the mediators of health behavior, emotion, and social support to decrease mortality risk. All links between Religious Engagement and mortality are positive but indirect through positive Religious Support, Emotionality, and lifestyle mediators. However, Church Activity has a direct positive effect on mortality as well as indirect effects through, Religious Support, Emotionality, and lifestyle mediators (diet and exercise). The models were invariant by gender and for both Blacks and Whites.

Evidence for water-mediated mechanisms in coral–algal interactions

Science.gov (United States)

Jorissen, Hendrikje; Skinner, Christina; Osinga, Ronald; de Beer, Dirk

2016-01-01

Although many coral reefs have shifted from coral-to-algal dominance, the consequence of such a transition for coral–algal interactions and their underlying mechanisms remain poorly understood. At the microscale, it is unclear how diffusive boundary layers (DBLs) and surface oxygen concentrations at the coral–algal interface vary with algal competitors and competitiveness. Using field observations and microsensor measurements in a flow chamber, we show that coral (massive Porites) interfaces with thick turf algae, macroalgae, and cyanobacteria, which are successful competitors against coral in the field, are characterized by a thick DBL and hypoxia at night. In contrast, coral interfaces with crustose coralline algae, conspecifics, and thin turf algae, which are poorer competitors, have a thin DBL and low hypoxia at night. Furthermore, DBL thickness and hypoxia at the interface with turf decreased with increasing flow speed, but not when thick turf was upstream. Our results support the importance of water-mediated transport mechanisms in coral–algal interactions. Shifts towards algal dominance, particularly dense assemblages, may lead to thicker DBLs, higher hypoxia, and higher concentrations of harmful metabolites and pathogens along coral borders, which in turn may facilitate algal overgrowth of live corals. These effects may be mediated by flow speed and orientation. PMID:27512146

Mechanisms and mediators of hypertension induced by erythropoietin and related molecules.

Science.gov (United States)

Agarwal, Rajiv

2017-12-08

Hypertension is a common but frequently overlooked adverse effect of erythropoietin (EPO) therapy. Underreporting of hypertension with EPO is likely due to either more aggressively managing hypertension through the prescription of antihypertensive drugs or closer attention to dry weight. The purpose and focus of this review is to critically evaluate the mechanisms of EPO-induced hypertension. Preclinical data are considered first, followed by clinical data where available. Mediated by a variety of molecules, there is an imbalance in the vascular tone favoring net vasoconstriction that mediates EPO-induced hypertension. Animal studies show the primary importance of chronic kidney disease in the genesis of EPO-induced hypertension. Preclinical studies show deranged regulation of the nitric oxide, endothelins and porstanoids and the sympathoadrenal and renin-angiotensin pathways as causes of EPO-induced hypertension. Human studies suggest that EPO administration is also associated with increased responsiveness to catecholamines and angiotensin II on vascular tissue; in addition, hypoxia-induced vasodilation may be impaired in those with EPO-induced hypertension. There is little evidence for EPO as a direct vasoconstrictor or its effect on blood viscosity as a mechanism of EPO-induced hypertension. EPO-induced hypertension, at least in part, appears to be independent of an increase in hemoglobin, because experiments show that hemoglobin may be increased by EPO without an increase in blood pressure (BP) by simply treating the animals with EPO-binding protein and that treatment with EPO in the setting of iron deficiency may not increase hemoglobin but may still increase BP. However, experimental data are not consistent across studies and better mechanistic designs are needed, especially in patients with chronic kidney disease, to dissect the precise mechanism of EPO-induced hypertension. Animal studies suggest that hypoxia-inducible factor stablizers may induce

The Prevalence of Eosinophilic Esophagitis in Pediatric Patients with IgE-Mediated Food Allergy.

Science.gov (United States)

Hill, David A; Dudley, Jesse W; Spergel, Jonathan M

Eosinophilic esophagitis (EoE) is an allergic inflammatory disease that is triggered by food allergens and characterized by progressive esophageal dysfunction. Recently, EoE has been identified in patients who underwent oral immunotherapy (OIT) for IgE-mediated food allergy, suggesting an association. We sought to ascertain whether significant associations exist between IgE-mediated food allergies and EoE. Using the analysis of electronic medical record data and manual chart review, we examined our subspecialty care network of 35,528 children and adolescents to identify and characterize patients with IgE-mediated and EoE food allergy. The most common food allergens were defined, and the prevalence of EoE in patients with IgE-mediated food allergy was determined. Logistic regression was used to measure the extent to which IgE-mediated food allergy to specific foods is associated with EoE. The most common causes of EoE were milk, soy, egg, grains, and meats, an allergen pattern that is distinct from that of IgE-mediated food allergy. The prevalence of EoE in patients with IgE-mediated food allergy was higher than that reported in the general population (4.7% vs 0.04%). The distribution of IgE-mediated food allergens in patients with EoE was similar to that of the general population, and IgE-mediated allergy to egg (2.27; 1.91-2.64), milk (4.19; 3.52-4.97), or shellfish (1.55; 1.24-1.92) was significantly associated with an EoE diagnosis. Our findings support a clinical association between these conditions that has implications for the management of children with food allergy, and particular relevance to patients undergoing OIT. Copyright © 2016 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

Towards improving treatment for childhood OCD: Analyzing mediating mechanisms & non-response

NARCIS (Netherlands)

Wolters, L.H.

2013-01-01

What are mediating mechanisms in cognitive behavioral therapy (CBT) for childhood obsessive-compulsive disorder (OCD)? For whom does CBT work and for whom is CBT less effective? What should be recommended for those children who do not sufficiently benefit from CBT? The studies described in the

Mechanism and kinetics of dithiobenzoate-mediated RAFT polymerization. I. The current situation

NARCIS (Netherlands)

Barner-Kowollik, C.; Buback, M.; Charleux, B.; Coote, M.L.; Drache, M.; Fukuda, T.; Goto, A.; Klumperman, B.; Lowe, A.B.; McLeary, J.B.; Moad, G.; Monteiro, M.J.; Sanderson, R.D.; Tonge, M.P.; Vana, P.

2006-01-01

Investigations into the kinetics and mechanism of dithiobenzoate-mediated Reversible Addition-Fragmentation Chain Transfer (RAFT) polymerizations, which exhibit nonideal kinetic behavior, such as induction periods and rate retardation, are comprehensively reviewed. The appreciable uncertainty in the

Plasmon field enhancement oscillations induced by strain-mediated coupling between a quantum dot and mechanical oscillator.

Science.gov (United States)

He, Yong

2017-06-23

We utilize the surface plasmon field of a metal nanoparticle (MNP) to show strain-mediated coupling in a quantum dot-mechanical resonator hybrid system including a quantum dot (QD) embedded within a conical nanowire (NW) and a MNP in the presence of an external field. Based on the numerical solutions of the master equation, we find that a slow oscillation, originating from the strain-mediated coupling between the QD and the NW, appears in the time evolution of the plasmon field enhancement. The results show that the period (about [Formula: see text]) of the slow oscillation is equal to that of the mechanical resonator of NW, which suggests that the time-resolved measurement of the plasmon field enhancement can be easily achieved based on the current experimental conditions. Its amplitude increases with the increasing strain-mediated coupling strength, and under certain conditions there is a linear relationship between them. The slow oscillation of the plasmon field enhancement provides valuable tools for measurements of the mechanical frequency and the strain-mediated coupling strength.

Feedback-Mediated Upper Extremities Exercise: Increasing Patient Motivation in Poststroke Rehabilitation

Directory of Open Access Journals (Sweden)

Maša D. Popović

2014-01-01

Full Text Available Purpose. This proof-of-concept study investigated whether feedback-mediated exercise (FME of the affected arm of hemiplegic patients increases patient motivation and promotes greater improvement of motor function, compared to no-feedback exercise (NFE. Method. We developed a feedback-mediated treatment that uses gaming scenarios and allows online and offline monitoring of both temporal and spatial characteristics of planar movements. Twenty poststroke hemiplegic inpatients, randomly assigned to the FME and NFE group, received therapy five days a week for three weeks. The outcome measures were evaluated from the following: (1 the modified drawing test (mDT, (2 received therapy time—RTT, and (3 intrinsic motivation inventory—IMI. Results. The FME group patients showed significantly higher improvement in the speed metric (P<0.01, and smoothness metric (P<0.01, as well as higher RTT (P<0.01. Significantly higher patient motivation is observed in the FME group (interest/enjoyment subscale (P<0.01 and perceived competence subscale (P<0.01. Conclusion. Prolonged endurance in training and greater improvement in certain areas of motor function, as well as very high patient motivation and strong positive impressions about the treatment, suggest the positive effects of feedback-mediated treatment and its high level of acceptance by patients.

The Mediated MIMIC Model for Understanding the Underlying Mechanism of DIF

Science.gov (United States)

Cheng, Ying; Shao, Can; Lathrop, Quinn N.

2016-01-01

Due to its flexibility, the multiple-indicator, multiple-causes (MIMIC) model has become an increasingly popular method for the detection of differential item functioning (DIF). In this article, we propose the mediated MIMIC model method to uncover the underlying mechanism of DIF. This method extends the usual MIMIC model by including one variable…

Cellular mechanisms of estradiol-mediated sexual differentiation of the brain.

Science.gov (United States)

Wright, Christopher L; Schwarz, Jaclyn S; Dean, Shannon L; McCarthy, Margaret M

2010-09-01

Gonadal steroids organize the developing brain during a perinatal sensitive period and have enduring consequences for adult behavior. In male rodents testicular androgens are aromatized in neurons to estrogens and initiate multiple distinct cellular processes that ultimately determine the masculine phenotype. Within specific brain regions, overall cell number and dendritic morphology are the principal targets for hormonal organization. Recent advances have been made in elucidating the cellular mechanisms by which the neurological underpinnings of sexually dimorphic physiology and behavior are determined. These include estradiol-mediated prostaglandin synthesis, presynaptic release of glutamate, postsynaptic changes in glutamate receptors and changes in cell adhesion molecules. Sex differences in cell death are mediated by hormonal modulation of survival and death factors such as TNFalpha and Bcl-2/BAX. Copyright 2010 Elsevier Ltd. All rights reserved.

Complement-mediated solubilization of immune complexes. Solubilization inhibition and complement factor levels in SLE patients

DEFF Research Database (Denmark)

Baatrup, Gunnar; Petersen, Ivan; Kappelgaard, E

1984-01-01

Thirty-two of 36 serum samples from 19 SLE patients showed reduced capacity to mediate complement-dependent solubilization of immune complexes (IC). SLE patients with nephritis exerted the lowest complement-mediated solubilization capacity (CMSC) whereas sera from patients with inactive disease g...

Optimism on quality of life in Portuguese chronic patients: moderator/mediator?

Science.gov (United States)

Vilhena, Estela; Pais-Ribeiro, José; Silva, Isabel; Pedro, Luísa; Meneses, Rute F; Cardoso, Helena; Silva, António Martins da; Mendonça, Denisa

2014-07-01

optimism is an important variable that has consistently been shown to affect adjustment to quality of life in chronic diseases. This study aims to clarify if dispositional optimism exerts a moderating or a mediating influence on the personality traits-quality of life association, in Portuguese chronic patients. multiple regression models were used to test the moderation and mediation effects of dispositional optimism in quality of life. A sample of 729 patients was recruited in Portugal's main hospitals and completed self-reported questionnaires assessing socio-demographic and clinical variables, personality, dispositional optimism, quality of life (QoL) and subjective well-being (SWB). the results of the regression models showed that dispositional optimism did not moderate the relationships between personality traits and quality of life. After controlling for gender, age, education level and severity of disease perception, the effects of personality traits on QoL and in SWB were mediated by dispositional optimism (partially and completely), except for the links between neuroticism/openness to experience and physical health. dispositional optimism is more likely to play a mediating, rather than a moderating role in personality traits-quality of life pathway in Portuguese chronic patients, suggesting that "the expectation that good things will happen" contributes to a better quality of life and subjective well-being.

Change in patients' interpersonal impacts as a mediator of the alliance-outcome association in treatment for chronic depression.

Science.gov (United States)

Constantino, Michael J; Laws, Holly B; Coyne, Alice E; Greenberg, Roger P; Klein, Daniel N; Manber, Rachel; Rothbaum, Barbara O; Arnow, Bruce A

2016-12-01

Theories posit that chronically depressed individuals have hostile and submissive interpersonal styles that undermine their interpersonal effectiveness and contribute to the cause and maintenance of their depression. Recent findings support this theory and demonstrate that chronically depressed patients' interpersonal impacts on their therapist become more adaptive (i.e., less hostile and submissive, and more friendly and assertive) during a targeted chronic depression treatment: cognitive-behavioral analysis system of psychotherapy (CBASP). In this study, the authors examined whether such changes in interpersonal impacts (as rated by clinicians' experiences of interacting with their patients) mediated the association between early patient-rated alliance quality and final session depression. Data derived from a large trial for chronic depression that compared the efficacy of CBASP, nefazodone, and their combination. The current subsample (N = 220) included patients in the CBASP and combined conditions who completed at least 1 depression assessment and the alliance measure, and whose therapists completed at least 1 interpersonal impacts assessment. Mediation models were fit using a bootstrapping procedure for assessing indirect effects. As hypothesized, results supported a mediating effect; higher early alliance predicted decreases in patient hostile-submissiveness during therapy, which in turn related to lower final session depression (indirect effect B = -.02, 95% confidence interval: -.07, -.001). This indirect effect accounted for 13% of the total effect of alliance on depression. There was no moderating effect of treatment condition on the indirect effect. Results further support CBASP change theory and suggest a candidate mechanism of the alliance's effect on outcome. (PsycINFO Database Record (c) 2016 APA, all rights reserved).

Mechanical ventilation in neurosurgical patients

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Keshav Goyal

2013-01-01

Full Text Available Mechanical ventilation significantly affects cerebral oxygenation and cerebral blood flow through changes in arterial carbon dioxide levels. Neurosurgical patients might require mechanical ventilation for correction and maintenance of changes in the pulmonary system that occur either due to neurosurgical pathology or following surgery during the acute phase. This review discusses the basics of mechanical ventilation relevant to the neurosurgeon in the day-to-day management of neurosurgical patient requiring artificial support of the respiration.

Ego mechanisms of defense are associated with patients? preference of treatment modality independent of psychological distress in end-stage renal disease

OpenAIRE

Hyphantis, Thomas; Katsoudas, Spiros; Voudiclari, Sonia

2010-01-01

Several parameters mediate the selection of treatment modality in end-stage renal disease (ESRD). The nephrology community suggests that patient preference should be the prime determinant of modality choice. We aimed to test whether ego mechanisms of defense are associated with patients? treatment modality preferences, independent of psychological distress. In 58 eligible ESRD patients who had themselves chosen their treatment modality, we administered the Symptom Distress Checklist-90-R and ...

Why did soft drink consumption decrease but screen time not? Mediating mechanisms in a school-based obesity prevention program

Directory of Open Access Journals (Sweden)

Brug Johannes

2008-08-01

Full Text Available Abstract Objectives This paper aims to identify the mediating mechanisms of a school-based obesity prevention program (DOiT. Methods The DOiT-program was implemented in Dutch prevocational secondary schools and evaluated using a controlled, cluster-randomised trial (September 2003 to May 2004. We examined mediators of effects regarding (1 consumption of sugar containing beverages (SCB; (2 consumption of high caloric snacks; (3 screen-viewing behaviour; and (4 active commuting to school. To improve these behaviours the DOiT-program tried to influence the following potentially mediating variables: attitude, subjective norm, perceived behavioural control, and habit-strength. Results Both in boys (n = 418 and girls (n = 436 the DOiT-intervention reduced SCB consumption (between group difference in boys = -303.5 ml/day, 95% CI: -502.4;-104.5, between group difference in girls = -222.3 ml/day, 95% CI: -371.3;-73.2. The intervention did not affect the other examined behaviours. In girls, no intervention effect on hypothetical mediators was found nor evidence of any mediating mechanisms. Boys in intervention schools improved their attitude towards decreasing SCB consumption, while this behaviour became less of a habit. Indeed, attitude and habit strength were significant mediators of the DOiT-intervention's effect (4.5 and 3.8%, respectively on SCB consumption among boys. Conclusion Our findings imply that interventions aimed at EBRB-change should be gender-specific. Future studies aimed at reducing SCB consumption among boys should target attitude and habit strength as mediating mechanisms. Our study did not resolve the mediating mechanisms in girls. Trial registration International Standard Randomised Controlled Trial Number Register ISRCTN87127361

Somatosensory amplification mediates sex differences in psychological distress among cardioverter-defibrillator patients

DEFF Research Database (Denmark)

Versteeg, Henneke; Baumert, Jens; Kolb, Christof

2010-01-01

The present study examined whether female patients with an implantable cardioverter defibrillator (ICD) report more psychological distress than male patients, and whether somatosensory amplification mediates this relationship. Design: Consecutive ICD patients (N = 241; 33% women) participating in...

Emotion regulation and emotional distress: The mediating role of hope on reappraisal and anxiety/depression in newly diagnosed cancer patients.

Science.gov (United States)

Peh, Chao Xu; Liu, Jianlin; Bishop, George D; Chan, Hui Yu; Chua, Shi Min; Kua, Ee Heok; Mahendran, Rathi

2017-08-01

A proportion of newly diagnosed cancer patients may experience anxiety and depression. Emotion suppression has been associated with poorer psychoemotional outcomes, whereas reappraisal may be an adaptive emotion regulation strategy. Few studies have examined potential mechanisms linking reappraisal to psychoemotional outcomes in cancer patients. This study aims to replicate findings on reappraisal and suppression and further examines if hope mediates the association between reappraisal and anxiety/depression in patients newly diagnosed with cancer. Participants were 144 adult cancer patients (65.3% female, mean age = 48.96 years, SD = 9.23). Patients completed a set of study questionnaires, including the Emotion Regulation Questionnaire, Adult Hope Scale, and the Hospital Anxiety and Depression Scale. Path analysis was used to examine if hope mediated the association between reappraisal and anxiety/depression. Prevalence of anxiety was 39.6% and depression was 25.0%. Reappraisal and hope were correlated with lower anxiety and depression, whereas suppression was correlated with higher anxiety and depression. The hypothesized mediation model provided fit to the data, comparative fit index = 0.95, Tucker-Lewis index = 0.94, root-mean-square-error of approximation = 0.05. There was a significant indirect effect of reappraisal on anxiety and depression via hope, b = -0.95, SE = 0.42, 95% confidence interval = -1.77 to -0.12, whereas the direct effect of reappraisal was nonsignificant. The study findings suggest that hope mediated the association between reappraisal and anxiety/depression outcomes. Moreover, the high prevalence of anxiety and depression implies a need for healthcare providers to attend to the psychoemotional needs of newly diagnosed cancer patients. Copyright © 2016 John Wiley & Sons, Ltd.

A host defense mechanism involving CFTR-mediated bicarbonate secretion in bacterial prostatitis.

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Chen Xie

Full Text Available BACKGROUND: Prostatitis is associated with a characteristic increase in prostatic fluid pH; however, the underlying mechanism and its physiological significance have not been elucidated. METHODOLOGY/PRINCIPAL FINDINGS: In this study a primary culture of rat prostatic epithelial cells and a rat prostatitis model were used. Here we reported the involvement of CFTR, a cAMP-activated anion channel conducting both Cl(- and HCO(3(-, in mediating prostate HCO(3(- secretion and its possible role in bacterial killing. Upon Escherichia coli (E. coli-LPS challenge, the expression of CFTR and carbonic anhydrase II (CA II, along with several pro-inflammatory cytokines was up-regulated in the primary culture of rat prostate epithelial cells. Inhibiting CFTR function in vitro or in vivo resulted in reduced bacterial killing by prostate epithelial cells or the prostate. High HCO(3(- content (>50 mM, rather than alkaline pH, was found to be responsible for bacterial killing. The direct action of HCO(3(- on bacterial killing was confirmed by its ability to increase cAMP production and suppress bacterial initiation factors in E. coli. The relevance of the CFTR-mediated HCO(3(- secretion in humans was demonstrated by the upregulated expression of CFTR and CAII in human prostatitis tissues. CONCLUSIONS/SIGNIFICANCE: The CFTR and its mediated HCO(3(- secretion may be up-regulated in prostatitis as a host defense mechanism.

Optimism on quality of life in Portuguese chronic patients: moderator/mediator?

Directory of Open Access Journals (Sweden)

Estela Vilhena

2014-07-01

Full Text Available Objective: optimism is an important variable that has consistently been shown to affect adjustment to quality of life in chronic diseases. This study aims to clarify if dispositional optimism exerts a moderating or a mediating influence on the personality traits-quality of life association, in Portuguese chronic patients. Methods: multiple regression models were used to test the moderation and mediation effects of dispositional optimism in quality of life. A sample of 729 patients was recruited in Portugal's main hospitals and completed self-reported questionnaires assessing socio-demographic and clinical variables, personality, dispositional optimism, quality of life (QoL and subjective well-being (SWB. Results: the results of the regression models showed that dispositional optimism did not moderate the relationships between personality traits and quality of life. After controlling for gender, age, education level and severity of disease perception, the effects of personality traits on QoL and in SWB were mediated by dispositional optimism (partially and completely, except for the links between neuroticism/openness to experience and physical health. Conclusion: dispositional optimism is more likely to play a mediating, rather than a moderating role in personality traits-quality of life pathway in Portuguese chronic patients, suggesting that "the expectation that good things will happen" contributes to a better quality of life and subjective well-being.

Psychosocial influencers and mediators of treatment adherence in haemodialysis patients.

Science.gov (United States)

Oh, Hyun Soo; Park, Ji Suk; Seo, Wha Sook

2013-09-01

This article is a report of the development and testing of the hypothetical model that illustrates relationships between treatment adherence and its psychosocial influencing factors and to elucidate the direct and indirect (mediating) effects of factors on treatment adherence. Poor adherence has been consistently reported in haemodialysis patients. Much research has showed various influencing factors of adherence, but these studies have failed to identify consistent influencing factors. This study was performed using a non-experimental, cross-sectional design. The study subjects were 150 end-stage renal failure patients on haemodialysis at a university hospital located in Incheon, South Korea. Data were collected over 10 months (June 2010-April 2011). The hypothetical model provided a good fit with data. Haemodialysis-related knowledge, perceived barrier to adherence, self-efficacy on adherence, and healthcare provider support had significant effects on adherence. Self-efficacy was found to mediate barrier-adherence and family support-adherence relationships. Self-efficacy in combination with barrier, family support, and healthcare provider support was found to mediate the depression-adherence relationship. Strategies aimed at the development of successful adherence interventions should focus on reducing perceived barriers and enhancing self-efficacy and knowledge. It can be suggested that efforts to improve the healthcare provider-patient relationship would enhance adherence. In depressive patients, strategies that promote self-efficacy and the support of family or healthcare providers could diminish the negative impact of depression on adherence. © 2013 Blackwell Publishing Ltd.

Interleukin 2 and alpha interferon induced in vitro modulation of spontaneous cell mediated cytotoxicity in patients with cancer of the uterine cervix undergoing radiotherapy

International Nuclear Information System (INIS)

Radhakrishna Pillai, M.; Balaram, P.; Padmanabhan, T.K.; Abraham, T.; Nair, M.K.; Regional Cancer Centre, Trivandrum

1989-01-01

In vitro modulation of spontaneous cell mediated cytotoxicity by interferon and interleukin 2 was carried out using peripheral blood lymphocytes from patients with cancer of the uterine cervix before and at different intervals after commencement of radiation treatment. A total of 150 patients with various stages of the disease were included and cytotoxicity was measured using the single cell cytotoxic assay. These results indicate a beneficial effect in vitro of interleukin 2 and interferon in augmenting spontaneous cell mediated cytotoxicity, a possibly vital antitumour immune mechanism in patients with relatively early cervix cancer. Natural killer cell, lymphokine activated killer cell and interferon activated killer cell activity was depressed immediately following radiotherapy. The activity of these cell types later on increased above pretreatment levels in patients with stages I, IIA and IIB. A similar rebound above pretreatment levels was not observed in patients with stages III and IV. (orig.)

Secretion management in the mechanically ventilated patient.

Science.gov (United States)

Branson, Richard D

2007-10-01

Secretion management in the mechanically ventilated patient includes routine methods for maintaining mucociliary function, as well as techniques for secretion removal. Humidification, mobilization of the patient, and airway suctioning are all routine procedures for managing secretions in the ventilated patient. Early ambulation of the post-surgical patient and routine turning of the ventilated patient are common secretion-management techniques that have little supporting evidence of efficacy. Humidification is a standard of care and a requisite for secretion management. Both active and passive humidification can be used. The humidifier selected and the level of humidification required depend on the patient's condition and the expected duration of intubation. In patients with thick, copious secretions, heated humidification is superior to a heat and moisture exchanger. Airway suctioning is the most important secretion removal technique. Open-circuit and closed-circuit suctioning have similar efficacy. Instilling saline prior to suctioning, to thin the secretions or stimulate a cough, is not supported by the literature. Adequate humidification and as-needed suctioning are the foundation of secretion management in the mechanically ventilated patient. Intermittent therapy for secretion removal includes techniques either to simulate a cough, to mechanically loosen secretions, or both. Patient positioning for secretion drainage is also widely used. Percussion and postural drainage have been widely employed for mechanically ventilated patients but have not been shown to reduce ventilator-associated pneumonia or atelectasis. Manual hyperinflation and insufflation-exsufflation, which attempt to improve secretion removal by simulating a cough, have been described in mechanically ventilated patients, but neither has been studied sufficiently to support routine use. Continuous lateral rotation with a specialized bed reduces atelectasis in some patients, but has not been shown

Deciphering potential mechanisms of anaerobic soil disinfestation (ASD)-mediated control of Pratylenchus penetrans

Science.gov (United States)

Pratylenchus penetrans is a component of the apple replant disease (ARD) causal pathogen complex. The potential role for biological mechanisms contributing to ASD-mediated suppression of P. penetrans was examined in greenhouse study using orchard soil with a history of ARD. Populations of P. penetra...

Protocol: developing a conceptual framework of patient mediated knowledge translation, systematic review using a realist approach.

Science.gov (United States)

Gagliardi, Anna R; Légaré, France; Brouwers, Melissa C; Webster, Fiona; Wiljer, David; Badley, Elizabeth; Straus, Sharon

2011-03-22

Patient involvement in healthcare represents the means by which to achieve a healthcare system that is responsive to patient needs and values. Characterization and evaluation of strategies for involving patients in their healthcare may benefit from a knowledge translation (KT) approach. The purpose of this knowledge synthesis is to develop a conceptual framework for patient-mediated KT interventions. A preliminary conceptual framework for patient-mediated KT interventions was compiled to describe intended purpose, recipients, delivery context, intervention, and outcomes. A realist review will be conducted in consultation with stakeholders from the arthritis and cancer fields to explore how these interventions work, for whom, and in what contexts. To identify patient-mediated KT interventions in these fields, we will search MEDLINE, the Cochrane Library, and EMBASE from 1995 to 2010; scan references of all eligible studies; and examine five years of tables of contents for journals likely to publish quantitative or qualitative studies that focus on developing, implementing, or evaluating patient-mediated KT interventions. Screening and data collection will be performed independently by two individuals. The conceptual framework of patient-mediated KT options and outcomes could be used by healthcare providers, managers, educationalists, patient advocates, and policy makers to guide program planning, service delivery, and quality improvement and by us and other researchers to evaluate existing interventions or develop new interventions. By raising awareness of options for involving patients in improving their own care, outcomes based on using a KT approach may lead to greater patient-centred care delivery and improved healthcare outcomes.

Protocol: developing a conceptual framework of patient mediated knowledge translation, systematic review using a realist approach

Directory of Open Access Journals (Sweden)

Wiljer David

2011-03-01

Full Text Available Abstract Background Patient involvement in healthcare represents the means by which to achieve a healthcare system that is responsive to patient needs and values. Characterization and evaluation of strategies for involving patients in their healthcare may benefit from a knowledge translation (KT approach. The purpose of this knowledge synthesis is to develop a conceptual framework for patient-mediated KT interventions. Methods A preliminary conceptual framework for patient-mediated KT interventions was compiled to describe intended purpose, recipients, delivery context, intervention, and outcomes. A realist review will be conducted in consultation with stakeholders from the arthritis and cancer fields to explore how these interventions work, for whom, and in what contexts. To identify patient-mediated KT interventions in these fields, we will search MEDLINE, the Cochrane Library, and EMBASE from 1995 to 2010; scan references of all eligible studies; and examine five years of tables of contents for journals likely to publish quantitative or qualitative studies that focus on developing, implementing, or evaluating patient-mediated KT interventions. Screening and data collection will be performed independently by two individuals. Conclusions The conceptual framework of patient-mediated KT options and outcomes could be used by healthcare providers, managers, educationalists, patient advocates, and policy makers to guide program planning, service delivery, and quality improvement and by us and other researchers to evaluate existing interventions or develop new interventions. By raising awareness of options for involving patients in improving their own care, outcomes based on using a KT approach may lead to greater patient-centred care delivery and improved healthcare outcomes.

Protocol: developing a conceptual framework of patient mediated knowledge translation, systematic review using a realist approach

Science.gov (United States)

2011-01-01

Background Patient involvement in healthcare represents the means by which to achieve a healthcare system that is responsive to patient needs and values. Characterization and evaluation of strategies for involving patients in their healthcare may benefit from a knowledge translation (KT) approach. The purpose of this knowledge synthesis is to develop a conceptual framework for patient-mediated KT interventions. Methods A preliminary conceptual framework for patient-mediated KT interventions was compiled to describe intended purpose, recipients, delivery context, intervention, and outcomes. A realist review will be conducted in consultation with stakeholders from the arthritis and cancer fields to explore how these interventions work, for whom, and in what contexts. To identify patient-mediated KT interventions in these fields, we will search MEDLINE, the Cochrane Library, and EMBASE from 1995 to 2010; scan references of all eligible studies; and examine five years of tables of contents for journals likely to publish quantitative or qualitative studies that focus on developing, implementing, or evaluating patient-mediated KT interventions. Screening and data collection will be performed independently by two individuals. Conclusions The conceptual framework of patient-mediated KT options and outcomes could be used by healthcare providers, managers, educationalists, patient advocates, and policy makers to guide program planning, service delivery, and quality improvement and by us and other researchers to evaluate existing interventions or develop new interventions. By raising awareness of options for involving patients in improving their own care, outcomes based on using a KT approach may lead to greater patient-centred care delivery and improved healthcare outcomes. PMID:21426573

How do physicians discuss e-health with patients? the relationship of physicians' e-health beliefs to physician mediation styles.

Science.gov (United States)

Fujioka, Yuki; Stewart, Erin

2013-01-01

A survey of 104 physicians examined the role of physicians' evaluation of the quality of e-health and beliefs about the influence of patients' use of e-health in how physicians discuss e-health materials with patients. Physicians' lower (poor) evaluation of the quality of e-health content predicted more negative mediation (counter-reinforcement of e-health content). Perceived benefits of patients' e-health use predicted more positive (endorsement of e-health content). Physician's perceived concerns (negative influence) regarding patients' e-health use were not a significant predictor for their mediation styles. Results, challenging the utility of restrictive mediation, suggested reconceptualizing it as redirective mediation in a medical interaction. The study suggested that patient-generated e-health-related inquiries invite physician mediation in medical consultations. Findings and implications are discussed in light of the literature of physician-patient interaction, incorporating the theory of parental mediation of media into a medical context.

Protocol: developing a conceptual framework of patient mediated knowledge translation, systematic review using a realist approach

OpenAIRE

Wiljer David; Webster Fiona; Brouwers Melissa C; Légaré France; Gagliardi Anna R; Badley Elizabeth; Straus Sharon

2011-01-01

Abstract Background Patient involvement in healthcare represents the means by which to achieve a healthcare system that is responsive to patient needs and values. Characterization and evaluation of strategies for involving patients in their healthcare may benefit from a knowledge translation (KT) approach. The purpose of this knowledge synthesis is to develop a conceptual framework for patient-mediated KT interventions. Methods A preliminary conceptual framework for patient-mediated KT interv...

Trastuzumab mediates antibody-dependent cell-mediated cytotoxicity and phagocytosis to the same extent in both adjuvant and metastatic HER2/neu breast cancer patients.

Science.gov (United States)

Petricevic, Branka; Laengle, Johannes; Singer, Josef; Sachet, Monika; Fazekas, Judit; Steger, Guenther; Bartsch, Rupert; Jensen-Jarolim, Erika; Bergmann, Michael

2013-12-12

Monoclonal antibodies (mAb), such as trastuzumab are a valuable addition to breast cancer therapy. Data obtained from neoadjuvant settings revealed that antibody-dependent cell-mediated cytotoxicity (ADCC) is a major mechanism of action for the mAb trastuzumab. Conflicting results still call into question whether disease progression, prolonged treatment or concomitant chemotherapy influences ADCC and related immunological phenomena. We analyzed the activity of ADCC and antibody-dependent cell-mediated phagocytosis (ADCP) of peripheral blood mononuclear cells (PBMCs) from human epidermal growth factor receptor 2 (HER2/neu) positive breast cancer patients receiving trastuzumab therapy either in an adjuvant (n = 13) or metastatic (n = 15) setting as well as from trastuzumab treatment-naive (t-naive) HER2/neu negative patients (n = 15). PBMCs from healthy volunteers (n = 24) were used as controls. ADCC and ADCP activity was correlated with the expression of antibody binding Fc-gamma receptor (FcγR)I (CD64), FcγRII (CD32) and FcγRIII (CD16) on CD14+ (monocytes) and CD56+ (NK) cells, as well as the expression of CD107a+ (LAMP-1) on CD56+ cells and the total amount of CD4+CD25+FOXP3+ (Treg) cells. In metastatic patients, markers were correlated with progression-free survival (PFS). ADCC activity was significantly down regulated in metastatic, adjuvant and t-naive patient cohorts as compared to healthy controls. Reduced ADCC activity was inversely correlated with the expression of CD107a on CD56+ cells in adjuvant patients. ADCC and ADCP activity of the patient cohorts were similar, regardless of treatment duration or additional chemotherapy. PFS in metastatic patients inversely correlated with the number of peripheral Treg cells. The reduction of ADCC in patients as compared to healthy controls calls for adjuvant strategies, such as immune-enhancing agents, to improve the activity of trastuzumab. However, efficacy of trastuzumab-specific ADCC and ADCP appears not to

Electroporation driven delivery of both an IL-12 expressing plasmid and cisplatin synergizes to inhibit B16 melanoma tumor growth through an NK cell mediated tumor killing mechanism.

Science.gov (United States)

Kim, Ha; Sin, Jeong-Im

2012-11-01

Combined therapy using chemotherapeutic drugs and immunotherapeutics offers some promise for treating patients with cancer. In this study, we evaluated whether cisplatin delivered by intratumoral (IT)-electroporation (EP) might enhance antitumor activity against established B16 melanoma and whether further addition of intramuscular (IM)-EP of IL-12 cDNA to IT-EP of cisplatin might augment antitumor therapeutic activity, with a focus on the underlining antitumor mechanism(s). When tumor (7 mm)-bearing animals were treated locally with cisplatin by IT-EP, they showed tumor growth inhibition significantly more than those without IT-EP. Moreover, IL-12 cDNA delivered by IM-EP was also able to inhibit tumor growth significantly more than control vector delivery. This tumor growth inhibition was mediated by NK cells, but not CD4+ T or CD8+ T cells, as determined by immune cell subset depletion and IFN-γ induction. Moreover, concurrent therapy using IT-EP of cisplatin plus IM-EP of IL-12 cDNA displayed antitumor therapeutic synergy. This therapeutic synergy appeared to be mediated by increased sensitivity of cisplatin-treated tumors to NK cell-mediated tumor killing. Taken together, these data support that cisplatin delivery by IT-EP plus IL-12 gene delivery by IM-EP are more effective at inducing antitumor therapeutic responses through increased sensitivity of cisplatin-treated tumors to NK cell-mediated tumor killing. This combined approach might have some implication for treating melanoma in patients.

Mechanisms and ecological implications of plant-mediated interactions between belowground and aboveground insect herbivores

NARCIS (Netherlands)

Papadopoulou, G.V.; Dam, N.M. van

2017-01-01

Plant-mediated interactions between belowground (BG) and aboveground (AG) herbivores have received increasing interest recently. However, the molecular mechanisms underlying ecological consequences of BG–AG interactions are not fully clear yet. Herbivore-induced plant defenses are complex and

DMPD: Mechanisms of selection mediated by interleukin-7, the preBCR, and hemokinin-1during B-cell development. [Dynamic Macrophage Pathway CSML Database

Lifescience Database Archive (English)

Full Text Available 14962188 Mechanisms of selection mediated by interleukin-7, the preBCR, and hemokin...ng) (.svg) (.html) (.csml) Show Mechanisms of selection mediated by interleukin-7, the preBCR, and hemokinin...-1during B-cell development. PubmedID 14962188 Title Mechanisms of selection medi

Indirect Calorimetry in Mechanically Ventilated Patients

DEFF Research Database (Denmark)

Allingstrup, Matilde Jo; Kondrup, Jens; Perner, Anders

2017-01-01

Background and Aims: The 2 currently available indirect calorimeters, CCM Express Indirect Calorimeter (MedGraphics, St Paul, MN) and Quark RMR ICU Indirect Calorimeter (COSMED, Rome, Italy), have not been validated against a gold standard in mechanically ventilated patients. Our aim was to do so...... using a gold-standard, modified Tissot bell-spirometer method in mechanically ventilated patients who were hemodynamically, respiratory, and metabolically stable. Methods: We studied 30 patients undergoing general anesthesia and major gynecological surgery. We measured oxygen consumption ((Formula...... of 77 (167) with limits of agreement −249 to 404 kcal/d. Conclusions: The QUARK RMR ICU Indirect Calorimeter compared better with the gold standard for values of (Formula presented.) O2 and REE than did the CCM Express Indirect Calorimeter in mechanically ventilated patients who were circulatory...

Circadian clocks govern calorie restriction-mediated life span extension through BMAL1- and IGF-1-dependent mechanisms.

Science.gov (United States)

Patel, Sonal A; Chaudhari, Amol; Gupta, Richa; Velingkaar, Nikkhil; Kondratov, Roman V

2016-04-01

Calorie restriction (CR) increases longevity in many species by unknown mechanisms. The circadian clock was proposed as a potential mediator of CR. Deficiency of the core component of the circadian clock-transcriptional factor BMAL1 (brain and muscle ARNT [aryl hydrocarbon receptor nuclear translocator]-like protein 1)-results in accelerated aging. Here we investigated the role of BMAL1 in mechanisms of CR. The 30% CR diet increased the life span of wild-type (WT) mice by 20% compared to mice on anad libitum(AL) diet but failed to increase life span ofBmal1(-/-)mice. BMAL1 deficiency impaired CR-mediated changes in the plasma levels of IGF-1 and insulin. We detected a statistically significantly reduction of IGF-1 in CRvs.AL by 50 to 70% in WT mice at several daily time points tested, while inBmal1(-/-)the reduction was not significant. Insulin levels in WT were reduced by 5 to 9%, whileBmal1(-/-)induced it by 10 to 35% at all time points tested. CR up-regulated the daily average expression ofBmal1(by 150%) and its downstream target genesPeriods(by 470% forPer1and by 130% forPer2). We propose that BMAL1 is an important mediator of CR, and activation of BMAL1 might link CR mechanisms with biologic clocks.-Patel, S. A., Chaudhari, A., Gupta, R., Velingkaar, N., Kondratov, R. V. Circadian clocks govern calorie restriction-mediated life span extension through BMAL1- and IGF-1-dependent mechanisms. © FASEB.

Respiratory mechanics by least squares fitting in mechanically ventilated patients: application on flow-limited COPD patients.

Science.gov (United States)

Volta, Carlo A; Marangoni, Elisabetta; Alvisi, Valentina; Capuzzo, Maurizia; Ragazzi, Riccardo; Pavanelli, Lina; Alvisi, Raffaele

2002-01-01

Although computerized methods of analyzing respiratory system mechanics such as the least squares fitting method have been used in various patient populations, no conclusive data are available in patients with chronic obstructive pulmonary disease (COPD), probably because they may develop expiratory flow limitation (EFL). This suggests that respiratory mechanics be determined only during inspiration. Eight-bed multidisciplinary ICU of a teaching hospital. Eight non-flow-limited postvascular surgery patients and eight flow-limited COPD patients. Patients were sedated, paralyzed for diagnostic purposes, and ventilated in volume control ventilation with constant inspiratory flow rate. Data on resistance, compliance, and dynamic intrinsic positive end-expiratory pressure (PEEPi,dyn) obtained by applying the least squares fitting method during inspiration, expiration, and the overall breathing cycle were compared with those obtained by the traditional method (constant flow, end-inspiratory occlusion method). Our results indicate that (a) the presence of EFL markedly decreases the precision of resistance and compliance values measured by the LSF method, (b) the determination of respiratory variables during inspiration allows the calculation of respiratory mechanics in flow limited COPD patients, and (c) the LSF method is able to detect the presence of PEEPi,dyn if only inspiratory data are used.

Ethnic inequalities in doctor-patient communication regarding personal care plans: the mediating effects of positive mental wellbeing.

Science.gov (United States)

Umeh, Kanayo F

2017-04-06

There is limited understanding of ethnic inequalities in doctor-patient communication regarding personal care plans (PCPs). This study investigated the mediating effects of positive mental wellbeing on differences in PCP-related doctor-patient communication amongst South Asian and Caucasian UK residents. Data from 10,980 respondents to the 2013 Health Survey for England was analysed using bootstrapping methods. Constructs from the WEMWBS (Warwick and Edinburgh Mental Wellbeing Scale) (Stewart-Brown, S., and K. Janmohamed. 2008. Warwick, UK) were assessed as mediators of relations between ethnicity and several doctor-patient communication variables, including PCP-related interactions; (a) had a PCP-related discussion about a long-term condition with a doctor/nurse, and (b) had this conversation within the past year, (c) agreed to a PCP with a health professional; and (d) talked to a doctor in the past 2 weeks. Bootstrapped mediation analysis (Hayes, A. F. 2013. Introduction to Mediation, Moderation, and Conditional Process Analysis: A Regression-based Approach. New York, NY: The Guilford Press) showed that three positive mind-sets mediated associations between ethnicity and doctor-patient contact, including PCP-related communication. Being able to make up one's mind (ab = -0.05; BC a CI [-0.14, 0.01]) mediated the effect of ethnicity on agreeing to a PCP, while having energy to spare (ab = 0.07; BC a CI [-0.04, 0.12]), and feeling good about oneself (ab = 0.03; BC a CI [0.01, 0.07]), mediated ethnic effects on talking to a doctor during the past fortnight. The mediating effect of reported energy persisted after controlling for medical history, perceived health, and other covariates. Ethnic disparities in doctor-patient interaction, including PCP-related communication, are partly explained by positive mental wellbeing. Gauging positive psychological moods in patients, particularly self-worth, self-perceived vigour and decisiveness, are relevant to

Artificial humidification for the mechanically ventilated patient.

Science.gov (United States)

Selvaraj, N

Caring for patients who are mechanically ventilated poses many challenges for critical care nurses. It is important to humidify the patient's airways artificially to prevent complications such as ventilator-associated pneumonia. There is no gold standard to determine which type of humidification is best for patients who are artificially ventilated. This article provides an overview of commonly used artificial humidification for mechanically ventilated patients and discusses nurses' responsibilities in caring for patients receiving artificial humidification.

Sun-mediated mechanical LINC between nucleus and cytoskeleton regulates βcatenin nuclear access.

Science.gov (United States)

Uzer, Gunes; Bas, Guniz; Sen, Buer; Xie, Zhihui; Birks, Scott; Olcum, Melis; McGrath, Cody; Styner, Maya; Rubin, Janet

2018-06-06

βcatenin acts as a primary intracellular signal transducer for mechanical and Wnt signaling pathways to control cell function and fate. Regulation of βcatenin in the cytoplasm has been well studied but βcatenin nuclear trafficking and function remains unclear. In a previous study we showed that, in mesenchymal stem cells (MSC), mechanical blockade of adipogenesis relied on inhibition of βcatenin destruction complex element GSK3β (glycogen synthase kinase 3β) to increase nuclear βcatenin as well as the function of Linker of Cytoskeleton and Nucleoskeleton (LINC) complexes, suggesting that these two mechanisms may be linked. Here we show that shortly after inactivation of GSK3β due to either low intensity vibration (LIV), substrate strain or pharmacologic inhibition, βcatenin associates with the nucleoskeleton, defined as the insoluble nuclear fraction that provides structure to the integrated nuclear envelope, nuclear lamina and chromatin. Co-depleting LINC elements Sun-1 and Sun-2 interfered with both nucleoskeletal association and nuclear entry of βcatenin, resulting in decreased nuclear βcatenin levels. Our findings reveal that the insoluble structural nucleoskeleton actively participates in βcatenin dynamics. As the cytoskeleton transmits applied mechanical force to the nuclear surface to influence the nucleoskeleton and its LINC mediated interaction, our results suggest a pathway by which LINC mediated connectivity may play a role in signaling pathways that depend on nuclear access of βcatenin. Copyright © 2018 Elsevier Ltd. All rights reserved.

How does MBCT for depression work? studying cognitive and affective mediation pathways.

Directory of Open Access Journals (Sweden)

Tim Batink

Full Text Available Mindfulness based cognitive therapy (MBCT is a non-pharmacological intervention to reduce current symptoms and to prevent recurrence of major depressive disorder. At present, it is not well understood which underlying mechanisms during MBCT are associated with its efficacy. The current study (n = 130 was designed to examine the roles of mindfulness skills, rumination, worry and affect, and the interplay between those factors, in the mechanisms of change in MBCT for residual depressive symptoms. An exploratory but systematic approach was chosen using Sobel-Goodman mediation analyses to identify mediators on the pathway from MBCT to reduction in depressive symptoms. We replicated earlier findings that therapeutic effects of MBCT are mediated by changes in mindfulness skills and worry. Second, results showed that changes in momentary positive and negative affect significantly mediated the efficacy of MBCT, and also mediated the effect of worry on depressive symptoms. Third, within the group of patients with a prior history of ≤ 2 episodes of MDD, predominantly changes in cognitive and to a lesser extent affective processes mediated the effect of MBCT. However, within the group of patients with a prior history of ≥ 3 episodes of MDD, only changes in affect were significant mediators for the effect of MBCT.[corrected] Nederlands Trial Register NTR1084.

Distinct mechanisms act in concert to mediate cell cycle arrest.

Science.gov (United States)

Toettcher, Jared E; Loewer, Alexander; Ostheimer, Gerard J; Yaffe, Michael B; Tidor, Bruce; Lahav, Galit

2009-01-20

In response to DNA damage, cells arrest at specific stages in the cell cycle. This arrest must fulfill at least 3 requirements: it must be activated promptly; it must be sustained as long as damage is present to prevent loss of genomic information; and after the arrest, cells must re-enter into the appropriate cell cycle phase to ensure proper ploidy. Multiple molecular mechanisms capable of arresting the cell cycle have been identified in mammalian cells; however, it is unknown whether each mechanism meets all 3 requirements or whether they act together to confer specific functions to the arrest. To address this question, we integrated mathematical models describing the cell cycle and the DNA damage signaling networks and tested the contributions of each mechanism to cell cycle arrest and re-entry. Predictions from this model were then tested with quantitative experiments to identify the combined action of arrest mechanisms in irradiated cells. We find that different arrest mechanisms serve indispensable roles in the proper cellular response to DNA damage over time: p53-independent cyclin inactivation confers immediate arrest, whereas p53-dependent cyclin downregulation allows this arrest to be sustained. Additionally, p21-mediated inhibition of cyclin-dependent kinase activity is indispensable for preventing improper cell cycle re-entry and endoreduplication. This work shows that in a complex signaling network, seemingly redundant mechanisms, acting in a concerted fashion, can achieve a specific cellular outcome.

Impact of Patient-centered eHealth Applications on Patient Outcomes: A Review on the Mediating Influence of Human Factor Issues.

Science.gov (United States)

Wildenbos, G A; Peute, L W; Jaspers, M W M

2016-11-10

To examine the evidence of the impact of patient- centered eHealth applications on patient care and to analyze if and how reported human factor issues mediated the outcomes. We searched PubMed (2014-2015) for studies evaluating the impact of patient-centered eHealth applications on patient care (behavior change, self-efficacy, and patient health-related outcomes). The Systems Engineering Initiative for Patient Safety (SEIPS 2.0) model was used as a guidance framework to identify the reported human factors possibly impacting the effectiveness of an eHealth intervention. Of the 348 potentially relevant papers, 10 papers were included for data analysis. None of the 10 papers reported a negative impact of the eHealth intervention. Seven papers involved a randomized controlled trial (RCT) study. Six of these RCTs reported a positive impact of the eHealth intervention on patient care. All 10 papers reported on human factor issues possibly mediating effects of patient-centered eHealth. Human factors involved patient characteristics, perceived social support, and (type of) interaction between patient and provider. While the amount of patient-centered eHealth interventions increases, many questions remain as to whether and to what extent human factors mediate their use and impact. Future research should adopt a formal theory-driven approach towards human factors when investigating those factors' influence on the effectiveness of these interventions. Insights could then be used to better tailor the content and design of eHealth solutions according to patient user profiles, so as to enhance eHealth interventions impact on patient behavior, self-efficacy, and health-related outcomes.

Association between Perceived Discrimination in Healthcare Settings and HIV Medication Adherence: Mediating Psychosocial Mechanisms.

Science.gov (United States)

Turan, Bulent; Rogers, Anna Joy; Rice, Whitney S; Atkins, Ghislaine C; Cohen, Mardge H; Wilson, Tracey E; Adimora, Adaora A; Merenstein, Daniel; Adedimeji, Adebola; Wentz, Eryka L; Ofotokun, Igho; Metsch, Lisa; Tien, Phyllis C; Johnson, Mallory O; Turan, Janet M; Weiser, Sheri D

2017-12-01

There is insufficient research on the impact of perceived discrimination in healthcare settings on adherence to antiretroviral therapy (ART), particularly among women living with HIV, and even less is known about psychosocial mechanisms that may mediate this association. Cross-sectional analyses were conducted in a sample of 1356 diverse women living with HIV enrolled in the Women's Interagency HIV Study (WIHS), a multi-center cohort study. Indirect effects analysis with bootstrapping was used to examine the potential mediating roles of internalized stigma and depressive symptoms in the association between perceived discrimination in healthcare settings and ART adherence. Perceived discrimination in healthcare settings was negatively associated with optimal (95% or better) ART adherence (adjusted odds ratio (AOR) = 0.81, p = 0.02, 95% confidence interval (CI) [0.68, 0.97]). Furthermore, internalization of stigma and depressive symptoms mediated the perceived discrimination-adherence association: Serial mediation analyses revealed a significant indirect effect of perceived discrimination in healthcare settings on ART adherence, first through internalized HIV stigma, and then through depressive symptoms (B = - 0.08, SE = 0.02, 95% CI [- 0.12, - 0.04]). Perceiving discrimination in healthcare settings may contribute to internalization of HIV-related stigma, which in turn may lead to depressive symptoms, with downstream adverse effects on ART adherence among women. These findings can guide the design of interventions to reduce discrimination in healthcare settings, as well as interventions targeting psychosocial mechanisms that may impact the ability of women living with HIV to adhere to ART regimens.

Depression in obese patients with primary fibromyalgia: the mediating role of poor sleep and eating disorder features.

Science.gov (United States)

Senna, Mohammed K; Ahmad, Hamada S; Fathi, Warda

2013-03-01

Depression is a prominent feature in fibromyalgia syndrome. Patients with fibromyalgia syndrome who are obese, with poor sleep quality, and those who have recurrent episodes of binge eating are at greater risk to develop depression. The aim of this cross-sectional study was to examine the hypothesis that the relationship between obesity and depression in patients with primary fibromyalgia syndrome is mediated by poor sleep, binge eating disorder (BED), and weight and shape concern. This study included 131 patients with primary fibromyalgia syndrome. Participants completed the following questionnaires: Pittsburgh Sleep Quality Index, Beck Depression Inventory-II, Eating Disorder questionnaire, and Fibromyalgia Impact Questionnaire. Body mass index (BMI) provided the primary indicator of obesity. Sobel test showed that the conditions for complete mediation were satisfied on the weight and shape concern as mediator between BMI and depression because the association between BMI and depression score became insignificant after controlling of weight and shape concern. However, since the association between BMI and depression remained significant after BED and poor sleep score were controlled, thus for both mediators, the conditions for partial mediation on the depression were satisfied. The findings suggest that in patients with primary fibromyalgia syndrome, weight and shape concern, BED, and poor sleep quality are important mediators of the relationship between obesity and depression. We suggest that a greater focus on these mediators in depression treatment may be indicated.

Interfacial Mechanism in Lithium-Sulfur Batteries: How Salts Mediate the Structure Evolution and Dynamics.

Science.gov (United States)

Lang, Shuang-Yan; Xiao, Rui-Juan; Gu, Lin; Guo, Yu-Guo; Wen, Rui; Wan, Li-Jun

2018-06-08

Lithium-sulfur batteries possess favorable potential for energy-storage applications due to their high specific capacity and the low cost of sulfur. Intensive understanding of the interfacial mechanism, especially the polysulfide formation and transformation under complex electrochemical environment, is crucial for the build-up of advanced batteries. Here we report the direct visualization of interfacial evolution and dynamic transformation of the sulfides mediated by the lithium salts via real-time atomic force microscopy monitoring inside a working battery. The observations indicate that the lithium salts influence the structures and processes of sulfide deposition/decomposition during discharge/charge. Moreover, the distinct ion interaction and diffusion in electrolytes manipulate the interfacial reactions determining the kinetics of the sulfide transformation. Our findings provide deep insights into surface dynamics of lithium-sulfur reactions revealing the salt-mediated mechanisms at nanoscale, which contribute to the profound understanding of the interfacial processes for the optimized design of lithium-sulfur batteries.

mediation: R package for causal mediation analysis

OpenAIRE

Tingley, Dustin; Yamamoto, Teppei; Hirose, Kentaro; Keele, Luke; Imai, Kosuke

2012-01-01

In this paper, we describe the R package mediation for conducting causal mediation analysis in applied empirical research. In many scientific disciplines, the goal of researchers is not only estimating causal effects of a treatment but also understanding the process in which the treatment causally affects the outcome. Causal mediation analysis is frequently used to assess potential causal mechanisms. The mediation package implements a comprehensive suite of statistical tools for conducting su...

Mechanisms of Coronavirus Cell Entry Mediated by the Viral Spike Protein

Directory of Open Access Journals (Sweden)

Gary R. Whittaker

2012-06-01

Full Text Available Coronaviruses are enveloped positive-stranded RNA viruses that replicate in the cytoplasm. To deliver their nucleocapsid into the host cell, they rely on the fusion of their envelope with the host cell membrane. The spike glycoprotein (S mediates virus entry and is a primary determinant of cell tropism and pathogenesis. It is classified as a class I fusion protein, and is responsible for binding to the receptor on the host cell as well as mediating the fusion of host and viral membranes—A process driven by major conformational changes of the S protein. This review discusses coronavirus entry mechanisms focusing on the different triggers used by coronaviruses to initiate the conformational change of the S protein: receptor binding, low pH exposure and proteolytic activation. We also highlight commonalities between coronavirus S proteins and other class I viral fusion proteins, as well as distinctive features that confer distinct tropism, pathogenicity and host interspecies transmission characteristics to coronaviruses.

Ca2+ influx and ATP release mediated by mechanical stretch in human lung fibroblasts

International Nuclear Information System (INIS)

Murata, Naohiko; Ito, Satoru; Furuya, Kishio; Takahara, Norihiro; Naruse, Keiji; Aso, Hiromichi; Kondo, Masashi; Sokabe, Masahiro; Hasegawa, Yoshinori

2014-01-01

Highlights: • Uniaxial stretching activates Ca 2+ signaling in human lung fibroblasts. • Stretch-induced intracellular Ca 2+ elevation is mainly via Ca 2+ influx. • Mechanical strain enhances ATP release from fibroblasts. • Stretch-induced Ca 2+ influx is not mediated by released ATP or actin cytoskeleton. - Abstract: One cause of progressive pulmonary fibrosis is dysregulated wound healing after lung inflammation or damage in patients with idiopathic pulmonary fibrosis and severe acute respiratory distress syndrome. The mechanical forces are considered to regulate pulmonary fibrosis via activation of lung fibroblasts. In this study, the effects of mechanical stretch on the intracellular Ca 2+ concentration ([Ca 2+ ] i ) and ATP release were investigated in primary human lung fibroblasts. Uniaxial stretch (10–30% in strain) was applied to fibroblasts cultured in a silicone chamber coated with type I collagen using a stretching apparatus. Following stretching and subsequent unloading, [Ca 2+ ] i transiently increased in a strain-dependent manner. Hypotonic stress, which causes plasma membrane stretching, also transiently increased the [Ca 2+ ] i . The stretch-induced [Ca 2+ ] i elevation was attenuated in Ca 2+ -free solution. In contrast, the increase of [Ca 2+ ] i by a 20% stretch was not inhibited by the inhibitor of stretch-activated channels GsMTx-4, Gd 3+ , ruthenium red, or cytochalasin D. Cyclic stretching induced significant ATP releases from fibroblasts. However, the stretch-induced [Ca 2+ ] i elevation was not inhibited by ATP diphosphohydrolase apyrase or a purinergic receptor antagonist suramin. Taken together, mechanical stretch induces Ca 2+ influx independently of conventional stretch-sensitive ion channels, the actin cytoskeleton, and released ATP

Patients with migraine with aura have increased flow mediated dilation

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Altamura Claudia

2010-03-01

Full Text Available Abstract Background Endothelium-derived nitric oxide (NO mediates the arterial dilation following a flow increase (i.e. flow-mediated dilation, FMD, easily assessed in the brachial artery. NO is also involved in cerebral hemodynamics and it is supposed to trigger vascular changes occurring during migraine. This study aimed at investigating whether migraine patients present an altered response to NO also in the peripheral artery system. Methods We enrolled 21 migraineurs (10 with aura [MwA], 11 without aura [MwoA], and 13 controls. FMD was evaluated with ultrasound in all subjects by measuring the percentage increase of the brachial artery diameter induced by hyperaemia reactive to sustained cuff inflation around the arm above systolic pressure. FMD values were then normalized for shear stress. Results Normalized FMD values were higher in patients with MwA (28.5 10-2%.s than in controls (9.0 10-2%.s and patients with MwoA (13.7 10-2%.s (p Conclusions Migraineurs with aura present an excessive arterial response to hyperaemia, likely as an effect of an increased sensitivity to endothelium-derived nitric oxide. This phenomenon observed peripherally might reflect similar characteristics in the cerebral circulation.

Aerosol delivery in intubated, mechanically ventilated patients

International Nuclear Information System (INIS)

MacIntyre, N.R.; Silver, R.M.; Miller, C.W.; Schuler, F.; Coleman, R.E.

1985-01-01

To study the effects of respiratory failure and mechanical ventilation on aerosol delivery to the lungs, nuclear scans were performed after aerosolization of 5 to 9 mCi of Tc-99m diethylenetriamine pentaacetic acid in seven stable, intubated, and mechanically ventilated patients. The radioactivity reaching the lungs was 2.9 +/- .7% (mean +/- SD) of the administered dose, an amount significantly less than that in three healthy nonintubated subjects and also less than what would be expected in nonintubated subjects from other published reports. A subsequent study was performed in 15 additional mechanically ventilated patients who were receiving aerosolized bronchodilators through their endotracheal tube. In these patients, heart rate and lung mechanical function values before and after treatment were not significantly different. It is concluded from these studies that aerosol delivery in mechanically ventilated patients is significantly reduced and that this is probably due to a combination of suboptimal breathing pattern, intrinsic airway disease, and the endotracheal tube functioning as both a site for aerosol deposition through impaction as well as a barrier to gastrointestinal absorption

Abundant genetic overlap between blood lipids and immune-mediated diseases indicates shared molecular genetic mechanisms.

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Ole A Andreassen

Full Text Available Epidemiological studies suggest a relationship between blood lipids and immune-mediated diseases, but the nature of these associations is not well understood. We used genome-wide association studies (GWAS to investigate shared single nucleotide polymorphisms (SNPs between blood lipids and immune-mediated diseases. We analyzed data from GWAS (n~200,000 individuals, applying new False Discovery Rate (FDR methods, to investigate genetic overlap between blood lipid levels [triglycerides (TG, low density lipoproteins (LDL, high density lipoproteins (HDL] and a selection of archetypal immune-mediated diseases (Crohn's disease, ulcerative colitis, rheumatoid arthritis, type 1 diabetes, celiac disease, psoriasis and sarcoidosis. We found significant polygenic pleiotropy between the blood lipids and all the investigated immune-mediated diseases. We discovered several shared risk loci between the immune-mediated diseases and TG (n = 88, LDL (n = 87 and HDL (n = 52. Three-way analyses differentiated the pattern of pleiotropy among the immune-mediated diseases. The new pleiotropic loci increased the number of functional gene network nodes representing blood lipid loci by 40%. Pathway analyses implicated several novel shared mechanisms for immune pathogenesis and lipid biology, including glycosphingolipid synthesis (e.g. FUT2 and intestinal host-microbe interactions (e.g. ATG16L1. We demonstrate a shared genetic basis for blood lipids and immune-mediated diseases independent of environmental factors. Our findings provide novel mechanistic insights into dyslipidemia and immune-mediated diseases and may have implications for therapeutic trials involving lipid-lowering and anti-inflammatory agents.

A Patient-Specific Airway Branching Model for Mechanically Ventilated Patients

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Nor Salwa Damanhuri

2014-01-01

Full Text Available Background. Respiratory mechanics models have the potential to guide mechanical ventilation. Airway branching models (ABMs were developed from classical fluid mechanics models but do not provide accurate models of in vivo behaviour. Hence, the ABM was improved to include patient-specific parameters and better model observed behaviour (ABMps. Methods. The airway pressure drop of the ABMps was compared with the well-accepted dynostatic algorithm (DSA in patients diagnosed with acute respiratory distress syndrome (ARDS. A scaling factor (α was used to equate the area under the pressure curve (AUC from the ABMps to the AUC of the DSA and was linked to patient state. Results. The ABMps recorded a median α value of 0.58 (IQR: 0.54–0.63; range: 0.45–0.66 for these ARDS patients. Significantly lower α values were found for individuals with chronic obstructive pulmonary disease (P<0.001. Conclusion. The ABMps model allows the estimation of airway pressure drop at each bronchial generation with patient-specific physiological measurements and can be generated from data measured at the bedside. The distribution of patient-specific α values indicates that the overall ABM can be readily improved to better match observed data and capture patient condition.

Mediation analysis of severity of needs, service performance and outcomes for patients with mental disorders.

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Roux, Paul; Passerieux, Christine; Fleury, Marie-Josée

2016-12-01

Needs and service performance assessment are key components in improving recovery among individuals with mental disorders. To test the role of service performance as a mediating factor between severity of patients' needs and outcomes. A total of 339 adults with mental disorders were interviewed. A mediation analysis between severity of needs, service performance (adequacy of help, continuity of care and recovery orientation of services) and outcomes (personal recovery and quality of life) was carried out using structural equation modelling. The structural equation model provided a good fit with the data. An increase in needs was associated with lower service performance and worse outcomes, whereas higher service performance was associated with better outcomes. Service performance partially mediated the effect of patient needs on outcomes. Poorer service performance has a negative impact on outcomes for patients with the highest needs. Ensuring more efficient services for patients with high needs may help improve their recovery and quality of life. © The Royal College of Psychiatrists 2016.

Mother-Child Attachment and Cognitive Performance in Middle Childhood: An Examination of Mediating Mechanisms

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West, Katara K.; Mathews, Brittany L.; Kerns, Kathryn A.

2013-01-01

Although mother-child attachment has been shown to predict cognitive performance, there has been a lack of attention to the mediating mechanisms that explain these associations. In the present study, we investigated relations of early mother-child attachment and cognitive performance in middle childhood (the latter in terms of both academic…

Sympathetic mediated vasomotion and skin capillary permeability in diabetic patients with peripheral neuropathy

NARCIS (Netherlands)

Lefrandt, JD; Hoeven, JH; Roon, AM; Smit, AJ; Hoogenberg, K

Aims/hypothesis. A loss of sympathetic function could lead to changes in capillary fluid filtration in diabetic patients. We investigated whether a decreased sympathetically mediated vasomotion in the skin in diabetic patients with peripheral neuropathy is associated with an abnormal capillary

Coping mediates the effects of cognitive-behavioral therapy for alcohol use disorder among out-patient clients in Project MATCH when dependence severity is high.

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Roos, Corey R; Maisto, Stephen A; Witkiewitz, Katie

2017-09-01

There is inconsistent evidence that alcohol-specific coping is a mechanism of change in cognitive-behavioral therapy (CBT) for alcohol use disorder (AUD). Our primary aim was to test whether baseline dependence severity moderates the mediational effect of CBT on drinking outcomes via coping. Secondary data analysis of Project MATCH , a multi-site alcohol treatment trial in which participants, recruited in out-patient and aftercare arms, were randomized to three treatments: CBT, motivational enhancement therapy (MET) and Twelve-Step facilitation (TSF). Nine research sites in the United States. A total of 1063 adults with AUD. The primary outcomes were percentage days abstinent and percentage heavy drinking days at the 1-year follow-up. Coping was assessed with the Processes of Change Questionnaire . Dependence severity was measured with the Alcohol Dependence Scale . Among the full available sample (across treatment arms), there were no significant moderated mediation effects. Double moderated mediation analyses indicated that several moderated mediation effects were moderated by treatment arm (all P cognitive-behavioral therapy for alcohol use disorder was conditional on dependence severity. End-of-treatment coping mediated the positive treatment effects of cognitive-behavioral therapy on 1-year drinking outcomes among out-patient clients when dependence severity was high, but not when dependence severity was low or moderate. © 2017 Society for the Study of Addiction.

Quality of life and mediating role of patient scar assessment in burn patients.

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Oh, Hyunjin; Boo, Sunjoo

2017-09-01

In this study, we examined the plausibility of the mediating effect of the levels of patient scar assessment on the relationship between burn severity measured with total body surface area and burn-specific health-related quality of life (HRQL) among patients with burns in South Korea. In this cross sectional descriptive study, we collected data from 100 burn patients in three burn centers specializing in burn care in South Korea. Patient scar assessment, burn specific HRQL, and burn-related characteristics were self-reported with anonymous, paper-based surveys. The findings showed a positive correlation between burn severity, patient scar assessment, and HRQL in burn patients. The evidence of this paper is that quality of life after burns more determined by scar characteristics than burn severity. In the light of the poor HRQL in burn patients, the results of this study support that improving scar status could improve patients' HRQL. Health care providers should keep in mind that patients' perspectives of their scars would be a great indicator of their HRQL, so the providers' focus should be on intensive scar management intervention in their care. Copyright © 2017 Elsevier Ltd and ISBI. All rights reserved.

Estimation of Causal Mediation Effects for a Dichotomous Outcome in Multiple-Mediator Models using the Mediation Formula

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Wang, Wei; Nelson, Suchitra; Albert, Jeffrey M.

2013-01-01

Mediators are intermediate variables in the causal pathway between an exposure and an outcome. Mediation analysis investigates the extent to which exposure effects occur through these variables, thus revealing causal mechanisms. In this paper, we consider the estimation of the mediation effect when the outcome is binary and multiple mediators of different types exist. We give a precise definition of the total mediation effect as well as decomposed mediation effects through individual or sets ...

Surviving a Dry Future: Abscisic Acid (ABA)-Mediated Plant Mechanisms for Conserving Water under Low Humidity

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McAdam, Scott A. M.

2017-01-01

Angiosperms are able to respond rapidly to the first sign of dry conditions, a decrease in air humidity, more accurately described as an increase in the vapor pressure deficit between the leaf and the atmosphere (VPD), by abscisic acid (ABA)-mediated stomatal closure. The genes underlying this response offer valuable candidates for targeted selection of crop varieties with improved drought tolerance, a critical goal for current plant breeding programs, to maximize crop production in drier and increasingly marginalized environments, and meet the demands of a growing population in the face of a changing climate. Here, we review current understanding of the genetic mechanisms underpinning ABA-mediated stomatal closure, a key means for conserving water under dry conditions, examine how these mechanisms evolved, and discuss what remains to be investigated. PMID:29113039

Coping mediates the influence of personality on life satisfaction in patients with rheumatic diseases.

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Vollmann, Manja; Pukrop, Jörg; Salewski, Christel

2016-04-01

A rheumatic disease can severely impair a person's quality of life. The degree of impairment, however, is not closely related to objective indicators of disease severity. This study investigated the influence and the interplay of core psychological factors, i.e., personality and coping, on life satisfaction in patients with rheumatic diseases. Particularly, it was tested whether coping mediates the effects of personality on life satisfaction. In a cross-sectional design, 158 patients diagnosed with a rheumatic disease completed questionnaires assessing the Big 5 personality traits (BFI-10), several disease-related coping strategies (EFK) and life satisfaction (HSWBS). Data were analyzed using a complex multiple mediation analysis with the Big 5 personality traits as predictors, coping strategies as mediators and life satisfaction as outcome. All personality traits and seven of the nine coping strategies were associated with life satisfaction (rs > |0.16|, ps ≤ 0.05). The mediation analysis revealed that personality traits had no direct, but rather indirect effects on life satisfaction through coping. Neuroticism had a negative indirect effect on life satisfaction through less active problem solving and more depressive coping (indirect effects > -0.03, ps  0.06, ps rheumatic diseases. The interplay of these variables should be considered in psychological interventions for patients with rheumatic diseases.

Artificial humidification for the mechanically ventilated patient

OpenAIRE

Selvaraj, Nelson

2010-01-01

Caring for patients who are mechanically ventilated poses many\\ud challenges for critical care nurses. It is important to humidify the\\ud patient’s airways artificially to prevent complications such as\\ud ventilator-associated pneumonia. There is no gold standard to\\ud determine which type of humidification is best for patients who\\ud are artificially ventilated. This article provides an overview of\\ud commonly used artificial humidification for mechanically ventilated\\ud patients and discuss...

Avoidant coping partially mediates the relationship between patient problem behaviors and depressive symptoms in spousal Alzheimer caregivers.

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Mausbach, Brent T; Aschbacher, Kirstin; Patterson, Thomas L; Ancoli-Israel, Sonia; von Känel, Roland; Mills, Paul J; Dimsdale, Joel E; Grant, Igor

2006-04-01

Caring for a loved one with Alzheimer disease is a highly stressful experience that is associated with significant depressive symptoms. Previous studies indicate a positive association between problem behaviors in patients with Alzheimer disease (e.g., repeating questions, restlessness, and agitation) and depressive symptoms in their caregivers. Moreover, the extant literature indicates a robust negative relationship between escape-avoidance coping (i.e., avoiding people, wishing the situation would go away) and psychiatric well-being. The purpose of this study was to test a mediational model of the associations between patient problem behaviors, escape-avoidance coping, and depressive symptoms in Alzheimer caregivers. Ninety-five spousal caregivers (mean age: 72 years) completed measures assessing their loved ones' frequency of problem behaviors, escape-avoidance coping, and depressive symptoms. A mediational model was tested to determine if escape-avoidant coping partially mediated the relationship between patient problem behaviors and caregiver depressive symptoms. Patient problem behaviors were positively associated with escape-avoidance coping (beta = 0.38, p avoidance coping was positively associated with depressive symptoms (beta = 0.33, p avoidance coping. Sobel's test confirmed that escape-avoidance coping significantly mediated the relationship between problem behaviors and depressive symptoms (z = 2.07, p avoidance coping partially mediates the association between patient problem behaviors and depressive symptoms among elderly caregivers of spouses with dementia. This finding provides a specific target for psychosocial interventions for caregivers.

Local cell-mediated immune reactions in cancer patients

International Nuclear Information System (INIS)

Bilynskij, B.T.; Vasil'ev, N.V.; Volod'ko, N.A.; Akademiya Meditsinskikh Nauk SSSR, Tomsk. Onkologicheskij Nauchnyj Tsentr)

1988-01-01

The analysis of 178 cases of stage I-II breast cancer showed morphological features of local cell-mediated immune reactions to be of limited prognostic value. A comparative evaluation of some characteristics of cell surface receptors, such as ability to spontaneous rosette formation with sheep erythrocytes and sensitivty to theophylline, was carried out in lymphocyte samples obtained from tumor tissue and peripheral blood of 76 cancer patients subjected to preoperative radiotherapy. The said parameters were studied in breast cancer patients of rosette-forming cell reaction to theophylline were identified, the incidence of some of them being determined by the presence or absence of regional metastases. The level and functional activity of surface receptors of tumor mononuclear cells proved to influence prognosis

Nuclear overhauser enhancement mediated chemical exchange saturation transfer imaging at 7 Tesla in glioblastoma patients.

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Daniel Paech

Full Text Available BACKGROUND AND PURPOSE: Nuclear Overhauser Enhancement (NOE mediated chemical exchange saturation transfer (CEST is a novel magnetic resonance imaging (MRI technique on the basis of saturation transfer between exchanging protons of tissue proteins and bulk water. The purpose of this study was to evaluate and compare the information provided by three dimensional NOE mediated CEST at 7 Tesla (7T and standard MRI in glioblastoma patients. PATIENTS AND METHODS: Twelve patients with newly diagnosed histologically proven glioblastoma were enrolled in this prospective ethics committee-approved study. NOE mediated CEST contrast was acquired with a modified three-dimensional gradient-echo sequence and asymmetry analysis was conducted at 3.3 ppm (B1 = 0.7 µT to calculate the magnetization transfer ratio asymmetry (MTR(asym. Contrast enhanced T1 (CE-T1 and T2-weighted images were acquired at 3T and used for data co-registration and comparison. RESULTS: Mean NOE mediated CEST signal based on MTR(asym values over all patients was significantly increased (p<0.001 in CE-T1 tumor (-1.99 ± 1.22%, tumor necrosis (-1.36 ± 1.30% and peritumoral CEST hyperintensities (PTCH within T2 edema margins (-3.56 ± 1.24% compared to contralateral normal appearing white matter (-8.38 ± 1.19%. In CE-T1 tumor (p = 0.015 and tumor necrosis (p<0.001 mean MTR(asym values were significantly higher than in PTCH. Extent of the surrounding tumor hyperintensity was smaller in eight out of 12 patients on CEST than on T2-weighted images, while four displayed at equal size. In all patients, isolated high intensity regions (0.40 ± 2.21% displayed on CEST within the CE-T1 tumor that were not discernible on CE-T1 or T2-weighted images. CONCLUSION: NOE mediated CEST Imaging at 7 T provides additional information on the structure of peritumoral hyperintensities in glioblastoma and displays isolated high intensity regions within the CE-T1 tumor that cannot be acquired on CE-T1 or T2

Feline immunodeficiency virus envelope glycoprotein mediates apoptosis in activated PBMC by a mechanism dependent on gp41 function

International Nuclear Information System (INIS)

Garg, Himanshu; Joshi, Anjali; Tompkins, Wayne A.

2004-01-01

Feline Immunodeficiency Virus (FIV) is a lentivirus that causes immunodeficiency in cats, which parallels HIV-1-induced immunodeficiency in humans. It has been established that HIV envelope (Env) glycoprotein mediates T cell loss via a mechanism that requires CXCR4 binding. The Env glycoprotein of FIV, similar to HIV, requires CXCR4 binding for viral entry, as well as inducing membrane fusion leading to syncytia formation. However, the role of FIV Env in T cell loss and the molecular mechanisms governing this process have not been elucidated. We studied the role of Env glycoprotein in FIV-mediated T cell apoptosis in an in vitro model. Our studies demonstrate that membrane-expressed FIV Env induces apoptosis in activated feline peripheral blood mononuclear cells (PBMC) by a mechanism that requires CXCR4 binding, as the process was inhibited by CXCR4 antagonist AMD3100 in a dose-dependent manner. Interestingly, studies regarding the role of CD134, the recently identified primary receptor of FIV, suggest that binding to CD134 may not be important for induction of apoptosis in PBMC. However, inhibiting Env-mediated fusion post CXCR4 binding by FIV gp41-specific fusion inhibitor also inhibited apoptosis. Under similar conditions, a fusion-defective gp41 mutant was unable to induce apoptosis in activated PBMC. Our findings are the first report suggesting the potential of FIV Env to mediate apoptosis in bystander cells by a process that is dependent on gp41 function

Changes in cell-mediated immunity in patients undergoing radiotherapy

International Nuclear Information System (INIS)

Rafla, S.; Yang, S.J.; Meleka, F.

1978-01-01

The cell-mediated immune status of 147 patients who received radiotherapy was evaluated using in vitro tests (PHA, E-rosette, and spontaneous blastogenesis) both before and 6 weeks after the end of radiation. All patients have verified malignancies, involving the bronchus in 29 cases, breast in 28, female genital system in 26, head and neck in 20 and bladder in 15. Patients suffering from bronchogenic carcinomas or malignancies of the head and neck showed a relative high degree of immune suppression. Our findings indicate a trend towards some improvement in PHA reactivity, as well as in the percentage of E-rosette-forming cells after treatment, which is more noticeable in patients with pelvic or breast tumors. A relationship seems to exist between the tumor load and the immune status, which reverts to a normal pattern when the former is extinguished. Moreover, patients with poor clinical response display a profoundly depressed level of immune status without any improvement after treatment

Molecular mechanism underlying juvenile hormone-mediated repression of precocious larval-adult metamorphosis.

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Kayukawa, Takumi; Jouraku, Akiya; Ito, Yuka; Shinoda, Tetsuro

2017-01-31

Juvenile hormone (JH) represses precocious metamorphosis of larval to pupal and adult transitions in holometabolous insects. The early JH-inducible gene Krüppel homolog 1 (Kr-h1) plays a key role in the repression of metamorphosis as a mediator of JH action. Previous studies demonstrated that Kr-h1 inhibits precocious larval-pupal transition in immature larva via direct transcriptional repression of the pupal specifier Broad-Complex (BR-C). JH was recently reported to repress the adult specifier gene Ecdysone-induced protein 93F (E93); however, its mechanism of action remains unclear. Here, we found that JH suppressed ecdysone-inducible E93 expression in the epidermis of the silkworm Bombyx mori and in a B. mori cell line. Reporter assays in the cell line revealed that the JH-dependent suppression was mediated by Kr-h1. Genome-wide ChIP-seq analysis identified a consensus Kr-h1 binding site (KBS, 14 bp) located in the E93 promoter region, and EMSA confirmed that Kr-h1 directly binds to the KBS. Moreover, we identified a C-terminal conserved domain in Kr-h1 essential for the transcriptional repression of E93 Based on these results, we propose a mechanism in which JH-inducible Kr-h1 directly binds to the KBS site upstream of the E93 locus to repress its transcription in a cell-autonomous manner, thereby preventing larva from bypassing the pupal stage and progressing to precocious adult development. These findings help to elucidate the molecular mechanisms regulating the metamorphic genetic network, including the functional significance of Kr-h1, BR-C, and E93 in holometabolous insect metamorphosis.

Patient-mediated knowledge translation (PKT) interventions for clinical encounters: a systematic review

OpenAIRE

Gagliardi, Anna R.; L?gar?, France; Brouwers, Melissa C.; Webster, Fiona; Badley, Elizabeth; Straus, Sharon

2016-01-01

Background Patient-mediated knowledge translation (PKT) interventions engage patients in their own health care. Insight on which PKT interventions are effective is lacking. We sought to describe the type and impact of PKT interventions. Methods We performed a systematic review of PKT interventions, defined as strategies that inform, educate and engage patients in their own health care. We searched MEDLINE, EMBASE and the Cochrane Library from 2005 to 2014 for English language studies that eva...

Forespore engulfment mediated by a ratchet-like mechanism.

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Broder, Dan H; Pogliano, Kit

2006-09-08

A key step in bacterial endospore formation is engulfment, during which one bacterial cell engulfs another in a phagocytosis-like process that normally requires SpoIID, SpoIIM, and SpoIIP (DMP). We here describe a second mechanism involving the zipper-like interaction between the forespore protein SpoIIQ and its mother cell ligand SpoIIIAH, which are essential for engulfment when DMP activity is reduced or SpoIIB is absent. They are also required for the rapid engulfment observed during the enzymatic removal of peptidoglycan, a process that does not require DMP. These results suggest the existence of two separate engulfment machineries that compensate for one another in intact cells, thereby rendering engulfment robust. Photobleaching analysis demonstrates that SpoIIQ assembles a stationary structure, suggesting that SpoIIQ and SpoIIIAH function as a ratchet that renders forward membrane movement irreversible. We suggest that ratchet-mediated engulfment minimizes the utilization of chemical energy during this dramatic cellular reorganization, which occurs during starvation.

SUSY breaking mediation mechanisms and (g-2)μ, B→Xsγ, B→Xsl+l- and Bs→μ+μ-

International Nuclear Information System (INIS)

Baek, Seungwon; Ko, P.; Song, Wan Young

2003-01-01

We show that there are qualitative differences in correlations among (g-2)μ, B→X s γ, B→X l + l - and B s →μ + μ - in various SUSY breaking mediation mechanisms: minimal supergravity (mSUGRA), gauge mediation (GMSB), anomaly mediation (AMSB), guagino mediation (g-tildeMSB), weakly and strongly interacting string theories, and D brane models. After imposing the direct search limits on the Higgs boson and SUSY particle search limits and B→X s γ branching ratio, we find all the scenarios can accommodate the aμ≡(g-2)μ/2 in the range of (a few tens) x 10 -10 , and predict that the branching ratio for B→X s l + l - can differ from the standard model (SM) prediction by ±20% but no more. On the other hand, the B s →μ + μ - is sensitive to the SUSY breaking mediation mechanisms through the pseudoscalar and stop masses (m A and mt-tilde 1 ), and the stop mixing angle. In the GMSB with a small messenger number, the AMSB, the g-tildeMSB and the noscale scenarios, one finds that B(B s →μ + μ - ) -8 , which is below the search limit at the Tevatron Run II. Only the mSUGRA or string inspired models can generate a large branching ratio for this decay. (author)

Specific efficacy expectations mediate exercise compliance in patients with COPD.

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Kaplan, R M; Atkins, C J; Reinsch, S

1984-01-01

Social learning theory has generated two different approaches for the assessment of expectancies. Bandura argues that expectancies are specific and do not generalize. Therefore, he prefers measures of specific efficacy expectations. Others endorse the role of generalized expectancies measured by locus of control scales. The present study examines specific versus generalized expectancies as mediators of changes in exercise behavior among 60 older adult patients with Chronic Obstructive Pulmonary Disease. The patients were given a prescription to increase exercise and randomly assigned to experimental groups or control groups. All groups received attention but only experimental groups received training to increase their exercise. After 3 months, groups given specific training for compliance with walking significantly increased their activity in comparison to the control group receiving only attention. These changes were mediated by changes in perceived efficacy for walking, with efficacy expectations for other behaviors changing as a function of their similarity to walking. A generalized health locus of control expectancy measure was less clearly associated with behavior change. The results are interpreted as supporting Bandura's version of social theory.

FLOW MEDIATED DILATION AND CAROTID INTIMA MEDIA THICKNESS IN PATIENTS WITH CHRONIC GASTRITIS ASSOCIATED WITH HELICOBACTER PYLORI INFECTION.

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Judaki, Arezo; Norozi, Siros; Ahmadi, Mohammad Reza Hafezi; Ghavam, Samira Mis; Asadollahi, Khairollah; Rahmani, Asghar

2017-12-01

Endothelial dysfunction is one of the early stages of vascular diseases. The aim of this study was to investigate the endothelial dysfunction markers in patients with chronic gastritis associated with Helicobacter pylori (H. pylori) infection. By a cross sectional study, basic and clinical information of 120 participants (40 patients with positive H. pylori infection, 40 patients with negative H. pylori infection and 40 healthy people) were analyzed. Carotid intima media thickness and flow-mediated dilation levels were measured in all patients and controls. Soluble vascular cell adhesion molecule-1 (sVCAM-1) and intercellular adhesion molecule-1 (ICAM-1) were measured with Elisa for all subjects. IgG level was assessed in chronic gastritis patients. The flow-mediated dilation level in patients with positive H. pylori infection (0.17%±0.09) was significantly lower than those with negative H. pylori infection (0.21% ±0.10, Pgastritis. The levels of flow-mediated dilation, carotid intima media thickness and sICAM-1 were higher among patients with positive H. pylori infection. Patients with chronic gastritis associated with H. pylori infection are at risk of endothelial dysfunction due to flow-mediated dilation and carotid intima media thickness abnormalities and increased level of sICAM-1 and sVCAM-1.

Distinct evolution of TLR-mediated dendritic cell cytokine secretion in patients with limited and diffuse cutaneous systemic sclerosis.

NARCIS (Netherlands)

Bon, L. van; Popa, C.; Huibens, R.J.F.; Vonk, M.C.; York, M.; Simms, R.; Hesselstrand, R.; Wuttge, D.M.; Lafyatis, R.; Radstake, T.R.D.J.

2010-01-01

BACKGROUND: Systemic sclerosis (SSc) is an autoimmune disease and accumulating evidence suggests a role for Toll-like receptor (TLR)-mediated activation of dendritic cells (DCs). OBJECTIVE: To map TLR-mediated cytokine responses of DCs from patients with SSc. METHODS: 45 patients with SSc were

Mechanisms and mediation in survival analysis: towards an integrated analytical framework

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Jonathan Pratschke

2016-02-01

Full Text Available Abstract Background A wide-ranging debate has taken place in recent years on mediation analysis and causal modelling, raising profound theoretical, philosophical and methodological questions. The authors build on the results of these discussions to work towards an integrated approach to the analysis of research questions that situate survival outcomes in relation to complex causal pathways with multiple mediators. The background to this contribution is the increasingly urgent need for policy-relevant research on the nature of inequalities in health and healthcare. Methods The authors begin by summarising debates on causal inference, mediated effects and statistical models, showing that these three strands of research have powerful synergies. They review a range of approaches which seek to extend existing survival models to obtain valid estimates of mediation effects. They then argue for an alternative strategy, which involves integrating survival outcomes within Structural Equation Models via the discrete-time survival model. This approach can provide an integrated framework for studying mediation effects in relation to survival outcomes, an issue of great relevance in applied health research. The authors provide an example of how these techniques can be used to explore whether the social class position of patients has a significant indirect effect on the hazard of death from colon cancer. Results The results suggest that the indirect effects of social class on survival are substantial and negative (-0.23 overall. In addition to the substantial direct effect of this variable (-0.60, its indirect effects account for more than one quarter of the total effect. The two main pathways for this indirect effect, via emergency admission (-0.12, on the one hand, and hospital caseload, on the other, (-0.10 are of similar size. Conclusions The discrete-time survival model provides an attractive way of integrating time-to-event data within the field of

Mechanisms and mediation in survival analysis: towards an integrated analytical framework.

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Pratschke, Jonathan; Haase, Trutz; Comber, Harry; Sharp, Linda; de Camargo Cancela, Marianna; Johnson, Howard

2016-02-29

A wide-ranging debate has taken place in recent years on mediation analysis and causal modelling, raising profound theoretical, philosophical and methodological questions. The authors build on the results of these discussions to work towards an integrated approach to the analysis of research questions that situate survival outcomes in relation to complex causal pathways with multiple mediators. The background to this contribution is the increasingly urgent need for policy-relevant research on the nature of inequalities in health and healthcare. The authors begin by summarising debates on causal inference, mediated effects and statistical models, showing that these three strands of research have powerful synergies. They review a range of approaches which seek to extend existing survival models to obtain valid estimates of mediation effects. They then argue for an alternative strategy, which involves integrating survival outcomes within Structural Equation Models via the discrete-time survival model. This approach can provide an integrated framework for studying mediation effects in relation to survival outcomes, an issue of great relevance in applied health research. The authors provide an example of how these techniques can be used to explore whether the social class position of patients has a significant indirect effect on the hazard of death from colon cancer. The results suggest that the indirect effects of social class on survival are substantial and negative (-0.23 overall). In addition to the substantial direct effect of this variable (-0.60), its indirect effects account for more than one quarter of the total effect. The two main pathways for this indirect effect, via emergency admission (-0.12), on the one hand, and hospital caseload, on the other, (-0.10) are of similar size. The discrete-time survival model provides an attractive way of integrating time-to-event data within the field of Structural Equation Modelling. The authors demonstrate the efficacy

The mechanism of mediated oxidation of carboxylates with ferrocene as redox catalyst in absence of grafting effects. An experimental and theoretical approach

International Nuclear Information System (INIS)

Hernández-Muñoz, Lindsay S.; Galano, Annia; Astudillo-Sánchez, Pablo D.; Abu-Omar, Mahdi M.; González, Felipe J.

2014-01-01

Graphical abstract: - Highlights: • The mechanism of mediated oxidation of carboxylates. • Thermodynamics of the mediated Kolbe and Non-Kolbe mechanisms. • The oxidation of acetate and diphenylacetate ions by using ferrocene as redox catalyst. • Simulation and DFT calculations of the mediated oxidation of carboxylates. • Radical and carbocationic pathways in the carboxylate oxidation in acetonitrile. - Abstract: The oxidation of tetrabutylammonium carboxylates by using ferrocene derivatives as redox mediators has been recently used to perform the covalent grafting of carbon surfaces with organic and organometallic groups. Due to the intervention of this surface process, a partial description of the reaction mechanism has only been stated. Therefore, this article concerns about two features of the oxidation of carboxylates mediated by ferrocene. In the first part, it is discussed that in the oxidation of acetate ions by using ferrocene as redox catalyst, the gap between both oxidation potentials is very high, which means that the homogeneous electron transfer between the acetate ion and the electrochemically generated ferrocenium ion is energetically unfavorable. However, by using density functional theory calculations, it has been shown that the whole set of coupled chemical reactions involved either in a Kolbe or Non-Kolbe pathway drive the overall mechanisms towards a thermodynamically favorable situation. In order to avoid the strong covalent grafting process that occurs during the mediated oxidation of acetate ions, the second part of this work deals with the oxidation of tetrabutylammonium diphenylacetate by using ferrocene as a redox mediator in acetonitrile on glassy carbon electrodes. With this carboxylate, no electrode inhibition process occurs and, therefore cyclic voltammetry simulation was done to propose the electrochemical and chemical steps that are present when a carboxylate oxidation is performed in the presence of ferrocene derivatives

Mechanisms of Quality of Life and Social Support in Inflammatory Bowel Disease.

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Katz, Laura; Tripp, Dean A; Ropeleski, Mark; Depew, William; Curtis Nickel, J; Vanner, Stephen; Beyak, Michael J

2016-03-01

Cognitive and social factors are essential considerations in inflammatory bowel disease (IBD) patient management, but existing research is limited. This study aims to expand the IBD literature by examining the relationship between social supports and QoL, while examining mechanisms in these relationships. Consenting patients attending an IBD outpatient clinic were provided a survey package (N = 164). Regressions evaluated predictors of IBD-QoL, and catastrophizing and optimism were examined as mediators between social support and IBD-QoL. Diminished IBD-QoL was predicted by younger age, greater negative spousal responses, and less perceived spousal support. Mediation models showed helplessness catastrophizing to be the lone mediator, acting as a mechanism between both negative spousal responses and perceived spousal support with IBD-QoL. Social interaction variables are associated with IBD-QoL, but patients' experience of helplessness acts to reduce their ability to benefit from social support. Patient care should consider supportive social and cognitive factors to improve IBD-QoL.

Sleep Disturbance, Daytime Symptoms, and Functional Performance in Patients With Stable Heart Failure: A Mediation Analysis.

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Jeon, Sangchoon; Redeker, Nancy S

2016-01-01

Sleep disturbance is common among patients with heart failure (HF) who also experience symptom burden and poor functional performance. We evaluated the extent to which sleep-related, daytime symptoms (fatigue, excessive daytime sleepiness, and depressive symptoms) mediate the relationship between sleep disturbance and functional performance among patients with stable HF. We recruited patients with stable HF for this secondary analysis of data from a cross-sectional, observational study. Participants completed unattended ambulatory polysomnography from which the Respiratory Disturbance Index was calculated, along with a Six-Minute Walk Test, questionnaires to elicit sleep disturbance (Pittsburgh Sleep Quality Index, Insomnia Symptoms from the Sleep Habits Questionnaire), daytime symptoms (Center for Epidemiologic Studies Depression Scale, Global Fatigue Index, Epworth Sleepiness Scale), and self-reported functional performance (Medical Outcomes Study SF36 V2 Physical Function Scale). We used structural equation modeling with latent variables for the key analysis. Follow-up, exploratory regression analysis with bootstrapped samples was used to examine the extent to which individual daytime symptoms mediated effects of sleep disturbance on functional performance after controlling for clinical and demographic covariates. The sample included 173 New York Heart Association Class I-IV HF patients (n = 60/34.7% women; M = 60.7, SD = 16.07 years of age). Daytime symptoms mediated the relationship between sleep disturbance and functional performance. Fatigue and depression mediated the relationship between insomnia symptoms and self-reported functional performance, whereas fatigue and sleepiness mediated the relationship between sleep quality and functional performance. Sleepiness mediated the relationship between the respiratory index and self-reported functional performance only in people who did not report insomnia. Daytime symptoms explain the relationships between sleep

Mediation designs for tobacco prevention research

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MacKinnon, David P.; Taborga, Marcia P.; Morgan-Lopez, Antonio A.

2010-01-01

This paper describes research designs and statistical analyses to investigate how tobacco prevention programs achieve their effects on tobacco use. A theoretical approach to program development and evaluation useful for any prevention program guides the analysis. The theoretical approach focuses on action theory for how the program affects mediating variables and on conceptual theory for how mediating variables are related to tobacco use. Information on the mediating mechanisms by which tobacco prevention programs achieve effects is useful for the development of efficient programs and provides a test of the theoretical basis of prevention efforts. Examples of these potential mediating mechanisms are described including mediated effects through attitudes, social norms, beliefs about positive consequences, and accessibility to tobacco. Prior research provides evidence that changes in social norms are a critical mediating mechanism for successful tobacco prevention. Analysis of mediating variables in single group designs with multiple mediators are described as well as multiple group randomized designs which are the most likely to accurately uncover important mediating mechanisms. More complicated dismantling and constructive designs are described and illustrated based on current findings from tobacco research. Mediation analysis for categorical outcomes and more complicated statistical methods are outlined. PMID:12324176

Morphological and mechanical properties of polyamide 6/linear low density polyethylene blend compatibilized by electron-beam initiated mediation process

International Nuclear Information System (INIS)

Shin, Boo Young; Han, Do Hung

2014-01-01

The aim of this study was to compatibilize immiscible polyamide 6 (PA6)/linear low density polyethylene (LLDPE) blend by using electron-beam initiated mediation process. Glycidyl methacrylate (GMA) was chosen as a mediator for cross-copolymerization at the interface between PA6 and LLDPE. The exposure process was carried out to initiate cross-copolymerization by the medium of GMA at the interface between PA and LLDPE. The mixture of the PA6/LLDPE/GMA was prepared by using a twin-screw extruder, and then the mixture was exposed to electron-beam radiation at various doses at room temperature. To investigate the results of this compatibilization strategy, the morphological and mechanical properties of the blend were analyzed. Morphology study revealed that the diameters of the dispersion particles decreased and the interfacial adhesion increased with respect to irradiation doses. The elongation at break of the blends increases significantly with increasing irradiation dose up to 100 kGy while the tensile strength and the modulus increased nonlinearly with increasing irradiation dose. The reaction mechanisms of the mediation process with the GMA mediator at the interface between PA6 and LLDPE were estimated. - Highlights: • PA6/LLDPE blend was compatibilized by the electron-beam initiated mediation process. • Interfacial adhesion was significantly enhanced by the radiation initiated cross-copolymerization. • The elongation at break of blend irradiated at 100 kGy was 4 times higher than PA6. • The GMA as a mediator played a key role in the electron-beam initiated mediation process

Genistein-mediated inhibition of glycosaminoglycan synthesis, which corrects storage in cells of patients suffering from mucopolysaccharidoses, acts by influencing an epidermal growth factor-dependent pathway

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Barańska Sylwia

2009-03-01

Full Text Available Abstract Background Mucopolysaccharidoses (MPS are inherited metabolic disorders caused by mutations leading to dysfunction of one of enzymes involved in degradation of glycosaminoglycans (GAGs. Due to their impaired degradation, GAGs accumulate in cells of patients, which results in dysfunction of tissues and organs. Substrate reduction therapy is one of potential treatment of these diseases. It was demonstrated previously that genistein (4', 5, 7-trihydroxyisoflavone inhibits synthesis and reduces levels of GAGs in cultures of fibroblasts of MPS patients. Recent pilot clinical study indicated that such a therapy may be effective in MPS III (Sanfilippo syndrome. Methods To learn on details of the molecular mechanism of genistein-mediated inhibition of GAG synthesis, efficiency of this process was studied by measuring of incorporation of labeled sulfate, storage of GAGs in lysosomes was estimated by using electron microscopic techniques, and efficiency of phosphorylation of epidermal growth factor (EGF receptor was determined by using an ELISA-based assay with fluorogenic substrates. Results Effects of genistein on inhibition of GAG synthesis and accumulation in fibroblasts from patients suffering from various MPS types were abolished in the presence of an excess of EGF, and were partially reversed by an increased concentration of genistein. No such effects were observed when an excess of 17β-estradiol was used instead of EGF. Moreover, EGF-mediated stimulation of phsophorylation of the EGF receptor was impaired in the presence of genistein in both wild-type and MPS fibroblasts. Conclusion The results presented in this report indicate that the mechanism of genistein-mediated inhibition of GAG synthesis operates through epidermal growth factor (EGF-dependent pathway.

God image and happiness in chronic pain patients: the mediating role of disease interpretation.

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Dezutter, Jessie; Luyckx, Koen; Schaap-Jonker, Hanneke; Büssing, Arndt; Corveleyn, Jozef; Hutsebaut, Dirk

2010-05-01

The present study explored the role of the emotional experience of God (i.e., positive and negative God images) in the happiness of chronic pain (CP) patients. Framed in the transactional model of stress, we tested a model in which God images would influence happiness partially through its influence on disease interpretation as a mediating mechanism. We expected God images to have both a direct and an indirect (through the interpretation of disease) effect on happiness. A cross-sectional questionnaire design was adopted in order to measure demographics, pain condition, God images, disease interpretation, and happiness. One hundred thirty-six CP patients, all members of a national patients' association, completed the questionnaires. Correlational analyses showed meaningful associations among God images, disease interpretation, and happiness. Path analyses from a structural equation modeling approach indicated that positive God images seemed to influence happiness, both directly and indirectly through the pathway of positive interpretation of the disease. Ancillary analyses showed that the negative influence of angry God images on happiness disappeared after controlling for pain severity. The results indicated that one's emotional experience of God has an influence on happiness in CP patients, both directly and indirectly through the pathway of positive disease interpretation. These findings can be framed within the transactional theory of stress and can stimulate further pain research investigating the possible effects of religion in the adaptation to CP.

Immune-Mediated Neutropenia and Thrombocytopenia in a Patient with Ulcerative Colitis: An Unusual Hematological Association with IBD

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Young-In Kim

1995-01-01

Full Text Available Hematological manifestations of inflammatory bowel disease (IBD are well described in the literature. However, the combination of immune-mediated neutropenia and thrombocytopenia has only been reported once in association with IBD. A case is reported of immune-mediated neutropenia and thrombocytopenia in a patient with ulcerative colitis during a relapse. No obvious causes of these hematological abnormalities were found in the patient despite an exhaustive search. An immune-mediated process was confirmed by positive antineutrophil antibody and platelet-associated antibody in the patient’s serum, and the demonstration of binding of the patient’s immunoglobulin G to autologous neutrophils. The patient was treated with high-dose steroid, intravenous gamma-globulin and eventually splenectomy. The platelet count subsequently normalized; although the severe neutropenia recurred, it has subsequently improved without further treatment. Although a definitive cause-effect relationship cannot be established, the immune-mediated neutropenia and thrombocytopenia may be an unusual hematological manifestation associated with ulcerative colitis.

Mediating Effects of Patients' Stigma and Self-Efficacy on Relationships Between Doctors' Empathy Abilities and Patients' Cellular Immunity in Male Breast Cancer Patients.

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Yang, Ningxi; Cao, Yingnan; Li, Xiaoyan; Li, Shiyue; Yan, Hong; Geng, Qingshan

2018-06-12

BACKGROUND Doctors' empathy is closely related to patients' health. This study aimed to examine whether patients' stigma and self-efficacy play a mediating role in the relationship between doctors' empathy abilities and patients' cellular immunity in male patients with breast cancer. MATERIAL AND METHODS Doctors' empathy scores and patients' demographic data, disease condition, stigma, and self-efficacy were measured. Patient T cell subset was tested at admission and 3 months after the operation and was compared by paired t test. The multivariate linear regression model was applied to analyze the factors influencing the immune index. Pearson correlation analysis and structural equation modeling were applied to explore the relationships among patients' stigma, self-efficacy, and cellular immunity and doctors' empathy abilities. RESULTS At the 2 time points, only the change in NK subset was statistically significant, while the changes in percentage of CD3+, CD4+, CD8+, and B cells were not statistically significant. The doctors' empathy abilities were negatively correlated with patients' stigma and were positively related to patients' self-efficacy. Patients' stigma was negatively related to NK subset, while self-efficacy was positively associated with NK subset. Patients' stigma and self-efficacy played a mediating role in the relationship between doctors' empathy abilities and patients' NK subset, and stigma had a stronger effect than self-efficacy. CONCLUSIONS Doctors' empathy abilities affected breast cancer patients' NK subset through their stigma and self-efficacy. The mental health of male breast cancer patients need more attention and empathy education needs to be improved.

Tc1-mediated contact sensitivity reaction, its mechanism and regulation

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Magdalena Zemelka-Wiącek

2014-07-01

Full Text Available The contact hypersensitivity reaction (CHS to haptens is a classic example of cell-mediated immune response. In the effector phase, two stages can be distinguished: an early component, that appears only 2 hours after subsequent contact with the hapten, and the late component that develops approximately 24 hours later which is mediated by TCRαβ+ cells. The effector lymphocytes may be CD4+ T helper 1 (Th1 cells or CD8+ T cytotoxic 1 (Tc1 cells, which depends on the employed hapten and/or mice strain. NKT lymphocytes play the crucial role in the CHS initiation, by supporting B1 cells in the antigen-specific IgM antibodies production. The development of an early component is essential for the recruitment of T effector (Teff cells to the side of hapten deposition and for the complete expansion of inflammatory reaction. The CHS reaction is under T regulatory (Treg cells control, both in the induction phase as well as in the effector phase. A new view of a negative regulation of the Tc1 mediated CHS response is based on the suppression induced by epicutaneous (EC application of protein antigen. The DNP-BSA skin application, on a gauze patch, leads to a state of immunosuppression. This maneuver results in rising the population of Treg cells with TCRαβ+CD4+CD25+Foxp3+ phenotype. The mechanism of suppression requires direct contact between Treg cells and Teff cells and the participation of CTLA-4 molecule is also necessary. The described method of evoking immune tolerance via EC immunization may contribute to elaborate a new method of allergic contact dermatitis therapy. This is because of its effectiveness, ease of induction and non-invasive protein antigen application.

Mediating Mechanisms of Theory-Based Psychosocial Determinants on Behavioral Changes in a Middle School Obesity Risk Reduction Curriculum Intervention, Choice, Control, and Change.

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Gray, Heewon Lee; Contento, Isobel R; Koch, Pamela A; Noia, Jennifer Di

2016-10-01

A limited number of school-based intervention studies have explored mediating mechanisms of theory-based psychosocial variables on obesity risk behavior changes. The current study investigated how theory-based psychosocial determinants mediated changes in energy balance-related behaviors (EBRBs) among urban youth. A secondary analysis study was conducted using data from a cluster randomized controlled trial. Data from students at 10 middle schools in New York City (n = 1136) were used. The intervention, Choice, Control, and Change curriculum, was based on social cognitive and self-determination theories. Theory-based psychosocial determinants (goal intention, cognitive outcome expectations, affective outcome expectations, self-efficacy, perceived barriers, and autonomous motivation) and EBRBs were measured with self-report questionnaires. Mediation mechanisms were examined using structural equation modeling, Results: Mediating mechanisms for daily sugar-sweetened beverage (SSB) consumption and purposeful stair climbing were identified. Models with best fit indices (root mean square error of approximation = 0.039/0.045, normed fit index = 0.916/0.882; comparative fit index = 0.945/0.932; Tucker-Lewis index = 0.896/0.882, respectively) suggested that goal intention and reduced perceived barriers were significant proximal mediators for reducing SSB consumption among both boys and girls or increasing physical activity by stair climbing among boys. Cognitive outcome expectations, affective outcome expectations, self-efficacy, and autonomous motivation indirectly mediated behavioral changes through goal intention or perceived barriers (p behavioral outcome variances. Theory-based psychosocial determinants targeted in Choice, Control, and Change in fact mediated behavior changes in middle school students. Strategies targeting these mediators might benefit future success of behavioral interventions. Further studies are needed to determine other

Randomized, controlled trial of TNF-α antagonist in CTL-mediated severe cutaneous adverse reactions.

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Wang, Chuang-Wei; Yang, Lan-Yan; Chen, Chun-Bing; Ho, Hsin-Chun; Hung, Shuen-Iu; Yang, Chih-Hsun; Chang, Chee-Jen; Su, Shih-Chi; Hui, Rosaline Chung-Yee; Chin, See-Wen; Huang, Li-Fang; Lin, Yang Yu-Wei; Chang, Wei-Yang; Fan, Wen-Lang; Yang, Chin-Yi; Ho, Ji-Chen; Chang, Ya-Ching; Lu, Chun-Wei; Chung, Wen-Hung

2018-03-01

Cytotoxic T lymphocyte-mediated (CTL-mediated) severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), are rare but life-threatening adverse reactions commonly induced by drugs. Although high levels of CTL-associated cytokines, chemokines, or cytotoxic proteins, including TNF-α and granulysin, were observed in SJS-TEN patients in recent studies, the optimal treatment for these diseases remains controversial. We aimed to evaluate the efficacy, safety, and therapeutic mechanism of a TNF-α antagonist in CTL-mediated SCARs. We enrolled 96 patients with SJS-TEN in a randomized trial to compare the effects of the TNF-α antagonist etanercept versus traditional corticosteroids. Etanercept improved clinical outcomes in patients with SJS-TEN. Etanercept decreased the SCORTEN-based predicted mortality rate (predicted and observed rates, 17.7% and 8.3%, respectively). Compared with corticosteroids, etanercept further reduced the skin-healing time in moderate-to-severe SJS-TEN patients (median time for skin healing was 14 and 19 days for etanercept and corticosteroids, respectively; P = 0.010), with a lower incidence of gastrointestinal hemorrhage in all SJS-TEN patients (2.6% for etanercept and 18.2% for corticosteroids; P = 0.03). In the therapeutic mechanism study, etanercept decreased the TNF-α and granulysin secretions in blister fluids and plasma (45.7%-62.5% decrease after treatment; all P etanercept serves as an effective alternative for the treatment of CTL-mediated SCARs. ClinicalTrials.gov NCT01276314. Ministry of Science and Technology of Taiwan.

Ficolin-3-mediated lectin complement pathway activation in patients with subarachnoid hemorrhage

DEFF Research Database (Denmark)

Zanier, Elisa R; Zangari, Rosalia; Munthe-Fog, Lea

2014-01-01

OBJECTIVES: To assess the involvement of ficolin-3, the main initiator of the lectin complement pathway (LCP), in subarachnoid hemorrhage (SAH) pathology and outcome. METHODS: In this preliminary exploratory study, plasma concentration of ficolin-3 and of ficolin-3-mediated functional LCP activity...... the World Federation of Neurosurgical Societies grading scale; vasospasm, defined as neuro-worsening with angiographic confirmation of vessel narrowing; cerebral ischemia, defined as hypodense lesion on CT scan performed before discharge; and 6-month outcome, assessed using the Glasgow Outcome Scale....... RESULTS: In patients, no changes were detected for ficolin-3 compared with controls. Notably, however, ficolin-3-mediated functional LCP activity was reduced. Low levels of plasma ficolin-3 and ficolin-3-mediated functional LCP activity were related to SAH severity, vasospasm, and cerebral ischemia...

Sleep and dreaming: induction and mediation of REM sleep by cholinergic mechanisms.

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Hobson, J A

1992-12-01

The most important recent work on the neurobiology of sleep has focused on the precise cellular and biochemical mechanisms of rapid eye movement sleep mediation. Direct and indirect evidence implicates acetylcholine-containing neurons in the peribrachial pons as critical in the triggering and maintenance of rapid eye movement sleep. Other new studies provide support for the hypothesis that the cholinergic generator system is gated during waking by serotonergic and noradrenergic influences. A growing consensus regarding the basic neurobiology has stimulated new thinking about the brain basis of consciousness during waking and dreaming.

Ca{sup 2+} influx and ATP release mediated by mechanical stretch in human lung fibroblasts

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Murata, Naohiko [Department of Respiratory Medicine, Nagoya University Graduate School of Medicine, Nagoya 466-8550 (Japan); Ito, Satoru, E-mail: itori@med.nagoya-u.ac.jp [Department of Respiratory Medicine, Nagoya University Graduate School of Medicine, Nagoya 466-8550 (Japan); Furuya, Kishio [Mechanobiology Laboratory, Nagoya University Graduate School of Medicine, Nagoya 466-8550 (Japan); Takahara, Norihiro [Department of Respiratory Medicine, Nagoya University Graduate School of Medicine, Nagoya 466-8550 (Japan); Naruse, Keiji [Department of Cardiovascular Physiology, Okayama University Graduate School of Medicine, Okayama 700-8558 (Japan); Aso, Hiromichi; Kondo, Masashi [Department of Respiratory Medicine, Nagoya University Graduate School of Medicine, Nagoya 466-8550 (Japan); Sokabe, Masahiro [Mechanobiology Laboratory, Nagoya University Graduate School of Medicine, Nagoya 466-8550 (Japan); Hasegawa, Yoshinori [Department of Respiratory Medicine, Nagoya University Graduate School of Medicine, Nagoya 466-8550 (Japan)

2014-10-10

Highlights: • Uniaxial stretching activates Ca{sup 2+} signaling in human lung fibroblasts. • Stretch-induced intracellular Ca{sup 2+} elevation is mainly via Ca{sup 2+} influx. • Mechanical strain enhances ATP release from fibroblasts. • Stretch-induced Ca{sup 2+} influx is not mediated by released ATP or actin cytoskeleton. - Abstract: One cause of progressive pulmonary fibrosis is dysregulated wound healing after lung inflammation or damage in patients with idiopathic pulmonary fibrosis and severe acute respiratory distress syndrome. The mechanical forces are considered to regulate pulmonary fibrosis via activation of lung fibroblasts. In this study, the effects of mechanical stretch on the intracellular Ca{sup 2+} concentration ([Ca{sup 2+}]{sub i}) and ATP release were investigated in primary human lung fibroblasts. Uniaxial stretch (10–30% in strain) was applied to fibroblasts cultured in a silicone chamber coated with type I collagen using a stretching apparatus. Following stretching and subsequent unloading, [Ca{sup 2+}]{sub i} transiently increased in a strain-dependent manner. Hypotonic stress, which causes plasma membrane stretching, also transiently increased the [Ca{sup 2+}]{sub i}. The stretch-induced [Ca{sup 2+}]{sub i} elevation was attenuated in Ca{sup 2+}-free solution. In contrast, the increase of [Ca{sup 2+}]{sub i} by a 20% stretch was not inhibited by the inhibitor of stretch-activated channels GsMTx-4, Gd{sup 3+}, ruthenium red, or cytochalasin D. Cyclic stretching induced significant ATP releases from fibroblasts. However, the stretch-induced [Ca{sup 2+}]{sub i} elevation was not inhibited by ATP diphosphohydrolase apyrase or a purinergic receptor antagonist suramin. Taken together, mechanical stretch induces Ca{sup 2+} influx independently of conventional stretch-sensitive ion channels, the actin cytoskeleton, and released ATP.

Mechanism of supply chain coordination cased on dynamic capability framework-the mediating role of manufacturing capabilities

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Tiantian Gao

2014-10-01

Full Text Available Purpose: A critical issue has been absent from the conversation on supply chain coordination: how supply chain coordination influence the enterprise performance. This research proposes a new vision to research the performance mechanism of supply chain coordination capability as a dynamic capability. Manufacturing capabilities are existed as mediating role. Design/methodology/approach: Data from International Manufacturing Strategy Survey in 2009 is used to verify the mediating model by hierarchical regression analysis. Findings: The results show that supply chain coordination impacts the enterprise performance positively and indirect impacts the enterprise performance through quality, cost, flexibility. Research implications: This study presents an overview of the impact of supply chain coordination and manufacturing capabilities on enterprise performance, giving grasp for further research of the relationships that exist between them. Originality/value: This finding integrates insights from previous research in dynamic capability framework and supply chain management into a generalization and extension of the performance mechanism in manufacturing enterprises.

Health-related quality of life in patients with hepatocellular carcinoma: the mediation effects of illness perceptions and coping.

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Fan, Sheng-Yu; Eiser, Christine; Ho, Ming-Chih; Lin, Cheng-Yao

2013-06-01

The aims of this study were to explore health-related quality of life (HRQOL) in patients with hepatocellular carcinoma (HCC). We report the following: (1) differences in HRQOL between patients with HCC and the general population; (2) significant physical and psychological predictors of HRQOL; and (3) mediation effects of illness perceptions and coping on HRQOL. Patients with HCC (n = 286) from Taiwan completed standardized measures of HRQOL, illness perception (cognitive representations, emotional representations and illness comprehensibility) and coping (emotion-oriented and problem-orientation coping). Demographic and physical variables were also collected. Patients with HCC had worse global HRQOL, physical, role, cognitive and social functioning, but better emotional functioning than the general population. Physical variables and cognitive representation were significant predictors of global HRQOL, physical functioning and emotional functioning. Cognitive representation mediated the relationships between physical variables and global HRQOL, physical functioning and emotional functioning, but coping only mediated the relationship between cognitive representation and global HRQOL. The results suggest that physical variables have direct effects on global HRQOL and physical functioning, but there were also partial mediations through cognitive representation. The effect of physical variables on emotional functioning was mediated through cognitive and emotional representations. Patients with better performance status and positive illness perceptions tended to report better HRQOL, but those with negative illness perceptions and who used more emotion-oriented coping had worse HRQOL. Limitations of the work associated with use of theory and measures developed in Europe and the US are discussed, as are the clinical implications for patients with HCC. Copyright © 2012 John Wiley & Sons, Ltd.

Hyperammonemia in cirrhosis induces transcriptional regulation of myostatin by an NF-κB–mediated mechanism

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Qiu, Jia; Thapaliya, Samjhana; Runkana, Ashok; Yang, Yu; Tsien, Cynthia; Mohan, Maradumane L.; Narayanan, Arvind; Eghtesad, Bijan; Mozdziak, Paul E.; McDonald, Christine; Stark, George R.; Welle, Stephen; Naga Prasad, Sathyamangla V.; Dasarathy, Srinivasan

2013-01-01

Loss of muscle mass, or sarcopenia, is nearly universal in cirrhosis and adversely affects patient outcome. The underlying cross-talk between the liver and skeletal muscle mediating sarcopenia is not well understood. Hyperammonemia is a consistent abnormality in cirrhosis due to impaired hepatic detoxification to urea. We observed elevated levels of ammonia in both plasma samples and skeletal muscle biopsies from cirrhotic patients compared with healthy controls. Furthermore, skeletal muscle from cirrhotics had increased expression of myostatin, a known inhibitor of skeletal muscle accretion and growth. In vivo studies in mice showed that hyperammonemia reduced muscle mass and strength and increased myostatin expression in wild-type compared with postdevelopmental myostatin knockout mice. We postulated that hyperammonemia is an underlying link between hepatic dysfunction in cirrhosis and skeletal muscle loss. Therefore, murine C2C12 myotubes were treated with ammonium acetate resulting in intracellular concentrations similar to those in cirrhotic muscle. In this system, we demonstrate that hyperammonemia stimulated myostatin expression in a NF-κB–dependent manner. This finding was also observed in primary murine muscle cell cultures. Hyperammonemia triggered activation of IκB kinase, NF-κB nuclear translocation, binding of the NF-κB p65 subunit to specific sites within the myostatin promoter, and stimulation of myostatin gene transcription. Pharmacologic inhibition or gene silencing of NF-κB abolished myostatin up-regulation under conditions of hyperammonemia. Our work provides unique insights into hyperammonemia-induced myostatin expression and suggests a mechanism by which sarcopenia develops in cirrhotic patients. PMID:24145431

A higher form (of) mediation

International Nuclear Information System (INIS)

Verlinde, Herman; Wang, L-T; Yavin, Itay; Wijnholt, Martijn

2008-01-01

We exhibit a simple and robust mechanism for bulk mediation of supersymmetry breaking between hidden and visible sectors localized on geometrically separated D-branes in type II string theory. The mediation proceeds via RR p-forms that couple via linear Chern-Simons terms to the abelian vector bosons on the branes. From a 4-d low energy perspective, the mechanism reduces to U(1) mediation

Reclassifying Anaphylaxis to Neuromuscular Blocking Agents Based on the Presumed Patho-Mechanism: IgE-Mediated, Pharmacological Adverse Reaction or “Innate Hypersensitivity”?

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David Spoerl

2017-06-01

Full Text Available Approximately 60% of perioperative anaphylactic reactions are thought to be immunoglobulin IgE mediated, whereas 40% are thought to be non-IgE mediated hypersensitivity reactions (both considered non-dose-related type B adverse drug reactions. In both cases, symptoms are elicited by mast cell degranulation. Also, pharmacological reactions to drugs (type A, dose-related may sometimes mimic symptoms triggered by mast cell degranulation. In case of hypotension, bronchospasm, or urticarial rash due to mast cell degranulation, identification of the responsible mechanism is complicated. However, determination of the type of the underlying adverse drug reaction is of paramount interest for the decision of whether the culprit drug may be re-administered. Neuromuscular blocking agents (NMBA are among the most frequent cause of perioperative anaphylaxis. Recently, it has been shown that NMBA may activate mast cells independently from IgE antibodies via the human Mas-related G-protein-coupled receptor member X2 (MRGPRX2. In light of this new insight into the patho-mechanism of pseudo-allergic adverse drug reactions, in which as drug-receptor interaction results in anaphylaxis like symptoms, we critically reviewed the literature on NMBA-induced perioperative anaphylaxis. We challenge the dogma that NMBA mainly cause IgE-mediated anaphylaxis via an IgE-mediated mechanism, which is based on studies that consider positive skin test to be specific for IgE-mediated hypersensitivity. Finally, we discuss the question whether MRGPRX2 mediated pseudo-allergic reactions should be re-classified as type A adverse reactions.

Cognitive Deficits as a Mediator of Poor Occupational Function in Remitted Major Depressive Disorder Patients

Science.gov (United States)

Woo, Young Sup; Rosenblat, Joshua D.; Kakar, Ron; Bahk, Won-Myong; McIntyre, Roger S.

2016-01-01

Cognitive deficits in major depressive disorder (MDD) patients have been described in numerous studies. However, few reports have aimed to describe cognitive deficits in the remitted state of MDD and the mediational effect of cognitive deficits on occupational outcome. The aim of the current review is to synthesize the literature on the mediating and moderating effects of specific domains of cognition on occupational impairment among people with remitted MDD. In addition, predictors of cognitive deficits found to be vocationally important will be examined. Upon examination of the extant literature, attention, executive function and verbal memory are areas of consistent impairment in remitted MDD patients. Cognitive domains shown to have considerable impact on vocational functioning include deficits in memory, attention, learning and executive function. Factors that adversely affect cognitive function related to occupational accommodation include higher age, late age at onset, residual depressive symptoms, history of melancholic/psychotic depression, and physical/psychiatric comorbidity, whereas higher levels of education showed a protective effect against cognitive deficit. Cognitive deficits are a principal mediator of occupational impairment in remitted MDD patients. Therapeutic interventions specifically targeting cognitive deficits in MDD are needed, even in the remitted state, to improve functional recovery, especially in patients who have a higher risk of cognitive deficit. PMID:26792035

Central mechanisms mediating the hypophagic effects of oleoylethanolamide and N-acylphosphatidylethanolamines: different lipid signals?

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Adele eRomano

2015-06-01

Full Text Available The spread of ‘obesity epidemic’ and the poor efficacy of many anti-obesity therapies in the long-term highlight the need to develop novel efficacious therapy. This necessity stimulates a large research effort to find novel mechanisms controlling feeding and energy balance. Among these mechanisms a great deal of attention has been attracted by a family of phospholipid-derived signaling molecules that play an important role in the regulation of food-intake. They include N-acylethanolamines (NAEs and N-acylphosphatidylethanolamines (NAPEs. NAPEs have been considered for a long time simply as phospholipid precursors of the lipid mediator NAEs, but increasing body of evidence suggest a role in many physiological processes including the regulation of feeding behavior. Several observations demonstrated that among NAEs, oleoylethanolamide (OEA acts as a satiety signal, which is generated in the intestine, upon the ingestion of fat, and signals to the central nervous system. At this level different neuronal pathways, including oxytocinergic, noradrenergic, and histaminergic neurons, seem to mediate its hypophagic action. Similarly to NAEs, NAPEs (with particular reference to the N16:0 species levels were shown to be regulated by the fed state and this finding was initially interpreted as fluctuations of NAE precursors. However, the observation that exogenously administered NAPEs are able to inhibit food intake, not only in normal rats and mice but also in mice lacking the enzyme that converts NAPEs into NAEs, supported the hypothesis of a role of NAPE in the regulation of feeding behavior. Indirect observations suggest that the hypophagic action of NAPEs might involve central mechanisms, although the molecular target remains unknown. The present paper reviews the role that OEA and NAPEs play in the mechanisms that control food intake, further supporting this group of phospholipids as optimal candidate for the development of novel anti

Ultrasound Microbubble Treatment Enhances Clathrin-Mediated Endocytosis and Fluid-Phase Uptake through Distinct Mechanisms.

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Farnaz Fekri

Full Text Available Drug delivery to tumors is limited by several factors, including drug permeability of the target cell plasma membrane. Ultrasound in combination with microbubbles (USMB is a promising strategy to overcome these limitations. USMB treatment elicits enhanced cellular uptake of materials such as drugs, in part as a result of sheer stress and formation of transient membrane pores. Pores formed upon USMB treatment are rapidly resealed, suggesting that other processes such as enhanced endocytosis may contribute to the enhanced material uptake by cells upon USMB treatment. How USMB regulates endocytic processes remains incompletely understood. Cells constitutively utilize several distinct mechanisms of endocytosis, including clathrin-mediated endocytosis (CME for the internalization of receptor-bound macromolecules such as Transferrin Receptor (TfR, and distinct mechanism(s that mediate the majority of fluid-phase endocytosis. Tracking the abundance of TfR on the cell surface and the internalization of its ligand transferrin revealed that USMB acutely enhances the rate of CME. Total internal reflection fluorescence microscopy experiments revealed that USMB treatment altered the assembly of clathrin-coated pits, the basic structural units of CME. In addition, the rate of fluid-phase endocytosis was enhanced, but with delayed onset upon USMB treatment relative to the enhancement of CME, suggesting that the two processes are distinctly regulated by USMB. Indeed, vacuolin-1 or desipramine treatment prevented the enhancement of CME but not of fluid phase endocytosis upon USMB, suggesting that lysosome exocytosis and acid sphingomyelinase, respectively, are required for the regulation of CME but not fluid phase endocytosis upon USMB treatment. These results indicate that USMB enhances both CME and fluid phase endocytosis through distinct signaling mechanisms, and suggest that strategies for potentiating the enhancement of endocytosis upon USMB treatment may

A systematic review: can one prescribe carbapenems to patients with IgE-mediated allergy to penicillins or cephalosporins?

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Kula, Brittany; Djordjevic, Gordana; Robinson, Joan L

2014-10-15

Cross-reactivity between penicillins or cephalosporins and carbapenems is anticipated as all have a beta lactam ring. However, the true incidence of immunoglobulin (Ig)E-mediated cross-reactivity is not known. A systematic review was conducted to collect and combine all published data on children and adults reported to have a clinical history of IgE-mediated hypersensitivity to a penicillin and/or cephalosporin who were subsequently given a carbapenem. Reactions were classified as proven, suspected, or possible IgE-mediated and non-IgE-mediated. Ten studies and 12 case reports describing 854 participants fit the study criteria. For patients with previous proven, suspected, or possible IgE-mediated penicillin reactions (N = 838), the incidence of any type of suspected hypersensitivity reaction to a carbapenem was 36/838 (4.3%; 95% confidence interval [CI], 3.1%-5.9%) and the incidence of proven (1/838), suspected (0/838), or possible (19/838) IgE-mediated reactions was 20/838 (2.4%; 95% CI, 1.6%-3.7%). Of the subset of patients with positive penicillin skin tests (n = 295), only 1 had a hypersensitivity reaction (0.3%; 95% CI, .06%-1.9%), and this was a possible IgE-mediated reaction. For patients with previous proven, suspected, or possible IgE-mediated cephalosporin reactions (N = 12), the incidence of any type of hypersensitivity reaction to a carbapenem was 3/12 (25%); this included 2 non-IgE-mediated reactions and 1 possible IgE-mediated reaction. The cross-reactivity between penicillins and carbapenems for IgE-mediated reactions is very low, but caution is still advised. Cross-reactivity rates may be higher between cephalosporins and carbapenems; however, minimal data are available. © The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Association between social support and post-traumatic stress disorder symptoms among Chinese patients with ovarian cancer: A multiple mediation model.

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Chunli Liu

Full Text Available Post-traumatic stress disorder (PTSD symptoms can develop after person experiences one or more traumatic events. Little research, however, has been done on PTSD symptoms of patients with ovarian cancer. The present study aimed to estimate the prevalence of PTSD symptoms in patients with ovarian cancer in China; the effects of demographic and clinical variables on PTSD symptoms; multiple mediation roles in the association between social support and PTSD symptoms in patients with ovarian cancer in China. We collected demographic and clinical information of patients with ovarian cancer in the first and second hospitals of China Medical University between January 1, 2014 and December 31, 2015. Qualified patients were asked to complete the Posttraumatic Stress Disorder Checklist-Civilian Version (PCL-C, Duke-UNC Functional Social Support Questionnaire, Herth Hope Index (HHI, and Resilience Scale-14 (RS-14. 201 patients provided responses. We performed hierarchical linear regression to assess the correlation between social support and PTSD symptoms and bootstrapping to test the mediating role of hope and resilience as potential mediators. After controlling demographic and clinical characteristics, social support negatively correlated with PTSD symptoms (β = -0.406, P < 0.01. Social support explained 14.7% of the variance in PTSD symptoms. Hope and resilience explained 17.0% of the variance in PTSD symptoms. The proportion of the hope mediating effect was 43.37% for social support and the proportion of the resilience mediating effect was 10.64% for social support. Hope and resilience partly mediated the correlation between social support and PTSD symptoms despite accounting for different proportions of the mediating effect. Future intervention plans should pay more attention to social support as well as hope and resilience to prevent, relieve and treat PTSD symptoms.

Association between social support and post-traumatic stress disorder symptoms among Chinese patients with ovarian cancer: A multiple mediation model

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Liu, Chunli; Zhang, Yi; Jiang, Hong; Wu, Hui

2017-01-01

Post-traumatic stress disorder (PTSD) symptoms can develop after person experiences one or more traumatic events. Little research, however, has been done on PTSD symptoms of patients with ovarian cancer. The present study aimed to estimate the prevalence of PTSD symptoms in patients with ovarian cancer in China; the effects of demographic and clinical variables on PTSD symptoms; multiple mediation roles in the association between social support and PTSD symptoms in patients with ovarian cancer in China. We collected demographic and clinical information of patients with ovarian cancer in the first and second hospitals of China Medical University between January 1, 2014 and December 31, 2015. Qualified patients were asked to complete the Posttraumatic Stress Disorder Checklist-Civilian Version (PCL-C), Duke-UNC Functional Social Support Questionnaire, Herth Hope Index (HHI), and Resilience Scale-14 (RS-14). 201 patients provided responses. We performed hierarchical linear regression to assess the correlation between social support and PTSD symptoms and bootstrapping to test the mediating role of hope and resilience as potential mediators. After controlling demographic and clinical characteristics, social support negatively correlated with PTSD symptoms (β = -0.406, P Social support explained 14.7% of the variance in PTSD symptoms. Hope and resilience explained 17.0% of the variance in PTSD symptoms. The proportion of the hope mediating effect was 43.37% for social support and the proportion of the resilience mediating effect was 10.64% for social support. Hope and resilience partly mediated the correlation between social support and PTSD symptoms despite accounting for different proportions of the mediating effect. Future intervention plans should pay more attention to social support as well as hope and resilience to prevent, relieve and treat PTSD symptoms. PMID:28475593

Cutaneous nociceptors lack sensitisation, but reveal μ-opioid receptor-mediated reduction in excitability to mechanical stimulation in neuropathy

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Schmidt Yvonne

2012-11-01

Full Text Available Abstract Background Peripheral nerve injuries often trigger a hypersensitivity to tactile stimulation. Behavioural studies demonstrated efficient and side effect-free analgesia mediated by opioid receptors on peripheral sensory neurons. However, mechanistic approaches addressing such opioid properties in painful neuropathies are lacking. Here we investigated whether opioids can directly inhibit primary afferent neuron transmission of mechanical stimuli in neuropathy. We analysed the mechanical thresholds, the firing rates and response latencies of sensory fibres to mechanical stimulation of their cutaneous receptive fields. Results Two weeks following a chronic constriction injury of the saphenous nerve, mice developed a profound mechanical hypersensitivity in the paw innervated by the damaged nerve. Using an in vitro skin-nerve preparation we found no changes in the mechanical thresholds and latencies of sensory fibres from injured nerves. The firing rates to mechanical stimulation were unchanged or reduced following injury. Importantly, μ-opioid receptor agonist [D-Ala2,N-Me-Phe4,Gly5]-ol-enkephalin (DAMGO significantly elevated the mechanical thresholds of nociceptive Aδ and C fibres. Furthermore, DAMGO substantially diminished the mechanically evoked discharges of C nociceptors in injured nerves. These effects were blocked by DAMGO washout and pre-treatment with the selective μ-opioid receptor antagonist Cys2-Tyr3-Orn5-Pen7-amide. DAMGO did not alter the responses of sensory fibres in uninjured nerves. Conclusions Our findings suggest that behaviourally manifested neuropathy-induced mechanosensitivity does not require a sensitised state of cutaneous nociceptors in damaged nerves. Yet, nerve injury renders nociceptors sensitive to opioids. Prevention of action potential generation or propagation in nociceptors might represent a cellular mechanism underlying peripheral opioid-mediated alleviation of mechanical hypersensitivity in neuropathy.

Depression and insomnia as mediators of the relationship between distress and quality of life in cancer patients.

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Cha, Kyeong Min; Chung, Young Ki; Lim, Ki Young; Noh, Jae Sung; Chun, Mison; Hyun, So Yeon; Kang, Dae Ryong; Oh, Min Jung; Kim, Nam Hee

2017-08-01

Distress in cancer patients leads to poorer quality of life (QOL) and negatively impacts survival. For efficient management of a patient's disease course, the interrelationships among distress, depression, insomnia, and QOL must be understood. This study aimed to investigate whether depression and insomnia mediate the relationship between distress and QOL in cancer patients. Cancer patients referred to a specialized psycho-oncology clinic (n=208) participated in this study. Distress, depression, insomnia, and QOL were measured with the following questionnaires: Distress Thermometer, Hospital Anxiety and Depression Scale, Insomnia Severity Index, and Functional Assessment of Cancer Therapy-General. Structural equation modeling and path analysis were performed to analyze the mediating effects of depression and insomnia on the relationship between distress and QOL. Distress exerted nearly equal direct (ß=-0.291, p=0.002) and indirect (mediated by depression and insomnia) (ß=-0.299, p=0.003) negative effects on QOL. Depression exhibited the largest direct negative effect on QOL. The indirect effects of distress on QOL through depression alone, through insomnia alone, and through an insomnia to depression pathway were all significant (ß=-0.122, p=0.011; ß=-0.102, p=0.002; and ß=-0.075, pDepression and insomnia, both individually and as part of an interrelated pathway, partially mediate the relationship between distress and QOL. Appropriate interventions to alleviate insomnia and depression may mitigate the negative impacts of distress on QOL in cancer patients. Copyright © 2017 Elsevier B.V. All rights reserved.

Why did soft drink consumption decrease but screen time not? Mediating mechanisms in a school-based obesity prevention program

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Chin A Paw, M.J.M.; Singh, A.S.; Brug, J.; Mechelen, van, W.

2008-01-01

Abstract Objectives This paper aims to identify the mediating mechanisms of a school-based obesity prevention program (DOiT). Methods The DOiT-program was implemented in Dutch prevocational secondary schools and evaluated using a controlled, cluster-randomised trial (September 2003 to May 2004). We examined mediators of effects regarding (1) consumption of sugar containing beverages (SCB); (2) consumption of high caloric snacks; (3) screen-viewing behaviour; and (4) active commuting to school...

Hierarchical mechanisms for transcription factor-mediated reprogramming of fibroblasts to neurons

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Wapinski, Orly L.; Vierbuchen, Thomas; Qu, Kun; Lee, Qian Yi; Chanda, Soham; Fuentes, Daniel R.; Giresi, Paul G.; Ng, Yi Han; Marro, Samuele; Neff, Norma F.; Drechsel, Daniela; Martynoga, Ben; Castro, Diogo S.; Webb, Ashley E.; Brunet, Anne; Guillemot, Francois; Chang, Howard Y.; Wernig, Marius

2013-01-01

SUMMARY Direct lineage reprogramming is a promising approach for human disease modeling and regenerative medicine with poorly understood mechanisms. Here we reveal a hierarchical mechanism in the direct conversion of fibroblasts into induced neuronal (iN) cells mediated by the transcription factors Ascl1, Brn2, and Myt1l. Ascl1 acts as an “on target” pioneer factor by immediately occupying most cognate genomic sites in fibroblasts. In contrast, Brn2 and Myt1l do not access fibroblast chromatin productively on their own; instead Ascl1 recruits Brn2 to Ascl1 sites genome-wide. A unique trivalent chromatin signature in the host cells predicts the permissiveness for Ascl1 pioneering activity among different cell types. Finally, we identified Zfp238 as a key Ascl1 target gene that can partially substitute for Ascl1 during iN cell reprogramming. Thus, precise match between pioneer factor and the chromatin context at key target genes is determinative for trans-differentiation to neurons and likely other cell types. PMID:24243019

Thioredoxin is involved in endothelial cell extracellular transglutaminase 2 activation mediated by celiac disease patient IgA.

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Cristina Antonella Nadalutti

Full Text Available PURPOSE: To investigate the role of thioredoxin (TRX, a novel regulator of extracellular transglutaminase 2 (TG2, in celiac patients IgA (CD IgA mediated TG2 enzymatic activation. METHODS: TG2 enzymatic activity was evaluated in endothelial cells (HUVECs under different experimental conditions by ELISA and Western blotting. Extracellular TG2 expression was studied by ELISA and immunofluorescence. TRX was analysed by Western blotting and ELISA. Serum immunoglobulins class A from healthy subjects (H IgA were used as controls. Extracellular TG2 enzymatic activity was inhibited by R281. PX12, a TRX inhibitor, was also employed in the present study. RESULTS: We have found that in HUVECs CD IgA is able to induce the activation of extracellular TG2 in a dose-dependent manner. Particularly, we noted that the extracellular modulation of TG2 activity mediated by CD IgA occurred only under reducing conditions, also needed to maintain antibody binding. Furthermore, CD IgA-treated HUVECs were characterized by a slightly augmented TG2 surface expression which was independent from extracellular TG2 activation. We also observed that HUVECs cultured in the presence of CD IgA evinced decreased TRX surface expression, coupled with increased secretion of the protein into the culture medium. Intriguingly, inhibition of TRX after CD IgA treatment was able to overcome most of the CD IgA-mediated effects including the TG2 extracellular transamidase activity. CONCLUSIONS: Altogether our findings suggest that in endothelial cells CD IgA mediate the constitutive activation of extracellular TG2 by a mechanism involving the redox sensor protein TRX.

[Lung-brain interaction in the mechanically ventilated patient].

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López-Aguilar, J; Fernández-Gonzalo, M S; Turon, M; Quílez, M E; Gómez-Simón, V; Jódar, M M; Blanch, L

2013-10-01

Patients with acute lung injury or acute respiratory distress syndrome (ARDS) admitted to the ICU present neuropsychological alterations, which in most cases extend beyond the acute phase and have an important adverse effect upon quality of life. The aim of this review is to deepen in the analysis of the complex interaction between lung and brain in critically ill patients subjected to mechanical ventilation. This update first describes the neuropsychological alterations occurring both during the acute phase of ICU stay and at discharge, followed by an analysis of lung-brain interactions during mechanical ventilation, and finally explores the etiology and mechanisms leading to the neurological disorders observed in these patients. The management of critical patients requires an integral approach focused on minimizing the deleterious effects over the short, middle or long term. Copyright © 2012 Elsevier España, S.L. y SEMICYUC. All rights reserved.

Causal mediation analysis with multiple causally non-ordered mediators.

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Taguri, Masataka; Featherstone, John; Cheng, Jing

2018-01-01

In many health studies, researchers are interested in estimating the treatment effects on the outcome around and through an intermediate variable. Such causal mediation analyses aim to understand the mechanisms that explain the treatment effect. Although multiple mediators are often involved in real studies, most of the literature considered mediation analyses with one mediator at a time. In this article, we consider mediation analyses when there are causally non-ordered multiple mediators. Even if the mediators do not affect each other, the sum of two indirect effects through the two mediators considered separately may diverge from the joint natural indirect effect when there are additive interactions between the effects of the two mediators on the outcome. Therefore, we derive an equation for the joint natural indirect effect based on the individual mediation effects and their interactive effect, which helps us understand how the mediation effect works through the two mediators and relative contributions of the mediators and their interaction. We also discuss an extension for three mediators. The proposed method is illustrated using data from a randomized trial on the prevention of dental caries.

Confirming the RNAi-mediated mechanism of action of siRNA-based cancer therapeutics in mice.

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Judge, Adam D; Robbins, Marjorie; Tavakoli, Iran; Levi, Jasna; Hu, Lina; Fronda, Anna; Ambegia, Ellen; McClintock, Kevin; MacLachlan, Ian

2009-03-01

siRNAs that specifically silence the expression of cancer-related genes offer a therapeutic approach in oncology. However, it remains critical to determine the true mechanism of their therapeutic effects. Here, we describe the preclinical development of chemically modified siRNA targeting the essential cell-cycle proteins polo-like kinase 1 (PLK1) and kinesin spindle protein (KSP) in mice. siRNA formulated in stable nucleic acid lipid particles (SNALP) displayed potent antitumor efficacy in both hepatic and subcutaneous tumor models. This was correlated with target gene silencing following a single intravenous administration that was sufficient to cause extensive mitotic disruption and tumor cell apoptosis. Our siRNA formulations induced no measurable immune response, minimizing the potential for nonspecific effects. Additionally, RNAi-specific mRNA cleavage products were found in tumor cells, and their presence correlated with the duration of target mRNA silencing. Histological biomarkers confirmed that RNAi-mediated gene silencing effectively inhibited the target's biological activity. This report supports an RNAi-mediated mechanism of action for siRNA antitumor effects, suggesting a new methodology for targeting other key genes in cancer development with siRNA-based therapeutics.

Computational studies on non-succinimide-mediated stereoinversion mechanism of aspartic acid residues assisted by phosphate

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Nakayoshi, Tomoki; Fukuyoshi, Shuichi; Takahashi, Ohgi; Oda, Akifumi

2018-03-01

Although nearly all of the amino acids that constitute proteins are l-amino acids, d-amino acid residues in human proteins have been recently reported. d-amino acid residues cause a change in the three-dimensional structure of proteins, and d-aspartic acid (Asp) residues are considered to be one of the causes of age-related diseases. The stereoinversion of Asp residues in peptides and proteins is thought to proceed via a succinimide intermediate; however, it has been reported that stereoinversion can occur even under conditions where a succinimide intermediate cannot be formed. In order to elucidate the non-succinimide-mediated stereoinversion pathway, we investigated the stereoinversion of l-Asp to d-Asp catalysed by phosphate and estimated the activation barrier using B3LYP/6-31+G(d,p) density functional theory (DFT) calculations. For the DFT calculations, a model compound in which the Asp residue is capped with acetyl and methyl-amino groups on the N- and C-termini, respectively, was used. The calculated activation barrier was not excessively high for the stereoinversion to occur in vivo. Therefore, this stereoinversion mechanism may compete with the succinimide-mediated mechanism.

Cytoprotective Mechanisms Mediated by Polyphenols from Chilean Native Berries against Free Radical-Induced Damage on AGS Cells.

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Ávila, Felipe; Theoduloz, Cristina; López-Alarcón, Camilo; Dorta, Eva; Schmeda-Hirschmann, Guillermo

2017-01-01

The prevalence of cytoprotective mechanisms induced by polyphenols such as activation of intracellular antioxidant responses (ICM) and direct free radical scavenging was investigated in native Chilean species of strawberries, raspberries, and currants. Human gastric epithelial cells were co- and preincubated with polyphenolic-enriched extracts (PEEs) from Chilean raspberries ( Rubus geoides ), strawberries ( Fragaria chiloensis ssp. chiloensis f . chiloensis ), and currants ( Ribes magellanicum ) and challenged with peroxyl and hydroxyl radicals. Cellular protection was determined in terms of cell viability, glyoxalase I and glutathione s-transferases activities, and carboxymethyl lysine (CML) and malondialdehyde levels. Our results indicate that cytoprotection induced by ICM was the prevalent mechanism for Rubus geoides and F. chiloensis . This agreed with increased levels of glyoxalase I and glutathione S-transferase activities in cells preincubated with PEEs. ORAC index indicated that F. chiloensis was the most efficient peroxyl radical scavenger. Moreover, ICM mediated by F. chiloensis was effective in protecting cells from CML accumulation in contrast to the protective effects induced by free radical scavenging. Our results indicate that although both polyphenol-mediated mechanisms can exert protective effects, ICM was the most prevalent in AGS cells. These results suggest a potential use of these native berries as functional food.

Kinin B1 Receptor Promotes Neurogenic Hypertension Through Activation of Centrally Mediated Mechanisms.

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Sriramula, Srinivas; Lazartigues, Eric

2017-12-01

Hypertension is associated with increased activity of the kallikrein-kinin system. Kinin B1 receptor (B1R) activation leads to vasoconstriction and inflammation. Despite evidence supporting a role for the B1R in blood pressure regulation, the mechanisms by which B1R could alter autonomic function and participate in the pathogenesis of hypertension remain unidentified. We sought to explore whether B1R-mediated inflammation contributes to hypertension and investigate the molecular mechanisms involved. In this study, we tested the hypothesis that activation of B1R in the brain is involved in the pathogenesis of hypertension, using the deoxycorticosterone acetate-salt model of neurogenic hypertension in wild-type and B1R knockout mice. Deoxycorticosterone acetate-salt treatment in wild-type mice led to significant increases in B1R mRNA and protein levels and bradykinin levels, enhanced gene expression of carboxypeptidase N supporting an increase in the B1R ligand, associated with enhanced blood pressure, inflammation, sympathoexcitation, autonomic dysfunction, and impaired baroreflex sensitivity, whereas these changes were blunted or prevented in B1R knockout mice. B1R stimulation was further shown to involve activation of the ASK1-JNK-ERK1/2 and NF-κB pathways in the brain. To dismiss potential developmental alterations in knockout mice, we further used B1R blockade selectively in the brain of wild-type mice. Supporting the central origin of this mechanism, intracerebroventricular infusion of a specific B1R antagonist, attenuated the deoxycorticosterone acetate-salt-induced increase in blood pressure in wild-type mice. Our data provide the first evidence of a central role for B1R-mediated inflammatory pathways in the pathogenesis of deoxycorticosterone acetate-salt hypertension and offer novel insights into possible B1R-targeted therapies for the treatment of neurogenic hypertension. © 2017 American Heart Association, Inc.

The S100A10 Pathway Mediates an Occult Hyperfibrinolytic Subtype in Trauma Patients.

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Gall, Lewis S; Vulliamy, Paul; Gillespie, Scarlett; Jones, Timothy F; Pierre, Rochelle S J; Breukers, Sabine E; Gaarder, Christine; Juffermans, Nicole P; Maegele, Marc; Stensballe, Jakob; Johansson, Pär I; Davenport, Ross A; Brohi, Karim

2018-03-19

To determine the characteristics of trauma patients with low levels of fibrinolysis as detected by viscoelastic hemostatic assay (VHA) and explore the underlying mechanisms of this subtype. Hyperfibrinolysis is a central component of acute traumatic coagulopathy but a group of patients present with low levels of VHA-detected fibrinolysis. There is concern that these patients may be at risk of thrombosis if empirically administered an antifibrinolytic agent. A prospective multicenter observational cohort study was conducted at 5 European major trauma centers. Blood was drawn on arrival, within 2 hours of injury, for VHA (rotation thromboelastometry [ROTEM]) and fibrinolysis plasma protein analysis including the fibrinolytic mediator S100A10. An outcomes-based threshold for ROTEM hypofibrinolysis was determined and patients grouped by this and by D-dimer (DD) levels. Nine hundred fourteen patients were included in the study. The VHA maximum lysis (ML) lower threshold was determined to be <5%. Heterogeneity existed among patients with low ML, with survivors sharing similar clinical and injury characteristics to patients with normal ML values (5-15%). Those who died were critically injured with a preponderance of traumatic brain injury and had a 7-fold higher DD level (died vs. survived: 103,170 vs. 13,672 ng/mL, P < 0.001). Patients with low ML and high DD demonstrated a hyperfibrinolytic biomarker profile, low tissue plasminogen activator levels but high plasma levels of S100A10. S100A10 was negatively correlated with %ML (r = -0.26, P < 0.001) and caused a significant reduction in %ML when added to whole blood ex-vivo. Patients presenting with low ML and low DD levels have low injury severity and normal outcomes. Conversely, patients with low ML but high DD levels are severely injured, functionally coagulopathic and have poor clinical outcomes. These patients have low tissue plasminogen activator levels and are not detectable by ROTEM. S100A10 is a cell

Pulmonary Mechanics and Mortality in Mechanically Ventilated Patients Without Acute Respiratory Distress Syndrome: A Cohort Study.

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Fuller, Brian M; Page, David; Stephens, Robert J; Roberts, Brian W; Drewry, Anne M; Ablordeppey, Enyo; Mohr, Nicholas M; Kollef, Marin H

2018-03-01

Driving pressure has been proposed as a major determinant of outcome in patients with acute respiratory distress syndrome (ARDS), but there is little data examining the association between pulmonary mechanics, including driving pressure, and outcomes in mechanically ventilated patients without ARDS. Secondary analysis from 1,705 mechanically ventilated patients enrolled in a clinical study that examined outcomes associated with the use of early lung-protective mechanical ventilation. The primary outcome was mortality and the secondary outcome was the incidence of ARDS. Multivariable models were constructed to: define the association between pulmonary mechanics (driving pressure, plateau pressure, and compliance) and mortality; and evaluate if driving pressure contributed information beyond that provided by other pulmonary mechanics. The mortality rate for the entire cohort was 26.0%. Compared with survivors, non-survivors had significantly higher driving pressure [15.9 (5.4) vs. 14.9 (4.4), P = 0.005] and plateau pressure [21.4 (5.7) vs. 20.4 (4.6), P = 0.001]. Driving pressure was independently associated with mortality [adjusted OR, 1.04 (1.01-1.07)]. Models related to plateau pressure also revealed an independent association with mortality, with similar effect size and interval estimates as driving pressure. There were 152 patients who progressed to ARDS (8.9%). Along with driving pressure and plateau pressure, mechanical power [adjusted OR, 1.03 (1.00-1.06)] was also independently associated with ARDS development. In mechanically ventilated patients, driving pressure and plateau pressure are risk factors for mortality and ARDS, and provide similar information. Mechanical power is also a risk factor for ARDS.

mediation: R Package for Causal Mediation Analysis

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Dustin Tingley

2014-09-01

Full Text Available In this paper, we describe the R package mediation for conducting causal mediation analysis in applied empirical research. In many scientific disciplines, the goal of researchers is not only estimating causal effects of a treatment but also understanding the process in which the treatment causally affects the outcome. Causal mediation analysis is frequently used to assess potential causal mechanisms. The mediation package implements a comprehensive suite of statistical tools for conducting such an analysis. The package is organized into two distinct approaches. Using the model-based approach, researchers can estimate causal mediation effects and conduct sensitivity analysis under the standard research design. Furthermore, the design-based approach provides several analysis tools that are applicable under different experimental designs. This approach requires weaker assumptions than the model-based approach. We also implement a statistical method for dealing with multiple (causally dependent mediators, which are often encountered in practice. Finally, the package also offers a methodology for assessing causal mediation in the presence of treatment noncompliance, a common problem in randomized trials.

Changes in illness perceptions mediated the effect of cognitive behavioural therapy in severe functional somatic syndromes

DEFF Research Database (Denmark)

Christensen, Sara Sletten; Frostholm, Lisbeth; Ørnbøl, Eva

2014-01-01

Objective Although there is substantial evidence that cognitive behavioural therapy alleviates symptoms in functional somatic syndromes, the mechanisms of change are less investigated. This study examined whether changes in illness perceptions mediated the effect of cognitive behavioural therapy....... Methods We analysed additional data from a randomised controlled trial comparing completers of cognitive behavioural group therapy (46 patients) to an enhanced usual care group (66 patients). Proposed mediators (illness perceptions) and primary (physical health) and secondary (somatic symptoms and illness...... worry) outcomes were assessed by means of questionnaires at referral, baseline, end of treatment, and 10 and 16 months after randomisation. Multiple mediation analysis determined whether (1) changes in specific illness perceptions during treatment mediated the effect of cognitive behavioural therapy...

Molecular Mechanisms Responsible for Neuron-Derived Conditioned Medium (NCM-Mediated Protection of Ischemic Brain.

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Chi-Hsin Lin

Full Text Available The protective value of neuron-derived conditioned medium (NCM in cerebral ischemia and the underlying mechanism(s responsible for NCM-mediated brain protection against cerebral ischemia were investigated in the study. NCM was first collected from the neuronal culture growing under the in vitro ischemic condition (glucose-, oxygen- and serum-deprivation or GOSD for 2, 4 or 6 h. Through the focal cerebral ischemia (bilateral CCAO/unilateral MCAO animal model, we discovered that ischemia/reperfusion (I/R-induced brain infarction was significantly reduced by NCM, given directly into the cistern magna at the end of 90 min of CCAO/MCAO. Immunoblocking and chemical blocking strategies were applied in the in vitro ischemic studies to show that NCM supplement could protect microglia, astrocytes and neurons from GOSD-induced cell death, in a growth factor (TGFβ1, NT-3 and GDNF and p-ERK dependent manner. Brain injection with TGFβ1, NT3, GDNF and ERK agonist (DADS alone or in combination, therefore also significantly decreased the infarct volume of ischemic brain. Moreover, NCM could inhibit ROS but stimulate IL-1β release from GOSD-treated microglia and limit the infiltration of IL-β-positive microglia into the core area of ischemic brain, revealing the anti-oxidant and anti-inflammatory activities of NCM. In overall, NCM-mediated brain protection against cerebral ischemia has been demonstrated for the first time in S.D. rats, due to its anti-apoptotic, anti-oxidant and potentially anti-glutamate activities (NCM-induced IL-1β can inhibit the glutamate-mediated neurotoxicity and restriction upon the infiltration of inflammatory microglia into the core area of ischemic brain. The therapeutic potentials of NCM, TGFβ1, GDNF, NT-3 and DADS in the control of cerebral ischemia in human therefore have been suggested and require further investigation.

Help seeking in aggressive and nonaggressive boys as a function of social or mechanical mediation of assistance.

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Shea, B J; Routh, D K; Cottrell, N B; Brecht, J M

1973-04-01

The behavior of preadolescent and adolescent boys, rated as aggressive and nonaggressive, was examined to test predictions from Bandura and Walters' social-learning theory and from Weiss and Miller's punishment model of audience-observation effects. The subjects were given a bogus motor task, actually insoluble, with help available on each trial. For half the subjects, help was given through the mediation of a social agent; for the rest, help was on a nonsocial, mechanically mediated basis. The groups for whom help was socially mediated made fewer help-seeking responses and decreased the number of such responses over successive trial blocks. The predictions from Bandura and Walters' theory were not supported, since neither age nor degree of aggressiveness had an effect on help-seeking responses. The results were, however, consistent with the punishment model of audience effects.

Neural mechanisms mediating degrees of strategic uncertainty.

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Nagel, Rosemarie; Brovelli, Andrea; Heinemann, Frank; Coricelli, Giorgio

2018-01-01

In social interactions, strategic uncertainty arises when the outcome of one's choice depends on the choices of others. An important question is whether strategic uncertainty can be resolved by assessing subjective probabilities to the counterparts' behavior, as if playing against nature, and thus transforming the strategic interaction into a risky (individual) situation. By means of functional magnetic resonance imaging with human participants we tested the hypothesis that choices under strategic uncertainty are supported by the neural circuits mediating choices under individual risk and deliberation in social settings (i.e. strategic thinking). Participants were confronted with risky lotteries and two types of coordination games requiring different degrees of strategic thinking of the kind 'I think that you think that I think etc.' We found that the brain network mediating risk during lotteries (anterior insula, dorsomedial prefrontal cortex and parietal cortex) is also engaged in the processing of strategic uncertainty in games. In social settings, activity in this network is modulated by the level of strategic thinking that is reflected in the activity of the dorsomedial and dorsolateral prefrontal cortex. These results suggest that strategic uncertainty is resolved by the interplay between the neural circuits mediating risk and higher order beliefs (i.e. beliefs about others' beliefs). © The Author(s) (2017). Published by Oxford University Press.

New insights into the molecular mechanism of E-cadherin-mediated cell adhesion by free energy calculations

DEFF Research Database (Denmark)

Doro, Fabio; Saladino, Giorgio; Belvisi, Laura

2015-01-01

Three-dimensional domain swapping is an important mode of protein association leading to the formation of stable dimers. Monomers associating via this mechanism mutually exchange a domain to form a homodimer. Classical cadherins, an increasingly important target for anticancer therapy, use domain...... swapping to mediate cell adhesion. However, despite its importance, the molecular mechanism of domain swapping is still debated. Here, we study the conformational changes that lead to activation and dimerization via domain swapping of E-cadherin. Using state-of-the-art enhanced sampling atomistic......" mechanism in which monomers in an active conformational state bind to form a homodimer, analogous to the conformational selection mechanism often observed in ligand-target binding. Moreover, we find that the open state population is increased in the presence of calcium ions at the extracellular boundary...

Controlled invasive mechanical ventilation strategies in obese patients undergoing surgery.

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Maia, Lígia de Albuquerque; Silva, Pedro Leme; Pelosi, Paolo; Rocco, Patricia Rieken Macedo

2017-06-01

The obesity prevalence is increasing in surgical population. As the number of obese surgical patients increases, so does the demand for mechanical ventilation. Nevertheless, ventilatory strategies in this population are challenging, since obesity results in pathophysiological changes in respiratory function. Areas covered: We reviewed the impact of obesity on respiratory system and the effects of controlled invasive mechanical ventilation strategies in obese patients undergoing surgery. To date, there is no consensus regarding the optimal invasive mechanical ventilation strategy for obese surgical patients, and no evidence that possible intraoperative beneficial effects on oxygenation and mechanics translate into better postoperative pulmonary function or improved outcomes. Expert commentary: Before determining the ideal intraoperative ventilation strategy, it is important to analyze the pathophysiology and comorbidities of each obese patient. Protective ventilation with low tidal volume, driving pressure, energy, and mechanical power should be employed during surgery; however, further studies are required to clarify the most effective ventilation strategies, such as the optimal positive end-expiratory pressure and whether recruitment maneuvers minimize lung injury. In this context, an ongoing trial of intraoperative ventilation in obese patients (PROBESE) should help determine the mechanical ventilation strategy that best improves clinical outcome in patients with body mass index≥35kg/m 2 .

VIPER: Chronic Pain after Amputation: Inflammatory Mechanisms, Novel Analgesic Pathways, and Improved Patient Safety

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2016-10-01

Whitney U test for evaluating differences in inflammatory mediators between groups (Case vs. Control) and used nonparametric correlations (Spearman’s rho...responses to acute pain. PAIN 2008;140:135–144. [10] Gordon S, Martinez FO. Alternative activation of macrophages: mechanism and functions...Concentrations in Cases vs. Controls. Mediator Case (n=36) Median (Range) Control (n=40) Median (Range) Mann- Whitney U Test (p value) IFN

Up-date on neuro-immune mechanisms involved in allergic and non-allergic rhinitis

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van Gerven, L.; Boeckxstaens, G.; Hellings, P.

2012-01-01

Non-allergic rhinitis (NAR) is a common disorder, which can be defined as chronic nasal inflammation, independent of systemic IgE-mediated mechanisms. Symptoms of NAR patients mimic those of allergic rhinitis (AR) patients. However, AR patients can easily be diagnosed with skin prick test or

Patient health communication mediating effects between gastrointestinal symptoms and gastrointestinal worry in pediatric inflammatory bowel disease

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To investigate the effects of patient health communication regarding their inflammatory bowel disease (IBD) to their health care providers and significant others in their daily life as a mediator in the relationship between gastrointestinal symptoms and gastrointestinal worry in pediatric patients. ...

Patient-specific mutations impair BESTROPHIN1’s essential role in mediating Ca2+-dependent Cl- currents in human RPE

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Li, Yao [Jonas Children’s Vision Care, and Bernard and Shirlee Brown Glaucoma Laboratory, Department of Ophthalmology and Pathology & Cell Biology, Edward S. Harkness Eye Institute, New York Presbyterian Hospital/Columbia University, New York, United States; Zhang, Yu [Department of Pharmacology and Physiology, School of Medicine and Dentistry, University of Rochester, Rochester, United States; Xu, Yu [Jonas Children’s Vision Care, and Bernard and Shirlee Brown Glaucoma Laboratory, Department of Ophthalmology and Pathology & Cell Biology, Edward S. Harkness Eye Institute, New York Presbyterian Hospital/Columbia University, New York, United States; Department of Ophthalmology, Xinhua Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China; Kittredge, Alec [Department of Pharmacology and Physiology, School of Medicine and Dentistry, University of Rochester, Rochester, United States; Ward, Nancy [Department of Pharmacology and Physiology, School of Medicine and Dentistry, University of Rochester, Rochester, United States; Chen, Shoudeng [Molecular Imaging Center, Department of Experimental Medicine, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, China; Tsang, Stephen H. [Jonas Children’s Vision Care, and Bernard and Shirlee Brown Glaucoma Laboratory, Department of Ophthalmology and Pathology & Cell Biology, Edward S. Harkness Eye Institute, New York Presbyterian Hospital/Columbia University, New York, United States; Yang, Tingting [Department of Pharmacology and Physiology, School of Medicine and Dentistry, University of Rochester, Rochester, United States

2017-10-24

Mutations in the human BEST1 gene lead to retinal degenerative diseases displaying progressive vision loss and even blindness. BESTROPHIN1, encoded by BEST1, is predominantly expressed in retinal pigment epithelium (RPE), but its physiological role has been a mystery for the last two decades. Using a patient-specific iPSC-based disease model and interdisciplinary approaches, we comprehensively analyzed two distinct BEST1 patient mutations, and discovered mechanistic correlations between patient clinical phenotypes, electrophysiology in their RPEs, and the structure and function of BESTROPHIN1 mutant channels. Our results revealed that the disease-causing mechanism of BEST1 mutations is centered on the indispensable role of BESTROPHIN1 in mediating the long speculated Ca2+-dependent Cl- current in RPE, and demonstrate that the pathological potential of BEST1 mutations can be evaluated and predicted with our iPSC-based ‘disease-in-a-dish’ approach. Moreover, we demonstrated that patient RPE is rescuable with viral gene supplementation, providing a proof-of-concept for curing BEST1-associated diseases.

Nostalgia-Evoked Inspiration: Mediating Mechanisms and Motivational Implications.

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Stephan, Elena; Sedikides, Constantine; Wildschut, Tim; Cheung, Wing-Yee; Routledge, Clay; Arndt, Jamie

2015-10-01

Six studies examined the nostalgia-inspiration link and its motivational implications. In Study 1, nostalgia proneness was positively associated with inspiration frequency and intensity. In Studies 2 and 3, the recollection of nostalgic (vs. ordinary) experiences increased both general inspiration and specific inspiration to engage in exploratory activities. In Study 4, serial mediational analyses supported a model in which nostalgia increases social connectedness, which subsequently fosters self-esteem, which then boosts inspiration. In Study 5, a rigorous evaluation of this serial mediational model (with a novel nostalgia induction controlling for positive affect) reinforced the idea that nostalgia-elicited social connectedness increases self-esteem, which then heightens inspiration. Study 6 extended the serial mediational model by demonstrating that nostalgia-evoked inspiration predicts goal pursuit (intentions to pursue an important goal). Nostalgia spawns inspiration via social connectedness and attendant self-esteem. In turn, nostalgia-evoked inspiration bolsters motivation. © 2015 by the Society for Personality and Social Psychology, Inc.

Mediators of physical activity change in a behavioral modification program for type 2 diabetes patients

Directory of Open Access Journals (Sweden)

Tudor-Locke Catrine E

2011-09-01

Full Text Available Abstract Background Many studies have reported significant behavioral impact of physical activity interventions. However, few have examined changes in potential mediators of change preceding behavioral changes, resulting in a lack of information concerning how the intervention worked. Our purpose was to examine mediation effects of changes in psychosocial variables on changes in physical activity in type 2 diabetes patients. Methods Ninety-two patients (62 ± 9 years, 30, 0 ± 2.5 kg/m2, 69% males participated in a randomized controlled trial. The 24-week intervention was based on social-cognitive constructs and consisted of a face-to-face session, telephone follow-ups, and the use of a pedometer. Social-cognitive variables and physical activity (device-based and self-reported were collected at baseline, after the 24-week intervention and at one year post-baseline. PA was measured by pedometer, accelerometer and questionnaire. Results Post-intervention physical activity changes were mediated by coping with relapse, changes in social norm, and social modeling from family members (p ≤ 0.05. One-year physical activity changes were mediated by coping with relapse, changes in social support from family and self-efficacy towards physical activity barriers (p ≤ 0.05 Conclusions For patients with type 2 diabetes, initiatives to increase their physical activity could usefully focus on strategies for resuming regular patterns of activity, on engaging family social support and on building confidence about dealing with actual and perceived barriers to activity. Trial Registration NCT00903500, ClinicalTrials.gov.

Mechanism of troponin elevations in patients with acute ischemic stroke

DEFF Research Database (Denmark)

Jensen, Jesper K.; Atar, Dan; Mickley, Hans

2007-01-01

the introduction of troponin in the diagnosis of acute myocardial infarction, this marker has been measured in a number of other conditions as well. One of these conditions is acute ischemic stroke, causing diagnostic dilemmas for clinicians. Because various electrocardiographic alterations have also been reported...... in these patients, it has been suggested that elevated troponin levels are somehow neurologically mediated, thus not caused by direct cardiac release. In conclusion, this review examines the available studies that systematically measured troponin in patients with acute ischemic stroke to properly interpret troponin...... elevations in these patients Udgivelsesdato: 2007-Mar-15...

Cytoprotective Mechanisms Mediated by Polyphenols from Chilean Native Berries against Free Radical-Induced Damage on AGS Cells

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Felipe Ávila

2017-01-01

Full Text Available The prevalence of cytoprotective mechanisms induced by polyphenols such as activation of intracellular antioxidant responses (ICM and direct free radical scavenging was investigated in native Chilean species of strawberries, raspberries, and currants. Human gastric epithelial cells were co- and preincubated with polyphenolic-enriched extracts (PEEs from Chilean raspberries (Rubus geoides, strawberries (Fragaria chiloensis ssp. chiloensis f. chiloensis, and currants (Ribes magellanicum and challenged with peroxyl and hydroxyl radicals. Cellular protection was determined in terms of cell viability, glyoxalase I and glutathione s-transferases activities, and carboxymethyl lysine (CML and malondialdehyde levels. Our results indicate that cytoprotection induced by ICM was the prevalent mechanism for Rubus geoides and F. chiloensis. This agreed with increased levels of glyoxalase I and glutathione S-transferase activities in cells preincubated with PEEs. ORAC index indicated that F. chiloensis was the most efficient peroxyl radical scavenger. Moreover, ICM mediated by F. chiloensis was effective in protecting cells from CML accumulation in contrast to the protective effects induced by free radical scavenging. Our results indicate that although both polyphenol-mediated mechanisms can exert protective effects, ICM was the most prevalent in AGS cells. These results suggest a potential use of these native berries as functional food.

Non-ionic iodinated contrast media related immediate reactions: A mechanism study of 27 patients.

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Zhai, Liqin; Guo, Xiangjie; Zhang, Haoyue; Jin, Qianqian; Zeng, Qiang; Tang, Xiaoxian; Gao, Cairong

2017-01-01

The underlying mechanism of non-ionic iodinated contrast media-related immediate reactions was evaluated in this study. Patients presenting at least grade II immediate reactions after non-ionic iodinated contrast media injection were enrolled. Basophil activation was evaluated by flow cytometry. The plasma concentration of human terminal complement complex SC5b-9, as well as concentrations of serum chymase, tryptase, human mast cell carboxypeptidase A3, human prostaglandin D2, and total IgE were measured by enzyme-linked immunosorbent assay. The basophil activation percentage was significantly higher in the study group than in the control group (17.94±21.06% vs 3.45±1.49%). The plasma concentration of human terminal complement complex SC5b-9 and concentrations of serum chymase, human mast cell carboxypeptidase A3, prostaglandin D2, tryptase, and total IgE were also significantly increased (236.99±318.21 vs 49.70±30.41ng/mL, 0.41±0.49 vs 0.09±0.06ng/mL, 1.17±0.67 vs 0.30±0.17ng/mL, 203.52±137.27 vs 102.28±48.72pg/mL, 3.81±0.22 vs 2.70±0.16ng/mL, 102.00±51.84 vs 19.97±2.75ng/mL, respectively). Both mast cells and basophils were activated in non-ionic iodinated contrast media to mediate immediate hypersensitivity, and mast cells may be involved. Different mechanisms, including IgE-dependent, complement-dependent, and direct membrane effects, contributed to mast cell and basophil activation. Individual patients may use a single or combined mechanism involving single or combined mast cells and basophils. Immediate reactions following non-ionic iodinated contrast media injection may be a mechanically heterogenous disease. Copyright © 2016. Published by Elsevier B.V.

Function and regulation of the Mediator complex.

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Conaway, Ronald C; Conaway, Joan Weliky

2011-04-01

Over the past few years, advances in biochemical and genetic studies of the structure and function of the Mediator complex have shed new light on its subunit architecture and its mechanism of action in transcription by RNA polymerase II (pol II). The development of improved methods for reconstitution of recombinant Mediator subassemblies is enabling more in-depth analyses of basic features of the mechanisms by which Mediator interacts with and controls the activity of pol II and the general initiation factors. The discovery and characterization of multiple, functionally distinct forms of Mediator characterized by the presence or absence of the Cdk8 kinase module have led to new insights into how Mediator functions in both Pol II transcription activation and repression. Finally, progress in studies of the mechanisms by which the transcriptional activation domains (ADs) of DNA binding transcription factors target Mediator have brought to light unexpected complexities in the way Mediator participates in signal transduction. Copyright © 2011 Elsevier Ltd. All rights reserved.

The neural mechanisms of affect infusion in social economic decision-making: A mediating role of the anterior insula

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Harlé, K.M.; Chang, L.J.; Wout, M. van 't; Sanfey, A.G.

2012-01-01

Though emotions have been shown to have sometimes dramatic effects on decision-making, the neural mechanisms mediating these biases are relatively unexplored. Here, we investigated how incidental affect (i.e. emotional states unrelated to the decision at hand) may influence decisions, and how these

Spermidine mediates degradation of ornithine decarboxylase by a non-lysosomal, ubiquitin-independent mechanism

International Nuclear Information System (INIS)

Glass, J.R.; Gerner, E.W.

1987-01-01

The mechanism of spermidine-induced ornithine decarboxylase (OCD, E.C. 4.1.1.17) inactivation was investigated using Chinese hamster ovary (CHO) cells, maintained in serum-free medium, which display a stabilization of ODC owing to the lack of accumulation of putrescine and spermidine. Treatment of cells with 10 μM exogenous spermidine leads to rapid decay of ODC activity accompanied by a parallel decrease in enzyme protein. Analysis of the decay of [ 35 S]methionine-labeled ODC and separation by two-dimensional electrophoresis revealed no detectable modification in ODC structure during enhanced degradation. Spermidine-mediated inactivation of ODC occurred in a temperature-dependent manner exhibiting pseudo-first-order kinetics over a temperature range of 22-37 0 C. In cultures treated continuously, an initial lag was observed after treatment with spermidine, followed by a rapid decline in activity as an apparent critical concentration of intracellular spermidine was achieved. Treating cells at 22 0 C for 3 hours with 10 μ M spermidine, followed by removal of exogenous polyamine, and then shifting to varying temperatures, resulted in rates of ODC inactivation identical with that determined with a continuous treatment. Arrhenius analysis showed that polyamine mediated inactivation of ODC occurred with an activation energy of approximately 16 kcal/mol. Treatment of cells with lysosomotrophic agents had no effect of ODC degradation. ODC turnover was not dependent on ubiquitin-dependent proteolysis. These data support the hypothesis that spermidine regulates ODC degradation via a mechanism requiring new protein synthesis, and that this occurs via a non-lysosomal, ubiquitin-independent pathway

Impact of emotional competence on supportive care needs, anxiety and depression symptoms of cancer patients: a multiple mediation model.

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Baudry, A-S; Lelorain, S; Mahieuxe, M; Christophe, V

2018-01-01

The aim of this study was to test the effect of intrapersonal and interpersonal emotional competence on cancer patients' supportive care needs, as mediated by anxiety and depression symptoms. Cross-sectional design: 137 cancer patients (42% breast or ovarian cancer, 58% gastrointestinal cancer) in 4 French hospitals completed the Profile of Emotional Competence (PEC), the Hospital Anxiety and Depression Scale (HADS), and the Supportive Care Needs Survey Short Form (SCNS-SF). Bootstrap methods with PROCESS Macro were used to test multiple mediation models. Emotional competence presented a direct or indirect beneficial effect on the satisfaction of supportive care needs, anxiety and depression symptoms. As expected, anxiety and depression symptoms had also strong positive correlations with unmet needs. All multiple mediation models were significant, except for physical needs: intrapersonal and interpersonal emotional competence impacted anxiety and depression symptoms, which in turn impacted psychological, sexual, care/support, and information needs. These innovative results show the important effect of patients' emotional competence on their supportive care need satisfaction, as mediated by anxiety and depression. Consequently, patients with high emotional competence may require less psychosocial input from medical clinicians. Thus, emotional competence may be integrated into health models and psychosocial interventions to improve patient adjustment. Further investigation is, however, needed to know which are the most beneficial specific emotional competences and at what point of the cancer pathway.

Effects of pleural effusion drainage on oxygenation, respiratory mechanics, and hemodynamics in mechanically ventilated patients.

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Razazi, Keyvan; Thille, Arnaud W; Carteaux, Guillaume; Beji, Olfa; Brun-Buisson, Christian; Brochard, Laurent; Mekontso Dessap, Armand

2014-09-01

In mechanically ventilated patients, the effect of draining pleural effusion on oxygenation is controversial. We investigated the effect of large pleural effusion drainage on oxygenation, respiratory function (including lung volumes), and hemodynamics in mechanically ventilated patients after ultrasound-guided drainage. Arterial blood gases, respiratory mechanics (airway, pleural and transpulmonary pressures, end-expiratory lung volume, respiratory system compliance and resistance), and hemodynamics (blood pressure, heart rate, and cardiac output) were recorded before and at 3 and 24 hours (H24) after pleural drainage. The respiratory settings were kept identical during the study period. The mean volume of effusion drained was 1,579 ± 684 ml at H24. Uncomplicated pneumothorax occurred in two patients. Respiratory mechanics significantly improved after drainage, with a decrease in plateau pressure and a large increase in end-expiratory transpulmonary pressure. Respiratory system compliance, end-expiratory lung volume, and PaO2/FiO2 ratio all improved. Hemodynamics were not influenced by drainage. Improvement in the PaO2/FiO2 ratio from baseline to H24 was positively correlated with the increase in end-expiratory lung volume during the same time frame (r = 0.52, P = 0.033), but not with drained volume. A high value of pleural pressure or a highly negative transpulmonary pressure at baseline predicted limited lung expansion following effusion drainage. A lesser improvement in oxygenation occurred in patients with ARDS. Drainage of large (≥500 ml) pleural effusion in mechanically ventilated patients improves oxygenation and end-expiratory lung volume. Oxygenation improvement correlated with an increase in lung volume and a decrease in transpulmonary pressure, but was less so in patients with ARDS.

Characterization of CD4+ T cell-mediated cytotoxicity in patients with multiple myeloma.

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Zhang, Xiaole; Gao, Lei; Meng, Kai; Han, Chunting; Li, Qiang; Feng, Zhenjun; Chen, Lei

2018-05-01

Multiple myeloma (MM) is an incurable cancer characterized by the development of malignant plasma cells. The CD8 T cell-mediated cytotoxicity is considered a major player in antitumor immunity, but in MM patients, the CD8 T cells displayed senescence markers and were functionally impaired. To investigate whether cytotoxic CD4 T cells could act as a treatment alternative in MM, we examined the frequency and function of naturally occurring cytotoxic CD4 T cells in MM patients. The cytotoxic CD4 T cells were identified as granzyme-A, granzyme B-, and perforin-expressing CD4 T cells, and their frequencies were significantly upregulated in MM patients when compared with healthy controls. The frequencies of cytotoxic CD4 T cells in MM patients were not associated with the frequencies of cytotoxic CD8 T cells, but were negatively associated with disease severity. Interestingly, the expression levels of inhibitory molecules, including PD-1 and CTLA-4, were significantly lower in cytotoxic CD4 T cells than in cytotoxic CD8 T cells. When co-incubated with autologous CD38 + CD138 + plasma cells, CD4 T cells were capable of eliminating plasma cells with varying degrees of efficacy. In MM patients, the frequency of circulating plasma cells was negatively correlated with the frequency of cytotoxic CD4 T cells. Therefore, CD4 T cell-mediated cytotoxicity existed naturally in MM patients and could potentially act as an option in antitumor therapies. Copyright © 2018 Elsevier Inc. All rights reserved.

Reduced expression IRF7 in nasal epithelial cells from smokers as a potential mechanism mediating enhanced susceptibility to influenza

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Rationale: Smokers are more susceptible to viral infections, including influenza virus, yet the mechanisms mediating this effect are not known. Methods: We have established an in vitro model of differentiated nasal epithelial cells from smokers, which maintain enhanced levels...

Association between social support and post-traumatic stress disorder symptoms among Chinese patients with ovarian cancer: A multiple mediation model.

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Liu, Chunli; Zhang, Yi; Jiang, Hong; Wu, Hui

2017-01-01

Post-traumatic stress disorder (PTSD) symptoms can develop after person experiences one or more traumatic events. Little research, however, has been done on PTSD symptoms of patients with ovarian cancer. The present study aimed to estimate the prevalence of PTSD symptoms in patients with ovarian cancer in China; the effects of demographic and clinical variables on PTSD symptoms; multiple mediation roles in the association between social support and PTSD symptoms in patients with ovarian cancer in China. We collected demographic and clinical information of patients with ovarian cancer in the first and second hospitals of China Medical University between January 1, 2014 and December 31, 2015. Qualified patients were asked to complete the Posttraumatic Stress Disorder Checklist-Civilian Version (PCL-C), Duke-UNC Functional Social Support Questionnaire, Herth Hope Index (HHI), and Resilience Scale-14 (RS-14). 201 patients provided responses. We performed hierarchical linear regression to assess the correlation between social support and PTSD symptoms and bootstrapping to test the mediating role of hope and resilience as potential mediators. After controlling demographic and clinical characteristics, social support negatively correlated with PTSD symptoms (β = -0.406, P accounting for different proportions of the mediating effect. Future intervention plans should pay more attention to social support as well as hope and resilience to prevent, relieve and treat PTSD symptoms.

Estimation of causal mediation effects for a dichotomous outcome in multiple-mediator models using the mediation formula.

Science.gov (United States)

Wang, Wei; Nelson, Suchitra; Albert, Jeffrey M

2013-10-30

Mediators are intermediate variables in the causal pathway between an exposure and an outcome. Mediation analysis investigates the extent to which exposure effects occur through these variables, thus revealing causal mechanisms. In this paper, we consider the estimation of the mediation effect when the outcome is binary and multiple mediators of different types exist. We give a precise definition of the total mediation effect as well as decomposed mediation effects through individual or sets of mediators using the potential outcomes framework. We formulate a model of joint distribution (probit-normal) using continuous latent variables for any binary mediators to account for correlations among multiple mediators. A mediation formula approach is proposed to estimate the total mediation effect and decomposed mediation effects based on this parametric model. Estimation of mediation effects through individual or subsets of mediators requires an assumption involving the joint distribution of multiple counterfactuals. We conduct a simulation study that demonstrates low bias of mediation effect estimators for two-mediator models with various combinations of mediator types. The results also show that the power to detect a nonzero total mediation effect increases as the correlation coefficient between two mediators increases, whereas power for individual mediation effects reaches a maximum when the mediators are uncorrelated. We illustrate our approach by applying it to a retrospective cohort study of dental caries in adolescents with low and high socioeconomic status. Sensitivity analysis is performed to assess the robustness of conclusions regarding mediation effects when the assumption of no unmeasured mediator-outcome confounders is violated. Copyright © 2013 John Wiley & Sons, Ltd.

Estimation of Causal Mediation Effects for a Dichotomous Outcome in Multiple-Mediator Models using the Mediation Formula

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Nelson, Suchitra; Albert, Jeffrey M.

2013-01-01

Mediators are intermediate variables in the causal pathway between an exposure and an outcome. Mediation analysis investigates the extent to which exposure effects occur through these variables, thus revealing causal mechanisms. In this paper, we consider the estimation of the mediation effect when the outcome is binary and multiple mediators of different types exist. We give a precise definition of the total mediation effect as well as decomposed mediation effects through individual or sets of mediators using the potential outcomes framework. We formulate a model of joint distribution (probit-normal) using continuous latent variables for any binary mediators to account for correlations among multiple mediators. A mediation formula approach is proposed to estimate the total mediation effect and decomposed mediation effects based on this parametric model. Estimation of mediation effects through individual or subsets of mediators requires an assumption involving the joint distribution of multiple counterfactuals. We conduct a simulation study that demonstrates low bias of mediation effect estimators for two-mediator models with various combinations of mediator types. The results also show that the power to detect a non-zero total mediation effect increases as the correlation coefficient between two mediators increases, while power for individual mediation effects reaches a maximum when the mediators are uncorrelated. We illustrate our approach by applying it to a retrospective cohort study of dental caries in adolescents with low and high socioeconomic status. Sensitivity analysis is performed to assess the robustness of conclusions regarding mediation effects when the assumption of no unmeasured mediator-outcome confounders is violated. PMID:23650048

Negative symptoms, anxiety, and depression as mechanisms of change of a 12-month trial of assertive community treatment as part of integrated care in patients with first- and multi-episode schizophrenia spectrum disorders (ACCESS I trial).

Science.gov (United States)

Schmidt, Stefanie J; Lange, Matthias; Schöttle, Daniel; Karow, Anne; Schimmelmann, Benno G; Lambert, Martin

2017-05-24

Assertive community treatment (ACT) has shown to be effective in improving both functional deficits and quality of life (QoL) in patients with severe mental illness. However, the mechanisms of this beneficial effect remained unclear. We examined mechanisms of change by testing potential mediators including two subdomains of negative symptoms, i.e. social amotivation as well as expressive negative symptoms, anxiety, and depression within a therapeutic ACT model (ACCESS I trial) in a sample of 120 first- and multi-episode patients with a schizophrenia spectrum disorder (DSM-IV). Path modelling served to test the postulated relationship between the respective treatment condition, i.e. 12-month ACT as part of integrated care versus standard care, and changes in functioning and QoL. The final path model resulted in 3 differential pathways that were all significant. Treatment-induced changes in social amotivation served as a starting point for all pathways, and had a direct beneficial effect on functioning and an additional indirect effect on it through changes in anxiety. Expressive negative symptoms were not related to functioning but served as a mediator between changes in social amotivation and depressive symptoms, which subsequently resulted in improvements in QoL. Our results suggest that social amotivation, expressive negative symptoms, depression, and anxiety functioned as mechanisms of change of ACCESS. An integrated and sequential treatment focusing on these mediators may optimise the generalisation effects on functioning as well as on QoL by targeting the most powerful mechanism of change that fits best to the individual patient.

Music interventions for mechanically ventilated patients.

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Bradt, Joke; Dileo, Cheryl

2014-01-01

Mechanical ventilation often causes major distress and anxiety in patients. The sensation of breathlessness, frequent suctioning, inability to talk, uncertainty regarding surroundings or condition, discomfort, isolation from others, and fear contribute to high levels of anxiety. Side effects of analgesia and sedation may lead to the prolongation of mechanical ventilation and, subsequently, to a longer length of hospitalization and increased cost. Therefore, non-pharmacological interventions should be considered for anxiety and stress management. Music interventions have been used to reduce anxiety and distress and improve physiological functioning in medical patients; however, their efficacy for mechanically ventilated patients needs to be evaluated. This review was originally published in 2010 and was updated in 2014. To update the previously published review that examined the effects of music therapy or music medicine interventions (as defined by the authors) on anxiety and other outcomes in mechanically ventilated patients. Specifically, the following objectives are addressed in this review.1. To conduct a meta-analysis to compare the effects of participation in standard care combined with music therapy or music medicine interventions with standard care alone.2. To compare the effects of patient-selected music with researcher-selected music.3. To compare the effects of different types of music interventions (e.g., music therapy versus music medicine). We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2014, Issue 2), MEDLINE (1950 to March 2014), CINAHL (1980 to March 2014), EMBASE (1980 to March 2014), PsycINFO (1967 to March 2014), LILACS (1982 to March 2014), Science Citation Index (1980 to March 2014), www.musictherapyworld.net (1 March 2008) (database is no longer functional), CAIRSS for Music (to March 2014), Proquest Digital Dissertations (1980 to March 2014), ClinicalTrials.gov (2000 to March 2014), Current

IgE-mediated allergy in elderly patients with asthma

Directory of Open Access Journals (Sweden)

Fumihiro Mitsunobu

1997-01-01

Full Text Available The incidence of a positive family history with asthma and levels of serum IgE and IgE antibodies were examined in 136 patients with asthma in relation to age at onset of the disease. The frequency of subjects with a family history of asthma ranged from 37.9 to 75.0% in all groups classified by age at onset. The frequency of patients with a high serum IgE level (≥ 150 IU/mL was higher (51.7–63.2% in all groups than the frequency of patients with a low serum level (< 150 IU/mL. The mean level of serum IgE was significantly higher in patients with a family history than in those without a family history, in subjects between the ages of 50 and 59 years at onset (mean age 63.4 years; P < 0.02 and in those over the age of 60 years at onset (74.0 years; P < 0.01. The number of patients with a positive RAST score either to house dust mite (HDM, cockroach, and Candida tended to decrease as the age at onset increased. However, the frequency of positive RAST to HDM was higher in patients with a family history and who were over the age of 50 years at onset compared with those patients between the ages of 40 and 49 years at onset, although the frequency was significantly higher in patients with family history than in those without family history (P < 0.02. These results suggest that IgE-mediated allergic reactions are significant not only in those patients who are younger, but also in elderly patients with asthma.

Dislocation-mediated strain hardening in tungsten: Thermo-mechanical plasticity theory and experimental validation

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Terentyev, Dmitry; Xiao, Xiazi; Dubinko, A.; Bakaeva, A.; Duan, Huiling

2015-12-01

A self-consistent thermo-mechanical model to study the strain-hardening behavior of polycrystalline tungsten was developed and validated by a dedicated experimental route. Dislocation-dislocation multiplication and storage, as well dislocation-grain boundary (GB) pinning were the major mechanisms underlying the evolution of plastic deformation, thus providing a link between the strain hardening behavior and material's microstructure. The microstructure of the polycrystalline tungsten samples has been thoroughly investigated by scanning and electron microscopy. The model was applied to compute stress-strain loading curves of commercial tungsten grades, in the as-received and as-annealed states, in the temperature range of 500-1000 °C. Fitting the model to the independent experimental results obtained using a single crystal and as-received polycrystalline tungsten, the model demonstrated its capability to predict the deformation behavior of as-annealed samples in a wide temperature range and applied strain. The relevance of the dislocation-mediated plasticity mechanisms used in the model have been validated using transmission electron microscopy examination of the samples deformed up to different amounts of strain. On the basis of the experimental validation, the limitations of the model are determined and discussed.

Omalizumab in the management of patients with allergic (IgE-mediated asthma

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Thomas Sandström

2009-05-01

Full Text Available Thomas SandströmDepartment of Respiratory Medicine and Allergy, University Hospital, Umeå, SwedenAbstract: Immunoglobulin E (IgE is central to the pathophysiology of allergic asthma. Omalizumab, an anti-IgE monoclonal antibody, binds to the FcεRI binding site on free IgE. As a result, circulating free IgE is reduced, IgE is prevented from attaching to mast cells and basophils, and FcεRI receptor expression is down-regulated. The inflammatory response to allergens and the acute and chronic effector phases of allergic inflammation are thereby attenuated. In clinical trials in adults and adolescents, omalizumab reduced asthma exacerbations, severe asthma exacerbations, inhaled corticosteroid requirements, and emergency visits, as well as significantly improving asthma-related quality of life, morning peak expiratory flow and asthma symptom scores in patients with severe allergic (IgE-mediated asthma. Results from clinical trials in children (< 12 years are consistent with those in the adult population. It is difficult to predict which patients will respond to omalizumab. Responders to omalizumab should be identified after a 16-week trial of therapy using the physician’s overall assessment. When treatment is targeted to these responders, omalizumab provides a cost-effective therapy for inadequately controlled severe allergic (IgE-mediated asthma. Long-term therapy with omalizumab shows the potential for disease-modification in asthma. Ongoing studies are also evaluating the use of omalizumab in other non-asthma IgE-mediated conditions.Keywords: omalizumab, IgE, allergic asthma

Hypothyroidism in Cancer Patients on Immune Checkpoint Inhibitors with anti-PD1 Agents: Insights on Underlying Mechanisms.

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Alhusseini, M; Samantray, J

2017-04-01

Background: Immune therapy using monoclonal antibodies against cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and programmed cell death 1 receptor (PD-1) for various cancers have been reported to cause thyroid dysfunction. Little is known, however, about the underlying pathogenic mechanisms and the course of hypothyroidism that subsequently develops. In this report, we use the change in thyroglobulin and thyroid antibody levels in patients on immune therapy who develop hypothyroidism to better understand its pathogenesis as well as examine the status of hypothyroidism in the long term. Methods: We report a case series of 10 patients who developed hypothyroidism after initiation of immune therapy (either anti-PD-1 alone or in combination with anti-CTLA-4). Available thyroid antibodies including anti-thyroglobulin (anti-Tg), anti-thyroid peroxidase (anti-TPO), and thyroid stimulating immunoglobulin (TSI) were noted during the initial thyroiditis phase as well as the hypothyroid phase. Persistence or remission of hypothyroidism was noted at 6 months. Summary: During the thyroiditis phase, 50% of the patients had elevated Tg titers, 40% had elevated anti-Tg, and 40% had elevated TSI. All of these titers decreased during the hypothyroid phase. Permanent hypothyroidism was noted in 80% of the cases. Conclusion: Hypothyroidism following initiation of immune therapy has immunologic and non-immunologic mediated mechanisms and is likely to be persistent. © Georg Thieme Verlag KG Stuttgart · New York.

Mechanisms of efferent-mediated responses in the turtle posterior crista.

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Holt, Joseph C; Lysakowski, Anna; Goldberg, Jay M

2006-12-20

To study the cellular mechanisms of efferent actions, we recorded from vestibular-nerve afferents close to the turtle posterior crista while efferent fibers were electrically stimulated. Efferent-mediated responses were obtained from calyx-bearing (CD, calyx and dimorphic) afferents and from bouton (B) afferents distinguished by their neuroepithelial locations into BT units near the torus and BM units at intermediate sites. The spike discharge of CD units is strongly excited by efferent stimulation, whereas BT and BM units are inhibited, with BM units also showing a postinhibitory excitation. Synaptic activity was recorded intracellularly after spikes were blocked. Responses of BT/BM units to single efferent shocks consist of a brief depolarization followed by a prolonged hyperpolarization. Both components reflect variations in hair-cell quantal release rates and are eliminated by pharmacological antagonists of alpha9/alpha10 nicotinic receptors. Blocking calcium-dependent SK potassium channels converts the biphasic response into a prolonged depolarization. Results can be explained, as in other hair-cell systems, by the sequential activation of alpha9/alpha10 and SK channels. In BM units, the postinhibitory excitation is based on an increased rate of hair-cell quanta and depends on the preceding inhibition. There is, in addition, an efferent-mediated, direct depolarization of BT/BM and CD fibers. In CD units, it is the exclusive efferent response. Nicotinic antagonists have different effects on hair-cell efferent actions and on the direct depolarization of CD and BT/BM units. Ultrastructural studies, besides confirming the efferent innervation of type II hair cells and calyx endings, show that turtle efferents commonly contact afferent boutons terminating on type II hair cells.

Curcumin-mediated regulation of intestinal barrier function: The mechanism underlying its beneficial effects.

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Ghosh, Siddhartha S; He, Hongliang; Wang, Jing; Gehr, Todd W; Ghosh, Shobha

2018-01-02

Curcumin has anti-inflammatory, anti-oxidant and anti-proliferative properties established largely by in vitro studies. Accordingly, oral administration of curcumin beneficially modulates many diseases including diabetes, fatty-liver disease, atherosclerosis, arthritis, cancer and neurological disorders such as depression, Alzheimer's or Parkinson's disease. However, limited bioavailability and inability to detect curcumin in circulation or target tissues has hindered the validation of a causal role. We established curcumin-mediated decrease in the release of gut bacteria-derived lipopolysaccharide (LPS) into circulation by maintaining the integrity of the intestinal barrier function as the mechanism underlying the attenuation of metabolic diseases (diabetes, atherosclerosis, kidney disease) by curcumin supplementation precluding the need for curcumin absorption. In view of the causative role of circulating LPS and resulting chronic inflammation in the development of diseases listed above, this review summarizes the mechanism by which curcumin affects the several layers of the intestinal barrier and, despite negligible absorption, can beneficially modulate these diseases.

Does adherence to treatment mediate the relationship between patients' treatment outcome expectancies and the outcomes of pain intensity and recovery from acute low back pain?

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Haanstra, Tsjitske M; Kamper, Steven J; Williams, Christopher M; Spriensma, Alette S; Lin, Chung-Wei Christine; Maher, Christopher G; de Vet, Henrica C W; Ostelo, Raymond W J G

2015-08-01

It is believed that patients' expectancies about the effectiveness of treatment influence their treatment outcomes, but the working mechanism is rarely studied in patients with low back pain. Theoretical models suggest that adherence to treatment may be an important pathway. The aim of this study was to assess the mediating role of adherence to treatment in the relationship between expectancies and the outcomes of recovery and pain intensity in patients with acute low back pain. This study used data from a randomized placebo-controlled trial of paracetamol for acute low back pain. Expectancies were measured with the Credibility Expectancy Questionnaire. Adherence was measured with a medication diary. Pain intensity was recorded daily in a diary on a 0 to 10 pain scale, and recovery was defined as the first of 7 consecutive days scoring 0 or 1 on a 6-point pain scale. Cox regression (dependent variable: recovery) and linear mixed-model analyses (dependent variable: daily pain intensity scores) were performed. The "difference in coefficients" approach was used to establish mediation. A total of 1573 participants were included in current analyses. There was a small but highly significant relationship between expectancies and outcomes; 3.3% of the relationship between expectancies and recovery and 14.2% of the relationship between expectancies and pain intensity were mediated by adherence to treatment. This study does not convincingly support the theory that adherence is a key pathway in the relationship between treatment outcome expectancies and recovery and pain intensity in this acute low back pain population.

Combined gauge-mediated and anomaly-mediated supersymmetry breaking and conformal sequestering

International Nuclear Information System (INIS)

Sundrum, Raman

2005-01-01

Anomaly-mediated supersymmetry breaking in the context of 4D conformally sequestered models is combined with Poppitz-Trivedi D-type gauge-mediation. The implementation of the two mediation mechanisms naturally leads to visible soft masses at the same scale so that they can cooperatively solve the μ and flavor problems of weak scale supersymmetry, as well as the tachyonic-slepton problem of pure anomaly-mediation. The tools are developed in a modular fashion for more readily fitting into the general program of optimizing supersymmetric dynamics in hunting for the most attractive weak scale phenomenologies combined with Planck-scale plausibility

Atomistic study of lipid membranes containing chloroform: looking for a lipid-mediated mechanism of anesthesia.

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Ramon Reigada

Full Text Available The molecular mechanism of general anesthesia is still a controversial issue. Direct effect by linking of anesthetics to proteins and indirect action on the lipid membrane properties are the two hypotheses in conflict. Atomistic simulations of different lipid membranes subjected to the effect of small volatile organohalogen compounds are used to explore plausible lipid-mediated mechanisms. Simulations of homogeneous membranes reveal that electrostatic potential and lateral pressure transversal profiles are affected differently by chloroform (anesthetic and carbon tetrachloride (non-anesthetic. Simulations of structured membranes that combine ordered and disordered regions show that chloroform molecules accumulate preferentially in highly disordered lipid domains, suggesting that the combination of both lateral and transversal partitioning of chloroform in the cell membrane could be responsible of its anesthetic action.

Self-stigma and treatment effectiveness in patients with anxiety disorders – a mediation analysis

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Ociskova M

2018-01-01

Full Text Available Marie Ociskova,1 Jan Prasko,1 Kristyna Vrbova,1 Petra Kasalova,1 Michaela Holubova,1 Ales Grambal,1 Klara Machu2 1Department of Psychiatry, Faculty of Medicine and Dentistry, Palacky University, University Hospital, Olomouc, 2Department of Psychology, Faculty of Arts, University of Ostrava, Ostrava, The Czech Republic Goal: The goal of this study was to explore the impact of self-stigma on the treatment outcomes in patients with anxiety disorders and to find possible mediators of this relationship. Method: Two hundred and nine patients with anxiety disorders, who were hospitalized in a psychotherapeutic department, attended the study. The average age was 39.2±12.4 years; two-thirds were women. Most of the patients used a long-term medication. The participants underwent either cognitive behavioral therapy (CBT or short psychodynamic therapy. The selection to the psychotherapy was not randomized. All individuals completed several scales – Beck Depression Inventory, the second edition (BDI-II, Beck Anxiety Inventory (BAI, Dissociative Experience Scale (DES, Sheehan Disability Scale (SDS, subjective Clinical Global Impression (subjCGI, and The Internalized Stigma of Mental Illness Scale (ISMI. A senior psychiatrist filled out the objective CGI (objCGI. Results: The patients significantly improved in the severity of anxiety (BAI, depression (BDI-II, and overall severity of the mental disorder (objCGI. The self-stigma predicted a lower change of the objCGI, but not a change of the anxiety and depressive symptoms severity. Anxiety, depressive symptoms, dissociation, and disability were assessed as possible mediators of the relationship between the self-stigma and the treatment change. None of them were significant. Conclusion: Self-stigma lowers the effectiveness of the combined treatment of anxiety disorders. Future research should explore other possible mediators influencing this relationship. Keywords: self-stigma, anxiety disorders, treatment

Functional disability in patients with low back pain: the mediator role of suffering and beliefs about pain control in patients receiving physical and chiropractic treatment.

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Pereira, M Graça; Roios, Edite; Pereira, Marta

Low back pain is the leading cause of disability worldwide. There is evidence that depression, anxiety, and external locus of control are negative predictors of functional disability in low back patients. This study focused on the mediator role of suffering and beliefs about pain control in the relationship between psychological morbidity and functional disability in patients receiving physical therapy and chiropractic treatment for chronic low back pain. The sample included 213 patients receiving chiropractic treatment and 125 receiving physical therapy, who answered the following instruments: Beliefs about Pain Control Questionnaire; Inventory of Subjective Experiences of Suffering in Illness; Oswestry Low Back Pain Disability Questionnaire; and the Hospital Anxiety and Depression Scales. Suffering was a mediator in the relationship between depression and functional disability in both treatment groups. Only beliefs related to external chance events mediated the relationship between depression and functional disability in the physical therapy group, but not in the chiropratic teratment group. Intervention should focus on suffering regardless of the type of treatment and target beliefs about pain control, in patients receiving physical therapy treatment since they seem to play a key role in functional disability in patients with low back pain. Copyright © 2017 Associação Brasileira de Pesquisa e Pós-Graduação em Fisioterapia. Publicado por Elsevier Editora Ltda. All rights reserved.

Nitroglycerin-mediated, but not flow-mediated vasodilation, is associated with blunted nocturnal blood pressure fall in patients with resistant hypertension.

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Fontes-Guerra, Priscila C A; Cardoso, Claudia R L; Muxfeldt, Elizabeth S; Salles, Gil F

2015-08-01

Endothelial function by flow-mediated (FMD) and nitroglycerin-mediated vasodilations (NMD) was scarcely investigated in resistant hypertension. We aimed to assess the independent correlates of FMD and NMD in resistant hypertensive patients, particularly their associations with ambulatory blood pressures (BP) and nocturnal BP fall patterns. In a cross-sectional study, 280 resistant hypertensive patients performed 24-h ambulatory BP monitoring, carotid-femoral pulse wave velocity, polysomnography, and brachial artery FMD and NMD by high-resolution ultrasonography. Independent correlates of FMD, NMD, and brachial artery diameter (BAD) were assessed by multiple linear and logistic regressions. Median (interquartile range) FMD was 0.75% (-0.6 to +4.4%) and NMD was 11.8% (7.1-18.4%). Baseline BAD and diabetes were independently associated with both FMD and NMD. Older age and prior cardiovascular diseases were associated with altered FMD, whereas higher night-time SBP and lower nocturnal SBP fall were associated with impaired NMD. Moreover, there was a significant gradient of impaired NMD according to blunted nocturnal BP decline patterns. BAD was independently associated with age, sex, BMI, albuminuria, and nocturnal SBP fall. Further adjustments to blood flow velocity, aortic stiffness, plasma aldosterone concentration, and sleep apnea did not change these relationships. NMD, but not FMD, is independently associated with unfavorable night-time BP levels and nondipping patterns, and may be a better cardiovascular risk marker in patients with resistant hypertension. BAD also may provide additional prognostic information.

Identifying cis-mediators for trans-eQTLs across many human tissues using genomic mediation analysis.

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Yang, Fan; Wang, Jiebiao; Pierce, Brandon L; Chen, Lin S

2017-11-01

The impact of inherited genetic variation on gene expression in humans is well-established. The majority of known expression quantitative trait loci (eQTLs) impact expression of local genes ( cis -eQTLs). More research is needed to identify effects of genetic variation on distant genes ( trans -eQTLs) and understand their biological mechanisms. One common trans -eQTLs mechanism is "mediation" by a local ( cis ) transcript. Thus, mediation analysis can be applied to genome-wide SNP and expression data in order to identify transcripts that are " cis -mediators" of trans -eQTLs, including those " cis -hubs" involved in regulation of many trans -genes. Identifying such mediators helps us understand regulatory networks and suggests biological mechanisms underlying trans -eQTLs, both of which are relevant for understanding susceptibility to complex diseases. The multitissue expression data from the Genotype-Tissue Expression (GTEx) program provides a unique opportunity to study cis -mediation across human tissue types. However, the presence of complex hidden confounding effects in biological systems can make mediation analyses challenging and prone to confounding bias, particularly when conducted among diverse samples. To address this problem, we propose a new method: Genomic Mediation analysis with Adaptive Confounding adjustment (GMAC). It enables the search of a very large pool of variables, and adaptively selects potential confounding variables for each mediation test. Analyses of simulated data and GTEx data demonstrate that the adaptive selection of confounders by GMAC improves the power and precision of mediation analysis. Application of GMAC to GTEx data provides new insights into the observed patterns of cis -hubs and trans -eQTL regulation across tissue types. © 2017 Yang et al.; Published by Cold Spring Harbor Laboratory Press.

Activity-dependent astrocyte swelling is mediated by pH-regulating mechanisms.

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Larsen, Brian Roland; MacAulay, Nanna

2017-10-01

During neuronal activity in the mammalian brain, the K + released into the synaptic space is initially buffered by the astrocytic compartment. In parallel, the extracellular space (ECS) shrinks, presumably due to astrocytic cell swelling. With the Na + /K + /2Cl - cotransporter and the Kir4.1/AQP4 complex not required for the astrocytic cell swelling in the hippocampus, the molecular mechanisms underlying the activity-dependent ECS shrinkage have remained unresolved. To identify these molecular mechanisms, we employed ion-sensitive microelectrodes to measure changes in ECS, [K + ] o and [H + ] o /pH o during electrical stimulation of rat hippocampal slices. Transporters and receptors responding directly to the K + and glutamate released into the extracellular space (the K + /Cl - cotransporter, KCC, glutamate transporters and G protein-coupled receptors) did not modulate the extracellular space dynamics. The HCO3--transporting mechanism, which in astrocytes mainly constitutes the electrogenic Na + / HCO3- cotransporter 1 (NBCe1), is activated by the K + -mediated depolarization of the astrocytic membrane. Inhibition of this transporter reduced the ECS shrinkage by ∼25% without affecting the K + transients, pointing to NBCe1 as a key contributor to the stimulus-induced astrocytic cell swelling. Inhibition of the monocarboxylate cotransporters (MCT), like-wise, reduced the ECS shrinkage by ∼25% without compromising the K + transients. Isosmotic reduction of extracellular Cl - revealed a requirement for this ion in parts of the ECS shrinkage. Taken together, the stimulus-evoked astrocytic cell swelling does not appear to occur as a direct effect of the K + clearance, as earlier proposed, but partly via the pH-regulating transport mechanisms activated by the K + -induced astrocytic depolarization and the activity-dependent metabolism. © 2017 Wiley Periodicals, Inc.

Mechanisms of endothelial dysfunction in resistance arteries from patients with end-stage renal disease.

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Leanid Luksha

Full Text Available The study focuses on the mechanisms of endothelial dysfunction in the uremic milieu. Subcutaneous resistance arteries from 35 end-stage renal disease (ESRD patients and 28 matched controls were studied ex-vivo. Basal and receptor-dependent effects of endothelium-derived factors, expression of endothelial NO synthase (eNOS, prerequisites for myoendothelial gap junctions (MEGJ, and associations between endothelium-dependent responses and plasma levels of endothelial dysfunction markers were assessed. The contribution of endothelium-derived hyperpolarizing factor (EDHF to endothelium-dependent relaxation was impaired in uremic arteries after stimulation with bradykinin, but not acetylcholine, reflecting the agonist-specific differences. Diminished vasodilator influences of the endothelium on basal tone and enhanced plasma levels of asymmetrical dimethyl L-arginine (ADMA suggest impairment in NO-mediated regulation of uremic arteries. eNOS expression and contribution of MEGJs to EDHF type responses were unaltered. Plasma levels of ADMA were negatively associated with endothelium-dependent responses in uremic arteries. Preserved responses of smooth muscle to pinacidil and NO-donor indicate alterations within the endothelium and tolerance of vasodilator mechanisms to the uremic retention products at the level of smooth muscle. We conclude that both EDHF and NO pathways that control resistance artery tone are impaired in the uremic milieu. For the first time, we validate the alterations in EDHF type responses linked to kinin receptors in ESRD patients. The association between plasma ADMA concentrations and endothelial function in uremic resistance vasculature may have diagnostic and future therapeutic implications.

Study on bystander effect and associated mechanism mediated through culture medium

International Nuclear Information System (INIS)

Tu Xumin; Lei Suwen; Zhang Zhixing; Lv Huimin

2005-01-01

Objective: To study the bystander effect and associated mechanism mediated through the irradiated cell culture medium. Methods: Splenic natural killer (NK) cells were obtained from healthy male ICR strain mice. Culture medium irradiated with different doses of 60 Co γ-rays was used for culturing Yac-I lymphoma cells. The degree of injury of the latter by activated NK cells was observed. A part of the culture media were pretreated with 1% DMSO, a scavenger of reactive oxygen species (ROS), in order to investigate the possible mechanism of a radiation-induced bystander response. Results: Severer injury was induced in Yac-I cells cultured in the media pre-irradiated with different doses of γ-rays than that in Yac-I cells cultured in unirradiated medium, as shown by increased sensitivity to murine splenic NK cells (P<0.01). Culturing Yac-I cells in DMSO-pretreated medium considerably reduced the activation of NK cells, especially in 0.25 Gy and 0.5 Gy γ-irradiated media. Therefore, it can be expected that DMSO can partly suppress ROS-induced bystander effect. Conclusion: The irradiated culture medium of Yac-I cells can trigger bystander effect. ROS likely plays an important role in radiation-induced bystander effect that can be partly suppressed by pretreatment with DMSO. (authors)

Impairment of flow-mediated dilation correlates with aortic dilation in patients with Marfan syndrome.

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Takata, Munenori; Amiya, Eisuke; Watanabe, Masafumi; Omori, Kazuko; Imai, Yasushi; Fujita, Daishi; Nishimura, Hiroshi; Kato, Masayoshi; Morota, Tetsuro; Nawata, Kan; Ozeki, Atsuko; Watanabe, Aya; Kawarasaki, Shuichi; Hosoya, Yumiko; Nakao, Tomoko; Maemura, Koji; Nagai, Ryozo; Hirata, Yasunobu; Komuro, Issei

2014-07-01

Marfan syndrome is an inherited disorder characterized by genetic abnormality of microfibrillar connective tissue proteins. Endothelial dysfunction is thought to cause aortic dilation in subjects with a bicuspid aortic valve; however, the role of endothelial dysfunction and endothelial damaging factors has not been elucidated in Marfan syndrome. Flow-mediated dilation, a noninvasive measurement of endothelial function, was evaluated in 39 patients with Marfan syndrome. Aortic diameter was measured at the aortic annulus, aortic root at the sinus of Valsalva, sinotubular junction and ascending aorta by echocardiography, and adjusted for body surface area (BSA). The mean value of flow-mediated dilation was 6.5 ± 2.4 %. Flow-mediated dilation had a negative correlation with the diameter of the ascending thoracic aorta (AscAd)/BSA (R = -0.39, p = 0.020) and multivariate analysis revealed that flow-mediated dilation was an independent factor predicting AscAd/BSA, whereas other segments of the aorta had no association. Furthermore, Brinkman index had a somewhat greater influence on flow-mediated dilation (R = -0.42, p = 0.008). Although subjects who smoked tended to have a larger AscAd compared with non-smokers (AscA/BSA: 17.3 ± 1.8 versus 15.2 ± 3.0 mm/m(2), p = 0.013), there was no significant change in flow-mediated dilation, suggesting that smoking might affect aortic dilation via an independent pathway. Common atherogenic risks, such as impairment of flow-mediated dilation and smoking status, affected aortic dilation in subjects with Marfan syndrome.

Molecular Mechanisms Underlying Renin-Angiotensin-Aldosterone System Mediated Regulation of BK Channels

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Zhen-Ye Zhang

2017-09-01

Full Text Available Large-conductance calcium-activated potassium channels (BK channels belong to a family of Ca2+-sensitive voltage-dependent potassium channels and play a vital role in various physiological activities in the human body. The renin-angiotensin-aldosterone system is acknowledged as being vital in the body's hormone system and plays a fundamental role in the maintenance of water and electrolyte balance and blood pressure regulation. There is growing evidence that the renin-angiotensin-aldosterone system has profound influences on the expression and bioactivity of BK channels. In this review, we focus on the molecular mechanisms underlying the regulation of BK channels mediated by the renin-angiotensin-aldosterone system and its potential as a target for clinical drugs.

Prayer and pain: the mediating role of positive re-appraisal.

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Dezutter, Jessie; Wachholtz, Amy; Corveleyn, Jozef

2011-12-01

The present study explored in a sample of Flemish pain patients the role of prayer as a possible individual factor in pain management. The focus on prayer as a personal religious factor fits with the current religious landscape in Western-Europe where personal religious factors are more important than organizational dimensions of religion. Our study is framed in the transactional theory of stress and coping by testing first, whether prayer was related with pain severity and pain tolerance and second, whether cognitive positive re-appraisal was a mediating mechanism in the association between prayer and pain. We expected that prayer would be related to pain tolerance in reducing the impact of the pain on patient's daily life, but not necessarily to pain severity. A cross-sectional questionnaire design was adopted in order to measure demographics, prayer, pain outcomes (i.e., pain severity and pain tolerance), and cognitive positive re-appraisal. Two hundred and two chronic pain (CP) patients, all members of a Flemish national patients association, completed the questionnaires. Correlational analyses showed that prayer was significantly related with pain tolerance, but not with pain severity. However, ancillary analyses revealed a moderational effect of religious affiliation in the relationship between prayer and pain severity as well as pain tolerance. Furthermore, mediation analysis revealed that cognitive positive re-appraisal was indeed an underlying mechanism in the relationship between prayer and pain tolerance. This study affirms the importance to distinguish between pain severity and pain tolerance, and indicates that prayer can play a role in pain management, especially for religious pain patients. Further, the findings can be framed within the transactional theory of stress and coping as the results indicate that positive re-appraisal might be an important underlying mechanism in the association between prayer and pain.

Predicting depression from illness severity in cardiovascular disease patients: self-efficacy beliefs, illness perception, and perceived social support as mediators.

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Greco, A; Steca, P; Pozzi, R; Monzani, D; D'Addario, M; Villani, A; Rella, V; Giglio, A; Malfatto, G; Parati, G

2014-04-01

Many studies have investigated the relationships between cardiovascular diseases and patients' depression; nevertheless, few is still known as regard the impact of illness severity on depression and whether psychosocial variables mediate this association. The aim of this study is to investigate the putative mediating role of illness representations, self-efficacy beliefs, and perceived social support on the relationship between illness severity and depression. A total of 75 consecutive patients with cardiovascular disease (80 % men; mean age = 65.44, SD = 10.20) were enrolled in an Italian hospital. Illness severity was measured in terms of left ventricular ejection fraction, whereas psychological factors were assessed using self-report questionnaires. The relationship between left ventricular ejection fraction and depression was mediated by identity illness perception, self-efficacy beliefs in managing cardiac risk factors, and perceived social support. The treatment of depression in cardiovascular disease patients may therefore benefit from a psychological intervention focused on patients' illness representations, self-efficacy beliefs, and their perceived social support.

Economic Evaluation of a Patient-Directed Music Intervention for ICU Patients Receiving Mechanical Ventilatory Support.

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Chlan, Linda L; Heiderscheit, Annette; Skaar, Debra J; Neidecker, Marjorie V

2018-05-04

Music intervention has been shown to reduce anxiety and sedative exposure among mechanically ventilated patients. Whether music intervention reduces ICU costs is not known. The aim of this study was to examine ICU costs for patients receiving a patient-directed music intervention compared with patients who received usual ICU care. A cost-effectiveness analysis from the hospital perspective was conducted to determine if patient-directed music intervention was cost-effective in improving patient-reported anxiety. Cost savings were also evaluated. One-way and probabilistic sensitivity analyses determined the influence of input variation on the cost-effectiveness. Midwestern ICUs. Adult ICU patients from a parent clinical trial receiving mechanical ventilatory support. Patients receiving the experimental patient-directed music intervention received a MP3 player, noise-canceling headphones, and music tailored to individual preferences by a music therapist. The base case cost-effectiveness analysis estimated patient-directed music intervention reduced anxiety by 19 points on the Visual Analogue Scale-Anxiety with a reduction in cost of $2,322/patient compared with usual ICU care, resulting in patient-directed music dominance. The probabilistic cost-effectiveness analysis found that average patient-directed music intervention costs were $2,155 less than usual ICU care and projected that cost saving is achieved in 70% of 1,000 iterations. Based on break-even analyses, cost saving is achieved if the per-patient cost of patient-directed music intervention remains below $2,651, a value eight times the base case of $329. Patient-directed music intervention is cost-effective for reducing anxiety in mechanically ventilated ICU patients.

Redox-Mediated and Ionizing-Radiation-Induced Inflammatory Mediators in Prostate Cancer Development and Treatment

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Miao, Lu; Holley, Aaron K.; Zhao, Yanming; St. Clair, William H.

2014-01-01

Abstract Significance: Radiation therapy is widely used for treatment of prostate cancer. Radiation can directly damage biologically important molecules; however, most effects of radiation-mediated cell killing are derived from the generated free radicals that alter cellular redox status. Multiple proinflammatory mediators can also influence redox status in irradiated cells and the surrounding microenvironment, thereby affecting prostate cancer progression and radiotherapy efficiency. Recent Advances: Ionizing radiation (IR)–generated oxidative stress can regulate and be regulated by the production of proinflammatory mediators. Depending on the type and stage of the prostate cancer cells, these proinflammatory mediators may lead to different biological consequences ranging from cell death to development of radioresistance. Critical Issues: Tumors are heterogeneous and dynamic communication occurs between stromal and prostate cancer cells, and complicated redox-regulated mechanisms exist in the tumor microenvironment. Thus, antioxidant and anti-inflammatory strategies should be carefully evaluated for each patient at different stages of the disease to maximize therapeutic benefits while minimizing unintended side effects. Future Directions: Compared with normal cells, tumor cells are usually under higher oxidative stress and secrete more proinflammatory mediators. Thus, redox status is often less adaptive in tumor cells than in their normal counterparts. This difference can be exploited in a search for new cancer therapeutics and treatment regimes that selectively activate cell death pathways in tumor cells with minimal unintended consequences in terms of chemo- and radio-resistance in tumor cells and toxicity in normal tissues. Antioxid. Redox Signal. 20, 1481–1500. PMID:24093432

Mechanisms of change in psychotherapy for depression: An empirical update and evaluation of research aimed at identifying psychological mediators.

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Lemmens, Lotte H J M; Müller, Viola N L S; Arntz, Arnoud; Huibers, Marcus J H

2016-12-01

We present a systematic empirical update and critical evaluation of the current status of research aimed at identifying a variety of psychological mediators in various forms of psychotherapy for depression. We summarize study characteristics and results of 35 relevant studies, and discuss the extent to which these studies meet several important requirements for mechanism research. Our review indicates that in spite of increased attention for the topic, advances in theoretical consensus about necessities for mechanism research, and sophistication of study designs, research in this field is still heterogeneous and unsatisfactory in methodological respect. Probably the biggest challenge in the field is demonstrating the causal relation between change in the mediator and change in depressive symptoms. The field would benefit from a further refinement of research methods to identify processes of therapeutic change. Recommendations for future research are discussed. However, even in the most optimal research designs, explaining psychotherapeutic change remains a challenge. Psychotherapy is a multi-dimensional phenomenon that might work through interplay of multiple mechanisms at several levels. As a result, it might be too complex to be explained in relatively simple causal models of psychological change. Copyright © 2016 Elsevier Ltd. All rights reserved.

Distinct mechanisms of loss of IFN-gamma mediated HLA class I inducibility in two melanoma cell lines

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Rodríguez, Teresa; Méndez, Rosa; Del Campo, Ana; Jiménez, Pilar; Aptsiauri, Natalia; Garrido, Federico; Ruiz-Cabello, Francisco

2007-01-01

The inability of cancer cells to present antigen on the cell surface via MHC class I molecules is one of the mechanisms by which tumor cells evade anti-tumor immunity. Alterations of Jak-STAT components of interferon (IFN)-mediated signaling can contribute to the mechanism of cell resistance to IFN, leading to lack of MHC class I inducibility. Hence, the identification of IFN-γ-resistant tumors may have prognostic and/or therapeutic relevance. In the present study, we investigated a mechanism of MHC class I inducibility in response to IFN-γ treatment in human melanoma cell lines. Basal and IFN-induced expression of HLA class I antigens was analyzed by means of indirect immunofluorescence flow cytometry, Western Blot, RT-PCR, and quantitative real-time RT-PCR (TaqMan ® Gene Expression Assays). In demethylation studies cells were cultured with 5-aza-2'-deoxycytidine. Electrophoretic Mobility Shift Assay (EMSA) was used to assay whether IRF-1 promoter binding activity is induced in IFN-γ-treated cells. Altered IFN-γ mediated HLA-class I induction was observed in two melanoma cells lines (ESTDAB-004 and ESTDAB-159) out of 57 studied, while treatment of these two cell lines with IFN-α led to normal induction of HLA class I antigen expression. Examination of STAT-1 in ESTDAB-004 after IFN-γ treatment demonstrated that the STAT-1 protein was expressed but not phosphorylated. Interestingly, IFN-α treatment induced normal STAT-1 phosphorylation and HLA class I expression. In contrast, the absence of response to IFN-γ in ESTDAB-159 was found to be associated with alterations in downstream components of the IFN-γ signaling pathway. We observed two distinct mechanisms of loss of IFN-γ inducibility of HLA class I antigens in two melanoma cell lines. Our findings suggest that loss of HLA class I induction in ESTDAB-004 cells results from a defect in the earliest steps of the IFN-γ signaling pathway due to absence of STAT-1 tyrosine-phosphorylation, while absence

Type D personality, self-efficacy, and medication adherence in patients with heart failure-A mediation analysis.

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Wu, Jia-Rong; Song, Eun Kyeung; Moser, Debra K

2015-01-01

Type D personality is associated with medication non-adherence. Both Type D personality and non-adherence are predictors of poor outcomes. Self-efficacy, which is modifiable, is also associated with medication adherence. To determine the relationships among Type D personality, self-efficacy, and medication adherence in 84 heart failure patients. Self-efficacy, Type D personality, medication adherence, demographic and clinical data were collected. Hierarchical linear regression was used. Type D patients were more likely to have lower self-efficacy (p = .023) and medication non-adherence (p = .027) than non-Type D patients. Low self-efficacy was associated with medication non-adherence (p mediation. Self-efficacy mediates the relationship between Type D personality and medication adherence. Developing and applying interventions to enhance self-efficacy may help to sever the link between Type D personality and poor outcomes. Copyright © 2015 Elsevier Inc. All rights reserved.

Physiologically based indices of volumetric capnography in patients receiving mechanical ventilation.

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Romero, P V; Lucangelo, U; Lopez Aguilar, J; Fernandez, R; Blanch, L

1997-06-01

Several indices of ventilatory heterogeneity can be identified from the expiratory CO2 partial pressure or CO2 elimination versus volume curves. The aims of this study were: 1) to analyse several computerizable indices of volumetric capnography in order to detect ventilatory disturbances; and 2) to establish the relationship between those indices and respiratory system mechanics in subjects with normal lungs and in patients with acute respiratory distress syndrome (ARDS), both receiving mechanical ventilation. We studied six normal subjects and five patients with early ARDS mechanically ventilated at three levels of tidal volume (VT). Respiratory system mechanics were assessed by end-expiratory and end-inspiratory occlusion methods, respectively. We determined Phase III slopes, Fletcher's efficiency index, Bohr's dead space (VD,Bohr/VT), and the ratio of alveolar ejection volume to tidal volume (VAE/VT) from expiratory capnograms, as a function of expired volume. Differences between normal subjects and ARDS patients were significant both for capnographic and mechanical parameters. Changes in VT significantly altered capnographic indices in normal subjects, but failed to change ventilatory mechanics and VAE/VT in ARDS patients. After adjusting for breathing pattern, VAE/VT exhibited the best correlation with the mechanical parameters. In conclusion, volumetric capnography, and, specifically, the ratio of alveolar ejection volume to tidal volume allows evaluation and monitoring of ventilatory disturbances in patients with adult respiratory distress syndrome.

Cardiovascular mechanisms of SSRI drugs and their benefits and risks in ischemic heart disease and heart failure.

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Andrade, Chittaranjan; Kumar, Chethan B; Surya, Sandarsh

2013-05-01

Depression and heart disease are commonly comorbid. Selective serotonin reuptake inhibitors (SSRIs) are commonly used to treat depression. In March 2011, we carried out a 15-year search of PubMed for preclinical and clinical publications related to SSRIs and ischemic heart disease (IHD) or congestive heart failure (CHF). We identify and discuss a number of mechanisms by which SSRIs may influence cardiovascular functioning and health outcomes in patients with heart disease; many of the mechanisms that we present have received little attention in previous reviews. We examine studies with positive, neutral, and negative outcomes in IHD and CHF patients treated with SSRIs. SSRIs influence cardiovascular functioning and health through several different mechanisms; for example, they inhibit serotonin-mediated and collagen-mediated platelet aggregation, reduce inflammatory mediator levels, and improve endothelial function. SSRIs improve indices of ventricular functioning in IHD and heart failure without adversely affecting electrocardiographic parameters. SSRIs may also be involved in favorable or unfavorable drug interactions with medications that influence cardiovascular functions. The clinical evidence suggests that, in general, SSRIs are safe in patients with IHD and may, in fact, exert a cardioprotective effect. The clinical data are less clear in patients with heart failure, and the evidence for benefits with SSRIs is weak.

Pain acceptance potentially mediates the relationship between pain catastrophizing and post-surgery outcomes among compensated lumbar fusion patients

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Dance C

2016-12-01

Full Text Available Cassie Dance,1 M. Scott DeBerard,1 Jessica Gundy Cuneo2 1Department of Psychology, Utah State University, Logan, UT, 2Department of Psychiatry, University of California, San Diego, CA, USA Purpose: Chronic low back pain is highly prevalent and often treatment recalcitrant condition, particularly among workers’ compensation patients. There is a need to identify psychological factors that may predispose such patients to pain chronicity. The primary aim of this study was to examine whether pain acceptance potentially mediated the relationship between pain catastrophizing and post-surgical outcomes in a sample of compensated lumbar fusion patients.Patients and methods: Patients insured with the Workers Compensation Fund of Utah and who were at least 2 years post-lumbar fusion surgery completed an outcome survey. These data were obtained from a prior retrospective-cohort study that administered measures of pain catastrophizing, pain acceptance, mental and physical health, and disability.Results: Of the 101 patients who completed the outcome survey, 75.2% were male with a mean age of 42.42 years and predominantly identified as White (97.0%. The majority of the participants had a posterior lumbar interbody fusion surgery. Pain acceptance, including activity engagement and pain willingness, was significantly correlated with better physical health and mental health, and lower disability rates. Pain catastrophizing was inversely correlated with measures of pain acceptance (activity engagement r=–0.67, p<0.01, pain willingness r=–0.73, p<0.01 as well as the outcome measures: mental health, physical health, and disability. Pain acceptance significantly mediated the relationship between pain catastrophizing and both mental and physical health and also the relationship between pain catastrophizing and disability. Conclusion: This study demonstrated that the relationship between pain catastrophizing and negative patient outcomes was potentially mediated

Right Frontotemporal Cortex Mediates the Relationship between Cognitive Insight and Subjective Quality of Life in Patients with Schizophrenia.

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Pu, Shenghong; Nakagome, Kazuyuki; Itakura, Masashi; Ohtachi, Hiroaki; Iwata, Masaaki; Nagata, Izumi; Kaneko, Koichi

2018-01-01

Although prior studies identified a relationship between cognitive insight and subjective quality of life (QOL) in patients with schizophrenia, the brain regions mediating this relationship remain unknown. Recent studies have shown that the ventrolateral prefrontal cortex may be particularly important for cognitive insight in individuals with schizophrenia. Here, we examined whether frontotemporal function mediates the relationship between cognitive insight and QOL in 64 participants, including 32 patients with schizophrenia and 32 healthy controls. Cognitive insight was measured using the Beck Cognitive Insight Scale (BCIS), while participants' subjective QOL was assessed using the Medical Outcomes Study 36-item Short-form Health Survey. Frontotemporal function was evaluated during a verbal fluency task using multichannel near-infrared spectroscopy. Consistent with previous findings, we found that frontotemporal function was impaired in patients with schizophrenia. Interestingly, our data also revealed that the right ventrolateral PFC and the right anterior part of the temporal cortex significantly mediated the relationship between the self-reflectiveness (SR) subscale of the BCIS and subjective QOL. These findings suggest that cognitive insight, particularly SR, is associated with subjective QOL in patients with schizophrenia via right frontotemporal function. The findings of this study provide important insight into a QOL model of schizophrenia, which may guide the development of cost-effective interventions that target frontotemporal function in patients with schizophrenia.

Pacemaker Therapy in Patients With Neurally Mediated Syncope and Documented Asystole Third International Study on Syncope of Uncertain Etiology (ISSUE-3) A Randomized Trial

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Brignole, Michele; Menozzi, Carlo; Moya, Angel; Andresen, Dietrich; Blanc, Jean Jacques; Krahn, Andrew D.; Wieling, Wouter; Beiras, Xulio; Deharo, Jean Claude; Russo, Vitantonio; Tomaino, Marco; Sutton, Richard; Tomaino, M.; Pescoller, F.; Donateo, P.; Oddone, D.; Russo, V.; Pierri, F.; Matino, M. G.; Vitale, E.; Massa, R.; Piccinni, G.; Melissano, D.; Menozzi, C.; Lolli, G.; Gulizia, M.; Francese, M.; Iorfida, M.; Golzio, P.; Gaggioli, G.; Laffi, M.; Rabjoli, F.; Cecchinato, C.; Ungar, A.; Rafanelli, M.; Chisciotti, V.; Morrione, A.; del Rosso, A.; Guernaccia, V.; Palella, M.; D'Agostino, C.; Campana, A.; Brigante, M.; Miracapillo, G.; Addonisio, L.; Proclemer, A.; Facchin, D.; Vado, A.; Knops, R. E.; Dekker, L. R. C.

2012-01-01

Background-The efficacy of cardiac pacing for prevention of syncopal recurrences in patients with neurally mediated syncope is controversial. We wanted to determine whether pacing therapy reduces syncopal recurrences in patients with severe asystolic neurally mediated syncope. Methods and

Soluble CD30 in patients with antibody-mediated rejection of the kidney allograft.

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Slavcev, Antonij; Honsova, Eva; Lodererova, Alena; Pavlova, Yelena; Sajdlova, Helena; Vitko, Stefan; Skibova, Jelena; Striz, Ilja; Viklicky, Ondrej

2007-07-01

The aim of our retrospective study was to evaluate the clinical significance of measurement of the soluble CD30 (sCD30) molecule for the prediction of antibody-mediated (humoral) rejection (HR). Sixty-two kidney transplant recipients (thirty-one C4d-positive and thirty-one C4d-negative patients) were included into the study. Soluble CD30 levels were evaluated before transplantation and during periods of graft function deterioration. The median concentrations of the sCD30 molecule were identical in C4d-positive and C4d-negative patients before and after transplantation (65.5 vs. 65.0 and 28.2 vs. 36.0 U/ml, respectively). C4d+ patients who developed DSA de novo had a tendency to have higher sCD30 levels before transplantation (80.7+/-53.6 U/ml, n=8) compared with C4d-negative patients (65.0+/-33.4 U/ml, n=15). Soluble CD30 levels were evaluated as positive and negative (>or=100 U/ml and sCD30 estimation with regard to finding C4d deposits in peritubular capillaries were determined. The sensitivity of sCD30+ testing was generally below 40%, while the specificity of the test, i.e. the likelihood that if sCD30 testing is negative, C4d deposits would be absent, was 82%. C4d+ patients who developed DSA de novo were evaluated separately; the specificity of sCD30 testing for the incidence of HR in this cohort was 86%. We could not confirm in our study that high sCD30 levels (>or=100 U/ml) might be predictive for the incidence of HR. Negative sCD30 values might be however helpful for identifying patients with a low risk for development of DSA and antibody-mediated rejection.

Insights into the molecular mechanism of RGL2-mediated inhibition of seed germination in Arabidopsis thaliana

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Stamm Petra

2012-10-01

Full Text Available Abstract Background Seed germination is of immense significance for agriculture and has been studied for centuries. Yet, our understanding of the molecular mechanisms underlying regulation of dormancy and germination is still in its infancy. Gibberellins are the key phytohormones that promote germination, and the DELLA protein RGL2 is the main signalling intermediate involved in this response. Germination is completely inhibited if functional RGL2 is overexpressed and/or stabilized; however, the molecular mechanisms of RGL2 function are still largely unknown. We therefore attempted to shed light onto some of the genetic events downstream of RGL2. Results Gene ontology of the transcriptome differentially regulated by RGL2, as well as extensive cross-comparison with other available microarray data indicates that RGL2-mediated inhibition of germination causes seeds to enter a state of dormancy. RGL2 also appears to differentially regulate a number of transcription factors, many of which are known to be involved in light- or phytohormone-mediated aspects of germination. A promoter analysis of differentially expressed genes identified an enrichment of several motifs that can be bound by specific transcription factors, for example GAMYB, ARF1, or Dof-type zinc fingers. We show that Dof-binding motifs indeed play a role in RGL2-mediated transcription. Using Chromatin Immunoprecipitation (ChIP, we show that RGL2 directly downregulates at least one cell wall modifying enzyme, which is predicted to constrain cell growth thereby leading to inhibition of seed germination. Conclusions Our results reveal that RGL2 controls various aspects of germination. Through the repression of cell wall modifying enzymes, cell growth is directly constrained to inhibit germination. Furthermore, RGL2 likely interacts with various types of proteins to regulate transcription, and differentially regulates several transcription factors. Collectively, our data indicate that

Primary sleep disorders can cause long-term sleep disturbance in patients with autoimmune mediated limbic encephalitis.

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Anderson, Kirstie N; Kelly, Thomas P; Griffiths, Timothy D

2013-07-01

Antibody mediated limbic encephalitis causes a sub acute encephalopathy with an amnestic syndrome, seizures and often an affective prodrome. Sleep disturbance including abnormal dream sleep and insomnia are described in a percentage of long-term survivors but there are very few detailed assessments of sleep disturbance in patients beyond the acute phase of illness. The objectives of this study were to understand the causes of sleep disturbance in the long-term survivors of antibody mediated limbic encephalitis. We screened twelve patients under long-term follow up with sleep questionnaires and went on to perform detailed sleep studies (polysomnography) in those who reported sleep disturbance. Two were found to have persistent, severe central and obstructive sleep apnoea and two others to have restless legs and periodic limb movements of sleep. This highlights the need to investigate sleep disturbance in this group of patients. Effective treatments may be available to improve quality of life and daytime function. Copyright © 2012 Elsevier B.V. All rights reserved.

Prevention of iron- and copper-mediated DNA damage by catecholamine and amino acid neurotransmitters, L-DOPA, and curcumin: metal binding as a general antioxidant mechanism.

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García, Carla R; Angelé-Martínez, Carlos; Wilkes, Jenna A; Wang, Hsiao C; Battin, Erin E; Brumaghim, Julia L

2012-06-07

Concentrations of labile iron and copper are elevated in patients with neurological disorders, causing interest in metal-neurotransmitter interactions. Catecholamine (dopamine, epinephrine, and norepinephrine) and amino acid (glycine, glutamate, and 4-aminobutyrate) neurotransmitters are antioxidants also known to bind metal ions. To investigate the role of metal binding as an antioxidant mechanism for these neurotransmitters, L-dihydroxyphenylalanine (L-DOPA), and curcumin, their abilities to prevent iron- and copper-mediated DNA damage were quantified, cyclic voltammetry was used to determine the relationship between their redox potentials and DNA damage prevention, and UV-vis studies were conducted to determine iron and copper binding as well as iron oxidation rates. In contrast to amino acid neurotransmitters, catecholamine neurotransmitters, L-DOPA, and curcumin prevent significant iron-mediated DNA damage (IC(50) values of 3.2 to 18 μM) and are electrochemically active. However, glycine and glutamate are more effective at preventing copper-mediated DNA damage (IC(50) values of 35 and 12.9 μM, respectively) than L-DOPA, the only catecholamine to prevent this damage (IC(50) = 73 μM). This metal-mediated DNA damage prevention is directly related to the metal-binding behaviour of these compounds. When bound to iron or copper, the catecholamines, amino acids, and curcumin significantly shift iron oxidation potentials and stabilize Fe(3+) over Fe(2+) and Cu(2+) over Cu(+), a factor that may prevent metal redox cycling in vivo. These results highlight the disparate antioxidant activities of neurotransmitters, drugs, and supplements and highlight the importance of considering metal binding when identifying antioxidants to treat and prevent neurodegenerative disorders.

Adipokines and the cardiovascular system: mechanisms mediating health and disease.

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Northcott, Josette M; Yeganeh, Azadeh; Taylor, Carla G; Zahradka, Peter; Wigle, Jeffrey T

2012-08-01

This review focuses on the role of adipokines in the maintenance of a healthy cardiovascular system, and the mechanisms by which these factors mediate the development of cardiovascular disease in obesity. Adipocytes are the major cell type comprising the adipose tissue. These cells secrete numerous factors, termed adipokines, into the blood, including adiponectin, leptin, resistin, chemerin, omentin, vaspin, and visfatin. Adipose tissue is a highly vascularised endocrine organ, and different adipose depots have distinct adipokine secretion profiles, which are altered with obesity. The ability of many adipokines to stimulate angiogenesis is crucial for adipose tissue expansion; however, excessive blood vessel growth is deleterious. As well, some adipokines induce inflammation, which promotes cardiovascular disease progression. We discuss how these 7 aforementioned adipokines act upon the various cardiovascular cell types (endothelial progenitor cells, endothelial cells, vascular smooth muscle cells, pericytes, cardiomyocytes, and cardiac fibroblasts), the direct effects of these actions, and their overall impact on the cardiovascular system. These were chosen, as these adipokines are secreted predominantly from adipocytes and have known effects on cardiovascular cells.

Link Between Positive Clinician-Conveyed Expectations of Treatment Effect and Pain Reduction in Knee Osteoarthritis, Mediated by Patient Self-Efficacy.

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Hsiao-Wei Lo, Grace; Balasubramanyam, Ajay S; Barbo, Andrea; Street, Richard L; Suarez-Almazor, Maria E

2016-07-01

A prior knee osteoarthritis (OA) trial found that provider-conveyed expectations for treatment success were associated with pain improvement. We hypothesized this relationship was mediated by patient self-efficacy, since expectations of improvement may enhance one's ability to control health behaviors, and therefore health. Our aim was to examine whether self-efficacy was a mediator of the relationship observed in this trial. A secondary analysis of a 3-arm (traditional acupuncture, sham acupuncture, and wait list) trial for knee OA was conducted. Those in the acupuncture groups were equally randomized to acupuncturists trained to communicate a high or neutral expectation of treatment success (e.g., using language conveying high or unclear likelihood that acupuncture would reduce knee pain). A modified Arthritis Self-Efficacy Questionnaire and the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain subscale were administered. Linear regression analyses were used to examine whether patient self-efficacy mediated the relationship between provider communication style and knee pain at 3 months. High-expectation provider communication was associated with patient self-efficacy, β coefficient of 0.14 (95% confidence interval [95% CI] 0.01, 0.28). Self-efficacy was associated with WOMAC pain, β coefficient of -9.29 (95% CI -11.11, -7.47), while controlling for the provider communication style. The indirect effect a × b of -1.36 for high versus neutral expectation (bootstrap 95% CI -2.80, -0.15; does not include 0), supports the conclusion that patient self-efficacy mediates the relationship between provider-communicated expectations of treatment effects and knee pain. Our findings suggest that clinician-conveyed expectations can enhance the benefit of treatments targeting knee OA symptoms, mediated by improved patient self-efficacy. © 2016, American College of Rheumatology.

Mediation and moderation: Testing relationships between symptom status, functional health, and quality of life in HIV patients

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Ryu, Ehri; West, Stephen G.; Sousa, Karen H.

2010-01-01

We extended Wilson and Cleary's (1995) health-related quality of life model to examine the relationships among symptoms status (Symptoms), functional health (Disability), and quality of life (QOL). Using a community sample (N = 956) of male HIV positive patients, we tested a mediation model in which the relationship between Symptoms and QOL is partially mediated by Disability. Common and unique ideas from three approaches to examining moderation of effects in mediational models (Edwards & Lambert, 2007; Preacher, Rucker, & Hayes, 2007; MacKinnon, 2008) were used to test whether (a) the direct relationship of Symptoms to QOL and (b) the relationship of Disability to QOL are moderated by age. In the mediation model, both the direct and the indirect (mediated) effects were significant. The direct relationship of Symptoms to QOL was significantly moderated by age, but the relationship of Disability to QOL was not. High Symptoms were associated with lower QOL at all ages, but that this relationship became stronger at older ages. We compare the three approaches and consider their advantages over traditional approaches to combining mediation and moderation. PMID:20706561

Are mediation clauses binding and mandatory?

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Constantinescu Miruna

2017-06-01

Full Text Available This study analyses the legal force of mediation clauses in the common law systems and civil law systems with a main focus on the Romanian approach. First, the introductory section illustrates the paradox between the concept of binding and mandatory effect and the mediation mechanism, a voluntary manner to settle disputes. Notwithstanding, the possibility to coerce the parties to engage into a mediation, the voluntary character of the process is illustrated by the parties’ freedom to decide whether they settle or not. Second, the role of mediation clause is analysed and its advantages are briefly described. Third, the non-compliance of the prior mediation mechanism is presented, the starting point of the discussion being represented by the manner in which the parties drafted the mediation clause. A carefully drafted mediation clause, reflecting the parties’ consent, can determine a court or an arbitral tribunal to enforce such clause. Fourth, the study ends by mentioning the approach adopted by different national courts, emphasizing the Romanian legal perspective.

Probing the role of HDACs and mechanisms of chromatin-mediated neuroplasticity.

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Haggarty, Stephen J; Tsai, Li-Huei

2011-07-01

Advancing our understanding of neuroplasticity and the development of novel therapeutics based upon this knowledge is critical in order to improve the treatment and prevention of a myriad of nervous system disorders. Epigenetic mechanisms of neuroplasticity involve the post-translational modification of chromatin and the recruitment or loss of macromolecular complexes that control neuronal activity-dependent gene expression. While over a century after Ramón y Cajal first described nuclear subcompartments and foci that we now know correspond to sites of active transcription with acetylated histones that are under epigenetic control, the rate and extent to which epigenetic processes act in a dynamic and combinatorial fashion to shape experience-dependent phenotypic and behavioral plasticity in response to various types of neuronal stimuli over a range of time scales is only now coming into focus. With growing recognition that a subset of human diseases involving cognitive dysfunction can be classified as 'chromatinopathies', in which aberrant chromatin-mediated neuroplasticity plays a causal role in the underlying disease pathophysiology, understanding the molecular nature of epigenetic mechanisms in the nervous system may provide important new avenues for the development of novel therapeutics. In this review, we discuss the chemistry and neurobiology of the histone deacetylase (HDAC) family of chromatin-modifying enzymes, outline the role of HDACs in the epigenetic control of neuronal function, and discuss the potential relevance of these epigenetic mechanisms to the development of therapeutics aiming to enhance memory and neuroplasticity. Finally, open questions, challenges, and critical needs for the field of 'neuroepigenetics' in the years to come will be summarized. Copyright © 2011 Elsevier Inc. All rights reserved.

Low-Intensity Ultrasound-Induced Anti-inflammatory Effects Are Mediated by Several New Mechanisms Including Gene Induction, Immunosuppressor Cell Promotion, and Enhancement of Exosome Biogenesis and Docking

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Qian Yang

2017-10-01

Full Text Available Background: Low-intensity ultrasound (LIUS was shown to be beneficial in mitigating inflammation and facilitating tissue repair in various pathologies. Determination of the molecular mechanisms underlying the anti-inflammatory effects of LIUS allows to optimize this technique as a therapy for the treatment of malignancies and aseptic inflammatory disorders.Methods: We conducted cutting-edge database mining approaches to determine the anti-inflammatory mechanisms exerted by LIUS.Results: Our data revealed following interesting findings: (1 LIUS anti-inflammatory effects are mediated by upregulating anti-inflammatory gene expression; (2 LIUS induces the upregulation of the markers and master regulators of immunosuppressor cells including MDSCs (myeloid-derived suppressor cells, MSCs (mesenchymal stem cells, B1-B cells and Treg (regulatory T cells; (3 LIUS not only can be used as a therapeutic approach to deliver drugs packed in various structures such as nanobeads, nanospheres, polymer microspheres, and lipidosomes, but also can make use of natural membrane vesicles as small as exosomes derived from immunosuppressor cells as a novel mechanism to fulfill its anti-inflammatory effects; (4 LIUS upregulates the expression of extracellular vesicle/exosome biogenesis mediators and docking mediators; (5 Exosome-carried anti-inflammatory cytokines and anti-inflammatory microRNAs inhibit inflammation of target cells via multiple shared and specific pathways, suggesting exosome-mediated anti-inflammatory effect of LIUS feasible; and (6 LIUS-mediated physical effects on tissues may activate specific cellular sensors that activate downstream transcription factors and signaling pathways.Conclusions: Our results have provided novel insights into the mechanisms underlying anti-inflammatory effects of LIUS, and have provided guidance for the development of future novel therapeutic LIUS for cancers, inflammatory disorders, tissue regeneration and tissue repair.

Cell-mediated immunity against human retinal extract, S-antigen, and interphotoreceptor retinoid binding protein in onchocercal chorioretinopathy

NARCIS (Netherlands)

van der Lelij, A.; Rothova, A.; Stilma, J. S.; Hoekzema, R.; Kijlstra, A.

1990-01-01

Autoimmune mechanisms are thought to be involved in the pathogenesis of onchocercal chorioretinopathy. Cell-mediated immune responses to human retinal S-antigen, interphotoreceptor retinoid binding protein (IRBP), and crude retinal extract were investigated in patients with onchocerciasis from

Ego mechanisms of defense are associated with patients' preference of treatment modality independent of psychological distress in end-stage renal disease.

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Hyphantis, Thomas; Katsoudas, Spiros; Voudiclari, Sonia

2010-03-24

Several parameters mediate the selection of treatment modality in end-stage renal disease (ESRD). The nephrology community suggests that patient preference should be the prime determinant of modality choice. We aimed to test whether ego mechanisms of defense are associated with patients' treatment modality preferences, independent of psychological distress. In 58 eligible ESRD patients who had themselves chosen their treatment modality, we administered the Symptom Distress Checklist-90-R and the Defense Style Questionnaire. Thirty-seven patients (53.4%) had chosen hemodialysis and 21 (46.6%) peritoneal dialysis. Patients who preferred peritoneal dialysis were younger (odds ratio [OR], 0.89; 95% confidence interval [CI]: 0.804-0.988), had received more education (OR, 8.84; 95% CI: 1.301-60.161), and were twice as likely to adopt an adaptive defense style as compared to patients who preferred hemodialysis (57.1% vs 27.0%, respectively; P psychological distress. Our findings indicate that the patient's personality should be taken into account, if we are to better define which modalities are best suited to which patients. Also, physicians should bear in mind passive-aggressive behaviors that warrant attention and intervention in patients who preferred hemodialysis.

Virological Mechanisms in the Coinfection between HIV and HCV

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Maria Carla Liberto

2015-01-01

Full Text Available Due to shared transmission routes, coinfection with Hepatitis C Virus (HCV is common in patients infected by Human Immunodeficiency Virus (HIV. The immune-pathogenesis of liver disease in HIV/HCV coinfected patients is a multifactorial process. Several studies demonstrated that HIV worsens the course of HCV infection, increasing the risk of cirrhosis and hepatocellular carcinoma. Also, HCV might increase immunological defects due to HIV and risk of comorbidities. A specific cross-talk among HIV and HCV proteins in coinfected patients modulates the natural history, the immune responses, and the life cycle of both viruses. These effects are mediated by immune mechanisms and by a cross-talk between the two viruses which could interfere with host defense mechanisms. In this review, we focus on some virological/immunological mechanisms of the pathogenetic interactions between HIV and HCV in the human host.

Cerebrospinal fluid neopterin analysis in neuropediatric patients: establishment of a new cut off-value for the identification of inflammatory-immune mediated processes.

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Marta Molero-Luis

Full Text Available OBJECTIVE: A high level of cerebrospinal fluid (CSF neopterin is a marker of central nervous system inflammatory-immune mediated processes. We aimed to assess data from 606 neuropediatric patients, describing the clinical and biochemical features of those neurological disorders presenting CSF neopterin values above a new cut-off value that was defined in our laboratory. METHODS: To establish the new CSF neopterin cut-off value, we studied two groups of patients: Group 1 comprised 68 patients with meningoencephalitis, and Group 2 comprised 52 children with a confirmed peripheral infection and no central nervous system involvement. We studied 606 CSF samples from neuropediatric patients who were classified into 3 groups: genetic diagnosis (A, acquired/unknown etiologic neurologic diseases (B and inflammatory-immune mediated processes (C. RESULTS: The CSF neopterin cut-off value was 61 nmol/L. Out of 606 cases, 56 presented a CSF neopterin level above this value. Group C had significantly higher CSF neopterin, protein and leukocyte values than the other groups. Sixteen of twenty-three patients in this group had a CSF neopterin level above the cut-off, whereas three and seven patients presented increased leukocyte and protein values, respectively. A significant association was found among CSF neopterin, proteins and leukocytes in the 606 patients. White matter disturbances were associated with high CSF neopterin concentrations. CONCLUSIONS: Although children with inflammatory-immune mediated processes presented higher CSF neopterin values, patients with other neurological disorders also showed increased CSF neopterin concentrations. These results stress the importance of CSF neopterin analysis for the identification of inflammatory-immune mediated processes.

Protective mechanism against cancer found in progeria patient cells

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NCI scientists have studied cells of patients with an extremely rare genetic disease that is characterized by drastic premature aging and discovered a new protective cellular mechanism against cancer. They found that cells from patients with Hutchinson Gi

Trait anxiety mediates the effect of stress exposure on post-traumatic stress disorder and depression risk in cardiac surgery patients.

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Kok, Lotte; Sep, Milou S; Veldhuijzen, Dieuwke S; Cornelisse, Sandra; Nierich, Arno P; van der Maaten, Joost; Rosseel, Peter M; Hofland, Jan; Dieleman, Jan M; Vinkers, Christiaan H; Joëls, Marian; van Dijk, Diederik; Hillegers, Manon H

2016-12-01

Post-traumatic stress disorder (PTSD) and depression are common after cardiac surgery. Lifetime stress exposure and personality traits may influence the development of these psychiatric conditions. Self-reported rates of PTSD and depression and potential determinants (i.e., trait anxiety and stress exposure) were established 1.5 to 4 years after cardiac surgery. Data was available for 1125 out of 1244 (90.4%) participants. Multivariable linear regressions were conducted to investigate mediating and/or moderating effects of trait anxiety on the relationship between stress exposure, and PTSD and depression. Pre-planned subgroup analyses were performed for both sexes. PTSD and depression symptoms were present in 10.2% and 13.1% of the participants, respectively. Trait anxiety was a full mediator of the association between stress exposure and depression in both the total cohort and female and male subgroups. Moreover, trait anxiety partially mediated the relationship between stress exposure and PTSD in the full cohort and the male subgroup, whereas trait anxiety fully mediated this relationship in female patients. Trait anxiety did not play a moderating role in the total patient sample, nor after stratification on gender. The unequal distribution of male (78%) and female patients (22%) might limit the generalizability of our findings. Furthermore, risk factors were investigated retrospectively and with variable follow-up time. In cardiac surgery patients, trait anxiety was found to be an important mediator of postoperative PTSD and depression. Prospective research is necessary to verify whether these factors are reliable screening measures of individuals' vulnerability for psychopathology development after cardiac surgery. Copyright © 2016 Elsevier B.V. All rights reserved.

Electroacupuncture improves burn-induced impairment in gastric motility mediated via the vagal mechanism in rats.

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Song, J; Yin, J; Sallam, H S; Bai, T; Chen, Y; Chen, J D Z

2013-10-01

Delayed gastric emptying (GE) is common in patients with severe burns. This study was designed to investigate effects and mechanisms of electroacupuncture (EA) on gastric motility in rats with burns. Male rats (intact and vagotomized) were implanted with gastric electrodes, chest and abdominal wall electrodes for investigating the effects of EA at ST-36 (stomach-36 or Zusanli) on GE, gastric slow waves, autonomic functions, and plasma interleukin 6 (IL-6) 6 and 24 h post severe burns. (i) Burn delayed GE (P Electroacupuncture improved GE 6 and 24 h post burn (P Electroacupuncture improved burn-induced gastric dysrhythmia. The percentage of normal slow waves was increased with EA 6 and 24 h post burn (P = 0.02). (iii) Electroacupuncture increased vagal activity assessed by the spectral analysis of heart rate variability (HRV). The high-frequency component reflecting vagal component was increased with EA 6 (P = 0.004) and 24 h post burn (P = 0.03, vs sham-EA). (iv) Electroacupuncture attenuated burn-induced increase in plasma IL-6 at both 6 (P = 0.03) and 24 h post burn (P = 0.003). Electroacupuncture at ST-36 improves gastric dysrhythmia and accelerates GE in rats with burns. The improvement seems to be mediated via the vagal pathway involving the inflammatory cytokine IL-6. © 2013 John Wiley & Sons Ltd.

Alcohol use disorders increase the risk for mechanical ventilation in medical patients.

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de Wit, Marjolein; Best, Al M; Gennings, Chris; Burnham, Ellen L; Moss, Marc

2007-07-01

Annually, more than 300,000 patients receive mechanical ventilation in an intensive care unit in the United States. The hospital mortality for ventilated patients may approach 50%, depending on the primary diagnosis. In trauma and surgical patients, a diagnosis of alcohol use disorder (AUD) is common and is associated with a prolonged duration of mechanical ventilation. The objective of this study is to determine whether the presence of AUD and the development of alcohol withdrawal are associated with an increased use and duration of mechanical ventilation in patients with medical disorders that commonly require intensive care unit admission. We performed a retrospective cohort study using the Nationwide Inpatient Sample, a large all-payer inpatient database representing approximately 1,000 hospitals. For the years 2002 to 2003, adult patients with 1 of the 6 most common diagnoses associated with medical intensive care unit admission were included in the study. Both univariate analysis and multivariable logistic regression were performed to determine whether AUD and alcohol withdrawal were independently associated with the use and duration of mechanical ventilation in these patients. There were a total 785,602 patients who fulfilled 1 of the 6 diagnoses, 26,577 (3.4%) had AUD, 3,967 (0.5%) had alcohol withdrawal, and 65,071 (8.3%) underwent mechanical ventilation (53% or =96 hours). Independent of the medical diagnosis, AUD was associated with an increased risk of requiring mechanical ventilation (13.7 vs 8.1%, odds ratio=1.49, 95% confidence interval [1.414; 1.574], palcohol withdrawal was associated with a longer duration of mechanical ventilation (57 vs 47%> or =96 hours, odds ratio=1.48, 95% confidence interval [1.266; 1.724], palcohol withdrawal is associated with a longer duration of mechanical ventilation.

Mechanism of arctigenin-mediated specific cytotoxicity against human lung adenocarcinoma cell lines.

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Susanti, Siti; Iwasaki, Hironori; Inafuku, Masashi; Taira, Naoyuki; Oku, Hirosuke

2013-12-15

The lignan arctigenin (ARG) from the herb Arctium lappa L. possesses anti-cancer activity, however the mechanism of action of ARG has been found to vary among tissues and types of cancer cells. The current study aims to gain insight into the ARG mediated mechanism of action involved in inhibiting proliferation and inducing apoptosis in lung adenocarcinoma cells. This study also delineates the cancer cell specificity of ARG by comparison with its effects on various normal cell lines. ARG selectively arrested the proliferation of cancer cells at the G0/G1 phase through the down-regulation of NPAT protein expression. This down-regulation occurred via the suppression of either cyclin E/CDK2 or cyclin H/CDK7, while apoptosis was induced through the modulation of the Akt-1-related signaling pathway. Furthermore, a GSH synthase inhibitor specifically enhanced the cytotoxicity of ARG against cancer cells, suggesting that the intracellular GSH content was another factor influencing the susceptibility of cancer cells to ARG. These findings suggest that specific cytotoxicity of ARG against lung cancer cells was explained by its selective modulation of the expression of NPAT, which is involved in histone biosynthesis. The cytotoxicity of ARG appeared to be dependent on the intracellular GSH level. Copyright © 2013 Elsevier GmbH. All rights reserved.

How Does Paying Attention Improve Sexual Functioning in Women? A Review of Mechanisms.

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Arora, Nikita; Brotto, Lori A

2017-07-01

Female sexual dysfunction (FSD), consisting of a constellation of distressing sexual symptoms, is highly prevalent worldwide. Given the central role played by psychological factors in the development of FSD, psychologically and in particular mindfulness-based interventions have arisen as potential treatment options for women. Although mindfulness-based interventions have been evaluated in samples of women with gynecologic cancer; a history of sexual abuse; multiple sclerosis; and spinal cord injury; and provoked vestibulodynia, the mechanisms by which mindfulness leads to improvements in sexual functioning are largely unstudied. To summarize the literature on mechanisms of mindfulness interventions in general and to hypothesize which mechanisms most likely apply to samples of women with FSD. Medline was searched with terms such as mindfulness, meditation, mediator, mode, moderator, mechanism, sex, and sexual dysfunction. Only studies that conducted a formal mediation or moderation analysis were included. We also conducted a broader review on mechanisms in other populations, with slightly modified inclusion criteria: the terms sex and sexual dysfunction were removed and only studies from 2012 to 2016 and studies that included an active mindfulness intervention were included. In general populations, trait mindfulness and decentering were the most common mechanisms identified for the efficacy of mindfulness. In four studies that examined mediators of improvement in samples with FSD, the following mediators were found to be significant: relationship satisfaction, genital self-image, interoceptive awareness, depressed mood, anxiety, and trait mindfulness, of which interoceptive awareness had the most supporting evidence. Clinicians and researchers can use the identified mediators of improvement (ie, interoceptive awareness, depression, and trait mindfulness) when making decisions about which patient might be more likely to benefit from a mindfulness-based approach to

TLR2-dependent inhibition of macrophage responses to IFN-gamma is mediated by distinct, gene-specific mechanisms.

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Sarah A Benson

2009-07-01

Full Text Available Mycobacterium tuberculosis uses multiple mechanisms to avoid elimination by the immune system. We have previously shown that M. tuberculosis can inhibit selected macrophage responses to IFN-gamma through TLR2-dependent and -independent mechanisms. To specifically address the role of TLR2 signaling in mediating this inhibition, we stimulated macrophages with the specific TLR2/1 ligand Pam(3CSK(4 and assayed responses to IFN-gamma. Pam(3CSK(4 stimulation prior to IFN-gamma inhibited transcription of the unrelated IFN-gamma-inducible genes, CIITA and CXCL11. Surface expression of MHC class II and secretion of CXCL11 were greatly reduced as well, indicating that the reduction in transcripts had downstream effects. Inhibition of both genes required new protein synthesis. Using chromatin immunoprecipitation, we found that TLR2 stimulation inhibited IFN-gamma-induced RNA polymerase II binding to the CIITA and CXCL11 promoters. Furthermore, TATA binding protein was unable to bind the TATA box of the CXCL11 promoter, suggesting that assembly of transcriptional machinery was disrupted. However, TLR2 stimulation affected chromatin modifications differently at each of the inhibited promoters. Histone H3 and H4 acetylation was reduced at the CIITA promoter but unaffected at the CXCL11 promoter. In addition, NF-kappaB signaling was required for inhibition of CXCL11 transcription, but not for inhibition of CIITA. Taken together, these results indicate that TLR2-dependent inhibition of IFN-gamma-induced gene expression is mediated by distinct, gene-specific mechanisms that disrupt binding of the transcriptional machinery to the promoters.

Depression and reduced heart rate variability after cardiac surgery: the mediating role of emotion regulation.

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Patron, Elisabetta; Messerotti Benvenuti, Simone; Favretto, Giuseppe; Gasparotto, Renata; Palomba, Daniela

2014-02-01

Heart rate variability (HRV), as an index of autonomic nervous system (ANS) functioning, is reduced by depression after cardiac surgery, but the underlying mechanisms of this relationship are poorly understood. Poor emotion regulation as a core symptom of depression has also been associated with altered ANS functioning. The present study aimed to examine whether emotion dysregulation could be a mediator of the depression-reduced HRV relationship observed after cardiac surgery. Self-reported emotion regulation and four-minute HRV were measured in 25 depressed and 43 nondepressed patients after cardiac surgery. Mediation analysis was conducted to evaluate emotion regulation as a mediator of the depression-reduced HRV relationship. Compared to nondepressed patients, those with depression showed lower standard deviation of normal-to-normal (NN) intervals (pbehavior partially mediated the effect of depression on LF n.u. and HF n.u. Results confirmed previous findings showing that depression is associated with reduced HRV, especially a reduced vagal tone and a sympathovagal imbalance, after cardiac surgery. This study also provides preliminary evidence that increased trait levels of suppression of emotion-expressive behavior may mediate the depression-related sympathovagal imbalance after cardiac surgery. Copyright © 2013 Elsevier B.V. All rights reserved.

Characterization of the mechanism of protection mediated by CS-D7, a monoclonal antibody to Staphylococcus aureus iron regulated surface determinant B (IsdB

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Gregory ePancari

2012-03-01

Full Text Available We previously reported the development of a human monoclonal antibody (CS-D7, IgG1 with specificity and affinity for the iron regulated surface determinant B (IsdB of Staphylococcus aureus. CS-D7 mediates opsonophagocytic killing in vitro and protection in a murine sepsis model. In light of recent data indicating that IsdB specific T cells (CD4+, Th17, not Ab, mediate protection after vaccination with IsdB, it is important to investigate the mechanism of protection mediated by CS-D7. The mAb was examined to determine if it blocked heme binding to IsdB in vitro. The mAb was not found to have heme blocking activity, nor did it prevent bacterial growth under in vivo conditions, in an implanted growth chamber. To assess the role of the mAb Fc a point mutation was introduced at aa 297 (CS-D7●N297A. This point mutation removes Fc effector functions. In vitro analysis of the mutein confirmed that it lacked measurable binding to FcγR, and that it did not fix complement. The mutein had dramatically reduced in vitro opsonic OP activity compared to CS-D7. Nonetheless, the mutein conferred protection equivalent to the wild type mAb in the murine sepsis model. Both wild type and mutein mAbs were efficacious in FcγR deletion mice (including both FcγRII-/- mice and FcγRIII-/- mice, indicating that these receptors were not essential for mAb mediated protection in vivo. Protection mediated by CS-D7 was lost in Balb/c mice depleted of C3 with cobra venom factor (CFV, was lost in mice depleted of superoxide dismutase (SOD in P47phox deletion mice, and was absent in SCID mice. Enhanced clearance of S. aureus in the liver of CS-D7 treated mice and enhanced production of INF-γ, but not of IL17, may play a role in the mechanism of protection mediated by the mAb. CS-D7 apparently mediates survival in challenged mice through a mechanism involving complement, phagocytes, and lymphocytes, but which does not depend on interaction with FcγR, or on blocking heme

A molecular mechanism for diacylglycerol-mediated promotion of negative caloric balance

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Yanai H

2009-12-01

Full Text Available Hidekatsu Yanai1,2, Yoshiharu Tomono3, Kumie Ito1,2, Yuji Hirowatari4, Hiroshi Yoshida1,5, Norio Tada1,21Department of Internal Medicine, 2Institute of Clinical Medicine and Research, 3Department of Nutrition, 5Department of Laboratory Medicine, Jikei University School of Medicine, chiba, Japan; 4Bioscience Division, Tosoh Corporation, Kanagawa, JapanAims: A substitution of diacylglycerol (DAG oil for triacylglycerol (TAG oil in diet has been reported to reduce body fat and body weight, possibly by increasing postprandial energy expenditure (EE. We have previously studied plasma serotonin, which increases EE and exists in the small intestine, in individuals who ingested TAG and DAG oil, and found that DAG ingestion elevates plasma serotonin levels by about 50% compared with TAG ingestion. We studied the molecular mechanisms for DAG-mediated increase in serotonin and EE.Methods: We studied effects of 1-monoacylglycerol and 2-monoacylglycerol, distinct digestive products of DAG and TAG, respectively, on serotonin release from the Caco-2 cells (the human intestinal cell line, n = 8. Further, we studied effects of 1- and 2-monoacylglycerol, and serotonin on expression of mRNA associated with β-oxidation, FA metabolism, and thermogenesis, in the Caco-2 cells (n = 5.Results: 1-monoacylglycerol (100 µM 1-monooleyl glycerol [1-MOG] significantly increased serotonin release from the Caco-2 cells compared with 2-monoacylglycerol (100 µM 2-MOG by 36.6%. Expression of mRNA of acyl-CoA oxidase (ACO, fatty acid translocase (FAT, and uncoupling protein-2 (UCP-2 were significantly higher in 100 µM 1-MOG-treated Caco-2 cells than 100 µM 2-MOG-treated cells by 12.8%, 23.7%, and 35.1%, respectively. Further, expression of mRNA of ACO, medium-chain acyl-CoA dehydrogenase, FAT, and UCP-2 were significantly elevated in serotonin (400 nM-treated Caco-2 cells compared with cells incubated without serotonin by 28.7%, 30.1%, and 39.2%, respectively.Conclusions: Our

Protection of HepG2 cells against acrolein toxicity by 2-cyano-3,12-dioxooleana-1,9-dien-28-imidazolide via glutathione-mediated mechanism.

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Shah, Halley; Speen, Adam M; Saunders, Christina; Brooke, Elizabeth A S; Nallasamy, Palanisamy; Zhu, Hong; Li, Y Robert; Jia, Zhenquan

2015-10-01

Acrolein is an environmental toxicant, mainly found in smoke released from incomplete combustion of organic matter. Several studies showed that exposure to acrolein can lead to liver damage. The mechanisms involved in acrolein-induced hepatocellular toxicity, however, are not completely understood. This study examined the cytotoxic mechanisms of acrolein on HepG2 cells. Acrolein at pathophysiological concentrations was shown to cause apoptotic cell death and an increase in levels of protein carbonyl and thiobarbituric acid reactive acid substances. Acrolein also rapidly depleted intracellular glutathione (GSH), GSH-linked glutathione-S-transferases, and aldose reductase, three critical cellular defenses that detoxify reactive aldehydes. Results further showed that depletion of cellular GSH by acrolein preceded the loss of cell viability. To further determine the role of cellular GSH in acrolein-mediated cytotoxicity, buthionine sulfoximine (BSO) was used to inhibit cellular GSH biosynthesis. It was observed that depletion of cellular GSH by BSO led to a marked potentiation of acrolein-mediated cytotoxicity in HepG2 cells. To further assess the contribution of these events to acrolein-induced cytotoxicity, triterpenoid compound 2-cyano-3,12-dioxooleana-1,9-dien-28-imidazolide (CDDO-Im) was used for induction of GSH. Induction of GSH by CDDO-Im afforded cytoprotection against acrolein toxicity in HepG2 cells. Furthermore, BSO significantly inhibited CDDO-Im-mediated induction in cellular GSH levels and also reversed cytoprotective effects of CDDO-Im in HepG2 cells. These results suggest that GSH is a predominant mechanism underlying acrolein-induced cytotoxicity as well as CDDO-Im-mediated cytoprotection. This study may provide understanding on the molecular action of acrolein which may be important to develop novel strategies for the prevention of acrolein-mediated toxicity. © 2014 by the Society for Experimental Biology and Medicine.

Humidification and secretion volume in mechanically ventilated patients.

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Solomita, Mario; Palmer, Lucy B; Daroowalla, Feroza; Liu, Jeffrey; Miller, Dori; LeBlanc, Deniese S; Smaldone, Gerald C

2009-10-01

To determine potential effects of humidification on the volume of airway secretions in mechanically ventilated patients. Water vapor delivery from devices providing non-heated-wire humidification, heated-wire humidification, and heat and moisture exchanger (HME) were quantified on the bench. Then, patients requiring 24-hour mechanical ventilation were exposed sequentially to each of these humidification devices, and secretions were removed and measured by suctioning every hour during the last 4 hours of the 24-hour study period. In vitro water vapor delivery was greater using non-heated-wire humidification, compared to heated-wire humidification and HME. In vivo, a total of 9 patients were studied. Secretion volume following humidification by non-heated-wire humidification was significantly greater than for heated-wire humidification and HME (P=.004). The volume of secretions appeared to be linked to humidification, as greater water vapor delivery measured in vitro was associated with greater secretion volume in vivo.

Guidelines for the Investigation of Mediating Variables in Business Research.

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MacKinnon, David P; Coxe, Stefany; Baraldi, Amanda N

2012-03-01

Business theories often specify the mediating mechanisms by which a predictor variable affects an outcome variable. In the last 30 years, investigations of mediating processes have become more widespread with corresponding developments in statistical methods to conduct these tests. The purpose of this article is to provide guidelines for mediation studies by focusing on decisions made prior to the research study that affect the clarity of conclusions from a mediation study, the statistical models for mediation analysis, and methods to improve interpretation of mediation results after the research study. Throughout this article, the importance of a program of experimental and observational research for investigating mediating mechanisms is emphasized.

Protein expression profiling of inflammatory mediators in human temporal lobe epilepsy reveals co-activation of multiple chemokines and cytokines

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Kan Anne A

2012-08-01

Full Text Available Abstract Mesial temporal lobe epilepsy (mTLE is a chronic and often treatment-refractory brain disorder characterized by recurrent seizures originating from the hippocampus. The pathogenic mechanisms underlying mTLE remain largely unknown. Recent clinical and experimental evidence supports a role of various inflammatory mediators in mTLE. Here, we performed protein expression profiling of 40 inflammatory mediators in surgical resection material from mTLE patients with and without hippocampal sclerosis, and autopsy controls using a multiplex bead-based immunoassay. In mTLE patients we identified 21 upregulated inflammatory mediators, including 10 cytokines and 7 chemokines. Many of these upregulated mediators have not previously been implicated in mTLE (for example, CCL22, IL-7 and IL-25. Comparing the three patient groups, two main hippocampal expression patterns could be distinguished, pattern I (for example, IL-10 and IL-25 showing increased expression in mTLE + HS patients compared to mTLE-HS and controls, and pattern II (for example, CCL4 and IL-7 showing increased expression in both mTLE groups compared to controls. Upregulation of a subset of inflammatory mediators (for example, IL-25 and IL-7 could not only be detected in the hippocampus of mTLE patients, but also in the neocortex. Principle component analysis was used to cluster the inflammatory mediators into several components. Follow-up analyses of the identified components revealed that the three patient groups could be discriminated based on their unique expression profiles. Immunocytochemistry showed that IL-25 IR (pattern I and CCL4 IR (pattern II were localized in astrocytes and microglia, whereas IL-25 IR was also detected in neurons. Our data shows co-activation of multiple inflammatory mediators in hippocampus and neocortex of mTLE patients, indicating activation of multiple pro- and anti-epileptogenic immune pathways in this disease.

Mechanisms of CDDO-imidazolide-mediated cytoprotection against acrolein-induced neurocytotoxicity in SH-SY5Y cells and primary human astrocytes.

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Speen, Adam; Jones, Colton; Patel, Ruby; Shah, Halley; Nallasamy, Palanisamy; Brooke, Elizabeth A S; Zhu, Hong; Li, Y Robert; Jia, Zhenquan

2015-10-01

Acrolein is a ubiquitous unsaturated aldehyde has been implicated in the pathogenesis of various neurological disorders. However, limited study has been conducted into potential therapeutic protection and underlying mechanism against acrolein-induced cytotoxicity via upregulation of cellular aldehyde-detoxification defenses. In this study we have utilized RA-differentiated human SH-SY5Y cells and primary human astrocytes to investigate the induction of glutathione (GSH) by the synthetic triterpenoid 2-cyano-3,12-dixooleana-1,9-dien-28-imidazolide (CDDO-Im) and the protective effects CDDO-Im-mediated antioxidant defenses on acrolein toxicity. Acrolein exposure to RA-differentiated SH-SY5Y cells resulted in a significant time dependent depletion of cellular GSH preceding a reduction in cell viability and LDH release. Further, we demonstrated the predominance of cellular GSH in protection against acrolein-induced cytotoxicity. Buthionine sulfoximine (BSO) at 25μM dramatically depleted GSH and significantly potentiated acrolein-induced cytotoxicity. Pretreatment of the cells with 100nM CDDO-Im afforded a dramatic protection against acrolein-induced cytotoxicity. Pretreatment of BSO and CDDO was found to prevent the CDDO-Im-mediated GSH induction and partially reversed the cytoprotective effects of CDDO-Im against acrolein cytotoxicity. Overall, this study represents for the first time the CDDO-Im mediated upregulation of GSH is a predominant mechanism against acrolein-induced neurotoxicity. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Non-minimal gauge mediation and moduli stabilization

International Nuclear Information System (INIS)

Jelinski, T.; Lalak, Z.; Pawelczyk, J.

2010-01-01

In this Letter we consider U(1) A -gauged Polonyi model with two spurions coupled to a twisted closed string modulus. This offers a consistent setup for metastable SUSY breakdown which allows for moduli stabilization and naturally leads to gauge or hybrid gauge/gravitational mediation mechanism. Due to the presence of the second spurion one can arrange for a solution of the μ and B μ problems in a version of modified Giudice-Masiero mechanism, which works both in the limit of pure gauge mediation and in the mixed regime of hybrid mediation.

Uncovering molecular structural mechanisms of signaling mediated by the prion protein

International Nuclear Information System (INIS)

Romano, Sebastian A.; Linden, Rafael; Silva, Jerson L.; Foguel, Debora

2009-01-01

The glycosyl phosphatidylinositol (GPI) - anchored prion protein (PrP c ), usually associated with neurodegenerative diseases, modulates various cellular responses and may scaffold multiprotein cell surface signaling complexes. Engagement of PrP c with the secretable cochaperone hop/STI 1 induces neurotrophic transmembrane signals through unknown molecular mechanisms. We addressed whether interaction of Pr P c and hop STI 1 entails structural rearrangements relevant for signaling. Circular dichroism and fluorescence spectroscopy showed that PrP c :hop/STI 1 interaction triggers loss of PrP helical structures, involving at least a perturbation of the Pr P c 143-153 beta-helix. Novel SAXS models revealed a significant C-terminal compaction of hop/STI 1 when bound to PrP c . Differing from a recent dimeric model of human hop/STI 1, both size exclusion chromatography and SAXS data support a monomeric form of free murine hop/STI 1. Changes in the Pr P c 143-153 beta-helix may engage the transmembrane signaling protein laminin receptor precursor and neural cell adhesion molecule, both of which bind that domain of Pr P c , and further ligands may be engaged by the tertiary structural changes of hop/STI 1. These reciprocal structural modifications indicate a versatile mechanism for signaling mediated by Pr P c :hop/STI 1 interaction, consistent with the hypothesis that Pr P c scaffolds multiprotein signaling complexes at the cell surface. (author)

Uncovering molecular structural mechanisms of signaling mediated by the prion protein

Energy Technology Data Exchange (ETDEWEB)

Romano, Sebastian A.; Linden, Rafael [Universidade Federal do Rio de Janeiro (IBCCF/UFRl), RJ (Brazil). Inst. de Biofisica Carlos Chagas Filho; Cordeiro, Yraima; Rocha e Lima, Luis M.T. da [Universidade Federal do Rio de Janeiro (FF/UFRl), RJ (Brazil). Fac. de Farmacia; Lopes, Marilene H. [Instituto Ludwig de Pesquisa de Cancer, Sao Paulo, SP (Brazil); Silva, Jerson L.; Foguel, Debora [Universidade Federal do Rio de Janeiro (IBqM/UFRl), RJ (Brazil). Inst. de Bioquimica Medica

2009-07-01

The glycosyl phosphatidylinositol (GPI) - anchored prion protein (PrP{sup c}), usually associated with neurodegenerative diseases, modulates various cellular responses and may scaffold multiprotein cell surface signaling complexes. Engagement of PrP{sup c} with the secretable cochaperone hop/STI 1 induces neurotrophic transmembrane signals through unknown molecular mechanisms. We addressed whether interaction of Pr P{sup c} and hop STI 1 entails structural rearrangements relevant for signaling. Circular dichroism and fluorescence spectroscopy showed that PrP{sup c}:hop/STI 1 interaction triggers loss of PrP helical structures, involving at least a perturbation of the Pr P{sup c}{sub 143-153} beta-helix. Novel SAXS models revealed a significant C-terminal compaction of hop/STI 1 when bound to PrP{sup c}. Differing from a recent dimeric model of human hop/STI 1, both size exclusion chromatography and SAXS data support a monomeric form of free murine hop/STI 1. Changes in the Pr P{sup c}{sub 143-153} beta-helix may engage the transmembrane signaling protein laminin receptor precursor and neural cell adhesion molecule, both of which bind that domain of Pr P{sup c}, and further ligands may be engaged by the tertiary structural changes of hop/STI 1. These reciprocal structural modifications indicate a versatile mechanism for signaling mediated by Pr P{sup c}:hop/STI 1 interaction, consistent with the hypothesis that Pr P{sup c} scaffolds multiprotein signaling complexes at the cell surface. (author)

The Impact of Self-management Knowledge and Support on the Relationships Among Self-efficacy, Patient Activation, and Self-management in Rural Patients With Heart Failure.

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Young, Lufei; Kupzyk, Kevin; Barnason, Susan

Self-management (SM) is an essential component of heart failure (HF) management. The mechanisms to improve SM behaviors are unclear. The objective of this study is to examine whether patient activation mediates the effect of self-efficacy on SM behaviors in rural HF patients. A secondary analysis was conducted using data collected from a randomized controlled trial aimed to improve SM behaviors. The main variables included were SM knowledge, self-efficacy, patient activation, and SM behaviors. Mediation analysis showed patient activation mediated the effect of self-efficacy on SM. Both self-efficacy and patient activation were significantly related to SM behaviors, respectively (r = 0.46, P self-efficacy was no longer directly related to SM behaviors when patient activation was entered into the final model (β = .17, P = .248). Self-management knowledge and support were significant moderators. In patients with high levels of SM knowledge, patient activation did not mediate the effect of self-efficacy on SM behaviors (β = .15, P = .47). When SM support was entered in the path model, patient activation was not a significant mediator between self-efficacy and SM behavior at high (β = .27, P = .27) or low (β = .27, P = .25) levels of SM support. Study findings suggest that targeted SM support for high-risk HF patients with low SM knowledge and support may be useful. In addition, strategies to increase patient activation may improve HF patients' SM confidence.

Effect of radiation on cell-mediated cytotoxicity and lymphocyte subpopulations in patients with ovarian carcinoma

International Nuclear Information System (INIS)

Kohorn, E.I.; Mitchell, M.S.; Dwyer, J.M.; Knowlton, A.H.; Klein-Angerer, S.

1978-01-01

Lymphocyte subpopulations and cell-mediated cytotoxicity (CMI) were studied during radiation therapy in 16 patients with ovarian carcinoma. The total lymphocyte count became depressed in all patients. The depression was more marked among T cells, while the proportion of B cells remained unaffected. In patients with Stage I and II ovarian cancer, CMI was depressed significantly by radiotherapy after 7 days of treatment, remained low at 14 days but recovered despite continuation of radiation. This depression of CMI occurred at a delivered dose of 1,000 rads with subsequent recovery. Patients with Stage III ovarian cancer given pelvic and abdominal radiation were found to have no consistent depression of CMI, a finding similar to that in Stage III ovarian carcinoma patients given chemotherapy

Causal mediation analysis with multiple mediators in the presence of treatment noncompliance.

Science.gov (United States)

Park, Soojin; Kürüm, Esra

2018-05-20

Randomized experiments are often complicated because of treatment noncompliance. This challenge prevents researchers from identifying the mediated portion of the intention-to-treated (ITT) effect, which is the effect of the assigned treatment that is attributed to a mediator. One solution suggests identifying the mediated ITT effect on the basis of the average causal mediation effect among compliers when there is a single mediator. However, considering the complex nature of the mediating mechanisms, it is natural to assume that there are multiple variables that mediate through the causal path. Motivated by an empirical analysis of a data set collected in a randomized interventional study, we develop a method to estimate the mediated portion of the ITT effect when both multiple dependent mediators and treatment noncompliance exist. This enables researchers to make an informed decision on how to strengthen the intervention effect by identifying relevant mediators despite treatment noncompliance. We propose a nonparametric estimation procedure and provide a sensitivity analysis for key assumptions. We conduct a Monte Carlo simulation study to assess the finite sample performance of the proposed approach. The proposed method is illustrated by an empirical analysis of JOBS II data, in which a job training intervention was used to prevent mental health deterioration among unemployed individuals. Copyright © 2018 John Wiley & Sons, Ltd.

Effects of exercise training on pulmonary mechanics and functional status in patients with prolonged mechanical ventilation.

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Chen, Yen-Huey; Lin, Hui-Ling; Hsiao, Hsiu-Feng; Chou, Lan-Ti; Kao, Kuo-Chin; Huang, Chung-Chi; Tsai, Ying-Huang

2012-05-01

The functional status and outcomes in patients with prolonged mechanical ventilation (PMV) are often limited by poor endurance and pulmonary mechanics, which result from the primary diseases or prolonged time bedridden. We evaluate the impact of exercise training on pulmonary mechanics, physical functional status, and hospitalization outcomes in PMV patients. Twenty-seven subjects with PMV in our respiratory care center (RCC) were divided randomly into an exercise training group (n = 12) and a control group (n = 15). The exercise program comprised 10 sessions of exercise training. The measurement of pulmonary mechanics and physical functional status (Functional Independence Measurement and Barthel index) were performed pre-study and post-study. The hospitalization outcomes included: days of mechanical ventilation, hospitalization days, and weaning and mortality rates during RCC stay. The training group had significant improvement in tidal volume (143.6 mL vs 192.5 mL, P = .02) and rapid shallow breathing index after training (162.2 vs 110.6, P = .009). No significant change was found in the control group except respiratory rate. Both groups had significant improvement in functional status during the study. However, the training group had greater changes in FIM score than the control group (44.6 vs 34.2, P = .024). The training group also had shorter RCC stay and higher weaning and survival rates than the control group, although no statistical difference was found. Subjects with PMV in our RCC demonstrated significant improvement in pulmonary mechanics and functional status after exercise training. The application of exercise training may be helpful for PMV patients to improve hospitalization outcomes.

Convergent RANK- and c-Met-mediated signaling components predict survival of patients with prostate cancer: an interracial comparative study.

Science.gov (United States)

Hu, Peizhen; Chung, Leland W K; Berel, Dror; Frierson, Henry F; Yang, Hua; Liu, Chunyan; Wang, Ruoxiang; Li, Qinlong; Rogatko, Andre; Zhau, Haiyen E

2013-01-01

We reported (PLoS One 6 (12):e28670, 2011) that the activation of c-Met signaling in RANKL-overexpressing bone metastatic LNCaP cell and xenograft models increased expression of RANK, RANKL, c-Met, and phosphorylated c-Met, and mediated downstream signaling. We confirmed the significance of the RANK-mediated signaling network in castration resistant clinical human prostate cancer (PC) tissues. In this report, we used a multispectral quantum dot labeling technique to label six RANK and c-Met convergent signaling pathway mediators simultaneously in formalin fixed paraffin embedded (FFPE) tissue specimens, quantify the intensity of each expression at the sub-cellular level, and investigated their potential utility as predictors of patient survival in Caucasian-American, African-American and Chinese men. We found that RANKL and neuropilin-1 (NRP-1) expression predicts survival of Caucasian-Americans with PC. A Gleason score ≥ 8 combined with nuclear p-c-Met expression predicts survival in African-American PC patients. Neuropilin-1, p-NF-κB p65 and VEGF are predictors for the overall survival of Chinese men with PC. These results collectively support interracial differences in cell signaling networks that can predict the survival of PC patients.

Anxiety, depression and autonomy-connectedness: The mediating role of alexithymia and assertiveness.

Science.gov (United States)

Rutten, Elisabeth A P; Bachrach, Nathan; van Balkom, Anton J L M; Braeken, Johan; Ouwens, Machteld A; Bekker, Marrie H J

2016-12-01

Autonomy-connectedness (self-awareness, sensitivity to others, and capacity for managing new situations) reflects the capacity for self-governance, including in social relationships. Evidence showed that autonomy-connectedness is related to anxiety and depression. Little is known about the underlying mechanisms. We hypothesized that alexithymia and assertiveness would mediate the relationships between autonomy-connectedness and anxiety and depression. Relationships among the variables were investigated in 100 patients with a mean age of 42.2 suffering from anxiety and/or depression using a cross-sectional design. The relationship between self-awareness and both anxiety and depression was mediated by alexithymia. For anxiety, there was also a direct effect of sensitivity to others that was not explained by either alexithymia or assertiveness. Assertiveness did not have any mediational effect. The results indicate that particularly alexithymia explains the association of autonomy-connectedness with anxiety and depression. The study confirmed the relevance of autonomy-connectedness in anxiety and depression. In treating symptoms of anxiety, it is advisable to give attention to normalizing the patient's sensitivity to others. Treatment of patients with symptoms of anxiety and depression should include assessment of emotional awareness and, in the case of impaired emotional awareness, should be tailored as to promote increased awareness. © 2015 The British Psychological Society.

Perceived medication adherence barriers mediating effects between gastrointestinal symptoms and health-related quality of life in pediatric inflammatory bowel disease.

Science.gov (United States)

Varni, James W; Shulman, Robert J; Self, Mariella M; Saeed, Shehzad A; Zacur, George M; Patel, Ashish S; Nurko, Samuel; Neigut, Deborah A; Franciosi, James P; Saps, Miguel; Denham, Jolanda M; Dark, Chelsea Vaughan; Bendo, Cristiane B; Pohl, John F

2018-01-01

The primary objective was to investigate the mediating effects of patient-perceived medication adherence barriers in the relationship between gastrointestinal symptoms and generic health-related quality of life (HRQOL) in adolescents with inflammatory bowel disease (IBD). The secondary objective explored patient health communication and gastrointestinal worry as additional mediators with medication adherence barriers in a serial multiple mediator model. The Pediatric Quality of Life Inventory™ Gastrointestinal Symptoms, Medicines, Communication, Gastrointestinal Worry, and Generic Core Scales were completed in a 9-site study by 172 adolescents with IBD. Gastrointestinal Symptoms Scales measuring stomach pain, constipation, or diarrhea and perceived medication adherence barriers were tested for bivariate and multivariate linear associations with HRQOL. Mediational analyses were conducted to test the hypothesized mediating effects of perceived medication adherence barriers as an intervening variable between gastrointestinal symptoms and HRQOL. The predictive effects of gastrointestinal symptoms on HRQOL were mediated in part by perceived medication adherence barriers. Patient health communication was a significant additional mediator. In predictive analytics models utilizing multiple regression analyses, demographic variables, gastrointestinal symptoms (stomach pain, constipation, or diarrhea), and perceived medication adherence barriers significantly accounted for 45, 38, and 29 percent of the variance in HRQOL (all Ps barriers explain in part the effects of gastrointestinal symptoms on HRQOL in adolescents with IBD. Patient health communication to healthcare providers and significant others further explain the mechanism in the relationship between gastrointestinal symptoms, perceived medication adherence barriers, and HRQOL.

Physiological Mechanisms Mediating the Coupling between Heart Period and Arterial Pressure in Response to Postural Changes in Humans

OpenAIRE

Silvani, Alessandro; Calandra-Buonaura, Giovanna; Johnson, Blair D.; van Helmond, Noud; Barletta, Giorgio; Cecere, Anna G.; Joyner, Michael J.; Cortelli, Pietro

2017-01-01

The upright posture strengthens the coupling between heart period (HP) and systolic arterial pressure (SAP) consistently with a greater contribution of the arterial baroreflex to cardiac control, while paradoxically decreasing cardiac baroreflex sensitivity (cBRS). To investigate the physiological mechanisms that mediate the coupling between HP and SAP in response to different postures, we analyzed the cross-correlation functions between low-frequency HP and SAP fluctuations and estimated cBR...

Music preferences of mechanically ventilated patients participating in a randomized controlled trial.

Science.gov (United States)

Heiderscheit, Annie; Breckenridge, Stephanie J; Chlan, Linda L; Savik, Kay

2014-01-01

Mechanical ventilation (MV) is a life-saving measure and supportive modality utilized to treat patients experiencing respiratory failure. Patients experience pain, discomfort, and anxiety as a result of being mechanically ventilated. Music listening is a non-pharmacological intervention used to manage these psychophysiological symptoms associated with mechanical ventilation. The purpose of this secondary analysis was to examine music preferences of 107 MV patients enrolled in a randomized clinical trial that implemented a patient-directed music listening protocol to help manage the psychophysiological symptom of anxiety. Music data presented includes the music genres and instrumentation patients identified as their preferred music. Genres preferred include: classical, jazz, rock, country, and oldies. Instrumentation preferred include: piano, voice, guitar, music with nature sounds, and orchestral music. Analysis of three patients' preferred music received throughout the course of the study is illustrated to demonstrate the complexity of assessing MV patients and the need for an ongoing assessment process.

Receptor-mediated mechanism for the transport of prolactin from blood to cerebrospinal fluid

International Nuclear Information System (INIS)

Walsh, R.J.; Slaby, F.J.; Posner, B.I.

1987-01-01

Prolactin (PRL) interacts with areas of the central nervous system which reside behind the blood-brain barrier. While vascular PRL does not cross this barrier, it is readily accessible to the cerebrospinal fluid (CSF) from which it may gain access to the PRL-responsive areas of the brain. Studies were undertaken to characterize the mechanism responsible for the translocation of PRL from blood to CSF. Rats were given external jugular vein injections of [ 125 -I]iodo-PRL in the presence or absence of an excess of unlabeled ovine PRL (oPRL), human GH, bovine GH, or porcine insulin. CSF and choroid plexus were removed 60 min later. CSF samples were electrophoresed on sodium dodecyl sulfate-polyacrylamide slab gels and resultant autoradiographs were analyzed with quantitative microdensitometry. The data revealed that unlabeled lactogenic hormones, viz. oPRL and human GH, caused a statistically significant inhibition of [ 125 I]iodo-PRL transport from blood to CSF. In contrast, nonlactogenic hormones, viz bovine GH and insulin, had no effect on [ 125 I]iodo-PRL transport into the CSF. An identical pattern of competition was observed in the binding of hormone to the choroid plexus. Furthermore, vascular injections of [ 125 I]iodo-PRL administered with a range of concentrations of unlabeled oPRL revealed a dose-response inhibition in the transport of [ 125 I]iodo-PRL from blood to CSF. The study demonstrates that PRL enters the CSF by a specific, PRL receptor-mediated transport mechanism. The data is consistent with the hypothesis that the transport mechanism resides at the choroid plexus. The existence of this transport mechanism reflects the importance of the cerebroventricular system in PRL-brain interactions

Molecular mechanisms of FK506-induced hypertension in solid organ transplantation patients

Institute of Scientific and Technical Information of China (English)

Wang Jianglin; Guo Ren; Liu Shikun; Chen Qingjie; Zuo Shanru; Yang Meng; Zuo Xiaocong

2014-01-01

Objective Tacrolimus (FK506) is an immunosuppressive drug,which is widely used to prevent rejection of transplanted organs.However,chronic administration of FK506 leads to hypertension in solid organ transplantation patients,and its molecular mechanisms are much more complicated.In this review,we will discuss the above-mentioned molecular mechanisms of FK506-induced hypertension in solid organ transplantation subjects.Data sources The data analyzed in this review were mainly from relevant articles without restriction on the publication date reported in PubMed.The terms "FK506" or "tacrolimus" and "hypertension"were used for the literature search.Study selection Original articles with no limitation of research design and critical reviews containing data relevant to FK506-induced hypertension and its molecular mechanisms were retrieved,reviewed and analyzed.Results There are several molecular mechanisms attributed to FK506-induced hypertension in solid organ transplantation subjects.First,FK506 binds FK506 binding protein 12 and its related isoform 12.6 (FKBP12/12.6) and removes them from intracellular ryanodine receptors that induce a calcium ion leakage from the endoplasmic/sarcoplasmic reticulum.The conventional protein kinase C beta II (cPKCβⅡ)-mediated phosphorylation of endothelial nitric oxide (NO) synthase at Thr495,which reduces the production of NO,was activated by calcium ion leakage.Second,transforming growth factor receptor/SMAD2/3 signaling activation plays an important role in Treg/Th17 cell imbalance in T cells which toget converge to cause inflammation,endothelial dysfunction,and hypertension following tacrolimus treatment.Third,the activation of with-no-K(Lys) kinases/STE20/SPS1-related proline/alanine-rich kinase/thiazide-sensitive sodium chloride co-transporter (WNKs/SPAK/NCC) pathway has a central role in tacrolimus-induced hypertension.Finally,the enhanced activity of renal renin-angiotensin-aldosterone system seems to play a crucial role in

The Role of Mediators in the Indirect Effects of Religiosity on Therapeutic Compliance in African Migrant HIV-Positive Patients.

Science.gov (United States)

Mambet Doue, Constance; Roussiau, Nicolas

2016-12-01

This research investigates the indirect effects of religiosity (practice and belief) on therapeutic compliance in 81 HIV-positive patients who are migrants from sub-Saharan Africa (23 men and 58 women). Using analyses of mediation and standard multiple regression, including a resampling procedure by bootstrapping, the role of these mediators (magical-religious beliefs and nonuse of toxic substances) was tested. The results show that, through magical-religious beliefs, religiosity has a negative indirect effect, while with the nonuse of toxic substances, religious practice has a positive indirect effect. Beyond religiosity, the role of mediators is highlighted in the interaction with therapeutic compliance.

Spontaneous blood pressure oscillations in mechanically ventilated patients with sepsis

DEFF Research Database (Denmark)

Berg, Ronan M G; Plovsing, Ronni R; Greve, Anders M

2016-01-01

OBJECTIVE: In the present hypothesis-generating study, we investigated whether spontaneous blood pressure oscillations are suppressed to lower frequencies, and whether abolished oscillations are associated with an adverse outcome in mechanically ventilated patients with sepsis. METHODS: We...... retrospectively subjected invasive steady-state blood pressure recordings from 65 mechanically ventilated patients with sepsis to spectral analysis. Modified spectral bands were visually identified by plotting spectral power against frequency. RESULTS: Modified middle-frequency and low-frequency (MF' and LF......') oscillations were absent in 9% and 22% of the patients, respectively. In patients in whom spontaneous blood pressure oscillations were preserved, the MF' oscillations occurred at 0.021 Hz (median, interquartile range 0.013-0.030), whereas the LF' oscillations occurred at 0.009 Hz (median, interquartile range 0...

Examining the Relationship Between Pain Catastrophizing and Suicide Risk in Patients with Rheumatic Disease: the Mediating Role of Depression, Perceived Social Support, and Perceived Burdensomeness.

Science.gov (United States)

Shim, Eun -Jung; Song, Yeong Wook; Park, Seung-Hee; Lee, Kwang-Min; Go, Dong Jin; Hahm, Bong-Jin

2017-08-01

Little research has examined the role of pain catastrophizing (PC) in predicting suicide among patients with rheumatic disease or the mechanisms through which it works. This study examines whether depression, perceived social support (PSS), and perceived burdensomeness (PB) mediate the relationship between PC and suicide risk. It also examines the relative importance of sociodemographic, clinical, and psychological factors in predicting suicide risk. Three hundred sixty patients from a rheumatology clinic in Korea completed measures of pain catastrophizing, social support, depression, and perceived burdensomeness. In hierarchical multiple regression analysis, the PC magnification, PB, physical disability, and PSS were significantly related to suicide risk. Results of the serial multiple mediation analysis indicated that the total indirect effect of PC magnification on suicide risk was significant while the direct effect was not. Four specific indirect effects of PC magnification were found to be statistically significant. First of all, PC magnification was associated with suicide risk through PB and through depression and PB. PC magnification was also associated with suicide risk through depression and PSS. Lastly, PC magnification was associated with suicide risk through depression, PSS, and PB. The identified pathways through which PC affects suicide risk suggest the importance of depression, PSS, and PB. Evaluation and intervention targeted at physical disability and the psychological factors of PC magnification, depression, PSS, and PB may be integrated into the management of suicide risk in patients with rheumatic disease.

The role of appraisal and coping style in relation with societal participation in fatigued patients with multiple sclerosis: a cross-sectional multiple mediator analysis.

Science.gov (United States)

van den Akker, Lizanne Eva; Beckerman, Heleen; Collette, Emma Hubertine; Bleijenberg, Gijs; Dekker, Joost; Knoop, Hans; de Groot, Vincent

2016-10-01

To determine the relationship between appraisal and societal participation in fatigued patients with Multiple Sclerosis (MS), and whether this relation is mediated by coping styles. 265 severely-fatigued MS patients. Appraisal, a latent construct, was created from the General Self-Efficacy Scale and the helplessness and acceptance subscales of the Illness Cognition Questionnaire. Coping styles were assessed using the Coping Inventory Stressful Situations (CISS21) and societal participation was assessed using the Impact on Participation and Autonomy. A multiple mediator model was developed and tested by structural equation modeling on cross-sectional data. We corrected for confounding by disease-related factors. Mediation was determined using a product-of-coefficients approach. A significant relationship existed between appraisal and participation (β = 0.21, 95 % CI 0.04-0.39). The pathways via coping styles were not significant. In patients with severe MS-related fatigue, appraisal and societal participation show a positive relationship that is not mediated by coping styles.

Recent advances in behavioral addiction treatments: focusing on mechanisms of change.

Science.gov (United States)

Longabaugh, Richard; Magill, Molly

2011-10-01

In the latter half of the 20th century, research on behavioral treatments for addictions aimed to develop and test effective treatments. Among the treatments found to be at least moderately effective, direct comparisons failed to reveal consistent superiority of one approach over another. This ubiquitous finding held true despite underlying theories that differed markedly in their proposed causal processes related to patient change. In the 21st century, the focus of treatment research is increasingly on how treatment works for whom rather than whether it works. Studies of active treatment ingredients and mechanisms of behavioral change, while promising, have yielded inconsistent results. Simple mediation analysis may need to be expanded via inclusion of models testing for moderated mediation, mediated moderation, and conditional indirect effects. Examples are offered as to how these more complex models can lead to increased understanding of the conditions under which specific treatment interventions will be effective and mechanisms of change operative in improving behavioral treatments for addictions.

The role of social media use in improving cancer survivors' emotional well-being: a moderated mediation study.

Science.gov (United States)

Jiang, Shaohai

2017-06-01

In the USA, levels of emotional well-being among cancer survivors remain low. Social media is recognized as important to improve their emotional well-being. However, little is known about social mechanisms that underlie the impact of health-related social media in cancer care. This study proposed a moderated mediation model to signify a pathway linking social media use to emotional well-being. Four-hundred and fifty-nine cancer survivors identified through the 2013 US-based Health Information National Trends Survey were included for data analysis. First, structural equation modeling was conducted to examine the path from social media use to emotional well-being, mediated by patient activation. Second, hierarchical regression was performed to test the moderation effect of emotion management. Last, a normal theory-based approach was used to explore the final moderated mediation model. The effect of health-related social media use on emotional well-being was completely mediated by patient activation. Also, emotion management positively moderated the effect of patient activation on emotional well-being. Last, emotion management positively moderated the mediation pathway from health-related social media use to patient activation, and finally, to emotional well-being. Health-related social media, by itself, is not sufficient to bring about improvement in cancer survivors' emotional well-being. Patient activation and emotion management play a significant role. In future interventions designed to improve cancer survivors' emotional health, health practitioners should not only encourage cancer survivors to use social media for health purposes, but also activate them in the course of care, and improve their emotion self-management skills.

Early alveolar and systemic mediator release in patients at different risks for ARDS after multiple trauma.

Science.gov (United States)

Raymondos, Konstantinos; Martin, Michael U; Schmudlach, Tanja; Baus, Stefan; Weilbach, Christian; Welte, Tobias; Krettek, Christian; Frink, Michael; Hildebrand, Frank

2012-02-01

Alveolar IL-8 has been reported to early identify patients at-risk to develop ARDS. However, it remains unknown how alveolar IL-8 is related to pulmonary and systemic inflammation in patients predisposed for ARDS. We studied 24 patients 2-6h after multiple trauma. Patients with IL-8 >200 pg/ml in bronchoalveolar lavage (BAL) were assigned to the group at high risk for ARDS (H, n = 8) and patients with BAL IL-8 mediators. The enhanced alveolar and systemic inflammation associated with alveolar IL-8 release should be considered to identify high-risk patients for pulmonary complications after multiple trauma to adjust surgical and other treatment strategies to the individual risk profile. Copyright © 2011 Elsevier Ltd. All rights reserved.

Role of 5-hydroxytryptamine mechanisms in mediating the effects of small intestinal glucose on blood pressure and antropyloroduodenal motility in older subjects

NARCIS (Netherlands)

Gentilcore, Diana; Little, Tanya J.; Feinle-Bisset, Christine; Samsom, Melvin; Smout, André J. P. M.; Horowitz, Michael; Jones, Karen L.

2007-01-01

Postprandial hypotension is an important clinical problem, particularly in the elderly. 5-Hydroxytryptamine3 (5-HT3) mechanisms may be important in the regulation of splanchnic blood flow and blood pressure (BP), and in mediating the effects of small intestinal nutrients on gastrointestinal

THE EFFECTS OF HOSPITAL QUALITY OF CARE ON PATIENT BELONGING: STRUCTURAL EQUALITY MODEL AND MEDIATION

Directory of Open Access Journals (Sweden)

Ali Rıza FİRUZAN

2017-09-01

Full Text Available The aim of the study is to measure the effects of perceived and expected service quality levels on patient loyalty. In total, 370 patients participated in this research. The Structural Equation Modeling (SEM method to test the causal relationship model. The corresponding model in the study emerged as acceptable fit with the model. The result of the study indicate that perceived service quality and patient loyalty are statistically significant and positively related to each other. Additionally, perceived service quality has found to be an important mediator between expected service quality and patient loyalty. After patients have treatment in corresponding hospital, they have been affected by service quality as mush as cost of medication. As patient satisfaction increases, their loyalty increases. It is suggested to hospital management that they might course of action to patients for improving Reliability and Assurance SERVQUAL factors

Central neuropeptide Y plays an important role in mediating the adaptation mechanism against chronic stress in male rats.

Science.gov (United States)

Yang, Yu; Babygirija, Reji; Zheng, Jun; Shi, Bei; Sun, Weinan; Zheng, Xiaojiao; Zhang, Fan; Cao, Yu

2018-02-07

Exposure to continuous life stress often causes gastrointestinal (GI) symptoms. Studies have shown that neuropeptide Y (NPY) counteracts the biological actions of corticotrophin-releasing factor (CRF), and is involved in the termination of the stress response. However, in chronic repeated restraint stress (CRS) conditions, the actions of NPY on GI motility remain controversial. To evaluate the role of NPY in mediation of the adaptation mechanism and GI motility in CRS conditions, a CRS rat model was set up. Central CRF and NPY expression levels were analyzed, serum corticosterone and NPY concentrations were measured, and GI motor function was evaluated. The NPY Y1 receptor antagonist BIBP-3226 was centrally administered before stress loading, and on days, 1-5, of repeated stress, the central CRF and the serum corticosterone concentrations were measured. In addition, gastric and colonic motor functions were evaluated. The elevated central CRF expression and corticosterone concentration caused by acute stress began to fall after 3 days of stress loading, while central NPY expression and serum NPY began to increase. GI dysmotility also returned to a normal level. Pretreatment with BIBP-3226 abolished the adaptation mechanism, and significantly increased CRF expression and the corticosterone concentration, which resulted in delayed gastric emptying and accelerated fecal pellet output. Inhibited gastric motility and enhanced distal colonic motility were also recorded. CRS-produced adaptation, over-expressed central CRF, and GI dysmotility observed in acute restraint stress were restored to normal levels. Central NPY via the Y1 receptor plays an important role in mediating the adaptation mechanism against chronic stress. Copyright © 2018 Endocrine Society.

Music preferences of mechanically ventilated patients participating in a randomized controlled trial

Science.gov (United States)

Heiderscheit, Annie; Breckenridge, Stephanie J.; Chlan, Linda L.; Savik, Kay

2014-01-01

Mechanical ventilation (MV) is a life-saving measure and supportive modality utilized to treat patients experiencing respiratory failure. Patients experience pain, discomfort, and anxiety as a result of being mechanically ventilated. Music listening is a non-pharmacological intervention used to manage these psychophysiological symptoms associated with mechanical ventilation. The purpose of this secondary analysis was to examine music preferences of 107 MV patients enrolled in a randomized clinical trial that implemented a patient-directed music listening protocol to help manage the psychophysiological symptom of anxiety. Music data presented includes the music genres and instrumentation patients identified as their preferred music. Genres preferred include: classical, jazz, rock, country, and oldies. Instrumentation preferred include: piano, voice, guitar, music with nature sounds, and orchestral music. Analysis of three patients’ preferred music received throughout the course of the study is illustrated to demonstrate the complexity of assessing MV patients and the need for an ongoing assessment process. PMID:25574992

Outcomes management of mechanically ventilated patients: utilizing informatics technology.

Science.gov (United States)

Smith, K R

1998-11-01

This article examines an informatics system developed for outcomes management of the mechanically ventilated adult population, focusing on weaning the patient from mechanical ventilation. The link between medical informatics and outcomes management is discussed, along with the development of methods, tools, and data sets for outcomes management of the mechanically ventilated adult population at an acute care academic institution. Pros and cons of this system are identified, and specific areas for improvement of future health care outcomes medical informatics systems are discussed.

Behavioral and Nondirective Guided Self-Help for Parents of Children with Externalizing Behavior: Mediating Mechanisms in a Head-To-Head Comparison.

Science.gov (United States)

Katzmann, Josepha; Hautmann, Christopher; Greimel, Lisa; Imort, Stephanie; Pinior, Julia; Scholz, Kristin; Döpfner, Manfred

2017-05-01

Parent training (PT) delivered as a guided self-help intervention may be a cost- and time-effective intervention in the treatment of children with externalizing disorders. In face-to-face PT, parenting strategies have repeatedly been identified as mediating mechanisms for the decrease of children's problem behavior. Few studies have examined possible mediating effects in guided self-help interventions for parents. The present study aimed to investigate possible mediating variables of a behaviorally oriented guided self-help program for parents of children with externalizing problems compared to a nondirective intervention in a clinical sample. A sample of 110 parents of children with externalizing disorders (80 % boys) were randomized to either a behaviorally oriented or a nondirective guided self-help program. Four putative mediating variables were examined simultaneously in a multiple mediation model using structural equation modelling. The outcomes were child symptoms of ADHD and ODD as well as child externalizing problems, assessed at posttreatment. Analyses showed a significant indirect effect for dysfunctional parental attributions in favor of the group receiving the behavioral program, and significant effects of the behavioral program on positive and negative parenting and parental self-efficacy, compared to the nondirective intervention. Our results indicate that a decrease of dysfunctional parental attributions leads to a decrease of child externalizing problems when parents take part in a behaviorally oriented guided self-help program. However, none of the putative mediating variables could explain the decrease in child externalizing behavior problems in the nondirective group. A change in dysfunctional parental attributions should be considered as a possible mediator in the context of PT.

Mediators Linking Childhood Adversities and Trauma to Suicidality in Individuals at Risk for Psychosis

Directory of Open Access Journals (Sweden)

Stefanie J. Schmidt

2017-11-01

Full Text Available Suicidality is highly prevalent in patients at clinical high risk (CHR for psychosis. Childhood adversities and trauma are generally predictive of suicidality. However, the differential effects of adversity/trauma-domains and CHR-criteria, i.e., ultra-high risk and basic symptom criteria, on suicidality remain unclear. Furthermore, the underlying mechanisms and, thus, worthwhile targets for suicide-prevention are still poorly understood. Therefore, structural equation modeling was used to test theory-driven models in 73 CHR-patients. Mediators were psychological variables, i.e., beliefs about one’s own competencies as well as the controllability of events and coping styles. In addition, symptomatic variables (depressiveness, basic symptoms, attenuated psychotic symptoms were hypothesized to mediate the effect of psychological mediators on suicidality as the final outcome variable. Results showed two independent pathways. In the first pathway, emotional and sexual but not physical adversity/trauma was associated with suicidality, which was mediated by dysfunctional competence/control beliefs, a lack of positive coping-strategies and depressiveness. In the second pathway, cognitive basic symptoms but not attenuated psychotic symptoms mediated the relationship between trauma/adversity and suicidality. CHR-patients are, thus, particularly prone to suicidality if adversity/trauma is followed by the development of depressiveness. Regarding the second pathway, this is the first study showing that adversity/trauma led to suicidality through an increased risk for psychosis as indicated by cognitive basic symptoms. As insight is generally associated with suicidality, this may explain why self-experienced basic symptoms increase the risk for it. Consequently, these mediators should be monitored regularly and targeted by integrated interventions as early as possible to enhance resilience against suicidality.

Features of borderline personality disorder as a mediator of the relation between childhood traumatic experiences and psychosis-like experiences in patients with mood disorder.

Science.gov (United States)

Baryshnikov, Ilya; Aaltonen, Kari; Suvisaari, Jaana; Koivisto, Maaria; Heikkinen, Martti; Joffe, Grigori; Isometsä, Erkki

2018-03-01

Psychosis-like experiences (PEs) are common in patients with non-psychotic disorders. Several factors predict reporting of PEs in mood disorders, including mood-associated cognitive biases, anxiety and features of borderline personality disorder (BPD). Childhood traumatic experiences (CEs), often reported by patients with BPD, are an important risk factor for mental disorders. We hypothesized that features of BPD may mediate the relationship between CEs and PEs. In this study, we investigated the relationships between self-reported PEs, CEs and features of BPD in patients with mood disorders. As part of the Helsinki University Psychiatric Consortium study, McLean Screening Instrument (MSI), Community Assessment of Psychic Experiences (CAPE-42) and Trauma and Distress Scale (TADS) were filled in by patients with mood disorders (n = 282) in psychiatric care. Correlation coefficients between total scores of scales and their dimensions were estimated, multiple regression and mediation analyses were conducted. Total scores of MSI correlated strongly with scores of the CAPE-42 dimension "frequency of positive symptoms" (rho = 0.56; p ≤ 0.001) and moderately with scores of TADS (rho = 0.4; p ≤ 0.001). Total score of MSI and its dimension "cognitive symptoms", including identity disturbance, distrustfulness and dissociative symptoms, fully mediated the relation between TADS and CAPE-42. Each cognitive symptom showed a partial mediating role (dissociative symptoms 43% (CI = 25-74%); identity disturbance 40% (CI = 30-73%); distrustfulness 18% (CI = 12-50%)). Self-reported cognitive-perceptual symptoms of BPD fully mediate, while affective, behavioural and interpersonal symptoms only partially mediate the relationships between CEs and PEs. Recognition of co-morbid features of BPD in patients with mood disorders reporting PEs is essential. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Plasma DNA Mediate Autonomic Dysfunctions and White Matter Injuries in Patients with Parkinson’s Disease

Directory of Open Access Journals (Sweden)

Meng-Hsiang Chen

2017-01-01

Full Text Available Background. Cardiovascular autonomic dysfunction is well known in Parkinson’s disease (PD presentation and it produces hypoperfusion of vital organs. The association between cardiovascular autonomic dysfunction and oxidative stress was examined in previous animal models. Oxidative stress and neuroinflammation were thought to have roles in PD pathogenesis. Owing to the relative low intrinsic antioxidative properties, brain white matter (WM is vulnerable to the oxidative stress. This study is conducted to examine possible relationships by using a hypothesis-driven mediation model. Methods. Twenty-nine patients with PD and 26 healthy controls participated in this study, with complete examinations of cardiac autonomic parameters, plasma DNA level, and WM integrity. A single-level three-variable mediation model was used to investigate the possible relationships. Results. The elevated serum oxidative stress biomarkers include plasma nuclear DNA and mitochondrial DNA, and poorer cardiac autonomic parameters and multiple regional microstructural WM changes are demonstrated. Further mediation analysis shows that plasma nuclear DNA served as the mediators between poorer baroreflex sensitivity and mean diffusivity changes in cingulum. Conclusions. These results provide a possible pathophysiology for how the poor baroreflex sensitivity and higher oxidative stress adversely impacted the WM integrity. This model could provide us with a piece of the puzzle of the entire PD pathogenesis.

Iron-Induced Damage in Cardiomyopathy: Oxidative-Dependent and Independent Mechanisms

Directory of Open Access Journals (Sweden)

Elena Gammella

2015-01-01

Full Text Available The high incidence of cardiomyopathy in patients with hemosiderosis, particularly in transfusional iron overload, strongly indicates that iron accumulation in the heart plays a major role in the process leading to heart failure. In this context, iron-mediated generation of noxious reactive oxygen species is believed to be the most important pathogenetic mechanism determining cardiomyocyte damage, the initiating event of a pathologic progression involving apoptosis, fibrosis, and ultimately cardiac dysfunction. However, recent findings suggest that additional mechanisms involving subcellular organelles and inflammatory mediators are important factors in the development of this disease. Moreover, excess iron can amplify the cardiotoxic effect of other agents or events. Finally, subcellular misdistribution of iron within cardiomyocytes may represent an additional pathway leading to cardiac injury. Recent advances in imaging techniques and chelators development remarkably improved cardiac iron overload detection and treatment, respectively. However, increased understanding of the pathogenic mechanisms of iron overload cardiomyopathy is needed to pave the way for the development of improved therapeutic strategies.

Role of 5-hydroxytryptamine mechanisms in mediating the effects of small intestinal glucose on blood pressure and antropyloroduodenal motility in older subjects

NARCIS (Netherlands)

Gentilcore, Diana; Little, Tanya J.; Feinle-Bisset, Christine; Samsom, Melvin; Smout, Andre J. P. M.; Horowitz, Michael; Jones, Karen L.

2007-01-01

5-hydroxytryptamine mechanisms in mediating the effects of small intestinal glucose on blood pressure and antropyloroduodenal motility in older subjects. Am J Physiol Gastrointest Liver Physiol 293: G692-G698, 2007. First published August 9, 2007; doi:10.1152/ajpgi.00199.2007.-Postprandial

Structural plasticity mediates distinct GAP-dependent GTP hydrolysis mechanisms in Rab33 and Rab5.

Science.gov (United States)

Majumdar, Soneya; Acharya, Abhishek; Prakash, Balaji

2017-12-01

The classical GTP hydrolysis mechanism, as seen in Ras, employs a catalytic glutamine provided in cis by the GTPase and an arginine supplied in trans by a GTPase activating protein (GAP). The key idea emergent from a large body of research on small GTPases is that GTPases employ a variety of different hydrolysis mechanisms; evidently, these variations permit diverse rates of GTPase inactivation, crucial for temporal regulation of different biological processes. Recently, we unified these variations and argued that a steric clash between active site residues (corresponding to positions 12 and 61 of Ras) governs whether a GTPase utilizes the cis-Gln or the trans-Gln (from the GAP) for catalysis. As the cis-Gln encounters a steric clash, the Rab GTPases employ the so-called dual finger mechanism where the interacting GAP supplies a trans-Gln for catalysis. Using experimental and computational methods, we demonstrate how the cis-Gln of Rab33 overcomes the steric clash when it is stabilized by a residue in the vicinity. In effect, this demonstrates how both cis-Gln- and trans-Gln-mediated mechanisms could operate in the same GTPase in different contexts, i.e. depending on the GAP that regulates its action. Interestingly, in the case of Rab5, which possesses a higher intrinsic GTP hydrolysis rate, a similar stabilization of the cis-Gln appears to overcome the steric clash. Taken together with the mechanisms seen for Rab1, it is evident that the observed variations in Rab and their GAP partners allow structural plasticity, or in other words, the choice of different catalytic mechanisms. © 2017 Federation of European Biochemical Societies.

Convergent RANK- and c-Met-mediated signaling components predict survival of patients with prostate cancer: an interracial comparative study.

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Peizhen Hu

Full Text Available We reported (PLoS One 6 (12:e28670, 2011 that the activation of c-Met signaling in RANKL-overexpressing bone metastatic LNCaP cell and xenograft models increased expression of RANK, RANKL, c-Met, and phosphorylated c-Met, and mediated downstream signaling. We confirmed the significance of the RANK-mediated signaling network in castration resistant clinical human prostate cancer (PC tissues. In this report, we used a multispectral quantum dot labeling technique to label six RANK and c-Met convergent signaling pathway mediators simultaneously in formalin fixed paraffin embedded (FFPE tissue specimens, quantify the intensity of each expression at the sub-cellular level, and investigated their potential utility as predictors of patient survival in Caucasian-American, African-American and Chinese men. We found that RANKL and neuropilin-1 (NRP-1 expression predicts survival of Caucasian-Americans with PC. A Gleason score ≥ 8 combined with nuclear p-c-Met expression predicts survival in African-American PC patients. Neuropilin-1, p-NF-κB p65 and VEGF are predictors for the overall survival of Chinese men with PC. These results collectively support interracial differences in cell signaling networks that can predict the survival of PC patients.

Cocaine/levamisole-associated autoimmune syndrome: a disease of neutrophil-mediated autoimmunity.

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Cascio, Michael J; Jen, Kuang-Yu

2018-01-01

Levamisole was previously used for its immunomodulatory properties to treat rheumatoid arthritis and some cancers. However, because of serious side-effects, it was taken off the market in the United States. Recently, levamisole has reemerged as a popular cocaine adulterant. Some individuals who consume levamisole-adulterated cocaine can develop a life-threatening autoimmune syndrome. In this review, the medical consequences of levamisole exposure and postulated mechanisms by which levamisole induces these adverse effects are discussed. Although agranulocytosis and cutaneous vasculitis are the major findings in patients who develop cocaine/levamisole-associated autoimmune syndrome (CLAAS), more recent experience indicates that other organ systems can be involved as well. Current studies point to neutrophil activation and neutrophil extracellular trap formation with subsequent antineutrophil cytoplasmic antibody-mediated tissue injury as a possible mechanism of CLAAS. In the past decade, the detrimental effects of levamisole have reemerged because of its popularity as a cocaine adulterant. Although infrequent, some individuals develop a systemic autoimmune syndrome characterized by immune-mediated agranulocytosis and antineutrophil cytoplasmic antibody-mediated vasculitis. Mechanistically, neutrophil antigens appear to be a major player in inducing CLAAS. Prompt cessation of levamisole exposure is key to treatment, although relapses are frequent because of the addictive effects of cocaine and the high prevalence of levamisole within the cocaine supply.

Pharmacotherapy and analysis of gaseous mediators in hypertensive patients

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Letícia Palota Eid

2015-02-01

Full Text Available OBJECTIVE To evaluate the effect of using antihypertensive classes of drugs of the calcium channel antagonists and inhibitors of angiotensin-converting enzyme in plasma concentrations of hydrogen sulfide and nitric oxide in patients with hypertension. METHODS Cross-sectional study with quantitative approach conducted with hypertensive patients in use of antihypertensive classes of drugs: angiotensin-converting enzyme inhibitors or calcium channel antagonists. RESULTS It was found that the concentration of plasma nitric oxide was significantly higher in hypertensive patients that were in use of angiotensin-converting enzyme inhibitors (p<0.03 and the hydrogen sulphide concentration was significantly higher in hypertensive plasma in use of calcium channel antagonists (p<0.002. CONCLUSION The findings suggest that these medications have as additional action mechanism the improvement of endothelial dysfunction by elevate plasma levels of vasodilatory substances.

The SMN1 common variant c.22 dupA in Chinese patients causes spinal muscular atrophy by nonsense-mediated mRNA decay in humans.

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Bai, JinLi; Qu, YuJin; Cao, YanYan; Yang, Lan; Ge, Lin; Jin, YuWei; Wang, Hong; Song, Fang

2018-02-20

Spinal muscular atrophy (SMA) is a common autosomal recessive neuromuscular disorder that is mostly caused by homozygous deletion of the SMN1 gene. Approximately 5%-10% of SMA patients are believed to have SMN1 variants. c.22 dupA (p.Ser8lysfs*23) has been identified as the most frequent variant in the Chinese SMA population and to be associated with a severe phenotype. However, the exact molecular mechanism of the variant on the pathogenesis of SMA is unclear. We observed that SMN1 mRNA and the SMN protein in the peripheral blood cells of a patient with c.22 dupA were lower than those of controls. The aim of this study is to investigate whether nonsense-mediated mRNA decay (NMD) plays a role in the mechanism of the c.22 dupA variant of the SMN1 gene as it causes SMA. Two lymphoblasts cell lines from two patients (patient 1 and 2) with the c.22 dupA, and one dermal fibroblasts cell line from patient 2 were included in our study. Two-stage validation of the NMD mechanism was supplied. We first measured the changes in the transcript levels of the SMN1 gene by real-time quantitative PCR after immortalized B-lymphoblasts and dermal fibroblasts cells of the SMA patients were treated with inhibitors of the NMD pathway, including puromycin and cyclohemide. Next, lentivirus-mediated knockdown of the key NMD factor-Up-frameshift protein 1 (UPF1)-was performed in the fibroblasts cell line to further clarify whether the variant led to NMD, as UPF1 recognizes abnormally terminated transcripts as NMD substrates during translation. SC35 1.7-kb transcripts, a physiological NMD substrate was determined to be a NMD positive gene in our experiments. The two inhibitors resulted in a dramatic escalation of the levels of the full-length SMN1 (fl-SMN1) transcripts. Additionally, the SC35 1.7-kb mRNA levels were also increased, suggesting that NMD pathway is suppressed by the two inhibitors. For the 3 cell lines, the fold increase of the SMN1 transcript levels of cycloheximide ranged

The ICU trial: a new admission policy for cancer patients requiring mechanical ventilation.

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Lecuyer, Lucien; Chevret, Sylvie; Thiery, Guillaume; Darmon, Michael; Schlemmer, Benoît; Azoulay, Elie

2007-03-01

Cancer patients requiring mechanical ventilation are widely viewed as poor candidates for intensive care unit (ICU) admission. We designed a prospective study evaluating a new admission policy titled The ICU Trial. Prospective study. Intensive care unit. One hundred eighty-eight patients requiring mechanical ventilation and having at least one other organ failure. Over a 3-yr period, all patients with hematologic malignancies or solid tumors proposed for ICU admission underwent a triage procedure. Bedridden patients and patients in whom palliative care was the only cancer treatment option were not admitted to the ICU. Patients at earliest phase of the malignancy (diagnosis ventilation, vasopressors, or dialysis after 3 days in the ICU died. Survival was 40% in mechanically ventilated cancer patients who survived to day 5 and 21.8% overall. If these results are confirmed in future interventional studies, we recommend ICU admission with full-code management followed by reappraisal on day 6 in all nonbedridden cancer patients for whom lifespan-extending cancer treatment is available.

Reactive Oxygen Species-Mediated Mechanisms of Action of Targeted Cancer Therapy

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Hanna-Riikka Teppo

2017-01-01

Full Text Available Targeted cancer therapies, involving tyrosine kinase inhibitors and monoclonal antibodies, for example, have recently led to substantial prolongation of survival in many metastatic cancers. Compared with traditional chemotherapy and radiotherapy, where reactive oxygen species (ROS have been directly linked to the mediation of cytotoxic effects and adverse events, the field of oxidative stress regulation is still emerging in targeted cancer therapies. Here, we provide a comprehensive review regarding the current evidence of ROS-mediated effects of antibodies and tyrosine kinase inhibitors, use of which has been indicated in the treatment of solid malignancies and lymphomas. It can be concluded that there is rapidly emerging evidence of ROS-mediated effects of some of these compounds, which is also relevant in the context of drug resistance and how to overcome it.

Magnitude and Mechanism of Siderophore-Mediated Competition at Low Iron Solubility in the Pseudomonas aeruginosa Pyochelin System

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Konstanze T. Schiessl

2017-10-01

Full Text Available A central question in microbial ecology is whether microbial interactions are predominantly cooperative or competitive. The secretion of siderophores, microbial iron chelators, is a model system for cooperative interactions. However, siderophores have also been shown to mediate competition by sequestering available iron and making it unavailable to competitors. The details of how siderophores mediate competition are not well understood, especially considering the complex distribution of iron phases in the environment. One pertinent question is whether sequestering iron through siderophores can indeed be effective in natural conditions; many natural environments are characterized by large pools of precipitated iron, and it is conceivable that any soluble iron that is sequestered by siderophores is replenished by the dissolution of these precipitated iron sources. Our goal here was to address this issue, and investigate the magnitude and mechanism of siderophore-mediated competition in the presence of precipitated iron. We combined experimental work with thermodynamic modeling, using Pseudomonas aeruginosa as a model system and ferrihydrite precipitates as the iron source with low solubility. Our experiments show that competitive growth inhibition by the siderophore pyochelin is indeed efficient, and that inhibition of a competitor can even have a stronger growth-promoting effect than solubilization of precipitated iron. Based on the results of our thermodynamic models we conclude that the observed inhibition of a competitor is effective because sequestered iron is only very slowly replenished by the dissolution of precipitated iron. Our research highlights the importance of competitive benefits mediated by siderophores, and underlines that the dynamics of siderophore production and uptake in environmental communities could be a signature of competitive, not just cooperative, dynamics.

Magnitude and Mechanism of Siderophore-Mediated Competition at Low Iron Solubility in the Pseudomonas aeruginosa Pyochelin System.

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Schiessl, Konstanze T; Janssen, Elisabeth M-L; Kraemer, Stephan M; McNeill, Kristopher; Ackermann, Martin

2017-01-01

A central question in microbial ecology is whether microbial interactions are predominantly cooperative or competitive. The secretion of siderophores, microbial iron chelators, is a model system for cooperative interactions. However, siderophores have also been shown to mediate competition by sequestering available iron and making it unavailable to competitors. The details of how siderophores mediate competition are not well understood, especially considering the complex distribution of iron phases in the environment. One pertinent question is whether sequestering iron through siderophores can indeed be effective in natural conditions; many natural environments are characterized by large pools of precipitated iron, and it is conceivable that any soluble iron that is sequestered by siderophores is replenished by the dissolution of these precipitated iron sources. Our goal here was to address this issue, and investigate the magnitude and mechanism of siderophore-mediated competition in the presence of precipitated iron. We combined experimental work with thermodynamic modeling, using Pseudomonas aeruginosa as a model system and ferrihydrite precipitates as the iron source with low solubility. Our experiments show that competitive growth inhibition by the siderophore pyochelin is indeed efficient, and that inhibition of a competitor can even have a stronger growth-promoting effect than solubilization of precipitated iron. Based on the results of our thermodynamic models we conclude that the observed inhibition of a competitor is effective because sequestered iron is only very slowly replenished by the dissolution of precipitated iron. Our research highlights the importance of competitive benefits mediated by siderophores, and underlines that the dynamics of siderophore production and uptake in environmental communities could be a signature of competitive, not just cooperative, dynamics.

Expression of the angiogenic mediator, angiopoietin-like 4, in the eyes of patients with proliferative sickle retinopathy.

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Kathleen Jee

Full Text Available The recent success of therapies directly targeting the angiogenic mediator, vascular endothelial growth factor (VEGF, for the treatment of proliferative diabetic retinopathy has encouraged clinicians to extend the use of anti-VEGF therapies for the treatment of another ischemic retinal vascular disease, proliferative sickle cell retinopathy (PSR, the most common cause of irreversible blindness in patients with sickle cell disease. However, results from case reports evaluating anti-VEGF therapies for PSR have been mixed. This highlights the need to identify alternative therapeutic targets for the treatment of retinal neovascularization in sickle cell patients. In this regard, angiopoietin-like 4 (ANGPTL4 is a novel angiogenic factor regulated by the transcription factor, hypoxia-inducible factor 1, the master regulator of angiogenic mediators (including VEGF in ischemic retinal disease. In an effort to identify alternative targets for the treatment of sickle cell retinopathy, we have explored the expression of ANGPTL4 in the eyes of patients with PSR. To this end, we examined expression and localization of ANGPTL4 by immunohistochemistry in autopsy eyes from patients with known PSR (n = 5 patients. Complementary studies were performed using enzyme-linked immunosorbent assays in aqueous (n = 8; 7 patients, 2 samples from one eye of same patient and vitreous (n = 3 patients samples from a second group of patients with active PSR. We detected expression of ANGPTL4 in neovascular tissue and in the ischemic inner retina in PSR, but not control, eyes. We further observed elevated expression of ANGPTL4 in the aqueous and vitreous of PSR patients compared to controls. These results suggest that ANGPTL4 could contribute to the development of retinal neovascularization in sickle cell patients and could therefore be a therapeutic target for the treatment of PSR.

IFN-Gamma-Dependent and Independent Mechanisms of CD4+ Memory T Cell-Mediated Protection from Listeria Infection

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Stephanie M. Meek

2018-02-01

Full Text Available While CD8+ memory T cells can promote long-lived protection from secondary exposure to intracellular pathogens, less is known regarding the direct protective mechanisms of CD4+ T cells. We utilized a prime/boost model in which mice are initially exposed to an acutely infecting strain of lymphocytic choriomeningitis virus (LCMV, followed by a heterologous rechallenge with Listeria monocytogenes recombinantly expressing the MHC Class II-restricted LCMV epitope, GP61–80 (Lm-gp61. We found that heterologous Lm-gp61 rechallenge resulted in robust activation of CD4+ memory T cells and that they were required for rapid bacterial clearance. We further assessed the relative roles of TNF and IFNγ in the direct anti-bacterial function of CD4+ memory T cells. We found that disruption of TNF resulted in a complete loss of protection mediated by CD4+ memory T cells, whereas disruption of IFNγ signaling to macrophages results in only a partial loss of protection. The protective effect mediated by CD4+ T cells corresponded to the rapid accumulation of pro-inflammatory macrophages in the spleen and an altered inflammatory environment in vivo. Overall, we conclude that protection mediated by CD4+ memory T cells from heterologous Listeria challenge is most directly dependent on TNF, whereas IFNγ only plays a minor role.

Criteria for Postoperative Mechanical Ventilation After Thymectomy in Patients With Myasthenia Gravis: A Retrospective Analysis.

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Chigurupati, Keerthi; Gadhinglajkar, Shrinivas; Sreedhar, Rupa; Nair, Muraleedharan; Unnikrishnan, Madathipat; Pillai, Manjusha

2018-02-01

To determine the criteria for postoperative mechanical ventilation after thymectomy in patients with Myasthenia Gravis. Retrospective study. Teritiary care centre. 77 Myasthenia gravis patients operated for thymectomy were studied. After obtaining clearance from Institutional ethics committee, medical records of 77 patients with MG, who were operated for thymectomy between January 2005 and December 2015 were reviewed in a retrospective manner. Perioperative variables collected from the patient records were demographic data, duration of the disease, Osserman and Genkin classification, Anti-acetylcholine antibody (AChR) positivity, preoperative daily dose of drug, history of preoperative myasthenic crisis, preoperative vital capacity, technique of anesthesia, drugs used for anesthesia, perioperative complications, and duration of postoperative mechanical ventilation. The patients were divided into two groups, group I and group II consisting of those who required postoperative ventilation for 300 minutes, respectively. The determinants of prolonged postoperative ventilation were studied. The requirement of mechanical ventilation was higher in patients with higher Osserman's grade of myasthenia gravis. Duration of the disease had no effect on the duration of mechanical ventilation in myasthenic patients post thymectomy (p = 0.89). The patients with a preoperative history of myasthenic crisis had a requirement for prolonged mechanical ventilation (p=0.03). Patients with preoperative vital capacity mechanical ventilation with p values mechanical ventilation (p=0.026). Preoperative dose of pyridostigmine and the choice of continuation or discontinuation of antcholinesterases on the day of surgery had no influence on the duration of mechanical ventilation (p value of 0.19 and 0.36 respectively). Epidural analgesia intra and postoperatively significantly reduced the requirement of mechanical ventilation (p=0.006). The predictors of postoperative ventilation in myasthenic

Do organizational strategies mediate nonverbal memory impairment in drug-naïve patients with obsessive-compulsive disorder?

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Shin, Na Young; Kang, Do-Hyung; Choi, Jung-Seok; Jung, Myung Hun; Jang, Joon Hwan; Kwon, Jun Soo

2010-07-01

The present study aimed to examine nonverbal memory and organizational skill functions in psychotropic-naïve patients with OCD. Forty-one drug-naïve, 41 medicated OCD patients and 41 healthy controls, all of whom were matched for gender, age, education and intelligence, were included in the study. The Rey-Osterrieth Complex Figure Test (RCFT) was administered to evaluate nonverbal memory ability and organizational skill. OCD patients demonstrated impaired nonverbal memory irrespective of medication status (F = 6.54, p organizational strategies (eta(2)p = .079), which mediated nonverbal memory impairment (Z = -2.20, p = .027). The difference of organizational skill between drug-naïve and control groups did not reach statistical significance (eta(2)p = .054) and the association between organization and nonverbal memory was weak in the drug-naïve sample (Z = -1.74, = .081). There was no significant difference between the patient groups in RCFT indices. Our findings suggest that the organizational strategies may not be an effective mediator of nonverbal memory impairment in OCD and indicate that the clinical characteristics may be important to be considered in future research. Further studies are needed to improve understanding of the nature of nonverbal memory dysfunction in OCD.

Immunoglobulin E-Mediated Autoimmunity

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Marcus Maurer

2018-04-01

Full Text Available The study of autoimmunity mediated by immunoglobulin E (IgE autoantibodies, which may be termed autoallergy, is in its infancy. It is now recognized that systemic lupus erythematosus, bullous pemphigoid (BP, and chronic urticaria, both spontaneous and inducible, are most likely to be mediated, at least in part, by IgE autoantibodies. The situation in other conditions, such as autoimmune uveitis, rheumatoid arthritis, hyperthyroid Graves’ disease, autoimmune pancreatitis, and even asthma, is far less clear but evidence for autoallergy is accumulating. To be certain of an autoallergic mechanism, it is necessary to identify both IgE autoantibodies and their targets as has been done with the transmembrane protein BP180 and the intracellular protein BP230 in BP and IL-24 in chronic spontaneous urticaria. Also, IgE-targeted therapies, such as anti-IgE, must have been shown to be of benefit to patients as has been done with both of these conditions. This comprehensive review of the literature on IgE-mediated autoallergy focuses on three related questions. What do we know about the prevalence of IgE autoantibodies and their targets in different diseases? What do we know about the relevance of IgE autoantibodies in different diseases? What do we know about the cellular and molecular effects of IgE autoantibodies? In addition to providing answers to these questions, based on a broad review of the literature, we outline the current gaps of knowledge in our understanding of IgE autoantibodies and describe approaches to address them.

Circulating histones are major mediators of systemic inflammation and cellular injury in patients with acute liver failure.

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Wen, Zongmei; Lei, Zhen; Yao, Lu; Jiang, Ping; Gu, Tao; Ren, Feng; Liu, Yan; Gou, Chunyan; Li, Xiuhui; Wen, Tao

2016-09-29

Acute liver failure (ALF) is a life-threatening systemic disorder. Here we investigated the impact of circulating histones, recently identified inflammatory mediators, on systemic inflammation and liver injury in murine models and patients with ALF. We analyzed histone levels in blood samples from 62 patients with ALF, 60 patients with chronic liver disease, and 30 healthy volunteers. We incubated patients' sera with human L02 hepatocytes and monocytic U937 cells to assess cellular damage and cytokine production. d-galactosamine plus lipopolysaccharide (GalN/LPS), concanavalin A (ConA), and acetaminophen (APAP) were given to C57BL/6N mice to induce liver injury, respectively, and the pathogenic role of circulating histones was studied. Besides, the protective effect of nonanticoagulant heparin, which can bind histones, was evaluated with in vivo and ex vivo investigations. We observed that circulating histones were significantly increased in patients with ALF, and correlated with disease severity and mortality. Significant systemic inflammation was also pronounced in ALF patients, which were associated with histone levels. ALF patients' sera induced significant L02 cell death and stimulated U937 cells to produce cytokines, which were abrogated by nonanticoagulant heparin. Furthermore, circulating histones were all released remarkably in GalN/LPS, ConA, and APAP-treated mice, and associated with high levels of inflammatory cytokines. Heparin reduced systemic inflammation and liver damage in mice, suggesting that it could interfere with histone-associated liver injury. Collectively, these findings demonstrate that circulating histones are critical mediators of systemic inflammation and cellular damage in ALF, which may be potentially translatable for clinical use.

Coping mediates the relationship between sense of coherence and mental quality of life in patients with chronic illness: a cross-sectional study.

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Kristofferzon, Marja-Leena; Engström, Maria; Nilsson, Annika

2018-04-05

The aim of the present study was to investigate relationships between sense of coherence, emotion-focused coping, problem-focused coping, coping efficiency, and mental quality of life (QoL) in patients with chronic illness. A model based on Lazarus' and Folkman's stress and coping theory tested the specific hypothesis: Sense of coherence has a direct and indirect effect on mental QoL mediated by emotion-focused coping, problem-focused coping, and coping efficiency in serial adjusted for age, gender, educational level, comorbidity, and economic status. The study used a cross-sectional and correlational design. Patients (n = 292) with chronic diseases (chronic heart failure, end-stage renal disease, multiple sclerosis, stroke, and Parkinson) completed three questionnaires and provided background data. Data were collected in 2012, and a serial multiple mediator model was tested using PROCESS macro for SPSS. The test of the conceptual model confirmed the hypothesis. There was a significant direct and indirect effect of sense of coherence on mental QoL through the three mediators. The model explained 39% of the variance in mental QoL. Self-perceived effective coping strategies are the most important mediating factors between sense of coherence and QoL in patients with chronic illness, which supports Lazarus' and Folkman's stress and coping theory.

Revealing critical mechanisms of BR-mediated apple nursery tree growth using iTRAQ-based proteomic analysis.

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Zheng, Liwei; Ma, Juanjuan; Zhang, Lizhi; Gao, Cai; Zhang, Dong; Zhao, Caiping; Han, Mingyu

2018-02-20

Brassinosteroid is identified as an important hormone. However, information about brassinosteroid has not been fully elucidated, and few studies concerned its role in apple. The aim of this work was to study the role of brassinosteroid for apple tree growth. In our study, the effect of brassinosteroid on apple nursery tree was analyzed. The biomass, cell size and xylem content of apple nursery tree were obviously evaluated by brassinosteroid treatment; mineral elements contents, photosynthesis indexes, carbohydrate level and hormone contents were significantly high in brassinosteroid treated trees. To explore the molecular mechanisms of these phenotypic differences, iTRAQ-based quantitative proteomics were used to identify the expression profiles of proteins in apple nursery tree shoot tips in response to brassinosteroid at a key period (14days after brassinosteroid treatment). A total of 175 differentially expressed proteins were identified. They were mainly involved in chlorophyII biosynthesis, photosynthesis, carbohydrate metabolism, glycolysis, citric acid cycle, respiratory action, hormone signal, cell growth and ligin metabolism. The findings in this study indicate that brassinosteroid mediating apple nursery tree growth may be mainly through energy metabolism. Important biological processes identified here can be useful theoretical basis and provide new insights into the molecular mechanisms of brassinosteroid. Brassinosteroid is very important for plant growth and development. However, the molecular mechanism of brassinosteroid mediating growth process is not perfectly clear in plant, especially in apple nursery tree. We used a combination of physiological and bioinformatics analysis to investigate the effects of brassinosteroid on apple nursery tree growth and development. The data reported here demonstrated that brassinosteroid regulates apple nursery tree growth mainly through energy metabolism. Therefore it can provide a theoretical basis from energy

Neuraminidase activity mediates IL-6 production by activated lupus-prone mesangial cells.

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Sundararaj, Kamala; Rodgers, Jessalyn I; Marimuthu, Subathra; Siskind, Leah J; Bruner, Evelyn; Nowling, Tamara K

2018-04-01

The development of nephritis is a leading cause of morbidity and mortality in lupus patients. Although the general pathophysiological progression of lupus nephritis is known, the molecular mediators and mechanisms are incompletely understood. Previously, we demonstrated that the glycosphingolipid (GSL) catabolic pathway is elevated in the kidneys of MRL/lpr lupus mice and human lupus patients with nephritis. Specifically, the activity of neuraminidase (NEU) and expression of Neu1, an enzyme in the GSL catabolic pathway is significantly increased. To better understand the role and mechanisms by which this pathway contributes to the progression of LN, we analyzed the expression and effects of NEU activity on the function of MRL/lpr lupus-prone mesangial cells (MCs). We demonstrate that NEU1 and NEU3 promote IL-6 production in MES13 MCs. Neu1 expression, NEU activity, and IL-6 production are significantly increased in stimulated primary MRL/lpr lupus-prone MCs, and blocking NEU activity inhibits IL-6 production. NEU1 and NEU3 expression overlaps IgG deposits in MCs in vitro and in renal sections from nephritic MRL/lpr mice. Together, our results suggest that NEU activity mediates IL-6 production in lupus-prone MCs possibly through an IgG-receptor complex signaling pathway.

Mitochondrial protection impairs BET bromodomain inhibitor-mediated cell death and provides rationale for combination therapeutic strategies.

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Lasorsa, E; Smonksey, M; Kirk, J S; Rosario, S; Hernandez-Ilizaliturri, F J; Ellis, L

2015-12-10

Inhibitors of the bromodomain and extraterminal domain family (BETI) have recently entered phase I clinical trials. In patients with advanced leukemia's, potent antileukemia activity was displayed with minimum dose-limiting toxicity. In preclinical models of hematological malignancies, including aggressive B-cell lymphomas, BETI induced cell-cycle arrest and apoptosis. However, the underlying cell death mechanisms are still not well understood. Dissecting the mechanisms required by BETI to mediate cell death would provide strong direction on how to best utilize BETI to treat patients with aggressive hematological malignancies. Herein, we provide understanding of the molecular mechanisms underlying BETI-mediated cell death using I-BET762. Induction of cell death occurred in primary murine and human B-cell lymphomas through apoptosis. Genetic dissection using Eμ-myc B-cell lymphoma compound mutants demonstrated that I-BET762-induced apoptosis does not require the p53 pathway. Furthermore, deletion of Apaf1, and thus the absence of a functional apoptosome, is associated with a delayed drug response but do not provide long-term resistance. Prolonged treatment of this model in fact fails to suppress the therapeutic efficacy of the drug and is associated with biochemical features of autophagy. However, lack of mitochondrial permeability completely inhibited I-BET762-mediated tumor cell death, indicating mitochondrial damage as key events for its activity. Combination of I-BET762 with BH3-only mimetics ABT-263 or obatoclax, restored sensitivity to I-BET762 lymphoma killing; however, success was determined by expression of Bcl-2 family antiapoptotic proteins. Our study provides critical insight for clinical decisions regarding the appropriate strategy for using BETI as a single agent or in combination to treat patients with aggressive B-cell lymphomas.

TNF is required for TLR ligand-mediated but not protease-mediated allergic airway inflammation.

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Whitehead, Gregory S; Thomas, Seddon Y; Shalaby, Karim H; Nakano, Keiko; Moran, Timothy P; Ward, James M; Flake, Gordon P; Nakano, Hideki; Cook, Donald N

2017-09-01

Asthma is associated with exposure to a wide variety of allergens and adjuvants. The extent to which overlap exists between the cellular and molecular mechanisms triggered by these various agents is poorly understood, but it might explain the differential responsiveness of patients to specific therapies. In particular, it is unclear why some, but not all, patients benefit from blockade of TNF. Here, we characterized signaling pathways triggered by distinct types of adjuvants during allergic sensitization. Mice sensitized to an innocuous protein using TLR ligands or house dust extracts as adjuvants developed mixed eosinophilic and neutrophilic airway inflammation and airway hyperresponsiveness (AHR) following allergen challenge, whereas mice sensitized using proteases as adjuvants developed predominantly eosinophilic inflammation and AHR. TLR ligands, but not proteases, induced TNF during allergic sensitization. TNF signaled through airway epithelial cells to reprogram them and promote Th2, but not Th17, development in lymph nodes. TNF was also required during the allergen challenge phase for neutrophilic and eosinophilic inflammation. In contrast, TNF was dispensable for allergic airway disease in a protease-mediated model of asthma. These findings might help to explain why TNF blockade improves lung function in only some patients with asthma.

Lysosomes as mediators of drug resistance in cancer.

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Zhitomirsky, Benny; Assaraf, Yehuda G

2016-01-01

Drug resistance remains a leading cause of chemotherapeutic treatment failure and cancer-related mortality. While some mechanisms of anticancer drug resistance have been well characterized, multiple mechanisms remain elusive. In this respect, passive ion trapping-based lysosomal sequestration of multiple hydrophobic weak-base chemotherapeutic agents was found to reduce the accessibility of these drugs to their target sites, resulting in a markedly reduced cytotoxic effect and drug resistance. Recently we have demonstrated that lysosomal sequestration of hydrophobic weak base drugs triggers TFEB-mediated lysosomal biogenesis resulting in an enlarged lysosomal compartment, capable of enhanced drug sequestration. This study further showed that cancer cells with an increased number of drug-accumulating lysosomes are more resistant to lysosome-sequestered drugs, suggesting a model of drug-induced lysosome-mediated chemoresistance. In addition to passive drug sequestration of hydrophobic weak base chemotherapeutics, other mechanisms of lysosome-mediated drug resistance have also been reported; these include active lysosomal drug sequestration mediated by ATP-driven transporters from the ABC superfamily, and a role for lysosomal copper transporters in cancer resistance to platinum-based chemotherapeutics. Furthermore, lysosomal exocytosis was suggested as a mechanism to facilitate the clearance of chemotherapeutics which highly accumulated in lysosomes, thus providing an additional line of resistance, supplementing the organelle entrapment of chemotherapeutics away from their target sites. Along with these mechanisms of lysosome-mediated drug resistance, several approaches were recently developed for the overcoming of drug resistance or exploiting lysosomal drug sequestration, including lysosomal photodestruction and drug-induced lysosomal membrane permeabilization. In this review we explore the current literature addressing the role of lysosomes in mediating cancer drug

Caenorhabditis elegans reveals a FxNPxY-independent low-density lipoprotein receptor internalization mechanism mediated by epsin1

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Kang, Yuan-Lin; Yochem, John; Bell, Leslie; Sorensen, Erika B.; Chen, Lihsia; Conner, Sean D.

2013-01-01

Low-density lipoprotein receptor (LDLR) internalization clears cholesterol-laden LDL particles from circulation in humans. Defects in clathrin-dependent LDLR endocytosis promote elevated serum cholesterol levels and can lead to atherosclerosis. However, our understanding of the mechanisms that control LDLR uptake remains incomplete. To identify factors critical to LDLR uptake, we pursued a genome-wide RNA interference screen using Caenorhabditis elegans LRP-1/megalin as a model for LDLR transport. In doing so, we discovered an unanticipated requirement for the clathrin-binding endocytic adaptor epsin1 in LDLR endocytosis. Epsin1 depletion reduced LDLR internalization rates in mammalian cells, similar to the reduction observed following clathrin depletion. Genetic and biochemical analyses of epsin in C. elegans and mammalian cells uncovered a requirement for the ubiquitin-interaction motif (UIM) as critical for receptor transport. As the epsin UIM promotes the internalization of some ubiquitinated receptors, we predicted LDLR ubiquitination as necessary for endocytosis. However, engineered ubiquitination-impaired LDLR mutants showed modest internalization defects that were further enhanced with epsin1 depletion, demonstrating epsin1-mediated LDLR endocytosis is independent of receptor ubiquitination. Finally, we provide evidence that epsin1-mediated LDLR uptake occurs independently of either of the two documented internalization motifs (FxNPxY or HIC) encoded within the LDLR cytoplasmic tail, indicating an additional internalization mechanism for LDLR. PMID:23242996

Psychological defense mechanisms in patients with syphilis at different stages of the disease

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Filonova A.V.

2015-09-01

Full Text Available Purpose: the study of psychological defense mechanisms in patients with syphilis at different stages of the disease. Material and methods. We used questionnaire Plutchik-Kellerman-Comte "life style Index". The study involved 257 people (118 women (46% and 139 men (54% aged 18 to 67 years (mean age — 23,5±8,9years. Results. In patients with primary syphilis primary mecha-protection scheme is "denying"; secondary syphilis of skin and mucus-purity membranes— "replacement"; syphilis latent early — "projection"; in patients with late syphilis — intellectualization. Thus, in patients with late forms of syphilis is dominated by more Mature mechanisms of protection (projection, rationalization. Patients with early forms use more primitive mechanisms (denial, substitution. Conclusion. The obtained data may be useful in the choice of methods of psychotherapy, the formation of patients more realistic (ADAP-tive installations for the treatment, restoration of family and other social relations, the prevention of distress and improving the quality of life of patients.

Ventilator associated pneumonia among patients on mechanical ventilation at tertiary care centres

International Nuclear Information System (INIS)

Rafiq, M.Y.; Ikram, A.; Ayyub, M.

2018-01-01

Objective: To determine the frequency of ventilator associated pneumonia (VAP) among patients on mechanical ventilation, and to identify the causative bacterial pathogens and antibiotic susceptibility pattern of isolated microorganisms in intensive care units of tertiary care settings. Study Design: Descriptive cross sectional. Place and Duration of Study: This study was conducted at Microbiology Department, Armed Forces Institute of Pathology (AFIP), Rawalpindi, from Dec 2014 to Aug 2015. Material and Methods: A total of 176 patients on mechanical ventilation were included in the study; patients having respiratory tract infection before putting on ventilator were excluded. Endotracheal aspirate (ETA) and Bronchoalveolar lavage (BAL) samples were collected aseptically from patients on mechanical ventilation on day zero i.e. the day on which the patient was put on ventilator to rule out any previous respiratory tract infection and then after 48 hours to observe the development of VAP. Samples were processed in the laboratory by standard culture techniques, pathogens were identified and their antibiotic susceptibility was performed as per CLSI guidelines. Results: Out of 176 patients on mechanical ventilation, 59 (33.5%) developed VAP. Acinetobacter baumanii being the predominant pathogen isolated from 32 (54.2%) patients followed by MRSA 11 (18.6%), Klebsiella pneumoniae 9 (15.2%), Pseudomonas aeruginosa 5 (8.47%) and Stenotrophomonas maltophila from 2 (3.38%) patients. Conclusion: Frequency of VAP is quite high in our setup, identification of causative bacterial pathogensand their antibiotic susceptibility pattern will not only help in providing effective treatment to the patients but will also help in the formulation of antibiogram according to local resistance patterns for empirical therapy and to reduce the morbidity and mortality. (author)

Lung-protective mechanical ventilation does not protect against acute kidney injury in patients without lung injury at onset of mechanical ventilation.

Science.gov (United States)

Cortjens, Bart; Royakkers, Annick A N M; Determann, Rogier M; van Suijlen, Jeroen D E; Kamphuis, Stephan S; Foppen, Jannetje; de Boer, Anita; Wieland, Cathrien W; Spronk, Peter E; Schultz, Marcus J; Bouman, Catherine S C

2012-06-01

Preclinical and clinical studies suggest that mechanical ventilation contributes to the development of acute kidney injury (AKI), particularly in the setting of lung-injurious ventilator strategies. To determine whether ventilator settings in critically ill patients without acute lung injury (ALI) at onset of mechanical ventilation affect the development of AKI. Secondary analysis of a randomized controlled trial (N = 150), comparing conventional tidal volume (V(T), 10 mL/kg) with low tidal volume (V(T), 6 mL/kg) mechanical ventilation in critically ill patients without ALI at randomization. During the first 5 days of mechanical ventilation, the RIFLE class was determined daily, whereas neutrophil gelatinase-associated lipocalin and cystatin C levels were measured in plasma collected on days 0, 2, and 4. Eighty-six patients had no AKI at inclusion, and 18 patients (21%) subsequently developed AKI, but without significant difference between ventilation strategies. (Cumulative hazard, 0.26 vs 0.23; P = .88.) The courses of neutrophil gelatinase-associated lipocalin and cystatin C plasma levels did not differ significantly between randomization groups. In the present study in critically patients without ALI at onset of mechanical ventilation, lower tidal volume ventilation did not reduce the development or worsening of AKI compared with conventional tidal volume ventilation. Copyright © 2012 Elsevier Inc. All rights reserved.

Mental Stress-Induced-Myocardial Ischemia in Young Patients With Recent Myocardial Infarction: Sex Differences and Mechanisms.

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Vaccarino, Viola; Sullivan, Samaah; Hammadah, Muhammad; Wilmot, Kobina; Al Mheid, Ibhar; Ramadan, Ronnie; Elon, Lisa; Pimple, Pratik M; Garcia, Ernest V; Nye, Jonathon; Shah, Amit J; Alkhoder, Ayman; Levantsevych, Oleksiy; Gay, Hawkins; Obideen, Malik; Huang, Minxuan; Lewis, Tené T; Bremner, J Douglas; Quyyumi, Arshed A; Raggi, Paolo

2018-02-20

Mental stress-induced myocardial ischemia (MSIMI) is frequent in patients with coronary artery disease and is associated with worse prognosis. Young women with a previous myocardial infarction (MI), a group with unexplained higher mortality than men of comparable age, have shown elevated rates of MSIMI, but the mechanisms are unknown. We studied 306 patients (150 women and 156 men) ≤61 years of age who were hospitalized for MI in the previous 8 months and 112 community controls (58 women and 54 men) frequency matched for sex and age to the patients with MI. Endothelium-dependent flow-mediated dilation and microvascular reactivity (reactive hyperemia index) were measured at rest and 30 minutes after mental stress. The digital vasomotor response to mental stress was assessed using peripheral arterial tonometry. Patients received 99m Tc-sestamibi myocardial perfusion imaging at rest, with mental (speech task) and conventional (exercise/pharmacological) stress. The mean age of the sample was 50 years (range, 22-61). In the MI group but not among controls, women had a more adverse socioeconomic and psychosocial profile than men. There were no sex differences in cardiovascular risk factors, and among patients with MI, clinical severity tended to be lower in women. Women in both groups showed a higher peripheral arterial tonometry ratio during mental stress but a lower reactive hyperemia index after mental stress, indicating enhanced microvascular dysfunction after stress. There were no sex differences in flow-mediated dilation changes with mental stress. The rate of MSIMI was twice as high in women as in men (22% versus 11%, P =0.009), and ischemia with conventional stress was similarly elevated (31% versus 16%, P =0.002). Psychosocial and clinical risk factors did not explain sex differences in inducible ischemia. Although vascular responses to mental stress (peripheral arterial tonometry ratio and reactive hyperemia index) also did not explain sex differences in

Holistic Care for Patients During Weaning from Mechanical Ventilation: A Qualitative Study.

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Khalafi, Ali; Elahi, Nasrin; Ahmadi, Fazlollah

2016-11-01

Weaning patients from mechanical ventilation is a complex and highly challenging process. It requires continuity of care, the overall assessment of patients, and a focus on all aspects of patients' needs by critical care nurses. The aim of the present study was to explore holistic care while patients are being weaned from mechanical ventilation from the perspective of the critical care nurses. The study was carried out in the intensive care units (ICUs) of six hospitals in Ahvaz, Iran, from 2014 to 2015. In this qualitative study, 25 ICU staff including nurses, nurse managers, and nurse educators were selected by means of purposive sampling. Semi-structured interviews were used for data collection. The interview transcripts were then analyzed using qualitative content analysis. The four main themes that emerged to explain nurses' experiences of holistic care when weaning patients from mechanical ventilation include continuous care, a holistic overview of the patient, promoting human dignity, and the overall development of well-being. It was found that avoiding routine pivotal expertise, increasing consciousness of the nonphysical aspects of patients while providing treatment and presenting exclusive care, utilizing experienced ICU nurses, and placing more emphasis on effective communication with patients in order to honor them as human beings can all enhance the holistic quality of care.

Real-time single-molecule tethered particle motion experiments reveal the kinetics and mechanisms of Cre-mediated site-specific recombination

Science.gov (United States)

Fan, Hsiu-Fang

2012-01-01

Tyrosine family recombinases (YRs) are widely utilized in genome engineering systems because they can easily direct DNA rearrangement. Cre recombinases, one of the most commonly used types of YRs, catalyze site-specific recombination between two loxP sites without the need for high-energy cofactors, other accessory proteins or a specific DNA target sequence between the loxP sites. Previous structural, analytical ultracentrifuge and electrophoretic analyses have provided details of the reaction kinetics and mechanisms of Cre recombinase activity; whether there are reaction intermediates or side pathways involved has been left unaddressed. Using tethered particle motion (TPM), the Cre-mediated site-specific recombination process has been delineated, from beginning to end, at the single-molecule level, including the formation of abortive complexes and wayward complexes blocking inactive nucleoprotein complexes from entering the recombination process. Reversibility in the strand-cleavage/-ligation process and the formation of a thermally stable Holliday junction intermediate were observed within the Cre-mediated site-specific recombination process. Rate constants for each elementary step, which explain the overall reaction outcomes under various conditions, were determined. Taking the findings of this study together, they demonstrate the potential of single-molecule methodology as an alternative approach for exploring reaction mechanisms in detail. PMID:22467208

IFNG-mediated immune responses enhance autophagy against Mycobacterium tuberculosis antigens in patients with active tuberculosis

Science.gov (United States)

Rovetta, Ana I; Peña, Delfina; Hernández Del Pino, Rodrigo E; Recalde, Gabriela M; Pellegrini, Joaquín; Bigi, Fabiana; Musella, Rosa M; Palmero, Domingo J; Gutierrez, Marisa; Colombo, María I; García, Verónica E

2015-01-01

Protective immunity against Mycobacterium tuberculosis (Mtb) requires IFNG. Besides, IFNG-mediated induction of autophagy suppresses survival of virulent Mtb in macrophage cell lines. We investigated the contribution of autophagy to the defense against Mtb antigen (Mtb-Ag) in cells from tuberculosis patients and healthy donors (HD). Patients were classified as high responders (HR) if their T cells produced significant IFNG against Mtb-Ag; and low responders (LR) when patients showed weak or no T cell responses to Mtb-Ag. The highest autophagy levels were detected in HD cells whereas the lowest quantities were observed in LR patients. Interestingly, upon Mtb-Ag stimulation, we detected a positive correlation between IFNG and MAP1LC3B-II/LC3-II levels. Actually, blockage of Mtb-Ag-induced IFNG markedly reduced autophagy in HR patients whereas addition of limited amounts of IFNG significantly increased autophagy in LR patients. Therefore, autophagy collaborates with human immune responses against Mtb in close association with specific IFNG secreted against the pathogen. PMID:25426782

Enteral alimentation and gastrointestinal bleeding in mechanically ventilated patients.

Science.gov (United States)

Pingleton, S K; Hadzima, S K

1983-01-01

The incidence of upper gastrointestinal (GI) bleeding in mechanically ventilated ICU patients receiving enteral alimentation was reviewed and compared to bleeding occurring in ventilated patients receiving prophylactic antacids or cimetidine. Of 250 patients admitted to our ICU during a 1-yr time period, 43 ventilated patients were studied. Patients in each group were comparable with respect to age, respiratory diagnosis, number of GI hemorrhage risk factors, and number of ventilator, ICU, and hospital days. Twenty-one patients had evidence of GI bleeding. Fourteen of 20 patients receiving antacids and 7 of 9 patients receiving cimetidine had evidence of GI bleeding. No bleeding occurred in 14 patients receiving enteral alimentation. Complications of enteral alimentation were few and none required discontinuation of enteral alimentation. Our preliminary data suggest the role of enteral alimentation in critically ill patients may include not only protection against malnutrition but also protection against GI bleeding.

Mediation Analysis: A Practitioner's Guide.

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VanderWeele, Tyler J

2016-01-01

This article provides an overview of recent developments in mediation analysis, that is, analyses used to assess the relative magnitude of different pathways and mechanisms by which an exposure may affect an outcome. Traditional approaches to mediation in the biomedical and social sciences are described. Attention is given to the confounding assumptions required for a causal interpretation of direct and indirect effect estimates. Methods from the causal inference literature to conduct mediation in the presence of exposure-mediator interactions, binary outcomes, binary mediators, and case-control study designs are presented. Sensitivity analysis techniques for unmeasured confounding and measurement error are introduced. Discussion is given to extensions to time-to-event outcomes and multiple mediators. Further flexible modeling strategies arising from the precise counterfactual definitions of direct and indirect effects are also described. The focus throughout is on methodology that is easily implementable in practice across a broad range of potential applications.

Coronary and peripheral endothelial function in HIV patients studied with positron emission tomography and flow-mediated dilation: relation to hypercholesterolemia

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Lebech, Anne-Mette [Copenhagen University Hospital, Department of Infectious Diseases, Hvidovre (Denmark); Hvidovre University Hospital, Department of Infectious Diseases, Hvidovre (Denmark); Kristoffersen, Ulrik Sloth; Kjaer, Andreas [Rigshospitalet University Hospital, Department of Clinical Physiology, Nuclear Medicine and PET, Copenhagen (Denmark); University of Copenhagen, Cluster for Molecular Imaging, Copenhagen (Denmark); Wiinberg, Niels; Petersen, Claus Leth [Frederiksberg University Hospital, Department of Clinical Physiology and Nuclear Medicine, Frederiksberg (Denmark); Kofoed, Kristian; Andersen, Ove [Copenhagen University Hospital, Department of Infectious Diseases, Hvidovre (Denmark); Copenhagen University Hospital, Clinical Research Unit, Hvidovre (Denmark); Hesse, Birger [Rigshospitalet University Hospital, Department of Clinical Physiology, Nuclear Medicine and PET, Copenhagen (Denmark); Gerstoft, Jan [Rigshospitalet University Hospital, Department of Infectious Diseases, Copenhagen (Denmark)

2008-11-15

The mechanisms underlying increased cardiovascular risk in HIV patients in antiretroviral therapy (ART) are not known. Our aim was to study the endothelial function of the coronary arteries by cardiac perfusion positron emission tomography (PET), in HIV patients with normal or high cholesterol levels. Flow mediated dilation (FMD) of the brachial artery and circulating endothelial markers were also assessed. HIV patients in ART with total cholesterol {<=} 5.5 mmol/L (215 mg/dL; n = 13) or total cholesterol {>=} 6.5 mmol/L (254 mg/dL; n = 12) and healthy controls (n = 14) were included. {sup 13}NH{sub 3} perfusion PET, FMD, and measurement of plasma levels of E-Selectin, ICAM-1, VCAM-1, tPAI-1, and hs-CRP were performed. Baseline myocardial perfusion and the coronary flow reserve measured by PET (3.2 {+-} 0.3, 3.2 {+-} 0.3 and 3.0 {+-} 0.3; ns) was similar in HIV patients with normal or high total cholesterol and controls. FMD did not differ between the groups and was 4.6 {+-} 1.1%, 5.1 {+-} 1.2%, and 4.6 {+-} 0.8%, respectively. Increased levels of plasma E-Selectin, ICAM-1, tPAI-1, and hs-CRP were found in HIV patients when compared to controls (p < 0.05). E-Selectin and ICAM-1 levels were higher in HIV patients receiving protease inhibitors (PI) compared to those not receiving PI (p < 0.05). None of the measured endothelial biomarkers differed between the normal and high cholesterol HIV groups. In ART-treated HIV patients with a low overall cardiovascular risk, no sign of endothelial dysfunction was found not even in hypercholesterolemic patients. Also, the increased level of plasma endothelial markers found in HIV patients was not related to hypercholesterolemia. (orig.)

Cardiac output estimation using pulmonary mechanics in mechanically ventilated patients

Directory of Open Access Journals (Sweden)

Hann Christopher E

2010-11-01

Full Text Available Abstract The application of positive end expiratory pressure (PEEP in mechanically ventilated (MV patients with acute respiratory distress syndrome (ARDS decreases cardiac output (CO. Accurate measurement of CO is highly invasive and is not ideal for all MV critically ill patients. However, the link between the PEEP used in MV, and CO provides an opportunity to assess CO via MV therapy and other existing measurements, creating a CO measure without further invasiveness. This paper examines combining models of diffusion resistance and lung mechanics, to help predict CO changes due to PEEP. The CO estimator uses an initial measurement of pulmonary shunt, and estimations of shunt changes due to PEEP to predict CO at different levels of PEEP. Inputs to the cardiac model are the PV loops from the ventilator, as well as the oxygen saturation values using known respiratory inspired oxygen content. The outputs are estimates of pulmonary shunt and CO changes due to changes in applied PEEP. Data from two published studies are used to assess and initially validate this model. The model shows the effect on oxygenation due to decreased CO and decreased shunt, resulting from increased PEEP. It concludes that there is a trade off on oxygenation parameters. More clinically importantly, the model also examines how the rate of CO drop with increased PEEP can be used as a method to determine optimal PEEP, which may be used to optimise MV therapy with respect to the gas exchange achieved, as well as accounting for the impact on the cardiovascular system and its management.

[Advances in molecular mechanisms of adaptive immunity mediated by type I-E CRISPR/Cas system--A review].

Science.gov (United States)

Sun, Dongchang; Qiu, Juanping

2016-01-04

To better adapt to the environment, prokaryocyte can take up exogenous genes (from bacteriophages, plasmids or genomes of other species) through horizontal gene transfer. Accompanied by the acquisition of exogenous genes, prokaryocyte is challenged by the invasion of 'selfish genes'. Therefore, to protect against the risk of gene transfer, prokaryocyte needs to establish mechanisms for selectively taking up or degrading exogenous DNA. In recent years, researchers discovered an adaptive immunity, which is mediated by the small RNA guided DNA degradation, prevents the invasion of exogenous genes in prokaryocyte. During the immune process, partial DNA fragments are firstly integrated.to the clustered regularly interspaced short palindromic repeats (CRISPR) located within the genome DNA, and then the mature CRISPR RNA transcript and the CRISPR associated proteins (Cas) form a complex CRISPR/Cas for degrading exogenous DNA. In this review, we will first briefly describe the CRISPR/Cas systems and then mainly focus on the recent advances of the function mechanism and the regulation mechanism of the type I-E CRISPR/Cas system in Escherichia coli.

Generation of ROS mediated by mechanical waves (ultrasound) and its possible applications.

Science.gov (United States)

Duco, Walter; Grosso, Viviana; Zaccari, Daniel; Soltermann, Arnaldo T

2016-10-15

The thermal decomposition of 9,10 diphenylanthracene peroxide (DPAO 2 ) generates DPA and a mix of triplet and singlet molecular oxygen. For DPAO 2 the efficiency to produce singlet molecular oxygen is 0.35. On the other hand, it has shown that many thermal reactions can be carried out through the interaction of molecules with ultrasound. Ultrasound irradiation can create hydrodynamic stress (sonomechanical process), inertial cavitation (pyrolitic process) and long range effects mediated by radicals or ROS. Sonochemical reactions can be originated by pyrolytic like process, shock mechanical waves, thermal reactions and radical and ROS mediated reactions. Sonolysis of pure water can yield hydrogen or hydroxyl radicals and hydrogen peroxide (ROS). When DPAO 2 in 1,4 dioxane solution is treated with 20 or 24kHz and different power intensity the production of molecular singlet oxygen is observed. Specific scavengers like tetracyclone (TC) are used to demonstrate it. The efficiency now is 0.85 showing that the sonochemical process is much more efficient that the thermal one. Another endoperoxide, artemisinin was also studied. Unlike the concept of photosensitizer of photodynamic therapy, in spite of large amount of reported results in literature, the term sonosensitizer and the sonosensitization process are not well defined. We define sonosensitized reaction as one in which a chemical species decompose as consequence of cavitation phenomena producing ROS or other radicals and some other target species does undergo a chemical reaction. The concept could be reach rapidly other peroxides which are now under experimental studies. For artemisinin, an important antimalarian and anticancer drug, was established that ultrasound irradiation increases the effectiveness of the treatment but without any explanation. We show that artemisinin is an endoperoxide and behaves as a sonosensitizer in the sense of our definition. Copyright © 2016 Elsevier Inc. All rights reserved.

Flow-mediated dilatation has no independent prognostic effect in patients with chest pain with or without ischaemic heart disease

DEFF Research Database (Denmark)

Ulriksen, Line Skjold; Malmqvist, Beata B; Hansen, Are

2009-01-01

OBJECTIVE: The purpose of this study was to assess the prognostic effect of flow-mediated dilatation (FMD) in patients with chest pain admitted to a coronary care unit. METHODS: Endothelium-dependent FMD in the brachial artery was examined in 223 patients with acute chest pain. All patients...... underwent a stress test at the time of admittance. On the basis of a positive stress test, a prior myocardial infarction (MI), prior percutaneous coronary intervention (PCI) or coronary bypass surgery (CABG), 137 patients were categorized as having ischaemic heart disease (IHD). RESULTS: Patients with IHD...

Mechanical sensitivity and psychological factors in patients with burning mouth syndrome.

Science.gov (United States)

Honda, Mika; Iida, Takashi; Kamiyama, Hirona; Masuda, Manabu; Kawara, Misao; Svensson, Peter; Komiyama, Osamu

2018-05-18

The aim of this study was to compare mechanical sensitivity on the tongue using quantitative sensory testing (QST) and psychological factors using the General Health Questionnaire (GHQ) between burning mouth syndrome (BMS) patients and healthy participants. Participants comprised 20 female BMS patients (68.1 ± 7.4 years) and 20 healthy females (65.4 ± 4.6 years). Psychological factors were evaluated with GHQ. Tactile detection thresholds (TDT) and filament-prick pain detection thresholds (FPT) were used to evaluate mechanical sensitivity on the tongue in all participants. TDT and FPT were measured on the tongue within both the painful area and the non-painful area in BMS patients, and on the tongue on both sides in healthy participants. As controls, TDT and FPT were measured with Semmes-Weinstein monofilaments on the skin of the mentum and palm in all participants. GHQ scores were significantly higher in BMS patients than in healthy participants (P = 0.024). No significant differences in TDT or FPT on the tongue, mentum, or palm were seen between BMS patients and healthy participants (P > 0.05). BMS patients showed no significant differences in TDT or FPT between the painful and non-painful areas on the tongue (P > 0.05). There were no significant correlations among TDT/FPT and GHQ score in BMS patients (P > 0.05). These findings could indicate a more important role for psychological factors than mechanical sensitivity in BMS pathophysiology. Pain on the tongue in elderly female patients with BMS may be more related to psychological factors.

Proliferating cell nuclear antigen binds DNA polymerase-β and mediates 1-methyl-4-phenylpyridinium-induced neuronal death.

Directory of Open Access Journals (Sweden)

Zhentao Zhang

Full Text Available The mechanisms leading to dopaminergic neuronal loss in the substantia nigra of patients with Parkinson disease (PD remain poorly understood. We recently reported that aberrant DNA replication mediated by DNA polymerase-β (DNA pol-β plays a causal role in the death of postmitotic neurons in an in vitro model of PD. In the present study, we show that both proliferating cell nuclear antigen (PCNA and DNA pol-β are required for MPP(+-induced neuronal death. PCNA binds to the catalytic domain of DNA pol-β in MPP(+-treated neurons and in post-mortem brain tissues of PD patients. The PCNA-DNA pol-β complex is loaded into DNA replication forks and mediates DNA replication in postmitotic neurons. The aberrant DNA replication mediated by the PCNA-DNA pol-β complex induces p53-dependent neuronal cell death. Our results indicate that the interaction of PCNA and DNA pol-β contributes to neuronal death in PD.

Neuroautonomic evaluation of patients with unexplained syncope: incidence of complex neurally mediated diagnoses in the elderly

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Rafanelli M

2014-02-01

Full Text Available Martina Rafanelli, Alessandro Morrione, Annalisa Landi, Emilia Ruffolo, Valentina M Chisciotti, Maria A Brunetti, Niccolò Marchionni, Andrea Ungar Syncope Unit, Cardiology and Geriatric Medicine, University of Florence and Azienda Ospedaliero-Universitaria Careggi, Florence, Italy Background: The incidence of syncope increases in individuals over the age of 70 years, but data about this condition in the elderly are limited. Little is known about tilt testing (TT, carotid sinus massage (CSM, or supine and upright blood pressure measurement related to age or about patients with complex diagnoses, for example, those with a double diagnosis, ie, positivity in two of these three tests. Methods: A total of 873 consecutive patients of mean age 66.5±18 years underwent TT, CSM, and blood pressure measurement in the supine and upright positions according to the European Society of Cardiology guidelines on syncope.1 Neuroautonomic evaluation was performed if the first-line evaluation (clinical history, physical examination, electrocardiogram was suggestive of neurally mediated syncope, or if the first-line evaluation was suggestive of cardiac syncope but this diagnosis was excluded after specific diagnostic tests according to European Society of Cardiology guidelines on syncope, or if certain or suspected diagnostic criteria were not present after the first-line evaluation. Results: A diagnosis was reached in 64.3% of cases. TT was diagnostic in 50.4% of cases, CSM was diagnostic in 11.8% of cases, and orthostatic hypotension was present in 19.9% of cases. Predictors of a positive tilt test were prodromal symptoms and typical situational syncope. Increased age and a pathologic electrocardiogram were predictors of carotid sinus syndrome. Varicose veins and alpha-receptor blockers, nitrates, and benzodiazepines were associated with orthostatic hypotension. Twenty-three percent of the patients had a complex diagnosis. The most frequent association was

[Impact of Uncertainty on the Quality of Life of Young Breast Cancer Patients: Focusing on Mediating Effect of Marital Intimacy].

Science.gov (United States)

Oh, Yeong Kyong; Hwang, Seon Young

2018-02-01

The purpose of this study was to examine the mediating effect of marital intimacy on the impact of uncertainty on the quality of life (QoL) of young breast cancer patients. This study used a pathway analysis with 154 young breast cancer cases in their early diagnosis stage at a medical center in Korea. Data were collected from November 2016 to February 2017 and analyzed using correlation analysis and pathway analysis. Uncertainty, marital intimacy, and 4 sub-scales of QoL showed a significant correlation. Marital intimacy was directly affected by uncertainty (β=-.39, p=.013) and 4 sub-scales of QoL were also affected by uncertainty. Among the 4 sub-scales of QoL, physical well-being (PWB) (β=.17, p=.026), social well-being (SWB) (β=.49, p=.010), and functional well-being (FWB) (β=.38, p=.009) were affected by marital intimacy but emotional well-being (EWB) was not affected by it. The mediating effect of marital intimacy on the impact of uncertainty on QoL was confirmed. Marital intimacy showed a significant indirect effect on PWB (β=-.07, p=.024), SWB (β=-.19, p=.008), and FWB (β=-.15, p=.005), and it means that marital intimacy has a partial mediating effect on the impact of uncertainty on PWB, SWB, and FWB. Effects of uncertainty on QoL was mediated by marital intimacy of young breast cancer patients in their early diagnosis stage. It suggests that marital intimacy needs to be considered in providing nursing intervention for young breast cancer patients. © 2018 Korean Society of Nursing Science.

Psychological Resilience, Affective Mechanisms, and Symptom Burden in a Tertiary Care Sample of Patients with Fibromyalgia

Science.gov (United States)

McAllister, Samantha J; Vincent, Ann; Hassett, Afton L; Whipple, Mary O; Oh, Terry H; Benzo, Roberto P; Toussaint, Loren L

2014-01-01

Research demonstrates that patients with fibromyalgia who have higher positive and lower negative affect have lower symptom burden. Affect has been shown to be associated with resilience. This study examined the relationship between affect, resilience, and fibromyalgia symptom burden in a clinical sample of patients with fibromyalgia. We hypothesized that (a) positive and negative affect would be associated with fibromyalgia symptom burden; (b) resilience would be associated with positive and negative affect; (c) resilience would be associated with fibromyalgia symptom burden; and (d) the connection between resilience and fibromyalgia symptom burden would be mediated by both positive and negative affect. A sample of 858 patients with fibromyalgia completed questionnaires. Mediation modeling revealed statistically significant direct effects of resilience on fibromyalgia symptom burden (β =−.10, P fibromyalgia symptom burden through affect (β =−.36, P fibromyalgia symptom burden. Our results suggest that improving affect through resiliency training could be studied as a modality for improving fibromyalgia symptom burden. PMID:24376184

Dark matter prospects in deflected mirage mediation

International Nuclear Information System (INIS)

Holmes, Michael; Nelson, Brent D.

2009-01-01

The recently introduced deflected mirage mediation (DMM) model is a string-motivated paradigm in which all three of the major supersymmetry-breaking transmission mechanisms are operative. We begin a systematic exploration of the parameter space of this rich model context, paying special attention to the pattern of gaugino masses which arise. In this work we focus on the dark matter phenomenology of the DMM model as such signals are the least influenced by the model-dependent scalar masses. We find that a large portion of the parameter space in which the three mediation mechanisms have a similar effective mass scale of 1 TeV or less will be probed by future direct and indirect detection experiments. Distinguishing deflected mirage mediation from the mirage model without gauge mediation will prove difficult without collider input, though we indicate how gamma ray signals may provide an opportunity for distinguishing between the two paradigms

The molecular mechanism of mediation of adsorbed serum proteins to endothelial cells adhesion and growth on biomaterials.

Science.gov (United States)

Yang, Dayun; Lü, Xiaoying; Hong, Ying; Xi, Tingfei; Zhang, Deyuan

2013-07-01

To explore molecular mechanism of mediation of adsorbed proteins to cell adhesion and growth on biomaterials, this study examined endothelial cell adhesion, morphology and viability on bare and titanium nitride (TiN) coated nickel titanium (NiTi) alloys and chitosan film firstly, and then identified the type and amount of serum proteins adsorbed on the three surfaces by proteomic technology. Subsequently, the mediation role of the identified proteins to cell adhesion and growth was investigated with bioinformatics analyses, and further confirmed by a series of cellular and molecular biological experiments. Results showed that the type and amount of adsorbed serum proteins associated with cell adhesion and growth was obviously higher on the alloys than on the chitosan film, and these proteins mediated endothelial cell adhesion and growth on the alloys via four ways. First, proteins such as adiponectin in the adsorbed protein layer bound with cell surface receptors to generate signal transduction, which activated cell surface integrins through increasing intracellular calcium level. Another way, thrombospondin 1 in the adsorbed protein layer promoted TGF-β signaling pathway activation and enhanced integrins expression. The third, RGD sequence containing proteins such as fibronectin 1, vitronectin and thrombospondin 1 in the adsorbed protein layer bound with activated integrins to activate focal adhesion pathway, increased focal adhesion formation and actin cytoskeleton organization and mediated cell adhesion and spreading. In addition, the activated focal adhesion pathway promoted the expression of cell growth related genes and resulted in cell proliferation. The fourth route, coagulation factor II (F2) and fibronectin 1 in the adsorbed protein layer bound with cell surface F2 receptor and integrin, activated regulation of actin cytoskeleton pathway and regulated actin cytoskeleton organization. Copyright © 2013 Elsevier Ltd. All rights reserved.

LDL oxidation by platelets propagates platelet activation via an oxidative stress-mediated mechanism.

Science.gov (United States)

Carnevale, Roberto; Bartimoccia, Simona; Nocella, Cristina; Di Santo, Serena; Loffredo, Lorenzo; Illuminati, Giulio; Lombardi, Elisabetta; Boz, Valentina; Del Ben, Maria; De Marco, Luigi; Pignatelli, Pasquale; Violi, Francesco

2014-11-01

Platelets generate oxidized LDL (ox-LDL) via NOX2-derived oxidative stress. We investigated if once generated by activated platelets ox-LDL can propagate platelet activation. Experiments were performed in platelets from healthy subjects (HS), hyper-cholesterolemic patients and patients with NOX2 hereditary deficiency. Agonist-stimulated platelets from HS added with LDL were associated with a dose-dependent increase of reactive oxidant species and ox-LDL. Agonist-stimulated platelets from HS added with a fixed dose of LDL (57.14 μmol/L) or added with homogenized human atherosclerotic plaque showed enhanced ox-LDL formation (approximately +50% and +30% respectively), which was lowered by a NOX2 inhibitor (approximately -35% and -25% respectively). Compared to HS, ox-LDL production was more pronounced in agonist-stimulated platelet rich plasma (PRP) from hyper-cholesterolemic patients but was almost absent in PRP from NOX2-deficient patients. Platelet aggregation and 8-iso-PGF2α-ΙΙΙ formation increased in LDL-treated washed platelets (+42% and +53% respectively) and PRP (+31% and +53% respectively). Also, LDL enhanced platelet-dependent thrombosis at arterial shear rate (+33%) but did not affect platelet activation in NOX2-deficient patients. Platelet activation by LDL was significantly inhibited by CD36 or LOX1 blocking peptides, two ox-LDL receptor antagonists, or by a NOX2 inhibitor. LDL-added platelets showed increased p38MAPK (+59%) and PKC (+51%) phosphorylation, p47(phox) translocation to platelet membrane (+34%) and NOX2 activation (+30%), which were inhibited by ox-LDL receptor antagonists. Platelets oxidize LDL, which in turn amplify platelet activation via specific ox-LDL receptors; both effects are mediated by NOX2 activation. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Mechanisms and mediation in survival analysis: towards an integrated analytical framework.

LENUS (Irish Health Repository)

Haase, Trutz

2016-02-29

A wide-ranging debate has taken place in recent years on mediation analysis and causal modelling, raising profound theoretical, philosophical and methodological questions. The authors build on the results of these discussions to work towards an integrated approach to the analysis of research questions that situate survival outcomes in relation to complex causal pathways with multiple mediators. The background to this contribution is the increasingly urgent need for policy-relevant research on the nature of inequalities in health and healthcare.

Dark Chocolate Acutely Improves Walking Autonomy in Patients With Peripheral Artery Disease

Science.gov (United States)

Loffredo, Lorenzo; Perri, Ludovica; Catasca, Elisa; Pignatelli, Pasquale; Brancorsini, Monica; Nocella, Cristina; De Falco, Elena; Bartimoccia, Simona; Frati, Giacomo; Carnevale, Roberto; Violi, Francesco

2014-01-01

Background NOX‐2, the catalytic subunit of NADPH oxidase, has a key role in the formation of reactive oxidant species and is implicated in impairing flow‐mediated dilation (FMD). Dark chocolate exerts artery dilatation via down‐regulating NOX2‐mediated oxidative stress. The aim of this study was to investigate whether dark chocolate improves walking autonomy in peripheral artery disease (PAD) patients via an oxidative stress‐mediated mechanism. Methods and Results FMD, serum levels of isoprostanes, nitrite/nitrate (NOx) and sNOX2‐dp, a marker of blood NOX2 activity, maximal walking distance (MWD) and maximal walking time (MWT) were studied in 20 PAD patients (14 males and 6 females, mean age: 69±9 years) randomly allocated to 40 g of dark chocolate (>85% cocoa) or 40 g of milk chocolate (≤35% cocoa) in a single blind, cross‐over design. The above variables were assessed at baseline and 2 hours after chocolate ingestion. Dark chocolate intake significantly increased MWD (+11%; Pchocolate intake. Serum epicatechin and its methylated metabolite significantly increased only after dark chocolate ingestion. Multiple linear regression analysis showed that Δ of MWD was independently associated with Δ of MWT (Pchocolate acutely improves walking autonomy with a mechanism possibly related to an oxidative stress‐mediated mechanism involving NOX2 regulation. Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT01947712. PMID:24990275

Humidification during mechanical ventilation in the adult patient.

Science.gov (United States)

Al Ashry, Haitham S; Modrykamien, Ariel M

2014-01-01

Humidification of inhaled gases has been standard of care in mechanical ventilation for a long period of time. More than a century ago, a variety of reports described important airway damage by applying dry gases during artificial ventilation. Consequently, respiratory care providers have been utilizing external humidifiers to compensate for the lack of natural humidification mechanisms when the upper airway is bypassed. Particularly, active and passive humidification devices have rapidly evolved. Sophisticated systems composed of reservoirs, wires, heating devices, and other elements have become part of our usual armamentarium in the intensive care unit. Therefore, basic knowledge of the mechanisms of action of each of these devices, as well as their advantages and disadvantages, becomes a necessity for the respiratory care and intensive care practitioner. In this paper, we review current methods of airway humidification during invasive mechanical ventilation of adult patients. We describe a variety of devices and describe the eventual applications according to specific clinical conditions.

Coping Styles Mediate the Relationship Between Self-esteem, Health Locus of Control, and Health-Promoting Behavior in Chinese Patients With Coronary Heart Disease.

Science.gov (United States)

Zou, Huijing; Tian, Qian; Chen, Yuxia; Cheng, Cheng; Fan, Xiuzhen

Health-promoting behavior plays an important role in reducing the burden of coronary heart disease. Self-esteem and health locus of control may contribute to health-promoting behavior, and coping styles may mediate these associations. The aims of our study were to examine whether self-esteem and health locus of control are associated with health-promoting behavior and examine the possible mediating effect of coping styles in patients with coronary heart disease. Health-promoting behavior, self-esteem, health locus of control, and coping styles were assessed in 272 hospitalized patients (60 ± 12 years, 61% male) with coronary heart disease. Hierarchical regression analysis was conducted to analyze the relationships between health-promoting behavior and other variables. Mediation effect was examined according to the methods of Baron and Kenny. The mean score for health-promoting behavior was 2.57 ± 0.51; 38.2% of patients (n = 104) scored lower than 2.5. Self-esteem (β = .139, P locus of control and health-promoting behavior. Confrontation plays a mediating role in the association among self-esteem, internal health locus of control, and health-promoting behavior. Strategies should be undertaken to encourage the use of confrontation coping style, which will facilitate health-promoting behavior.

Subunit architecture and functional modular rearrangements of the transcriptional mediator complex.

Science.gov (United States)

Tsai, Kuang-Lei; Tomomori-Sato, Chieri; Sato, Shigeo; Conaway, Ronald C; Conaway, Joan W; Asturias, Francisco J

2014-06-05

The multisubunit Mediator, comprising ∼30 distinct proteins, plays an essential role in gene expression regulation by acting as a bridge between DNA-binding transcription factors and the RNA polymerase II (RNAPII) transcription machinery. Efforts to uncover the Mediator mechanism have been hindered by a poor understanding of its structure, subunit organization, and conformational rearrangements. By overcoming biochemical and image analysis hurdles, we obtained accurate EM structures of yeast and human Mediators. Subunit localization experiments, docking of partial X-ray structures, and biochemical analyses resulted in comprehensive mapping of yeast Mediator subunits and a complete reinterpretation of our previous Mediator organization model. Large-scale Mediator rearrangements depend on changes at the interfaces between previously described Mediator modules, which appear to be facilitated by factors conducive to transcription initiation. Conservation across eukaryotes of Mediator structure, subunit organization, and RNA polymerase II interaction suggest conservation of fundamental aspects of the Mediator mechanism. Copyright © 2014 Elsevier Inc. All rights reserved.

Opening the window to the cogenesis with Affleck–Dine mechanism in gravity mediation

Energy Technology Data Exchange (ETDEWEB)

Kamada, Ayuki [Kavli Institute for the Physics and Mathematics of the Universe, University of Tokyo, Kashiwa, Chiba 277-8582 (Japan); Kawasaki, Masahiro [Kavli Institute for the Physics and Mathematics of the Universe, University of Tokyo, Kashiwa, Chiba 277-8582 (Japan); Institute for Cosmic Ray Research, University of Tokyo, Kashiwa, Chiba 277-8582 (Japan); Yamada, Masaki, E-mail: yamadam@icrr.u-tokyo.ac.jp [Institute for Cosmic Ray Research, University of Tokyo, Kashiwa, Chiba 277-8582 (Japan)

2013-02-12

The observed baryon and dark matter densities are equal up to a factor of 5. This observation indicates that the baryon asymmetry and dark matter have the same origin. The Affleck–Dine baryogenesis is one of the most promising mechanisms in this context. Q balls, which are often formed in the early Universe associated with the Affleck–Dine baryogenesis, decay both into supersymmetric particles and into quarks. Recently, it was pointed out that annihilation of squarks into quarks gives a dominant contribution to the Q-ball decay rate and the branching ratio of Q-ball decay into supersymmetric particles changes from the previous estimate. In this Letter, the scenario of baryon and dark matter cogenesis from Q ball in gravity mediation is revisited in respect of the improved Q-ball decay rates. It is found that the successful cogenesis takes place when a wino with mass 400–600 GeV is dark matter.

Reinforcing the membrane-mediated mechanism of action of the anti-tuberculosis candidate drug thioridazine with molecular simulations

DEFF Research Database (Denmark)

Kopec, Wojciech; Khandelia, Himanshu

2014-01-01

Thioridazine is a well-known dopamine-antagonist drug with a wide range of pharmacological properties ranging from neuroleptic to antimicrobial and even anticancer activity. Thioridazine is a critical component of a promising multi-drug therapy against M. tuberculosis. Amongst the various propose......-membrane interactions, and reinforce the wider, emerging view of action of many small, bioactive compounds....... mechanisms of action, the cell membrane-mediated one is peculiarly tempting due to the distinctive feature of phenothiazine drug family to accumulate in selected body tissues. In this study, we employ long-scale molecular dynamics simulations to investigate the interactions of three different concentrations...

The presence of plasmid-mediated resistance genes among uropathogenes isolated from diabetic and non-diabetic patients with chronic pyelonephritis

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O.I. Chub

2014-10-01

Full Text Available Increased multidrug resistance of extended-spectrum beta-lactamases (ESBLs compromises the efficacy of treatment of urinary tract infections. The objective of this study is to determine the prevalence of ESBL-producing uropathogens from patients with chronic pyelonephritis (CP and to evaluate the risk factors of these types of infections. Screening for the presence of plasmid-mediated ESBL was performed by polymerase chain reaction. Out of 105 patients, 22 (20.9% revealed strains with resistance genes: 11 (36.7%, 11 (36.7% and 8 (26.7% were identified to carry bla(TEM, bla(SHV and bla(CTX-M beta-lactamase genes, respectively. We have demonstrated that prevalence of the resistance among patients with CP combined with type 2 DM was 31.3%, while among patients with CP without type 2 DM was 27.4%; however the difference between these groups was not significant. The main factors related with appearance of plasmid-mediated resistance genes were age range above 55 years, Chronic Kidney Disease stage ІІІ and ІV, in-patient treatment history, history of using antibiotics last year. Isolation and detection of ESBL-producing strains are essential fоr the sеlection оf the mоst effеctive antibiоtic for the empiric trеatment.

Paradigms and mechanisms of inhalational anesthetics mediated neuroprotection against cerebral ischemic stroke.

Science.gov (United States)

Wang, Hailian; Li, Peiying; Xu, Na; Zhu, Ling; Cai, Mengfei; Yu, Weifeng; Gao, Yanqin

2016-01-01

Cerebral ischemic stroke is a leading cause of serious long-term disability and cognitive dysfunction. The high mortality and disability of cerebral ischemic stroke is urging the health providers, including anesthesiologists and other perioperative professioners, to seek effective protective strategies, which are extremely limited, especially for those perioperative patients. Intriguingly, several commonly used inhalational anesthetics are recently suggested to possess neuroprotective effects against cerebral ischemia. This review introduces multiple paradigms of inhalational anesthetic treatments that have been investigated in the setting of cerebral ischemia, such as preconditioning, proconditioning and postconditioning with a variety of inhalational anesthetics. The pleiotropic mechanisms underlying these inhalational anesthetics-afforded neuroprotection against stroke are also discussed in detail, including the common pathways shared by most of the inhalational anesthetic paradigms, such as anti-excitotoxicity, anti-apoptosis and anti-inflammation. There are also distinct mechanisms involved in specific paradigms, such as preserving blood brain barrier integrity, regulating cerebral blood flow and catecholamine release. The ready availability of these inhalational anesthetics bedside and renders them a potentially translatable stroke therapy attracting great efforts for understanding of the underlying mechanisms.

iTRAQ-based proteomic analysis reveals the mechanisms of silicon-mediated cadmium tolerance in rice (Oryza sativa) cells.

Science.gov (United States)

Ma, Jie; Sheng, Huachun; Li, Xiuli; Wang, Lijun

2016-07-01

Silicon (Si) can alleviate cadmium (Cd) stress in rice (Oryza sativa) plants, however, the understanding of the molecular mechanisms at the single-cell level remains limited. To address these questions, we investigated suspension cells of rice cultured in the dark environment in the absence and presence of Si with either short- (12 h) or long-term (5 d) Cd treatments using a combination of isobaric tags for relative and absolute quantitation (iTRAQ), fluorescent staining, and inductively coupled plasma mass spectroscopy (ICP-MS). We identified 100 proteins differentially regulated by Si under the short- or long-term Cd stress. 70% of these proteins were down-regulated, suggesting that Si may improve protein use efficiency by maintaining cells in the normal physiological status. Furthermore, we showed two different mechanisms for Si-mediated Cd tolerance. Under the short-term Cd stress, the Si-modified cell walls inhibited the uptake of Cd ions into cells and consequently reduced the expressions of glycosidase, cell surface non-specific lipid-transfer proteins (nsLTPs), and several stress-related proteins. Under the long-term Cd stress, the amount of Cd in the cytoplasm in Si-accumulating (+Si) cells was decreased by compartmentation of Cd into vacuoles, thus leading to a lower expression of glutathione S-transferases (GST). These results provide protein-level insights into the Si-mediated Cd detoxification in rice single cells. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Heme-Mediated Induction of CXCL10 and Depletion of CD34+ Progenitor Cells Is Toll-Like Receptor 4 Dependent.

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Carmen M Dickinson-Copeland

Full Text Available Plasmodium falciparum infection can cause microvascular dysfunction, cerebral encephalopathy and death if untreated. We have previously shown that high concentrations of free heme, and C-X-C motif chemokine 10 (CXCL10 in sera of malaria patients induce apoptosis in microvascular endothelial and neuronal cells contributing to vascular dysfunction, blood-brain barrier (BBB damage and mortality. Endothelial progenitor cells (EPC are microvascular endothelial cell precursors partly responsible for repair and regeneration of damaged BBB endothelium. Studies have shown that EPC's are depleted in severe malaria patients, but the mechanisms mediating this phenomenon are unknown. Toll-like receptors recognize a wide variety of pathogen-associated molecular patterns generated by pathogens such as bacteria and parasites. We tested the hypothesis that EPC depletion during malaria pathogenesis is a function of heme-induced apoptosis mediated by CXCL10 induction and toll-like receptor (TLR activation. Heme and CXCL10 concentrations in plasma obtained from malaria patients were elevated compared with non-malaria subjects. EPC numbers were significantly decreased in malaria patients (P < 0.02 and TLR4 expression was significantly elevated in vivo. These findings were confirmed in EPC precursors in vitro; where it was determined that heme-induced apoptosis and CXCL10 expression was TLR4-mediated. We conclude that increased serum heme mediates depletion of EPC during malaria pathogenesis.

Depression, patient characteristics, and attachment style: correlates and mediators of medication treatment adherence in a racially diverse primary care sample.

Science.gov (United States)

Hooper, Lisa M; Tomek, Sara; Roter, Debra; Carson, Kathryn A; Mugoya, George; Cooper, Lisa A

2016-03-01

The depth and breadth of problems related to depressive symptomatology and optimal treatment outcomes, including medication treatment adherence, have long been documented in the literature. Missing are clear explanations as to what factors and patient characteristics may account for lack of medication treatment adherence. The two objectives of the current study were to examine the predictive strength of depression, patient characteristics, and patient attachment style regarding medication treatment adherence and to consider the extent to which attachment styles mediate the relation between depression and medication treatment adherence. Participants in the present study were 237 racially diverse American primary care patients with a diagnosis of hypertension who were participants in a clinical trial. Depression, patient characteristics, attachment style, and medication treatment adherence were assessed. Partly consistent with our four hypotheses, the following results were found: (a) Black American, younger, never married, and poorer patients had lower medication treatment adherence (b) depression was significantly associated with lower self-reported medication adherence; (c) insecure-dismissing attachment style was related to lower medication adherence; and (d) insecure-dismissing attachment style mediates the relation between depression and medication treatment adherence by exacerbating the negative association. Physicians and other primary care providers should consider how depressive symptomatology, patient characteristics, and attachment style may inform the treatment plans they put forward and the extent to which patients may adhere to those treatment plans.

Tear Mediators in Corneal Ectatic Disorders.

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Dorottya Pásztor

Full Text Available To compare the concentrations of 11 tear mediators in order to reveal the biochemical difference between pellucid marginal degeneration (PMD and keratoconus (KC.We have designed a cross-sectional study in which patients with corneal ectasia based on slit-lamp biomicroscopy and Pentacam HR (keratometry values (K1, K2, Kmax, astigmatism, minimal radius of curvature (Rmin, corneal thickness (Apex and Min, indices (surface variation, vertical asymmetry, keratoconus, central keratoconus, height asymmetry and decentration were enrolled. Eyes of keratoconic patients were similar to the PMD patients in age and severity (K2, Kmax and Rmin. Non-stimulated tear samples were collected from nine eyes of seven PMD patients, 55 eyes of 55 KC patients and 24 eyes of 24 healthy controls. The mediators' (interleukin -6, -10, chemokine ligand 5, -8, -10, matrix metalloproteinase (MMP -9, -13, tissue inhibitor of metalloproteinases (TIMP-1, tissue plasminogen activator, plasminogen activator inhibitor, nerve growth factor concentrations were measured using Cytometric Bead Array.MMP-9 was the only mediator which presented relevant variances between the two patient groups (p = 0.005. The ratios of MMP-9 and TIMP-1 were 2.45, 0.40 and 0.23 in PMD, KC and the controls, respectively.As far as we are aware, this is the first study that aims to reveal the biochemical differences between PMD and KC. Further studies of biomarkers to investigate the precise role of these mediators need to be defined, and it is important to confirm the observed changes in a larger study to gain further insights into the molecular alterations in PMD.

Causal mechanisms of subjective cognitive dysfunction in schizophrenic and depressed patients

NARCIS (Netherlands)

van den Bosch, RJ; Rombouts, RP

We examined causal mechanisms of subjective cognitive (dis)abilities in schizophrenic and depressed patients, and in patient and normal control groups. This exploratory study included objective cognitive performance (Continuous Performance Task) as well as mood and mental effort ratings. Self-report

Heterotrimeric G proteins-mediated resistance to necrotrophic pathogens includes mechanisms independent of salicylic acid-, jasmonic acid/ethylene- and abscisic acid-mediated defense signaling.

Science.gov (United States)

Trusov, Yuri; Sewelam, Nasser; Rookes, James Edward; Kunkel, Matt; Nowak, Ekaterina; Schenk, Peer Martin; Botella, José Ramón

2009-04-01

Heterotrimeric G proteins are involved in the defense response against necrotrophic fungi in Arabidopsis. In order to elucidate the resistance mechanisms involving heterotrimeric G proteins, we analyzed the effects of the Gβ (subunit deficiency in the mutant agb1-2 on pathogenesis-related gene expression, as well as the genetic interaction between agb1-2 and a number of mutants of established defense pathways. Gβ-mediated signaling suppresses the induction of salicylic acid (SA)-, jasmonic acid (JA)-, ethylene (ET)- and abscisic acid (ABA)-dependent genes during the initial phase of the infection with Fusarium oxysporum (up to 48 h after inoculation). However, at a later phase it enhances JA/ET-dependent genes such as PDF1.2 and PR4. Quantification of the Fusarium wilt symptoms revealed that Gβ- and SA-deficient mutants were more susceptible than wild-type plants, whereas JA- and ET-insensitive and ABA-deficient mutants demonstrated various levels of resistance. Analysis of the double mutants showed that the Gβ-mediated resistance to F. oxysporum and Alternaria brassicicola was mostly independent of all of the previously mentioned pathways. However, the progressive decay of agb1-2 mutants was compensated by coi1-21 and jin1-9 mutations, suggesting that at this stage of F. oxysporum infection Gβ acts upstream of COI1 and ATMYC2 in JA signaling. © 2008 The Authors. Journal compilation © 2008 Blackwell Publishing Ltd.

Gratitude mediates quality of life differences between fibromyalgia patients and healthy controls.

Science.gov (United States)

Toussaint, Loren; Sirois, Fuschia; Hirsch, Jameson; Weber, Annemarie; Vajda, Christian; Schelling, Jorg; Kohls, Niko; Offenbacher, Martin

2017-09-01

Despite a growing literature on the benefits of gratitude for adjustment to chronic illness, little is known about gratitude in medical populations compared to healthy populations, or the degree to which potential deficits in gratitude might impact quality of life. The purpose of the present study was to (1) examine levels of gratitude and quality of life in fibromyalgia patients and healthy controls and (2) consider the role of gratitude in explaining quality of life differences between fibromyalgia patients and healthy controls. Participants were 173 fibromyalgia patients and 81 healthy controls. All participants completed measures of gratitude, quality of life, and socio-demographics. Although gratitude was positively associated with quality of life, levels of gratitude and quality of life were lower in the fibromyalgia sample relative to the healthy controls. This difference in gratitude partially mediated differences in quality of life between the two groups after controlling for socio-demographic variables. Our findings suggest that gratitude is a valuable positive psychological trait for quality of life in people with fibromyalgia. Interventions to improve gratitude in this patient population may also bring enhancement in quality of life.

Mechanism of nuclear factor of activated T-cells mediated FasL expression in corticosterone -treated mouse Leydig tumor cells

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Wang Qian

2008-06-01

Full Text Available Abstract Background Fas and FasL is important mediators of apoptosis. We have previously reported that the stress levels of corticosterone (CORT, glucocorticoid in rat increase expression of Fas/FasL and activate Fas/FasL signal pathway in rat Leydig cells, which consequently leads to apoptosis. Moreover, our another study showed that nuclear factor of activated T-cells (NFAT may play a potential role in up-regulation of FasL during CORT-treated rat Leydig cell. It is not clear yet how NFAT is involved in CORT-induced up-regulation of FasL. The aim of the present study is to investigate the molecular mechanisms of NFAT-mediated FasL expression in CORT-treated Leydig cells. Results Western blot analysis showed that NFAT2 expression is present in mouse Leydig tumor cell (mLTC-1. CORT-induced increase in FasL expression in mLTC-1 was ascertained by Western Blot analysis and CORT-induced increase in apoptotic frequency of mLTC-1 cells was detected by FACS with annexin-V labeling. Confocal imaging of NFAT2-GFP in mLTC-1 showed that high level of CORT stimulated NFAT translocation from the cytoplasm to the nucleus. RNA interference-mediated knockdown of NFAT2 significantly attenuated CORT-induced up-regulation of FasL expression in mLTC. These results corroborated our previous finding that NFAT2 is involved in CORT-induced FasL expression in rat Leydig cells and showed that mLTC-1 is a suitable model for investigating the mechanism of CORT-induced FasL expression. The analysis of reporter constructs revealed that the sequence between -201 and +71 of mouse FasL gene is essential for CORT-induced FasL expression. The mutation analysis demonstrated that CORT-induced FasL expression is mediated via an NFAT binding element located in the -201 to +71 region. Co-transfection studies with an NFAT2 expression vector and reporter construct containing -201 to +71 region of FasL gene showed that NFAT2 confer a strong inducible activity to the FasL promoter at its

Mechanical thrombectomy with snare in patients with acute ischemic stroke

International Nuclear Information System (INIS)

Gonzalez, Alejandro; Mayol, Antonio; Martinez, Eva; Gonzalez-Marcos, Jose R.; Gil-Peralta, Alberto

2007-01-01

We evaluated the efficacy and safety of thrombus extraction using a microsnare in patients with acute ischemic stroke (AIS). This was a prospective, observational, cohort study in which consecutive patients with AIS (<6 hours of ischemia for anterior circulation and <24 hours for posterior circulation) who had been previously excluded from intravenous tissue plasminogen activator (tPA) thrombolysis were included and followed-up for 3 months. Mechanical embolectomy with a microsnare of 2-4 mm was undertaken as the first treatment. Low-dose intraarterial thrombolysis or angioplasty was used if needed. TIMI grade and modified Rankin stroke scale (mRSS) score were used to evaluate vessel recanalization and clinical efficacy, respectively. Nine patients (mean age 55 years, range 17-69 years) were included. Their basal mean NIHSS score was 16 (range 12-24). In seven out of the nine patients (77.8%) the clot was removed, giving a TIMI grade of 3 in four patients and TIMI grade 2 in three patients. Occlusion sites were: middle cerebral artery (four), basilar artery (two) and anterior cerebral artery plus middle cerebral artery (one). The mean time for recanalization from the start of the procedure was 50 min (range 50-75 min). At 3 months, the mRSS score was 0 in two patients and 3-4 in three patients (two patients died). According to our results, the microsnare is a safe procedure for mechanical thrombectomy with a good recanalization rate. Further studies are required to determine the role of the microsnare in the treatment of AIS. (orig.)

HIV-1 adaptation studies reveal a novel Env-mediated homeostasis mechanism for evading lethal hypermutation by APOBEC3G.

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Terumasa Ikeda

2018-04-01

Full Text Available HIV-1 replication normally requires Vif-mediated neutralization of APOBEC3 antiviral enzymes. Viruses lacking Vif succumb to deamination-dependent and -independent restriction processes. Here, HIV-1 adaptation studies were leveraged to ask whether viruses with an irreparable vif deletion could develop resistance to restrictive levels of APOBEC3G. Several resistant viruses were recovered with multiple amino acid substitutions in Env, and these changes alone are sufficient to protect Vif-null viruses from APOBEC3G-dependent restriction in T cell lines. Env adaptations cause decreased fusogenicity, which results in higher levels of Gag-Pol packaging. Increased concentrations of packaged Pol in turn enable faster virus DNA replication and protection from APOBEC3G-mediated hypermutation of viral replication intermediates. Taken together, these studies reveal that a moderate decrease in one essential viral activity, namely Env-mediated fusogenicity, enables the virus to change other activities, here, Gag-Pol packaging during particle production, and thereby escape restriction by the antiviral factor APOBEC3G. We propose a new paradigm in which alterations in viral homeostasis, through compensatory small changes, constitute a general mechanism used by HIV-1 and other viral pathogens to escape innate antiviral responses and other inhibitions including antiviral drugs.

Polyamine modification by acrolein exclusively produces 1,5-diazacyclooctanes: a previously unrecognized mechanism for acrolein-mediated oxidative stress.

Science.gov (United States)

Tsutsui, Ayumi; Imamaki, Rie; Kitazume, Shinobu; Hanashima, Shinya; Yamaguchi, Yoshiki; Kaneda, Masato; Oishi, Shinya; Fujii, Nobutaka; Kurbangalieva, Almira; Taniguchi, Naoyuki; Tanaka, Katsunori

2014-07-28

Acrolein, a toxic unsaturated aldehyde generated as a result of oxidative stress, readily reacts with a variety of nucleophilic biomolecules. Polyamines, which produced acrolein in the presence of amine oxidase, were then found to react with acrolein to produce 1,5-diazacyclooctane, a previously unrecognized but significant downstream product of oxidative stress. Although diazacyclooctane formation effectively neutralized acrolein toxicity, the diazacyclooctane hydrogel produced through a sequential diazacyclooctane polymerization reaction was highly cytotoxic. This study suggests that diazacyclooctane formation is involved in the mechanism underlying acrolein-mediated oxidative stress.

Disturbed self concept mediates the relationship between childhood maltreatment and adult personality pathology.

Science.gov (United States)

Cohen, Lisa; Leibu, Olga; Tanis, Thachell; Ardalan, Firouz; Galynker, Igor

2016-07-01

Despite a robust literature documenting the relationship between childhood maltreatment and personality pathology in adulthood, there is far less clarity about the mechanism underlying this relationship. One promising candidate for such a linking mechanism is disturbance in the sense of self. This paper tests the hypothesis that disturbances in the sense of self mediate the relationship between childhood maltreatment and adult personality pathology. Specifically, we assess the self-related traits of stable self-image, self-reflective functioning, self-respect and feeling recognized. The sample included 113 non-psychotic psychiatric inpatients. Participants completed the Child Trauma Questionnaire (CTQ), the Personality Diagnostic Questionnaire-4 (PDQ-4+), and the self-reflexive functioning, stable self image, self-respect, and feeling recognized scales from the Severity Indices of Personality Problems (SIPP-118). A series of linear regressions was then performed to assess the direct and indirect effects of childhood trauma on personality disorder traits (PDQ-4+ total score), as mediated by self concept (SIPP-118 scales). Aroian tests assessed the statistical significance of each mediating effect. There was a significant mediating effect for all SIPP self concept variables, with a full mediating effect for the SIPP composite score and for SIPP feeling recognized and self-reflexive functioning, such that the direct effect of childhood trauma on personality did not retain significance after accounting for the effect of these variables. There was a partial mediating effect for SIPP stable self image and self-respect, such that the direct effect of the CTQ retained significance after accounting for these variables. SIPP feeling recognized had the strongest mediating effect. Multiple facets of self concept, particularly the degree to which an individual feels understood by other people, may mediate the relationship between childhood maltreatment and adult personality

Computational Analysis of Pharyngeal Swallowing Mechanics in Patients with Motor Neuron Disease: A Pilot Investigation.

Science.gov (United States)

Garand, K L; Schwertner, Ryan; Chen, Amy; Pearson, William G

2018-04-01

Swallowing impairment (dysphagia) is a common sequela in patients with motor neuron disease (MND). The purpose of this retrospective, observational pilot investigation was to characterize how pharyngeal swallowing mechanics are impacted in patients with MND using a comparison with healthy, non-dysphagic control group. Computational analysis of swallowing mechanics (CASM) was used to determine covariate biomechanics of pharyngeal swallowing from videofluoroscopic assessment in 15 patients with MND and 15 age- and sex-matched healthy controls. Canonical variant analysis with post hoc discriminate function analysis (DFA) was performed on coordinate data mapping functional muscle groups underlying pharyngeal swallowing. Differences in swallowing mechanics associated with group (MND; control), motor neuron predominance (upper; lower), onset (bulbar; spinal), and swallow task (thin, pudding) were evaluated and visualized. Pharyngeal swallowing mechanics differed significantly in patients with MND compared with healthy controls (D = 2.01, p mechanics by motor neuron predominance (D = 5.03, p mechanics of patients with MND differ from and are more heterogeneous than healthy controls. These findings suggest patients with MND may compensate reductions in pharyngeal shortening and tongue base retraction by extending the head and neck and increasing hyolaryngeal excursion. This work and further CASM investigations will lead to further insights into development and evaluation of targeted clinical treatments designed to prolong safe and efficient swallowing function in patients with MND.

Erythrocyte Saturation with IgG Is Required for Inducing Antibody-Mediated Immune Suppression and Impacts Both Erythrocyte Clearance and Antigen-Modulation Mechanisms.

Science.gov (United States)

Cruz-Leal, Yoelys; Marjoram, Danielle; Lazarus, Alan H

2018-02-15

Anti-D prevents hemolytic disease of the fetus and newborn, and this mechanism has been referred to as Ab-mediated immune suppression (AMIS). Anti-D, as well as other polyclonal AMIS-inducing Abs, most often induce both epitope masking and erythrocyte clearance mechanisms. We have previously observed that some Abs that successfully induce AMIS effects could be split into those that mediate epitope masking versus those that induce erythrocyte clearance, allowing the ability to analyze these mechanisms separately. In addition, AMIS-inducing activity has recently been shown to induce Ag modulation (Ag loss from the erythrocyte surface). To assess these mechanisms, we immunized mice with transgenic murine RBCs expressing a single Ag protein comprising a recombinant Ag composed of hen egg lysozyme, OVA sequences comprising aa 251-349, and the human Duffy transmembrane protein (HOD-Ag) with serial doses of polyclonal anti-OVA IgG as the AMIS-inducing Ab. The anti-OVA Ab induced AMIS in the absence of apparent epitope masking. AMIS occurred only when the erythrocytes appeared saturated with IgG. This Ab was capable of inducing HOD-RBC clearance, as well as loss of the OVA epitope at doses of Ab that caused AMIS effects. HOD-RBCs also lost reactivity with Abs specific for the hen egg lysozyme and Duffy portions of the Ag consistent with the initiation of Ag modulation and/or trogocytosis mechanisms. These data support the concept that an AMIS-inducing Ab that does not cause epitope masking can induce AMIS effects in a manner consistent with RBC clearance and/or Ag modulation. Copyright © 2018 by The American Association of Immunologists, Inc.

Mediator-dependent Nuclear Receptor Functions

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Chen, Wei; Roeder, Robert

2011-01-01

As gene-specific transcription factors, nuclear hormone receptors are broadly involved in many important biological processes. Their function on target genes requires the stepwise assembly of different coactivator complexes that facilitate chromatin remodeling and subsequent preinitiation complex (PIC) formation and function. Mediator has proved to be a crucial, and general, nuclear receptor-interacting coactivator, with demonstrated functions in transcription steps ranging from chromatin remodeling to subsequent PIC formation and function. Here we discuss (i) our current understanding of pathways that nuclear receptors and other interacting cofactors employ to recruit Mediator to target gene enhancers and promoters, including conditional requirements for the strong NR-Mediator interactions mediated by the NR AF2 domain and the MED1 LXXLLL motifs and (ii) mechanisms by which Mediator acts to transmit signals from enhancer-bound nuclear receptors to the general transcription machinery at core promoters to effect PIC formation and function. PMID:21854863

Mediation and Moderation: Testing Relationships between Symptom Status, Functional Health, and Quality of Life in HIV Patients

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Ryu, Ehri; West, Stephen G.; Sousa, Karen H.

2009-01-01

We extended Wilson and Cleary's (1995) health-related quality of life model to examine the relationships among symptom status (Symptoms), functional health (Disability), and quality of life (QOL). Using a community sample (N = 956) of male HIV positive patients, we tested a mediation model in which the relationship between Symptoms and QOL is…

Cardiac Rotational Mechanics As a Predictor of Myocardial Recovery in Heart Failure Patients Undergoing Chronic Mechanical Circulatory Support: A Pilot Study.

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Bonios, Michael J; Koliopoulou, Antigone; Wever-Pinzon, Omar; Taleb, Iosif; Stehlik, Josef; Xu, Weining; Wever-Pinzon, James; Catino, Anna; Kfoury, Abdallah G; Horne, Benjamin D; Nativi-Nicolau, Jose; Adamopoulos, Stamatis N; Fang, James C; Selzman, Craig H; Bax, Jeroen J; Drakos, Stavros G

2018-04-01

Impaired qualitative and quantitative left ventricular (LV) rotational mechanics predict cardiac remodeling progression and prognosis after myocardial infarction. We investigated whether cardiac rotational mechanics can predict cardiac recovery in chronic advanced cardiomyopathy patients. Sixty-three patients with advanced and chronic dilated cardiomyopathy undergoing implantation of LV assist device (LVAD) were prospectively investigated using speckle tracking echocardiography. Acute heart failure patients were prospectively excluded. We evaluated LV rotational mechanics (apical and basal LV twist, LV torsion) and deformational mechanics (circumferential and longitudinal strain) before LVAD implantation. Cardiac recovery post-LVAD implantation was defined as (1) final resulting LV ejection fraction ≥40%, (2) relative LV ejection fraction increase ≥50%, (iii) relative LV end-systolic volume decrease ≥50% (all 3 required). Twelve patients fulfilled the criteria for cardiac recovery (Rec Group). The Rec Group had significantly less impaired pre-LVAD peak LV torsion compared with the Non-Rec Group. Notably, both groups had similarly reduced pre-LVAD LV ejection fraction. By receiver operating characteristic curve analysis, pre-LVAD peak LV torsion of 0.35 degrees/cm had a 92% sensitivity and a 73% specificity in predicting cardiac recovery. Peak LV torsion before LVAD implantation was found to be an independent predictor of cardiac recovery after LVAD implantation (odds ratio, 0.65 per 0.1 degrees/cm [0.49-0.87]; P =0.014). LV rotational mechanics seem to be useful in selecting patients prone to cardiac recovery after mechanical unloading induced by LVADs. Future studies should investigate the utility of these markers in predicting durable cardiac recovery after the explantation of the cardiac assist device. © 2018 American Heart Association, Inc.

Intrinsic religiousness and well-being among cancer patients: the mediating role of control-related religious coping and self-efficacy for coping with cancer.

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Pérez, John E; Rex Smith, Amy

2015-04-01

We examined the relationship between intrinsic religiousness and well-being, with control-related religious coping and self-efficacy for coping with cancer as potential mediators of this relationship among cancer patients. In a cross-sectional design, 179 ambulatory cancer patients completed measures of intrinsic religiousness, religious coping, self-efficacy for coping with cancer, well-being, and demographic variables. Type of cancer, stage of cancer, and time since diagnosis were collected from electronic medical charts. In a path model, the positive association between intrinsic religiousness and three types of well-being--physical, functional, and social-was fully mediated by active religious surrender and self-efficacy for coping with cancer. In addition, the negative association between passive religious deferral and all four types of well-being--physical, functional, social, and emotional--was fully mediated by self-efficacy for coping with cancer. Finally, there was a negative direct association between pleading for God's direct intercession and emotional well-being. These findings suggest pathways by which intrinsic religiousness and control-related religious coping are linked to various dimensions of well-being among cancer patients.

Mediating effects of burden on quality of life for caregivers of first-time stroke patients discharged from the hospital within one year.

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Tsai, Yu-Hsia; Lou, Meei-Fang; Feng, Tsui-Hsia; Chu, Tsung-Lan; Chen, Ying-Jen; Liu, Hsueh-Erh

2018-04-25

Caregiver burden may be either a predictor or an outcome of caregiver quality of life (QoL). Patient or caregiver factors that directly affect caregiver QoL, predictors that are simultaneously shared with caregiver burden and QoL, and factors that affect caregiver QoL through caregiver burden are not well understood. This study explored predictors of caregiver QoL and identified whether caregiver burden is a mediator for caregivers of first-time stroke patients. This is a cross-sectional study. We recruited first-time stroke patients who had been discharged from the hospital within 1 year. We screened caregivers with two major inclusion criteria: age > 20 years old and being the family member who provides the most patient-care hours out of all family caregivers. Caregiver burden (Caregiver Strain Index, CSI), QoL (Caregiver Quality of Life Index, CQLI), and patient and caregiver characteristics were assessed with structured questionnaires. Multiple-regression and bootstrap analysis were conducted for data analysis. A total of 126 caregivers completed the questionnaires. Higher caregiver burdens, lower caregiver education level, lower self-rated health, lower monthly family income, and spouses who were responsible for medical fees were significant predictors of lower caregiver QoL. Poor self-rated health and monthly family income of $ 666 USD or below were the strongest predictors of caregiver QoL. Spouses who were responsible for medical fees and lower monthly family income had direct negative effects on caregiver QoL, but these factors exhibited no indirect mediating effect between caregiver characteristics and QoL through caregiver burden as a mediator. Caregiver education level at or below elementary school and poor or fair self-rated-health had direct negative effects on caregiver QoL, which were mediated by caregiver burden. Our study indicated predictors of caregiver QoL and the relationships with caregiver burden among first-time stroke survivors in the

HTLV-1 Tax protects against CD95-mediated apoptosis by induction of the cellular FLICE-inhibitory protein (c-FLIP).

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Krueger, Andreas; Fas, Stefanie C; Giaisi, Marco; Bleumink, Marc; Merling, Anette; Stumpf, Christine; Baumann, Sven; Holtkotte, Denise; Bosch, Valerie; Krammer, Peter H; Li-Weber, Min

2006-05-15

The HTLV-1 transactivator protein Tax is essential for malignant transformation of CD4 T cells, ultimately leading to adult T-cell leukemia/lymphoma (ATL). Malignant transformation may involve development of apoptosis resistance. In this study we investigated the molecular mechanisms by which HTLV-1 Tax confers resistance toward CD95-mediated apoptosis. We show that Tax-expressing T-cell lines derived from HTLV-1-infected patients express elevated levels of c-FLIP(L) and c-FLIP(S). The levels of c-FLIP correlated with resistance toward CD95-mediated apoptosis. Using an inducible system we demonstrated that both resistance toward CD95-mediated apoptosis and induction of c-FLIP are dependent on Tax. In addition, analysis of early cleavage of the BH3-only Bcl-2 family member Bid, a direct caspase-8 substrate, revealed that apoptosis is inhibited at a CD95 death receptor proximal level in Tax-expressing cells. Finally, using siRNA we directly showed that c-FLIP confers Tax-mediated resistance toward CD95-mediated apoptosis. In conclusion, our data suggest an important mechanism by which expression of HTLV-1 Tax may lead to immune escape of infected T cells and, thus, to persistent infection and transformation.

Mechanical Thrombectomy in Patients With Acute Ischemic Stroke: A Health Technology Assessment

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2016-01-01

Background In Ontario, current treatment for eligible patients who have an acute ischemic stroke is intravenous thrombolysis (IVT). However, there are some limitations and contraindications to IVT, and outcomes may not be favourable for patients with stroke caused by a proximal intracranial occlusion. An alternative is mechanical thrombectomy with newer devices, and a number of recent studies have suggested that this treatment is more effective for improving functional independence and clinical outcomes. The objective of this health technology assessment was to evaluate the clinical effectiveness and cost-effectiveness of new-generation mechanical thrombectomy devices (with or without IVT) compared to IVT alone (if eligible) in patients with acute ischemic stroke. Methods We conducted a systematic review of the literature, limited to randomized controlled trials that examined the effectiveness of mechanical thrombectomy using stent retrievers and thromboaspiration devices for patients with acute ischemic stroke. We assessed the quality of the evidence using the GRADE approach. We developed a Markov decision-analytic model to assess the cost-effectiveness of mechanical thrombectomy (with or without IVT) versus IVT alone (if eligible), calculated incremental cost-effectiveness ratios using a 5-year time horizon, and conducted sensitivity analyses to examine the robustness of the estimates. Results There was a substantial, statistically significant difference in rate of functional independence (GRADE: high quality) between those who received mechanical thrombectomy (with or without IVT) and IVT alone (odds ratio [OR] 2.39, 95% confidence interval [CI] 1.88–3.04). We did not observe a difference in mortality (GRADE: moderate quality) (OR 0.80, 95% CI 0.60–1.07) or symptomatic intracerebral hemorrhage (GRADE: moderate quality) (OR 1.11, 95% CI 0.66–1.87). In the base-case cost-utility analysis, which had a 5 year time horizon, the costs and effectiveness for

Induction of osteogenic differentiation of adipose derived stem cells by microstructured nitinol actuator-mediated mechanical stress.

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Sarah Strauß

Full Text Available The development of large tissue engineered bone remains a challenge in vitro, therefore the use of hybrid-implants might offer a bridge between tissue engineering and dense metal or ceramic implants. Especially the combination of the pseudoelastic implant material Nitinol (NiTi with adipose derived stem cells (ASCs opens new opportunities, as ASCs are able to differentiate osteogenically and therefore enhance osseointegration of implants. Due to limited knowledge about the effects of NiTi-structures manufactured by selective laser melting (SLM on ASCs the study started with an evaluation of cytocompatibility followed by the investigation of the use of SLM-generated 3-dimensional NiTi-structures preseeded with ASCs as osteoimplant model. In this study we could demonstrate for the first time that osteogenic differentiation of ASCs can be induced by implant-mediated mechanical stimulation without support of osteogenic cell culture media. By use of an innovative implant design and synthesis via SLM-technique we achieved high rates of vital cells, proper osteogenic differentiation and mechanically loadable NiTi-scaffolds could be achieved.

Change mechanisms of schema-centered group psychotherapy with personality disorder patients.

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Wolfgang Tschacher

Full Text Available BACKGROUND: This study addressed the temporal properties of personality disorders and their treatment by schema-centered group psychotherapy. It investigated the change mechanisms of psychotherapy using a novel method by which psychotherapy can be modeled explicitly in the temporal domain. METHODOLOGY AND FINDINGS: 69 patients were assigned to a specific schema-centered behavioral group psychotherapy, 26 to social skills training as a control condition. The largest diagnostic subgroups were narcissistic and borderline personality disorder. Both treatments offered 30 group sessions of 100 min duration each, at a frequency of two sessions per week. Therapy process was described by components resulting from principal component analysis of patients' session-reports that were obtained after each session. These patient-assessed components were Clarification, Bond, Rejection, and Emotional Activation. The statistical approach focused on time-lagged associations of components using time-series panel analysis. This method provided a detailed quantitative representation of therapy process. It was found that Clarification played a core role in schema-centered psychotherapy, reducing rejection and regulating the emotion of patients. This was also a change mechanism linked to therapy outcome. CONCLUSIONS/SIGNIFICANCE: The introduced process-oriented methodology allowed to highlight the mechanisms by which psychotherapeutic treatment became effective. Additionally, process models depicted the actual patterns that differentiated specific diagnostic subgroups. Time-series analysis explores Granger causality, a non-experimental approximation of causality based on temporal sequences. This methodology, resting upon naturalistic data, can explicate mechanisms of action in psychotherapy research and illustrate the temporal patterns underlying personality disorders.

Patients' experiences of being mechanically ventilated in an ICU

DEFF Research Database (Denmark)

Baumgarten, Mette; Poulsen, Ingrid

2015-01-01

and synthesise interpreted knowledge from qualitative studies about Patients' experiences of being mechanically ventilated in an ICU. METHOD: A qualitative metasynthesis was conducted on findings from nine qualitative studies performed in the period from 1994 to 2012. The studies were critically appraised...

The distressed (Type D) personality mediates the relationship between remembered parenting and psychological distress in cardiac patients

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Damen, Nikki L; Versteeg, Henneke; van Helmondt, Sanne J

2013-01-01

Objective: Both the distressed (Type D) personality (i.e. the combination of negative affectivity and social inhibition traits) and dysfunctional parenting styles are associated with anxiety and depression. As parenting styles have been related to personality development, dysfunctional parenting...... styles may also be associated with Type D personality. We examined whether remembered parenting was associated with anxiety and depression in cardiac patients and whether Type D personality mediated this relationship. Methods: Our sample comprised 435 patients treated with percutaneous coronary...... intervention (PCI) and 123 patients with congestive heart failure (CHF). Patients completed the Hospital Anxiety and Depression Scale, Type D Scale (DS14), and Remembered Relationship with Parents (RRP(10)) scale. Results: Remembered parenting was significantly associated with higher anxiety and depression...

Prediction of Risk Behaviors in HIV-infected Patients Based on Family Functioning: The Mediating Roles of Lifestyle and Risky Decision Making

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Fariba Ebrahim Babaei

2017-09-01

Full Text Available Background and Objective: Risk behaviors are more common in the HIV-positive patients than that in the general population. These behaviors are affected by various factors, such as biological, familial, and social determinants, peer group, media, and lifestyle. Low family functioning is one of the important factors predicting risk behaviors. Regarding this, the present study aimed to investigate the role of family functioning in predicting risk behaviors in the HIV-infected patients based on the mediating roles of risky decision making and lifestyle. Materials and Methods: This descriptive correlational study was conducted on 147 HIV-positive patients selected through convenience sampling technique. The data were collected using the health promoting lifestyle profile-2 (HPLP-2, family adaptability and cohesion scale IV (FACES-IV, balloon analogue risk task (BART, and risk behavior assessment in social situation. The data were analyzed using structural equation modeling method in LISREL 8.8 software. Results: According to the results, there was an indirect relationship between family functioning and risk behaviors. Furthermore, family functioning both directly and indirectly affected the risk behaviors through two mediators of lifestyle and risky decision making. Conclusion: As the findings indicated, family functioning directly contributed to risk behaviors. Moreover, this variable indirectly affected risk behaviors through the mediating roles of risky decision making and lifestyle. Consequently, the future studies should focus more deeply on family functioning role in the risk behaviors of the HIV-infected patients.

Animal Assisted Interactions to Alleviate Psychological Symptoms in Patients on Mechanical Ventilation.

Science.gov (United States)

Hetland, Breanna; Bailey, Tanya; Prince-Paul, Maryjo

2017-12-01

Mechanical ventilation is a common life support intervention for critically ill patients that can cause stressful psychological symptoms. Animal assisted interactions have been used in variety of inpatient settings to reduce symptom burden and promote overall well-being. Due to the severity of illness associated with critical care, use of highly technological equipment, and heightened concern for infection control and patient safety, animal-assisted interaction has not been widely adopted in the intensive care unit. This case study of the therapeutic interaction between a canine and a mechanically ventilated patient provides support for the promotion of animal-assisted interactions as an innovative symptom management strategy in the intensive care unit.

Mechanisms for the antihyperglycemic effect of sitagliptin in patients with type 2 diabetes

DEFF Research Database (Denmark)

Muscelli, Elza; Casolaro, Arturo; Gastaldelli, Amalia

2012-01-01

Dipeptidyl peptidase IV (DPP-4) inhibitors improve glycemic control in patients with type 2 diabetes. The underlying mechanisms (incretin effect, β-cell function, endogenous glucose production) are not well known.......Dipeptidyl peptidase IV (DPP-4) inhibitors improve glycemic control in patients with type 2 diabetes. The underlying mechanisms (incretin effect, β-cell function, endogenous glucose production) are not well known....

Effects of staff training on the care of mechanically ventilated patients: a prospective cohort study.

Science.gov (United States)

Bloos, F; Müller, S; Harz, A; Gugel, M; Geil, D; Egerland, K; Reinhart, K; Marx, G

2009-08-01

Adherence to guidelines to avoid complications associated with mechanical ventilation is often incomplete. The goal of this study was to assess whether staff training in pre-defined interventions (bundle) improves the quality of care in mechanically ventilated patients. This study was performed on a 50-bed intensive care unit of a tertiary care university hospital. Application of a ventilator bundle consisting of semirecumbent positioning, lung protective ventilation in patients with acute lung injury (ALI), ulcer prophylaxis, and deep vein thrombosis prophylaxis (DVTP) was assessed before and after staff training in post-surgical patients requiring mechanical ventilation for at least 24 h. A total of 133 patients before and 141 patients after staff training were included. Overall bundle adherence increased from 15 to 33.8% (Pposition was achieved in 24.9% of patient days before and 46.9% of patient days after staff training (P90% was achieved in both groups. Median tidal volume in patients with ALI remained unaltered. Days on mechanical ventilation were reduced from 6 (interquartile range 2.0-15.0) to 4 (2.0-9.0) (P=0.017). Rate of ventilator-associated pneumonia (VAP), ICU length of stay, and ICU mortality remained unaffected. In patients with VAP, the median ICU length of stay was reduced by 9 days (P=0.04). Staff training by an ICU change team improved compliance to a pre-defined ventilator bundle. This led to a reduction in the days spent on mechanical ventilation, despite incomplete bundle implementation.

Bed Microenvironment in Hospital Patient Rooms with Natural or Mechanical Ventilation

DEFF Research Database (Denmark)

Melikov, Arsen Krikor; Li, Yuguo; Georgiev, Emanuil

2012-01-01

We studied how to provide patients in bed with thermally comfortable microenvironment in both naturally and mechanically ventilated hospital rooms for both winter and summer seasons. A climate chamber was used to resemble a hospital room and thermal manikin to simulate a patient lying in a bed...

Interplay between cooperation-enhancing mechanisms in evolutionary games with tag-mediated interactions

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Hadzibeganovic, Tarik; Stauffer, Dietrich; Han, Xiao-Pu

2018-04-01

Cooperation is fundamental for the long-term survival of biological, social, and technological networks. Previously, mechanisms for the enhancement of cooperation, such as network reciprocity, have largely been studied in isolation and with often inconclusive findings. Here, we present an evolutionary, multiagent-based, and spatially explicit computer model to specifically address the interactive interplay between such mechanisms. We systematically investigate the effects of phenotypic diversity, network structure, and rewards on cooperative behavior emerging in a population of reproducing artificial decision makers playing tag-mediated evolutionary games. Cooperative interactions are rewarded such that both the benefits of recipients and costs of donators are affected by the reward size. The reward size is determined by the number of cooperative acts occurring within a given reward time frame. Our computational experiments reveal that small reward frames promote unconditional cooperation in populations with both low and high diversity, whereas large reward frames lead to cycles of conditional and unconditional strategies at high but not at low diversity. Moreover, an interaction between rewards and spatial structure shows that relative to small reward frames, there is a strong difference between the frequency of conditional cooperators populating rewired versus non-rewired networks when the reward frame is large. Notably, in a less diverse population, the total number of defections is comparable across different network topologies, whereas in more diverse environments defections become more frequent in a regularly structured than in a rewired, small-world network of contacts. Acknowledging the importance of such interaction effects in social dilemmas will have inevitable consequences for the future design of cooperation-enhancing protocols in large-scale, distributed, and decentralized systems such as peer-to-peer networks.

Paradigms and mechanisms of inhalational anesthetics mediated neuroprotection against cerebral ischemic stroke

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Hailian Wang

2016-01-01

Full Text Available Cerebral ischemic stroke is a leading cause of serious long-term disability and cognitive dysfunction. The high mortality and disability of cerebral ischemic stroke is urging the health providers, including anesthesiologists and other perioperative professioners, to seek effective protective strategies, which are extremely limited, especially for those perioperative patients. Intriguingly, several commonly used inhalational anesthetics are recently suggested to possess neuroprotective effects against cerebral ischemia. This review introduces multiple paradigms of inhalational anesthetic treatments that have been investigated in the setting of cerebral ischemia, such as preconditioning, proconditioning and postconditioning with a variety of inhalational anesthetics. The pleiotropic mechanisms underlying these inhalational anesthetics-afforded neuroprotection against stroke are also discussed in detail, including the common pathways shared by most of the inhalational anesthetic paradigms, such as anti-excitotoxicity, anti-apoptosis and anti-inflammation. There are also distinct mechanisms involved in specific paradigms, such as preserving blood brain barrier integrity, regulating cerebral blood flow and catecholamine release. The ready availability of these inhalational anesthetics bedside and renders them a potentially translatable stroke therapy attracting great efforts for understanding of the underlying mechanisms.

Fcγ receptor-mediated inflammation inhibits axon regeneration.

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Gang Zhang

Full Text Available Anti-glycan/ganglioside antibodies are the most common immune effectors found in patients with Guillain-Barré Syndrome, which is a peripheral autoimmune neuropathy. We previously reported that disease-relevant anti-glycan autoantibodies inhibited axon regeneration, which echo the clinical association of these antibodies and poor recovery in Guillain-Barré Syndrome. However, the specific molecular and cellular elements involved in this antibody-mediated inhibition of axon regeneration are not previously defined. This study examined the role of Fcγ receptors and macrophages in the antibody-mediated inhibition of axon regeneration. A well characterized antibody passive transfer sciatic nerve crush and transplant models were used to study the anti-ganglioside antibody-mediated inhibition of axon regeneration in wild type and various mutant and transgenic mice with altered expression of specific Fcγ receptors and macrophage/microglia populations. Outcome measures included behavior, electrophysiology, morphometry, immunocytochemistry, quantitative real-time PCR, and western blotting. We demonstrate that the presence of autoantibodies, directed against neuronal/axonal cell surface gangliosides, in the injured mammalian peripheral nerves switch the proregenerative inflammatory environment to growth inhibitory milieu by engaging specific activating Fcγ receptors on recruited monocyte-derived macrophages to cause severe inhibition of axon regeneration. Our data demonstrate that the antibody orchestrated Fcγ receptor-mediated switch in inflammation is one mechanism underlying inhibition of axon regeneration. These findings have clinical implications for nerve repair and recovery in antibody-mediated immune neuropathies. Our results add to the complexity of axon regeneration in injured peripheral and central nervous systems as adverse effects of B cells and autoantibodies on neural injury and repair are increasingly recognized.

Natural evolution of skin-test sensitivity in patients with IgE-mediated hypersensitivity to cephalosporins.

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Romano, A; Gaeta, F; Valluzzi, R L; Zaffiro, A; Caruso, C; Quaratino, D

2014-06-01

There are studies demonstrating that skin-test sensitivity to penicillins can decrease over time and that allergic patients may lose sensitivity if the responsible compounds are avoided. With regard to subjects with IgE-mediated hypersensitivity to cephalosporins, however, such studies are lacking. We evaluated prospectively in a 5-year follow-up 72 cephalosporin-allergic patients. After the first evaluation, patients were classified into two groups according to their patterns of allergologic-test positivity: to both penicillins and cephalosporins (group A), or only to cephalosporins (group B). Skin tests and serum-specific IgE assays were repeated 1 year later and, in case of persistent positivity, 3 and 5 years after the first allergologic examination. Seven (43.7%) of the 16 subjects of group A and 38 (67.8%) of the 56 patients of group B became negative; one was lost to follow-up. Patients of group B became negative sooner and more frequently than group A subjects. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Locus of control, quality of life, anxiety, and depression among Malaysian breast cancer patients: The mediating role of uncertainty.

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Pahlevan Sharif, Saeed

2017-04-01

The main objective of this study was to investigate the mediating role of uncertainty in the relationship between locus of control with quality of life, anxiety, and depression. A descriptive and correlational survey was conducted in a private hospital in Kuala Lumpur, Malaysia. A convenience sample of 118 Malaysian breast cancer patients voluntarily participated in the study and responded to a set of questionnaires including: socio-demographic questionnaire, the short form of Locus of Control Scale, the Functional Assessment of Cancer Therapy-Breast (FACT-B), the Hospital Anxiety and Depression Scale (HADS), and the Short-Form Mishel Uncertainty in Illness Scale (SF-MUIS). The results revealed that breast cancer patients with higher internal locus of control and lower external locus of control experience a higher quality of life, lower anxiety, and lower depression. Also, uncertainty mediated the relationship between locus of control with quality of life and depression (quasi-significant). The findings indicated the need for early, targeted psychological interventions seeking to gradually shift cancer patients' locus of control from external to internal in order to improve their quality of life and reduce their depression and anxiety. Moreover, health care providers by providing relevant information to cancer patients, especially for externally oriented patients, can reduce their uncertainty which in turn would improve their quality of life. Copyright © 2017 Elsevier Ltd. All rights reserved.

Exploring mechanisms of change in cognitive therapy and interpersonal psychotherapy for adult depression.

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Lemmens, Lotte H J M; Galindo-Garre, Francisca; Arntz, Arnoud; Peeters, Frenk; Hollon, Steven D; DeRubeis, Robert J; Huibers, Marcus J H

2017-07-01

The present study explored the temporal relationships between change in five candidate causal mechanisms and change in depressive symptoms in a randomized comparison of individual Cognitive Therapy (CT) and Interpersonal Psychotherapy (IPT) for adult depression. Furthermore, hypotheses concerning the mediation of change in these treatments were tested. Patients were 151 depressed adult outpatients treated with either CT (n = 76) or IPT (n = 75). Depression severity was assessed with the BDI-II. Candidate mediators included both therapy-specific as well as common factors. Measures were taken multiple times over the course of treatment (baseline, mid-, and post-treatment). Pearson's correlations and Latent-Difference-Score models were used to examine the direct and indirect relationships between (change in) the candidate mediators and (subsequent) (change in) depression. Patients showed improvement on all measures. No differential effects in pre- to post-treatment changes were observed between the two conditions. However, change in interpersonal functioning occurred more rapidly in IPT. Only little empirical support for the respective theoretical models of change in CT and IPT was found. Future studies should pay special attention to the timing of assessments and within-patient variance. Copyright © 2017 Elsevier Ltd. All rights reserved.

Polyarene mediators for mediated redox flow battery

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Delnick, Frank M.; Ingersoll, David; Liang, Chengdu

2018-01-02

The fundamental charge storage mechanisms in a number of currently studied high energy redox couples are based on intercalation, conversion, or displacement reactions. With exception to certain metal-air chemistries, most often the active redox materials are stored physically in the electrochemical cell stack thereby lowering the practical gravimetric and volumetric energy density as a tradeoff to achieve reasonable power density. In a general embodiment, a mediated redox flow battery includes a series of secondary organic molecules that form highly reduced anionic radicals as reaction mediator pairs for the reduction and oxidation of primary high capacity redox species ex situ from the electrochemical cell stack. Arenes are reduced to stable anionic radicals that in turn reduce a primary anode to the charged state. The primary anode is then discharged using a second lower potential (more positive) arene. Compatible separators and solvents are also disclosed herein.

Best (but oft-forgotten) practices: mediation analysis.

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Fairchild, Amanda J; McDaniel, Heather L

2017-06-01

This contribution in the "Best (but Oft-Forgotten) Practices" series considers mediation analysis. A mediator (sometimes referred to as an intermediate variable, surrogate endpoint, or intermediate endpoint) is a third variable that explains how or why ≥2 other variables relate in a putative causal pathway. The current article discusses mediation analysis with the ultimate intention of helping nutrition researchers to clarify the rationale for examining mediation, avoid common pitfalls when using the model, and conduct well-informed analyses that can contribute to improving causal inference in evaluations of underlying mechanisms of effects on nutrition-related behavioral and health outcomes. We give specific attention to underevaluated limitations inherent in common approaches to mediation. In addition, we discuss how to conduct a power analysis for mediation models and offer an applied example to demonstrate mediation analysis. Finally, we provide an example write-up of mediation analysis results as a model for applied researchers. © 2017 American Society for Nutrition.

Influence of operation and irradiation on cell-mediated immunity in patients with oral cancer

International Nuclear Information System (INIS)

Tominaga, Kazuhiro; Tominaga, Naohiro; Tokuhisa, Michio

1995-01-01

To evaluate the influence of operation and irradiation on cell-mediated immunity in patients with primary oral squamous cell carcinoma, several parameters, including NK activity, LAK activity, and IL-2 production, were selected. Twenty-two patients who underwent operation and/or irradiation from 1989 to 1993 were evaluated. Perioperatively, no significant change of immunologic parameters was observed except increased number of peripheral leukocytes at two weeks after operation. Immediately and/or one month after irradiation, significantly decreased numbers of leukocytes and lymphocytes as well as significantly depressed levels of blastoid transformation of lymphocytes, LAK activity, and IL-2 production were observed. By three months after irradiation, values of immunologic parameters returned to preirradiation values. The number of monocytes and level of NK activity showed little change after irradiation. (author)

Nosocomial Pneumonia in Mechanically Ventilated Patients Receiving Ranitidine or Sucralfate as Stress Ulcer Prophylaxis

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Smita Prakash

2008-01-01

We concluded that stress ulcer prophylaxis with ranitidine increases the risk for late- onset pneumonia in mechanically ventilated critically ill patients by favoring gastric colonization by gram- negative bacilli compared with sucralfate. In patients receiving mechanical ventilation, the use of sucralfate may be preferable to H 2 blockers.

Partial protoporphyrinogen oxidase (PPOX gene deletions, due to different Alu-mediated mechanisms, identified by MLPA analysis in patients with variegate porphyria

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Barbaro Michela

2013-01-01

Full Text Available Abstract Variegate porphyria (VP is an autosomal dominantly inherited hepatic porphyria. The genetic defect in the PPOX gene leads to a partial defect of protoporphyrinogen oxidase, the penultimate enzyme of heme biosynthesis. Affected individuals can develop cutaneous symptoms in sun-exposed areas of the skin and/or neuropsychiatric acute attacks. The identification of the genetic defect in VP families is of crucial importance to detect the carrier status which allows counseling to prevent potentially life threatening neurovisceral attacks, usually triggered by factors such as certain drugs, alcohol or fasting. In a total of 31 Swedish VP families sequence analysis had identified a genetic defect in 26. In the remaining five families an extended genetic investigation was necessary. After the development of a synthetic probe set, MLPA analysis to screen for single exon deletions/duplications was performed. We describe here, for the first time, two partial deletions within the PPOX gene detected by MLPA analysis. One deletion affects exon 5 and 6 (c.339-197_616+320del1099 and has been identified in four families, most probably after a founder effect. The other extends from exon 5 to exon 9 (c.339-350_987+229del2609 and was found in one family. We show that both deletions are mediated by Alu repeats. Our findings emphasize the usefulness of MLPA analysis as a complement to PPOX gene sequencing analysis for comprehensive genetic diagnostics in patients with VP.

Flow-Mediated Dilatation and Asymmetric Dimethylarginine Do Not Predict Mortality in Peritoneal Dialysis Patients

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Sami Uzun

2017-09-01

Full Text Available Aim: Asymmetric dimethylarginine (ADMA is associated with increased coronary artery disease risk through endothelial dysfunction in dialysis patients. We aimed to investigate the role of flow-mediated dilatation (FMD, a non-invasive indicator of endothelial function, and ADMA in mortality in peritoneal dialysis (PD patients. Methods: PD patients aged 18-80 years; with dialysis duration of at least three months were included. FMD measurement and ADMA levels were recorded. Outcome of the patients on the third year were analyzed with binary logistic analyses. Results: The mean age of the 55 patients was 53±15 years and the mean follow-up duration was 36 months. Mean FMD and ADMA levels were 10.6±6.4% and 81.8±48.0 mol/L, respectively. Eighteen patients died during follow-up. Age, presence of diabetes mellitus and ischemic heart disease, ultrafiltration amount and serum albumin level were related with mortality while gender, weekly Kt/V and ADMA levels were not. There was no significant relationship between ADMA level and FMD (p=0.873. FMD was negatively correlated with systolic and diastolic blood pressures (p=0.001, p<0.001, respectively. Hypertension was found to be the most important single factor determining FMD (p=0.037. Conclusion: Estimating endothelial function by FMD or measuring serum ADMA levels may not be useful for predicting mortality in PD patients.

Relationship between Humor and Subjective Well-Being with regard to Mediating Role of Resilience in Caregivers of Patients with Spinal Injury

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M. Abbasi

2017-04-01

Full Text Available Aims: Family members are the main components of the care system for injured spinal cord patients. Taking care of such patients is a tense responsibility. The purpose of this study was to investigate the relationship between humor and subjective well-being with regard to the mediating role of resilience in caregivers of patients with spinal cord injury. Instruments & Methods: In this descriptive-correlational study, 219 caregivers of spinal cord injured patients referred to Borna Scientific-Sport Institute in Isfahan in 2016 were selected using available sampling. Data were collected using Subjective Well-Being Scale (SWBS, Resilience Scale and Sense of Humor Questionnaire (SHQ. Data analysis was performed by Amos 18 software, using Structural Equation Modeling (SEM and Bootstrap test. Finding: Correlation between humor and resilience with subjective well-being was significant (p<0.001. The proposed model was good-fitting model (p<0.05. There was also a significant indirect relationship between humor and subjective well-being through resilience (β=0.22; p<0.006. Conclusion: Psychological resilience in relationship between humor and subjective well-being as mediator plays an important role in improving the psychological state of caregivers of patients with spinal cord injury.

Mechanical Energy Recovery during Walking in Patients with Parkinson Disease.

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Mariangela Dipaola

Full Text Available The mechanisms of mechanical energy recovery during gait have been thoroughly investigated in healthy subjects, but never described in patients with Parkinson disease (PD. The aim of this study was to investigate whether such mechanisms are preserved in PD patients despite an altered pattern of locomotion. We consecutively enrolled 23 PD patients (mean age 64±9 years with bilateral symptoms (H&Y ≥II if able to walk unassisted in medication-off condition (overnight suspension of all dopaminergic drugs. Ten healthy subjects (mean age 62±3 years walked both at their 'preferred' and 'slow' speeds, to match the whole range of PD velocities. Kinematic data were recorded by means of an optoelectronic motion analyzer. For each stride we computed spatio-temporal parameters, time-course and range of motion (ROM of hip, knee and ankle joint angles. We also measured kinetic (Wk, potential (Wp, total (WtotCM energy variations and the energy recovery index (ER. Along with PD progression, we found a significant correlation of WtotCM and Wp with knee ROM and in particular with knee extension in terminal stance phase. Wk and ER were instead mainly related to gait velocity. In PD subjects, the reduction of knee ROM significantly diminished both Wp and WtotCM. Rehabilitation treatments should possibly integrate passive and active mobilization of knee to prevent a reduction of gait-related energetic components.

Acute Systolic Heart Failure Associated with Complement-Mediated Hemolytic Uremic Syndrome

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John L. Vaughn

2015-01-01

Full Text Available Complement-mediated hemolytic uremic syndrome (otherwise known as atypical HUS is a rare disorder of uncontrolled complement activation that may be associated with heart failure. We report the case of a 49-year-old female with no history of heart disease who presented with microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury. Given her normal ADAMSTS13 activity, evidence of increased complement activation, and renal biopsy showing evidence of thrombotic microangiopathy, she was diagnosed with complement-mediated HUS. She subsequently developed acute hypoxemic respiratory failure secondary to pulmonary edema requiring intubation and mechanical ventilation. A transthoracic echocardiogram showed evidence of a Takotsubo cardiomyopathy with an estimated left ventricular ejection fraction of 20%, though ischemic cardiomyopathy could not be ruled out. Treatment was initiated with eculizumab. After several failed attempts at extubation, she eventually underwent tracheotomy. She also required hemodialysis to improve her uremia and hypervolemia. After seven weeks of hospitalization and five doses of eculizumab, her renal function and respiratory status improved, and she was discharged in stable condition on room air and independent of hemodialysis. Our case illustrates a rare association between acute systolic heart failure and complement-mediated HUS and highlights the potential of eculizumab in stabilizing even the most critically-ill patients with complement-mediated disease.

Activation of Proinflammatory Responses in Cells of the Airway Mucosa by Particulate Matter: Oxidant- and Non-Oxidant-Mediated Triggering Mechanisms

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Johan Øvrevik

2015-07-01

Full Text Available Inflammation is considered to play a central role in a diverse range of disease outcomes associated with exposure to various types of inhalable particulates. The initial mechanisms through which particles trigger cellular responses leading to activation of inflammatory responses are crucial to clarify in order to understand what physico-chemical characteristics govern the inflammogenic activity of particulate matter and why some particles are more harmful than others. Recent research suggests that molecular triggering mechanisms involved in activation of proinflammatory genes and onset of inflammatory reactions by particles or soluble particle components can be categorized into direct formation of reactive oxygen species (ROS with subsequent oxidative stress, interaction with the lipid layer of cellular membranes, activation of cell surface receptors, and direct interactions with intracellular molecular targets. The present review focuses on the immediate effects and responses in cells exposed to particles and central down-stream signaling mechanisms involved in regulation of proinflammatory genes, with special emphasis on the role of oxidant and non-oxidant triggering mechanisms. Importantly, ROS act as a central second-messenger in a variety of signaling pathways. Even non-oxidant mediated triggering mechanisms are therefore also likely to activate downstream redox-regulated events.

IFN-Gamma-Dependent and Independent Mechanisms of CD4⁺ Memory T Cell-Mediated Protection from Listeria Infection.

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Meek, Stephanie M; Williams, Matthew A

2018-02-13

While CD8⁺ memory T cells can promote long-lived protection from secondary exposure to intracellular pathogens, less is known regarding the direct protective mechanisms of CD4⁺ T cells. We utilized a prime/boost model in which mice are initially exposed to an acutely infecting strain of lymphocytic choriomeningitis virus (LCMV), followed by a heterologous rechallenge with Listeria monocytogenes recombinantly expressing the MHC Class II-restricted LCMV epitope, GP 61-80 (Lm-gp61). We found that heterologous Lm-gp61 rechallenge resulted in robust activation of CD4⁺ memory T cells and that they were required for rapid bacterial clearance. We further assessed the relative roles of TNF and IFNγ in the direct anti-bacterial function of CD4⁺ memory T cells. We found that disruption of TNF resulted in a complete loss of protection mediated by CD4⁺ memory T cells, whereas disruption of IFNγ signaling to macrophages results in only a partial loss of protection. The protective effect mediated by CD4⁺ T cells corresponded to the rapid accumulation of pro-inflammatory macrophages in the spleen and an altered inflammatory environment in vivo. Overall, we conclude that protection mediated by CD4⁺ memory T cells from heterologous Listeria challenge is most directly dependent on TNF, whereas IFNγ only plays a minor role.

Ligand-Receptor Interaction-Mediated Transmembrane Transport of Dendrimer-like Soft Nanoparticles: Mechanisms and Complicated Diffusive Dynamics.

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Liang, Junshi; Chen, Pengyu; Dong, Bojun; Huang, Zihan; Zhao, Kongyin; Yan, Li-Tang

2016-05-09

Nearly all nanomedical applications of dendrimer-like soft nanoparticles rely on the functionality of attached ligands. Understanding how the ligands interact with the receptors in cell membrane and its further effect on the cellular uptake of dendrimer-like soft nanoparticles is thereby a key issue for their better application in nanomedicine. However, the essential mechanism and detailed kinetics for the ligand-receptor interaction-mediated transmembrane transport of such unconventional nanoparticles remain poorly elucidated. Here, using coarse-grained simulations, we present the very first study of molecular mechanism and kinetics behaviors for the transmembrane transport of dendrimer-like soft nanoparticles conjugated with ligands. A phase diagram of interaction states is constructed through examining ligand densities and membrane tensions that allows us to identify novel endocytosis mechanisms featured by the direct wrapping and the penetration-extraction vesiculation. The results provide an in-depth insight into the diffusivity of receptors and dendrimer in the membrane plane and demonstrate how the ligand density influences receptor diffusion and uptake kinetics. It is interesting to find that the ligand-conjugated dendrimers present superdiffusive behaviors on a membrane, which is revealed to be driven by the random fluctuation dynamics of the membrane. The findings facilitate our understanding of some recent experimental observations and could establish fundamental principles for the future development of such important nanomaterials for widespread nanomedical applications.

Gaugino-Assisted Anomaly Mediation

International Nuclear Information System (INIS)

Kaplan, David Elazzar; Kribs, Graham D.

2000-01-01

We present a model of supersymmetry breaking mediated through a small extra dimension. Standard model matter multiplets and a supersymmetry-breaking (or ''hidden'') sector are confined to opposite four-dimensional boundaries while gauge multiplets live in the bulk. The hidden sector does not contain a singlet and the dominant contribution to gaugino masses is via anomaly-mediated supersymmetry breaking. Scalar masses get contributions from both anomaly mediation and a tiny hard breaking of supersymmetry by operators on the hidden-sector boundary. These operators contribute to scalar masses at one loop and in most of parameter space, their contribution dominates. Thus it is easy to make all squared scalar masses positive. As no additional fields or symmetries are required below the Planck scale, we consider this the simplest working model of anomaly mediation. The gaugino spectrum is left untouched and the phenomenology of the model is roughly similar to anomaly mediated supersymmetry breaking with a universal scalar mass added. We identify the main differences in the spectrum between this model and other approaches. We also discuss mechanisms for generating the μ term and constraints on additional bulk fields. (author)

Patient-mediated knowledge translation (PKT) interventions for clinical encounters: a systematic review.

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Gagliardi, Anna R; Légaré, France; Brouwers, Melissa C; Webster, Fiona; Badley, Elizabeth; Straus, Sharon

2016-02-29

Patient-mediated knowledge translation (PKT) interventions engage patients in their own health care. Insight on which PKT interventions are effective is lacking. We sought to describe the type and impact of PKT interventions. We performed a systematic review of PKT interventions, defined as strategies that inform, educate and engage patients in their own health care. We searched MEDLINE, EMBASE and the Cochrane Library from 2005 to 2014 for English language studies that evaluated PKT interventions delivered immediately before, during or upon conclusion of clinical encounters to individual patients with arthritis or cancer. Data were extracted on study characteristics, PKT intervention (theory, content, delivery, duration, personnel, timing) and outcomes. Interventions were characterized by type of patient engagement (inform, activate, collaborate). We performed content analysis and reported summary statistics. Of 694 retrieved studies, 16 were deemed eligible (5 arthritis, 11 cancer; 12 RCTs, 4 cohort studies; 7 low, 3 uncertain, 6 high risk of bias). PKT interventions included print material in 10 studies (brochures, booklets, variety of print material, list of websites), electronic material in 10 studies (video, computer program, website) and counselling in 2 studies. They were offered before, during and after consultation in 4, 1 and 4 studies, respectively; as single or multifaceted interventions in 10 and 6 studies, respectively; and by clinicians, health educators, researchers or volunteers in 4, 3, 5 and 1 study, respectively. Most interventions informed or activated patients. All studies achieved positive impact in one or more measures of patient knowledge, decision-making, communication and behaviour. This was true regardless of condition, PKT intervention, timing, personnel, type of engagement or delivery (single or multifaceted). No studies assessed patient harms, or interventions for providers to support PKT intervention delivery. Two studies evaluated

Optimizing Oxygenation in the Mechanically Ventilated Patient: Nursing Practice Implications.

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Barton, Glenn; Vanderspank-Wright, Brandi; Shea, Jacqueline

2016-12-01

Critical care nurses constitute front-line care provision for patients in the intensive care unit (ICU). Hypoxemic respiratory compromise/failure is a primary reason that patients require ICU admission and mechanical ventilation. Critical care nurses must possess advanced knowledge, skill, and judgment when caring for these patients to ensure that interventions aimed at optimizing oxygenation are both effective and safe. This article discusses fundamental aspects of respiratory physiology and clinical indices used to describe oxygenation status. Key nursing interventions including patient assessment, positioning, pharmacology, and managing hemodynamic parameters are discussed, emphasizing their effects toward mitigating ventilation-perfusion mismatch and optimizing oxygenation. Copyright © 2016 Elsevier Inc. All rights reserved.

Contribution of Large Genomic Rearrangements in Italian Lynch Syndrome Patients: Characterization of a Novel Alu-Mediated Deletion

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Francesca Duraturo

2013-01-01

Full Text Available Lynch syndrome is associated with germ-line mutations in the DNA mismatch repair (MMR genes, mainly MLH1 and MSH2. Most of the mutations reported in these genes to date are point mutations, small deletions, and insertions. Large genomic rearrangements in the MMR genes predisposing to Lynch syndrome also occur, but the frequency varies depending on the population studied on average from 5 to 20%. The aim of this study was to examine the contribution of large rearrangements in the MLH1 and MSH2 genes in a well-characterised series of 63 unrelated Southern Italian Lynch syndrome patients who were negative for pathogenic point mutations in the MLH1, MSH2, and MSH6 genes. We identified a large novel deletion in the MSH2 gene, including exon 6 in one of the patients analysed (1.6% frequency. This deletion was confirmed and localised by long-range PCR. The breakpoints of this rearrangement were characterised by sequencing. Further analysis of the breakpoints revealed that this rearrangement was a product of Alu-mediated recombination. Our findings identified a novel Alu-mediated rearrangement within MSH2 gene and showed that large deletions or duplications in MLH1 and MSH2 genes are low-frequency mutational events in Southern Italian patients with an inherited predisposition to colon cancer.

Risk factors for endotracheal intubation and mechanical ventilation in patients with opioids intoxication

International Nuclear Information System (INIS)

Mirmoghtadaee, P.; Mood, N.E.; Sabzghabaee, A.M.; Yaraghi, A.

2012-01-01

Objectives: Patients poisoned with opioids sometimes need endotracheal intubation with or without the use of mechanical ventilation. This study was done to determine the prognostic risk factors for of the need for endotracheal intubation and mechanical ventilation. Methodology: In this cross-sectional study which was performed in Isfahan (Iran), one hundred (n=100) opioid poisoned patients whom their overdoses were diagnosed by their full and reliable history, physical examination and positive response to naloxone; vital signs at the hospital admission, blood biochemistry, ABG details and also the type and estimated dosage of opioid, route of consumption, and their need to mechanical ventilation were evaluated. Results: Patients were mostly aged between 20-40 years old. Seventy nine patients were male and 26 cases (21 men) required endotracheal intubation and 15 cases (14 men) needed both intubation and mechanical ventilation. The most consumed opiates among the poisoned patients were opium (35%), heroin (16%), Tramadol (15%), Methadone (9%), crack (6%), Diphenoxylate (4%) and others (15%). There was a significant difference between the mean heart rates and respiratory rate of the patients who were connected to the ventilator and others (99.8 +- 21.8 and 87.3 +- 16.3; p=0.01). The lower level of consciousness [OR: 2.2 95% Confidence Interval (CI): 1.2-4.2], and lower admission level of hemoglobin (OR: 3.6; CI:1.2-10.8) were among the factors for predicting the need for intubation and ventilation. Conclusion: Determining the risk factors with prognostic value for the need to intubation or ventilation seems to be necessary for improving the standard of therapy in opioids poisoned patients. (author)

Mechanisms of change in interpersonal therapy (IPT).

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Lipsitz, Joshua D; Markowitz, John C

2013-12-01

Although interpersonal therapy (IPT) has demonstrated efficacy for mood and other disorders, little is known about how IPT works. We present interpersonal change mechanisms that we hypothesize account for symptom change in IPT. Integrating relational theory and insights based on research findings regarding stress, social support, and illness, IPT highlights contextual factors thought to precipitate and maintain psychiatric disorders. It frames therapy around a central interpersonal problem in the patient's life, a current crisis or relational predicament that is disrupting social support and increasing interpersonal stress. By mobilizing and working collaboratively with the patient to resolve this problem, IPT seeks to activate several interpersonal change mechanisms. These include: 1) enhancing social support, 2) decreasing interpersonal stress, 3) facilitating emotional processing, and 4) improving interpersonal skills. We hope that articulating these mechanisms will help therapists to formulate cases and better maintain focus within an IPT framework. Here we propose interpersonal mechanisms that might explain how IPT's interpersonal focus leads to symptom change. Future work needs to specify and test candidate mediators in clinical trials. We anticipate that pursuing this more systematic strategy will lead to important refinements and improvements in IPT and enhance its application in a range of clinical populations. © 2013.

Regulation of metabolism by the Mediator complex.

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Youn, Dou Yeon; Xiaoli, Alus M; Pessin, Jeffrey E; Yang, Fajun

2016-01-01

The Mediator complex was originally discovered in yeast, but it is conserved in all eukaryotes. Its best-known function is to regulate RNA polymerase II-dependent gene transcription. Although the mechanisms by which the Mediator complex regulates transcription are often complicated by the context-dependent regulation, this transcription cofactor complex plays a pivotal role in numerous biological pathways. Biochemical, molecular, and physiological studies using cancer cell lines or model organisms have established the current paradigm of the Mediator functions. However, the physiological roles of the mammalian Mediator complex remain poorly defined, but have attracted a great interest in recent years. In this short review, we will summarize some of the reported functions of selective Mediator subunits in the regulation of metabolism. These intriguing findings suggest that the Mediator complex may be an important player in nutrient sensing and energy balance in mammals.

Confounding in statistical mediation analysis: What it is and how to address it.

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Valente, Matthew J; Pelham, William E; Smyth, Heather; MacKinnon, David P

2017-11-01

Psychology researchers are often interested in mechanisms underlying how randomized interventions affect outcomes such as substance use and mental health. Mediation analysis is a common statistical method for investigating psychological mechanisms that has benefited from exciting new methodological improvements over the last 2 decades. One of the most important new developments is methodology for estimating causal mediated effects using the potential outcomes framework for causal inference. Potential outcomes-based methods developed in epidemiology and statistics have important implications for understanding psychological mechanisms. We aim to provide a concise introduction to and illustration of these new methods and emphasize the importance of confounder adjustment. First, we review the traditional regression approach for estimating mediated effects. Second, we describe the potential outcomes framework. Third, we define what a confounder is and how the presence of a confounder can provide misleading evidence regarding mechanisms of interventions. Fourth, we describe experimental designs that can help rule out confounder bias. Fifth, we describe new statistical approaches to adjust for measured confounders of the mediator-outcome relation and sensitivity analyses to probe effects of unmeasured confounders on the mediated effect. All approaches are illustrated with application to a real counseling intervention dataset. Counseling psychologists interested in understanding the causal mechanisms of their interventions can benefit from incorporating the most up-to-date techniques into their mediation analyses. (PsycINFO Database Record (c) 2017 APA, all rights reserved).

Mechanisms of acquired resistance to EGFR-tyrosine kinase inhibitor in Korean patients with lung cancer

International Nuclear Information System (INIS)

Ji, Wonjun; Lee, Dae Ho; Lee, Jae Cheol; Choi, Chang-Min; Rho, Jin Kyung; Jang, Se Jin; Park, Young Soo; Chun, Sung-Min; Kim, Woo Sung; Lee, Jung-Shin; Kim, Sang-We

2013-01-01

Despite an initial good response to epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI), resistance to treatment eventually develops. Although several resistance mechanisms have been discovered, little data exist regarding Asian patient populations. Among patients at a tertiary referral hospital in Korea who initially responded well to gefitinib and later acquired resistance to treatment, we selected those with enough tissues obtained before EGFR-TKI treatment and after the onset of resistance to examine mutations by mass spectrometric genotyping technology (Asan-Panel), MET amplification by fluorescence in situ hybridization (FISH), and analysis of AXL status, epithelial-to-mesenchymal transition (EMT) and neuroendocrine markers by immunohistochemistry. Twenty-six patients were enrolled, all of whom were diagnosed with adenocarcinoma with EGFR mutations (19del: 16, L858R: 10) except one (squamous cell carcinoma with 19del). Secondary T790M mutation was detected in 11 subjects (42.3%) and four of these patients had other co-existing resistance mechanisms; increased AXL expression was observed in 5/26 patients (19.2%), MET gene amplification was noted in 3/26 (11.5%), and one patient acquired a mutation in the phosphatidylinositol-4, 5-bisphosphate 3-kinase catalytic subunit alpha isoform (PIK3CA) gene. None of the patients exhibited EMT; however, increased CD56 expression suggesting neuroendocrine differentiation was observed in two patients. Interestingly, conversion from L858R-mutant to wild-type EGFR occurred in one patient. Seven patients (26.9%) did not exhibit any known resistance mechanisms. Patients with a T790M mutation showed a more favorable prognosis. The mechanisms and frequency of acquired EGFR-TKI resistance in Koreans are comparable to those observed in Western populations; however, more data regarding the mechanisms that drive EGFR-TKI resistance are necessary

The Influence of Receptor-Mediated Interactions on Reaction-Diffusion Mechanisms of Cellular Self-organisation

KAUST Repository

Klika, Václav

2011-11-10

Understanding the mechanisms governing and regulating self-organisation in the developing embryo is a key challenge that has puzzled and fascinated scientists for decades. Since its conception in 1952 the Turing model has been a paradigm for pattern formation, motivating numerous theoretical and experimental studies, though its verification at the molecular level in biological systems has remained elusive. In this work, we consider the influence of receptor-mediated dynamics within the framework of Turing models, showing how non-diffusing species impact the conditions for the emergence of self-organisation. We illustrate our results within the framework of hair follicle pre-patterning, showing how receptor interaction structures can be constrained by the requirement for patterning, without the need for detailed knowledge of the network dynamics. Finally, in the light of our results, we discuss the ability of such systems to pattern outside the classical limits of the Turing model, and the inherent dangers involved in model reduction. © 2011 Society for Mathematical Biology.

Emotional support and well-being of midlife women: role-specific mastery as a mediational mechanism.

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Martire, L M; Stephens, M A; Townsend, A L

1998-09-01

This study examined the relationships among emotional support, mastery, and well-being for 258 women who simultaneously occupied the roles of wife, mother, parent care provider, and employee. Its primary aim was to determine if a greater sense of mastery in each of these 4 roles could explain the relationship between emotional support from the partner or partners in the same role (the husband, children, impaired parent, or work supervisor) and better psychological well-being (less depressive symptomatology and more life satisfaction). Findings revealed that more emotional support from each of the 4 role partners was related to a greater sense of mastery in that same role. Furthermore, for each of the roles of wife, mother, and employee, role-specific mastery was a mediating mechanism in the relationship between support from the role partner or partners and better well-being.

Mechanism underlying the absence of ischemic changes on the exercise electrocardiogram in patients with abnormal exercise thallium-201 imaging and coronary artery disease

International Nuclear Information System (INIS)

Coplan, N.L.; Horowitz, S.F.; Hoffman, D.P.; Goldman, M.E.; Machac, J.

1985-01-01

Patients with coronary artery disease may have reversible abnormalities on a thallium myocardial perfusion study without simultaneous ischemic changes on the exercise electrocardiogram, but the mechanisms responsible for this disparity have not been fully elucidated. A group of 37 patients with angiographically demonstrated coronary artery disease and abnormal thallium perfusion imaging were divided into two groups on the basis of their exercise electrocardiographic ST segment response. Thirteen patients (Group A) had no significant electrocardiographic changes with exercise, while 24 patients (Group B) had ST changes consistent with ischemia during the test. There were no significant differences in clinical or angiographic characteristics between the two groups. Stress test results showed a similar mean duration of exercise in the two groups, but the patients in Group A achieved a significantly lower mean maximal heart rate and mean maximal double product. These results suggest that exercise thallium-electrocardiogram discordance is mediated by the level of myocardial workload achieved. An abnormal perfusion scan accompanying an exercise electrocardiogram which does not demonstrate any ischemic ST change may occur when there is sufficient increase in myocardial oxygen demand to result in differential augmentation of myocardial blood flow, but insufficient imbalance of supply and demand to result in signs of ischemia on the surface electrocardiogram

Pain in Patients with Pancreatic Cancer: Prevalence, Mechanisms, Management and Future Developments.

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Koulouris, Andreas I; Banim, Paul; Hart, Andrew R

2017-04-01

Pain affects approximately 80% of patients with pancreatic cancer, with half requiring strong opioid analgesia, namely: morphine-based drugs on step three of the WHO analgesic ladder (as opposed to the weak opioids: codeine and tramadol). The presence of pain is associated with reduced survival. This article reviews the literature regarding pain: prevalence, mechanisms, pharmacological, and endoscopic treatments and identifies areas for research to develop individualized patient pain management pathways. The online literature review was conducted through: PubMed, Clinical Key, Uptodate, and NICE Evidence. There are two principal mechanisms for pain: pancreatic duct obstruction and pancreatic neuropathy which, respectively, activate mechanical and chemical nociceptors. In pancreatic neuropathy, several histological, molecular, and immunological changes occur which correlate with pain including: transient receptor potential cation channel activation and mast cell infiltration. Current pain management is empirical rather etiology-based and is informed by the WHO analgesic ladder for first-line therapies, and then endoscopic ultrasound-guided celiac plexus neurolysis (EUS-CPN) in patients with resistant pain. For EUS-CPN, there is only one clinical trial reporting a benefit, which has limited generalizability. Case series report pancreatic duct stenting gives effective analgesia, but there are no clinical trials. Progress in understanding the mechanisms for pain and when this occurs in the natural history, together with assessing new therapies both pharmacological and endoscopic, will enable individualized care and may improve patients' quality of life and survival.

Nurses' communication with patients who are mechanically ventilated in intensive care: the Botswana experience.

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Dithole, K S; Sibanda, S; Moleki, M M; Thupayagale-Tshweneagae, G

2016-09-01

Communication is an integral part of nursing practice not just only for therapeutic reasons but also for sharing information. Nurses working in intensive care experience challenges when communicating with patients who are mechanically ventilated due to lack of knowledge and skill. These challenges infringe on the patients' rights to receive information and as such they may impact negatively on the patients' outcomes. This study determined the existing knowledge and skills of intensive care nurses working with mechanically ventilated patients in Botswana. A retrospective descriptive and explorative research design with a quantitative approach was used to audit patients' records. This was augmented by further interviewing nurses for their knowledge and skills when communicating with ventilated patients within the two intensive care units in Botswana. The American Association of Critical Nurses Synergy Model was used to guide the study. One hundred and fifty-nine (159) patients' files were audited and 50 nurses chosen by purposive sampling completed a self-administered 42-item questionnaire. Statistical Package for Social Sciences version 10 and Microsoft Excel were used to analyse the data. Assessment of patients' ability to communicate was recorded in more than 90% of files audited. Four per cent (4%) of the respondents only communicated essential information and no other strategies or devices were used to aid communication. Communication with ventilated patients can be quite challenging to nurses working in the intensive care unit. There is a need for communication skills training to ensure that all nurses working with mechanically ventilated patients are properly trained, equipped and capable of communicating effectively with the patient. A greater understanding of communication dynamics with the intensive care unit with patients who are mechanically ventilated is crucial to enable nurses to improve their care and improve patients' comfort. Incorporating

Immune-mediated neuropathies our experience over 3 years

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Sadanandavalli Retnaswami Chandra

2018-01-01

Full Text Available Introduction: Immune-mediated peripheral neuropathy is the term applied to a spectrum of peripheral nerve disorders where immune dysregulation plays a role. Therefore, they are treatable. We analyzed the cases seen in the past 3 years by us and evaluated the clinical, laboratory, and outcome parameters in these patients. Patients and Methods: Consecutive patients seen by the authors and diagnosed as immune-mediated neuropathy were analyzed for etiology, pathology, and outcome assessed. Results: A total of sixty patients, 31 acute and 29 chronic neuropathies, were identified. Their subtypes treatment and outcome assessed. Males were significantly more in both acute and chronic cases. Miller Fisher 4, AMAN 1, paraplegic type 1, motor dominant type 19, Sensory-motor 1, MADSAM 3, Bifacial 2. Nonsystemic vasculitis was seen in 16 out of 29 chronic neuropathy and HIV, POEMS, and diabetes mellitus one each. Discussion: There is a spectrum of immune-mediated neuropathy which varies in clinical course, response to treatment, etc., Small percentage of uncommon cases are seen. In this group, mortality was nil and morbidity was minimal. Conclusion: Immune-mediated neuropathies are treatable and hence should be diagnosed early for good quality outcome.