Toxic effects of brake wear particles on epithelial lung cells in vitro

Background: Fine particulate matter originating from traffic correlates with increased morbidity and mortality. An important source of traffic particles is brake wear of cars which contributes up to 20% of the total traffic emissions. The aim of this study was to evaluate potential toxicological effects of human epithelial lung cells exposed to freshly generated brake wear particles. Results: An exposure box was mounted around a car's braking system. Lung cells cultured at the air-liquid interface were then exposed to particles emitted from two typical braking behaviours ("full stop" and "normal deceleration"). The particle size distribution as well as the brake emission components like metals and carbons was measured on-line, and the particles deposited on grids for transmission electron microscopy were counted. The tight junction arrangement was observed by laser scanning microscopy. Cellular responses were assessed by measurement of lactate dehydrogenase (cytotoxicity), by investigating the production of reactive oxidative species and the release of the pro-inflammatory mediator interleukin-8. The tight junction protein occludin density decreased significantly (p < 0.05) with increasing concentrations of metals on the particles (iron, copper and manganese, which were all strongly correlated with each other). Occludin was also negatively correlated with the intensity of reactive oxidative species. The concentrations of interleukin-8 were significantly correlated with increasing organic carbon concentrations. No correlation was observed between occludin and interleukin-8, nor between reactive oxidative species and interleukin-8. Conclusion: These findings suggest that the metals on brake wear particles damage tight junctions with a mechanism involving oxidative stress. Brake wear particles also increase pro-inflammatory responses. However, this might be due to another mechanism than via oxidative stress. [Authors]

Towards storage and access of electronic theses: A proposal of its organisation for the Consortium of Catalan Libraries

Els objectius d'aquest informe són realitzar un estudi de la tècnica en la digitalització, l'emmagatzematge i l'accés a les tesis doctorals electròniques, per tal de fer una proposta d’organització al Consorci de Biblioteques Universitàries de Catalunya (CBUC). Actualment, tot i que existeixen diverses iniciatives a Europa, és als EUA on la digitalització de tesis doctorals s’ha desenvolupat més amb la creació de la Networked Digital Library for Theses and Dissertation (NDLTD), i ha estat qui ha definit els estàndards en aquest camp. En el següent informe es planteja i es recomana al CBUC l’adhesió institucional a l’NDLTD per poder gaudir de la seva experiència.

Can smaller-scale comprehensive cancer centers provide outstanding care in abdominal and thoracic pediatric solid tumor surgery? Results of a 14-year retrospective single-center analysis.

PURPOSE: Quality of care and its measurement represent a considerable challenge for pediatric smaller-scale comprehensive cancer centers (pSSCC) providing surgical oncology services. It remains unclear whether center size and/or yearly case-flow numbers influence the quality of care, and therefore impact outcomes for this population of patients. PATIENTS AND METHODS: We performed a 14-year, retrospective, single-center analysis, assessing adherence to treatment protocols and surgical adverse events as quality indicators in abdominal and thoracic pediatric solid tumor surgery. RESULTS: Forty-eight patients, enrolled in a research-associated treatment protocol, underwent 51 cancer-oriented surgical procedures. All the protocols contain precise technical criteria, indications, and instructions for tumor surgery. Overall, compliance with such items was very high, with 997/1,035 items (95 %) meeting protocol requirements. There was no surgical mortality. Twenty-one patients (43 %) had one or more complications, for a total of 34 complications (66 % of procedures). Overall, 85 % of complications were grade 1 or 2 according to Clavien-Dindo classification requiring observation or minor medical treatment. Case-sample and outcome/effectiveness data were comparable to published series. Overall, our data suggest that even with the modest caseload of a pSSCC within a Swiss tertiary academic hospital, compliance with international standards can be very high, and the incidence of adverse events can be kept minimal. CONCLUSION: Open and objective data sharing, and discussion between pSSCCs, will ultimately benefit our patient populations. Our study is an initial step towards the enhancement of critical self-review and quality-of-care measurements in this setting.

Empfehlungen zur Diagnostik und Therapie der behavioralen und psychologischen Symptome der Demenz (BPSD) [Recommendations for diagnosis and therapy of behavioral and psychological symptoms in dementia (BPSD)].

In patients with dementia, Behavioral and Psychological Symptoms of Dementia (BPSD) are frequent findings that accompany deficits caused by cognitive impairment and thus complicate diagnostics, therapy and care. BPSD are a burden both for affected individuals as well as care-givers, and represent a significant challenge for therapy of a patient population with high degree of multi-morbidity. The goal of this therapy-guideline issued by swiss professional associations is to present guidance regarding therapy of BPSD as attendant symptoms in dementia, based on evidence as well as clinical experience. Here it appears to be of particular importance to take into account professional experience, as at this point for most therapeutic options no sufficiently controlled clinical trials are available. A critical discussion of pharmaco-therapeutic intervention is necessary, as this patient-population is particularly vulnerable for medication side-effects. Finally, a particular emphasis is placed on incorporating and systematically reporting psycho-social and nursing options therapeutic intervention.

Patient versus general practitioner perception of problems with treatment adherence in type 2 diabetes: from adherence to concordance.

OBJECTIVES: To determine the prevalence of problems with treatment adherence among type-2 diabetic patients with regards to medication, dietary advice, and physical activity; to identify the associated clinical and psychosocial factors; and to investigate the degree of agreement between patient-perceived and GP-perceived adherence. METHODS: Consecutive patients were solicited during visits to 39 GPs. In total, 521 patients self-reported on treatment adherence, anxiety and depression, and disease perception. The GPs reported clinical and laboratory data and patients' adherence. A multivariate analysis identified the factors associated with adherence problems. RESULTS: Problems of adherence to medication, dietary advice, and physical activity recommendations were reported by 17%, 62%, and 47% of the patients, respectively. Six independent factors were found associated with adherence problems: young age, body-mass index (BMI) > 30 kg/m(2), glycosylated haemoglobin (HbA(1c)) > 8%, single life, depression, and perception of medication as a constraint. Agreement between patients' and GPs' assessments of treatment problems reached 70%. CONCLUSION: In type 2 diabetes, problems with dietary advice or physical activity are far more frequent than problems with medication, and not all physicians are fully aware of patients' problems. More active listening and shared decision-making should enhance adherence and improve outcomes.

Antibody-Mediated Trapping of Helminth Larvae Requires CD11b and Fcγ Receptor I.

Infections with intestinal helminths severely impact on human and veterinary health, particularly through the damage that these large parasites inflict when migrating through host tissues. Host immunity often targets the motility of tissue-migrating helminth larvae, which ideally should be mimicked by anti-helminth vaccines. However, the mechanisms of larval trapping are still poorly defined. We have recently reported an important role for Abs in the rapid trapping of tissue-migrating larvae of the murine parasite Heligmosomoides polygyrus bakeri. Trapping was mediated by macrophages (MΦ) and involved complement, activating FcRs, and Arginase-1 (Arg1) activity. However, the receptors and Ab isotypes responsible for MΦ adherence and Arg1 induction remained unclear. Using an in vitro coculture assay of H. polygyrus bakeri larvae and bone marrow-derived MΦ, we now identify CD11b as the major complement receptor mediating MΦ adherence to the larval surface. However, larval immobilization was largely independent of CD11b and instead required the activating IgG receptor FcγRI (CD64) both in vitro and during challenge H. polygyrus bakeri infection in vivo. FcγRI signaling also contributed to the upregulation of MΦ Arg1 expression in vitro and in vivo. Finally, IgG2a/c was the major IgG subtype from early immune serum bound by FcγRI on the MΦ surface, and purified IgG2c could trigger larval immobilization and Arg1 expression in MΦ in vitro. Our findings reveal a novel role for IgG2a/c-FcγRI-driven MΦ activation in the efficient trapping of tissue-migrating helminth larvae and thus provide important mechanistic insights vital for anti-helminth vaccine development.

Editorial research and the publication process in biomedicine and health: Report from the Esteve Foundation Discussion Group, December 2012.

Despite the fact that there are more than twenty thousand biomedical journals in the world, research into the work of editors and publication process in biomedical and health care journals is rare. In December 2012, the Esteve Foundation, a non-profit scientific institution that fosters progress in pharmacotherapy by means of scientific communication and discussion organized a discussion group of 7 editors and/or experts in peer review biomedical publishing. They presented findings of past editorial research, discussed the lack of competitive funding schemes and specialized journals for dissemination of editorial research, and reported on the great diversity of misconduct and conflict of interest policies, as well as adherence to reporting guidelines. Furthermore, they reported on the reluctance of editors to investigate allegations of misconduct or increase the level of data sharing in health research. In the end, they concluded that if editors are to remain gatekeepers of scientific knowledge they should reaffirm their focus on the integrity of the scientific record and completeness of the data they publish. Additionally, more research should be undertaken to understand why many journals are not adhering to editorial standards, and what obstacles editors face when engaging in editorial research.

Regulation of lymphocyte proliferation and death by FLIP.

Lymphocyte homeostasis is a balance between lymphocyte proliferation and lymphocyte death. Tight control of apoptosis is essential for immune function, because its altered regulation can result in cancer and autoimmunity. Signals from members of the tumour-necrosis-factor receptor (TNF-R) family, such as Fas and TNF-R1, activate the caspase cascade and result in lymphocyte death by apoptosis. Anti-apoptotic proteins, such as FLIP (also known as FLICE/caspase-8 inhibitory protein) have recently been identified. FLIP expression is tightly regulated in T cells and might be involved in the control of both T-cell activation and death. Abnormal expression of FLIP might have a role not only in autoimmune diseases, but also in tumour development and cardiovascular disorders.

Structural and functional characterization of (110)-oriented epitaxial La2/3Ca1/3MnO3 electrodes and SrTiO3 tunnel barriers

La2/3Ca1/3MnO3 (LCMO) films have been deposited on (110)-oriented SrTiO3 (STO) substrates. X-ray diffraction and high-resolution electron microscopy reveal that the (110) LCMO films are epitaxial and anisotropically in-plane strained, with higher relaxation along the [1¿10] direction than along the [001] direction; x-ray absorption spectroscopy data signaled the existence of a single intermediate Mn3+/4+ 3d-state at the film surface. Their magnetic properties are compared to those of (001) LCMO films grown simultaneously on (001) STO substrates It is found that (110) LCMO films present a higher Curie temperature (TC) and a weaker decay of magnetization when approaching TC than their (001) LCMO counterparts. These improved films have been subsequently covered by nanometric STO layers. Conducting atomic-force experiments have shown that STO layers, as thin as 0.8 nm, grown on top of the (110) LCMO electrode, display good insulating properties. We will show that the electric conductance across (110) STO layers, exponentially depending on the barrier thickness, is tunnel-like. The barrier height in STO (110) is found to be similar to that of STO (001). These results show that the (110) LCMO electrodes can be better electrodes than (001) LCMO for magnetic tunnel junctions, and that (110) STO are suitable insulating barriers.

Contribution of the gap junction proteins Connexin40 and Connexin43 to the control of blood pressure

Summary Cells in tissues and organs coordinate their activities by communicating with each other through intercellular channels named gap junctions. These channels are conduits between the cytoplasmic compartments of adjacent cells, allowing the exchange of small molecules which may be crucial for hormone secretion. Renin is normally secreted in a regulated manner by specific cells of the juxtaglomerular apparatus located within the renal cortex. Gap junctional communication may be requisite to maintain an accurate functioning in coordination of renin-producing cells, more especially as renin is of paramount importance for the control of blood pressure. Connexin43 (Cx43) and Cx40 form gap junctions that link in vivo the cells of the juxtaglomerular apparatus. Cx43 links the endothelial cells, whereas gap junctions made of Cx40 connect the endothelial cells, the renin secreting cells, as well as the endothelial cells of to the renin-secreting cells of the afferent arteriole. The observation that loss of Cx40 results in chronic hypertension associated with altered vasomotion and signal conduction along arterioles, has lead us to suggest that connexins may contribute to control blood pressure by participating to the integration of various mechanical, osmotic and electrochemical stimuli involved in the control of renin secretion and by mediating the adaptive changes of the vascular wall induced by elevated blood pressure and mechanical stress. We therefore postulated that the absence of Cx40 could have deleterious effects on the coordinated functioning of the renin-containing cells, hence accounting for hypertension. In the first part of my thesis, we reported that Cx40-deficient mice (Cx40) are hypertensive due to increased plasma renin levels and numbers of renin-producing cells. Besides, we demonstrated that prostaglandins and nitric oxide, which are possible mediators in the regulation of renin secretion by the macula densa, exert a critical role in the mechanisms controlling blood pressure ín Cx40 knockout hypertensive mice. In view of previous studies that stated avessel-specifc increase in the expression of Cx43 during renin-dependent hypertension, we hypothesized that Cx43 channels are particularly well-matched to integrate the response of cells constituting the vascular wall to hypertensive conditions. Using transgenic mice in which Cx43 was replaced by Cx32, we revealed that the replacement of Cx43 by Cx32 is associated with decreased expression and secretion of renin and prevent the renin-dependent hypertension which is normally induced in the 2K1C model. To gain insights into the regulation of connexins in two separate tissues exposed to the same fluid pressure, the second part of my thesis work was dedicated to the study of the impact of chronic hypertension and related hypertrophy on the expression of the cardiovascular connexins (Cx40, Cx37, Cx43 and Cx45) in mouse aorta and heart. Our results documented that the expression of connexins is differentially regulated in mouse aorta. according to the models of hypertension. Thus, blood pressure induces mechanical forces that differentially alter the expression of vascular connexins in order to respond to an adaptation of the aortic wall observed under pathological conditions. Altogether these data provide the first evidences that intercellular communication mediated by gap junctions is required for a proper renin secretion from the juxtaglomerular apparatus in order to control blood pressure.

Measurement and simulation of anisotropy in the Infrared and Raman spectra of beta-FeSi2 single crystals

In this paper we show that the orthorhombic phase of FeSi2 (stable at room temperature) displays a sizable anisotropy in the infrared spectra, with minor effects in the Raman data too. This fact is not trivial at all, since the crystal structure corresponds to a moderate distortion of the fluorite symmetry. Our analysis is carried out on small single crystals grown by flux transport, through polarization-resolved far-infrared reflectivity and Raman measurements. Their interpretation has been obtained by means of the simulated spectra with tight-binding molecular dynamics.

Fibronectin-binding proteins and clumping factor A in Staphylococcus aureus experimental endocarditis: FnBPA is sufficient to activate human endothelial cells.

Surface molecules of Staphylococcus aureus are involved in the colonization of vascular endothelium which is a crucial primary event in the pathogenesis of infective endocarditis (IE). The ability of these molecules to also launch endothelial procoagulant and proinflammatory responses, which characterize IE, is not known. In the present study we investigated the individual capacities of three prominent S. aureus surface molecules; fibronectin-binding protein A (FnBPA) and B (FnBPB) and clumping factor A (ClfA), to promote bacterial adherence to cultured human endothelial cells (ECs) and to activate phenotypic and functional changes in these ECs. Non-invasive surrogate bacterium Lactococcus lactis, which, by gene transfer, expressed staphylococcal FnBPA, FnBPB or ClfA molecules were used. Infection of ECs increased 50- to 100-fold with FnBPA- or FnBPB-positive recombinant lactococci. This coincided with EC activation, interleukin-8 secretion and surface expression of ICAM-1 and VCAM-1 and concomitant monocyte adhesion. Infection with ClfA-positive lactococci did not activate EC. FnBPA-positive L. lactis also induced a prominent tissue factor-dependent endothelial coagulation response that was intensified by cell-bound monocytes. Thus S. aureus FnBPs, but not ClfA, confer invasiveness and pathogenicity to non-pathogenic L. lactis organisms indicating that bacterium-EC interactions mediated by these adhesins are sufficient to evoke inflammation as well as procoagulant activity at infected endovascular sites.

Impact of prolonged antihypertensive duration of action on predicted clinical outcomes in imperfectly adherent patients: comparison of aliskiren, irbesartan and ramipril.

Background: Most patients miss occasional doses of antihypertensives. The use of 'forgiving' drugs (i.e. drugs with duration of action longer than the 24-h dosing interval) may allow an adequate blood pressure (BP) reduction to be maintained despite missed doses. Aim:To quantify the effects of adherence level and duration of action on estimated mean systolic BP (SBP) reduction and cardiovascular disease (CVD) risk. Method:For 1250 patients, we simulated 256-day dosing histories with realistically distributed drug holidays based on a study of electronically monitored dosing records. Adherence was set to the desired level by altering the proportion of doses missed. Mean office SBP-lowering effect (aliskiren 300 mg, -14.1 mmHg; irbesartan 300 mg, -13.3; ramipril 10 mg, -10.1 mmHg) and the rate of SBP increase after stopping treatment (off-rate; aliskiren, 1.0 mmHg/day; irbesartan, 3.6 mmHg/day; ramipril, 4.0 mmHg/day) were taken from the results of a randomised, double-blind trial. SBP was averaged over time and patient to estimate mean reductions in SBP and 10-year CVD risk (Framingham risk equation, baseline absolute 10-year CVD risk: 27%). Results:Predicted reductions in SBP and CVD risk with aliskiren were larger and less affected by imperfect adherence than the reductions with irbesartan or ramipril. For aliskiren, reducing adherence from 90% to 60% led to a predicted rise in SBP of 1.0 mmHg and three additional CVD events per 1000 treated patients; larger predicted differences were observed for irbesartan (2.5 mmHg; 7.5 events/1000 treated patients) and ramipril (2.2 mmHg; 6.7 events/1000 treated patients). Conclusion:To offset the effects of imperfect adherence, a common challenge with antihypertensives, for better BP management it may be prudent to prescribe 'forgiving' drugs.

Religious beliefs in schizophrenia: Their relevance for adherence to treatment

The study examined how religious beliefs and practices impact upon medication and illness representations in chronic schizophrenia. One hundred three stabilized patients were included in Geneva's outpatient public psychiatric facility in Switzerland. Interviews were conducted to investigate spiritual and religious beliefs and religious practices and religious coping. Medication adherence was assessed through questions to patients and to their psychiatrists and by a systematic blood drug monitoring. Thirty-two percent of patients were partially or totally nonadherent to oral medication. Fifty-eight percent of patients were Christians, 2% Jewish, 3% Muslim, 4% Buddhist, 14% belonged to various minority or syncretic religious movements, and 19% had no religious affiliation. Two thirds of the total sample considered spirituality as very important or even essential in everyday life. Fifty-seven percent of patients had a representation of their illness directly influenced by their spiritual beliefs (positively in 31% and negatively in 26%). Religious representations of illness were prominent in nonadherent patients. Thirty-one percent of nonadherent patients and 27% of partially adherent patients underlined an incompatibility or contradiction between their religion and taking medication, versus 8% of adherent patients. Religion and spirituality contribute to shaping representations of disease and attitudes toward medical treatment in patients with schizophrenia. This dimension should be on the agenda of psychiatrists working with patients with schizophrenia.

Role of sigmaB in the expression of Staphylococcus aureus cell wall adhesins ClfA and FnbA and contribution to infectivity in a rat model of experimental endocarditis.

Isogenic Staphylococcus aureus strains with different capacities to produce sigma(B) activity were analyzed for their ability to attach to fibrinogen- or fibronectin-coated surfaces or platelet-fibrin clots and to cause endocarditis in rats. In comparison to the sigma(B)-deficient strain, BB255, which harbors an rsbU mutation, both rsbU-complemented and sigma(B)-overproducing derivatives exhibited at least five times greater attachment to fibrinogen- and fibronectin-coated surfaces and showed increased adherence to platelet-fibrin clots. No differences in adherence were seen between BB255 and a DeltarsbUVWsigB isogen. Northern blotting analyses revealed that transcription of clfA, encoding fibrinogen-binding protein clumping factor A, and fnbA, encoding fibronectin-binding protein A, were positively influenced by sigma(B). Sigma(B) overproduction resulted in a statistically significant increase in positive spleen cultures and enhanced bacterial densities in both the aortic vegetations and spleens at 16 h postinoculation. In contrast, at 72 h postinoculation, tissues infected with the sigma(B) overproducer had lower bacterial densities than did those infected with BB255. These results suggest that although sigma(B) appears to increase the adhesion of S. aureus to various host cell-matrix proteins in vitro, it has limited effect on pathogenesis in the rat endocarditis model. Sigma(B) appears to have a transient enhancing effect on bacterial density in the early stages of infection that is lost during progression.