PReS-FINAL-2177: Safety and lack of autoantibody production following influenza H1N1 vaccination in patients with juvenile idiopathic arthritis (JIA)

Introduction Vaccination is an effective tool against several infectious agents including influenza. In 2010, the Advisory Committee on Immunization Practices (ACIP) recommended influenza A H1N1/2009 immunization for high risk groups, including juvenile idiopathic arthritis (JIA) patients and more recently the EULAR task force reinforced the importance of vaccination in immunosuppressed pediatric rheumatologic patients. We have recently shown that Influenza A H1N1/2009 vaccination generated protective antibody production with short-term safety profile among 93 JIA patients, but the possible impact of the vaccine in autoimmune response in JIA have not been studied. Therefore, we aimed to assess the production of some autoantibodies generated following influenza H1N1 vaccination in JIA patients. Objectives To assess the autoimmune response and H1N1 serology following influenza H1N1 vaccination in patients with JIA. Methods Cepa A/California/7/2009 (NYMC X-179A) anti-H1N1 was used to vaccinate JIA patients: 1 dose of immunization was given to all participants and those <9yrs of age received a second booster 3 weeks apart. Sera were analyzed before and 3 weeks following complete vaccination. Serology against H1N1 virus was performed by hemagglutination inhibition antibody assay, rheumatoid factor (RF) by latex fixation test, antinuclear antibodies (ANA) by IIF, IgM and IgG anticardiolipin (aCL) by ELISA.Results Among 98 JIA patients that were vaccinated, 58 sera were available for this study. Mean age of 58 JIA patients was 23.9 ± 9.5 yrs, 38 were females and 20 males with mean disease duration of 14.7 ± 10.1 yrs. JIA subtypes were: 33 (57%) poliarticular, 10 (17%) oligoarticular, 6 (10%) systemic and 9 (16%) other. Sixteen patients were off drugs while 42 (72%) were under different pharmacotherapy: 32 (55%) were on 1 DMARD/IS, 10 (17%) on 2 DMARDs/IS, 19 (33%) antimalarials, 29 (50%) MTX, 8(14%) sulfasalazine, 6 (10%) anti-TNFs, 4 (7%) abatacept; no patient was using prednisone >0.5 mg/kg/d. Seroprotection rates against H1N1 influenza increased from 23 to 83% and seroconversion rates were achieved in 78% JIA. Prior to vaccination, 31(53.4%) JIA patients were ANA+, 6(10.3%) RF+, and 4 (7%) IgM + IgG aCL+. After complete H1N1 vaccination, positivity for ANA remained the same whereas 1 patient became negative for IgG aCL, and another for RF, IgM and IgG aCL. One (1.7%) patient turned low titer IgG aCL+. Conclusion Vaccination of JIA patients against pandemic influenza A (H1N1) generated successful protective antibody production without the induction of autoantibody production, except for 1 patient that became positive for low titer IgG aCL, supporting its safety.

Pyridine nucleotide levels in zooplankton: laboratory work and field samples

[ES]La respiración es un proceso fisiológico común a todos los organismos marinos. En los estudios oceanográficos se ha determinado, comúnmente, mediante la cuantificación del consumo de oxígeno de organismos incubados en botellas. Esta metodología es tediosa y lenta, por lo que Packard et al. (1971) propusieron el uso del análisis bioquímico basado en la actividad de las enzimas implicadas en la respiración, el Sistema de Transporte de Electrones (ETS). Este análisis mide la velocidad máxima que dichas enzimas pueden tener, determinando la respiración potencial de los organismos. Dicha velocidad estará controlada por la disponibilidad intracelular de sus sustratos, los piridín nucleótidos (NADH y NADPH). En el presente trabajo, se ha analizado el metabolismo respiratorio, a través de medidas del ETS y de los piridín nucleótidos, tanto en el dinoflagelado Oxyrrhis marina en estudios de laboratorio, como en organismos recogidos del medio marino durante la campaña de circunnavegación MALASPINA 2010

Age-Group differences in perception of competence, goal orientatiom attitudes, and practice of pshysical activity of girls who attend military schools

[EN]This study analysed the differences in self-perception, goal orientation and participation in physical activity (PA) in girls (N= 244) attending military schools. Girls had moderately higher levels of perceived competence, and there were no significant differences between age-groups. The figure for task-orientation was higher than ego-orientation. Girls expressed a positive attitude toward school and PE. Most girls did not practiced PA outside school, but 63,9% were involved in school sports. It seems that the military educational institutions are being successful in helping students to adopt physically active lifestyles. The development of perception of competence, task-orientation, and favourable attitudes seem to be important factors to enhance the levels of PA among students.

Gamma-secretase modulators and inhibitors in Alzheimer's disease: influence of genetic background on efficacy and mechanism of action

According to the amyloid hypothesis, Alzheimer’s disease (AD) is caused by aberrant production or clearance of the amyloid-β (Aβ) peptides, and in particular of the longer more aggregation-prone Aβ42. The Aβ peptides are generated through successive proteolytic cleavage of the amyloid precursor protein (APP) by the β-site APP cleaving enzyme (BACE) and γ-secretase. γ-secretase produces Aβ peptides with variable C-termini ranging from Aβ34 to Aβ48, presumably by sequential trimming of longer into shorter peptides. γ-secretase is a multiprotein complex consisting of at least four different proteins and the presenilin proteins (PS1 or PS2) contain the catalytic center of the complex. In 2001 several non-steroidal anti-inflammatory drugs were identified as the founding members of a new class of γ-secretase modulators (GSMs) that can selectively reduce production of Aβ42. Concomitantly, these GSMs increase Aβ38 production indicating closely coordinated generation of Aβ42 and Aβ38 and a potential precursor-product relationship between these peptides. GSMs seem to exert their activity by direct modulation of γ-secretase. Support for this hypothesis is drawn from the finding that some PS mutations associated with early-onset familial AD (FAD) can modulate the cellular response to GSMs and to γ-secretase inhibitors (GSIs), which inhibit production of all Aβ peptides and are known to directly interact with PS. A particularly interesting FAD PS mutation is PS1-ΔExon9, a complex deletion mutant that blocks endoproteolysis of PS1 and renders cells completely non-responsive to GSMs. Studies presented in this thesis show that the diminished response of PS1-ΔExon9 to GSMs is mainly caused by its lack of endoproteolytic cleavage. Furthermore, we were able to demonstrate that a reduced response to GSMs and GSIs is not limited to PS1-ΔExon9 but is a common effect of aggressive FAD-associated PS1 mutations. Surprisingly, we also found that while the Aβ42 response to GSMs is almost completely abolished by these PS1 mutations, the accompanying Aβ38 increase was indistinguishable to wild-type PS1. Finally, the reduced response to GSIs was confirmed in a mouse model with transgenic expression of an aggressive FAD-associated PS1 mutation as a highly potent GSI failed to reduce Aβ42 levels in brain of these mice. Taken together, our findings provide clear evidence for independent generation of Aβ42 and Aβ38 peptides, and argue that the sequential cleavage model might be an oversimplification of the molecular mechanism of γ-secretase. Most importantly, our results highlight the significance of genetic background in drug discovery efforts aimed at γ-secretase, and indicate that the use of cellular models with transgenic expression of FAD-associated PS mutations might confound studies of the potency and efficacy of GSMs and GSIs. Therefore, such models should be strictly avoided in the ongoing preclinical development of these promising and potentially disease-modifying therapeutics for AD.

Activity and mechanisms of action of novel organosulfur derivatives of the HDAC inhibitor Valproic Acid in human experimental models of non-small-cell lung cancer

Non-small-cell lung cancer (NSCLC) represents the leading cause of cancer death worldwide, and 5-year survival is about 16% for patients diagnosed with advanced lung cancer and about 70-90% when the disease is diagnosed and treated at earlier stages. Treatment of NSCLC is changed in the last years with the introduction of targeted agents, such as gefitinib and erlotinib, that have dramatically changed the natural history of NSCLC patients carrying specific mutations in the EGFR gene, or crizotinib, for patients with the EML4-ALK translocation. However, such patients represent only about 15-20% of all NSCLC patients, and for the remaining individuals conventional chemotherapy represents the standard choice yet, but response rate to thise type of treatment is only about 20%. Development of new drugs and new therapeutic approaches are so needed to improve patients outcome. In this project we aimed to analyse the antitumoral activity of two compounds with the ability to inhibit histone deacethylases (ACS 2 and ACS 33), derived from Valproic Acid and conjugated with H2S, in human cancer cell lines derived from NSCLC tissues. We showed that ACS 2 represents the more promising agent. It showed strong antitumoral and pro-apoptotic activities, by inducing membrane depolarization, cytocrome-c release and caspase 3 and 9 activation. It was able to reduce the invasive capacity of cells, through inhibition of metalloproteinases expression, and to induce a reduced chromatin condensation. This last characteristic is probably responsible for the observed high synergistic activity in combination with cisplatin. In conclusion our results highlight the potential role of the ACS 2 compound as new therapeutic option for NSCLC patients, especially in combination with cisplatin. If validated in in vivo models, this compound should be worthy for phase I clinical trials.

The role of indigenous people in national development processes: Participation and marginalisation of indigenous Bedouin in South Sinai tourism development

The Bedouin of South Sinai have been significantly affected by the politics of external powers for a long time. However, never had the interest of external powers in Sinai been so strong as since the Israeli-Egyptian wars in the second half of the 20th century when Bedouin interests started to collide with Egypt’s plans for a development of luxury tourism in South Sinai. rnrnThe tourism boom that has started in the 1980s has brought economic and infrastructure development to the Bedouin and tourism has become the most important source of income for the Bedouin. However, while the absolute increase of tourists to Sinai has trickled down to the Bedouin to some extent, the participation of Bedouin in the overall tourism development is under-proportionate. Moreover, the Bedouin have become increasingly dependent on monetary income and consequently from tourism as the only significant source of income while at the same time they have lost much of their land as well as their self-determination.rnrnIn this context, the Bedouin livelihoods have become very vulnerable due to repeated depressions in the tourism industry as well as marginalization. Major marginalization processes the Bedouin are facing are the loss of land, barriers to market entry, especially increasingly strict rules and regulations in the tourism industry, as well as discrimination by the authorities. Social differentiation and Bedouin preferences are identified as further factors in Bedouin marginalization.rnrnThe strategies Bedouin have developed in response to all these problems are coping strategies, which try to deal with the present problem at the individual level. Basically no strategies have been developed at the collective level that would aim to actively shape the Bedouin’s present and future. Collective action has been hampered by a variety of factors, such as the speed of the developments, the distribution of power or the decay of tribal structures.rnWhile some Bedouin might be able to continue their tourism activities, a large number of informal jobs will not be feasible anymore. The majority of the previously mostly self-employed Bedouin will probably be forced to work as day-laborers who will have lost much of their pride, dignity, sovereignty and freedom. Moreover, with a return to subsistence being impossible for the majority of the Bedouin, it is likely that an increasing number of marginalized Bedouin will turn to illegal income generating activities such as smuggling or drug cultivation. This in turn will lead to further repression and discrimination and could escalate in a serious violent conflict between the Bedouin and the government.rnrnDevelopment plans and projects should address the general lack of civil rights, local participation and protection of minorities in Egypt and promote Bedouin community development and the consideration of Bedouin interests in tourism development.rnrnWether the political upheavals and the resignation of president Mubarak at the beginning of 2011 will have a positive effect on the situation of the Bedouin remains to be seen.rn

Work-related behavior and experience patterns and predictors of mental health in German physicians in medical practice

Background and Objectives: Work-related stress and burnout among physicians are of increasing relevance. The aim of this study was to investigate work-related behavior and experience patterns and predictors of mental health of physicians working in medical practice in Germany. Methods: We surveyed a stratified, random sample of 900 physicians from different specialties. The questionnaire included the standardized instruments Work-related Behavior and Experience Pattern (AVEM) and the Short Form-12 Health Survey (SF-12). Results: Only one third of physicians reported high or very high general satisfaction with their job, but 64% would choose to study medicine again. Only 18% of physicians presented a healthy behavior and experience pattern. Almost 40% presented a pattern of reduced motivation to work, 21% were at risk of overexertion, and 22% at risk for burnout. Willingness to study medicine again, fulfilled job expectations, professional years, marital status, and behavior patterns were significant predictors of mental health and accounted for 35.6% of the variance in mental health scores. Job-related perceptions also had a significant effect on burnout. Conclusions: The strong influence of work-related perceptions suggests a need for realistic expectation management in medical education, as well as support in stress management and coping strategies during medical training.

'New perspectives on well-known issues': patients' experiences and perceptions of safety in Swiss hospitals

Patients' reports of safety-related events and perceptions of safety can be a valuable source for hospitals. Patients of eight acute care hospitals in Switzerland were surveyed for safety-related events and concerns for safety. In workshops with hospitals areas for improvement were analyzed and priorities for change identified. To evaluate the benefit of the approach, semi-structured interviews were conducted with hospital risk managers. 3,983 patients returned the survey (55% response rate). 21.4% reported at least one definite safety event, and the mean number of 'definite' incidents per patient was 0.31 (95% CI=0.29 to 0.34). 3.2% were very concerned and 14.7% were somewhat concerned about medical errors and safety. Having experienced a safety-related event, younger age, length of stay, poor health and a poor education increased the probability of reporting concerns. With some exceptions, results confirmed the hospitals' a priori expectations regarding the strengths and weaknesses of their institutions. Risk managers emphasized the usability of results for their work and the special value of referring to the patient's perspective at their home institutions. A considerable fraction of patients subjectively experiences safety-related events and is concerned about safety. Patient-generated data introduced a new quality into the discussion of safety issues within hospitals, and some expected that patients' experiences and concerns could affect patient volumes. Though the study is limited by the short time horizon and the lack of follow-up, the results suggest that the described approach is feasible and can serve as a supplemental tool for risk identification and management.

Long-term course of lung clearance index between infancy and school-age in cystic fibrosis subjects

Multiple breath washout (MBW) measurements have recently been shown to be sensitive for detection of early cystic fibrosis (CF) lung disease, with the lung clearance index (LCI) being the most common measure for ventilation inhomogeneity. The aim of this observational study was to describe the longitudinal course of LCI from time of clinical diagnosis during infancy to school-age in eleven children with CF. Elevated LCI during infancy was present in seven subjects, especially in those with later clinical diagnosis. Tracking of LCI at follow-up was evident only in the four most severe cases. We provide the first longitudinal data describing the long-term course of LCI in a small group of infants with CF. Our findings support the clinical usefulness of MBW measurements to detect and monitor early lung disease in children with CF already present shortly after clinical diagnosis.

A longitudinal three-center study of craniofacial morphology at 6 and 12 years of age in patients with complete bilateral cleft lip and palate

In this longitudinal study, the craniofacial morphology and evaluated soft tissue profile changes, at 6 and 12 years of age in patients with complete bilateral cleft lip and palate (CBCLP) were compared. Lateral cephalograms from 148 patients with CBCLP, treated consecutively at three European cleft centers, Gothenburg (n (A) = 37), Nijmegen (n (B) = 26), and Oslo (n (C) = 85), were evaluated. Eighteen hard tissue and ten soft tissue landmarks were digitized. Paired t test, Pearson's correlation coefficients, and multiple regression models were applied for statistical analysis. ANOVA and Tukey-B, as a post hoc test, were used to evaluate the increments and compare centers. Hard and soft tissue data were superimposed using the generalized Procrustes analysis. For Nijmegen, the increments of the variables SNA, ANB, SN-NL, SN-ML, NL-ML, Snss, and Snpg were significantly different than the two other centers (p = 0.041 to <0.001). SNPg increments were significantly different between Nijmegen and Oslo (p = 0.002). The three cleft centers followed different treatment protocols, but the main differences in craniofacial morphology until 12 years of age were the growth pattern and the maxillary and upper incisor variables. Follow-up of these patients until facial growth has ceased, which may elucidate components for improving treatment outcome.