Enhanced generation of specific tumor-reactive CTL in vitro by selected Melan-A/MART-1 immunodominant peptide analogues.

The Melan-A/MART-1 gene, which is expressed by normal melanocytes as well as by most fresh melanoma samples and melanoma cell lines, codes for Ags recognized by tumor-reactive CTL. HLA-A*0201-restricted Melan-A-specific CTL recognize primarily the Melan-A(27-35) (AAGIGILTV) and the Melan-A(26-35) (EAAGIGILTV) peptides. The sequences of these two peptides are not necessarily optimal as far as binding to HLA-A*0201 is concerned, since both lack one of the dominant anchor amino acid residues (leucine or methionine) at position 2. In this study we introduced single amino acid substitutions in either one of the two natural peptide sequences with the aim of improving peptide binding to HLA-A*0201 and/or recognition by specific CTL. Surprisingly, analogues of the Melan-A(27-35) peptide, which bound more efficiently than the natural nonapeptide to HLA-A*0201, were poorly recognized by tumor-reactive CTL. In contrast, among the Melan-A(26-35) peptide analogues tested, the peptide ELAGIGILTV was not only able to display stable binding to HLA-A2.1 but was also recognized more efficiently than the natural peptide by two short-term cultured tumor-infiltrated lymph node cell cultures as well as by five of five tumor-reactive CTL clones. Moreover, in vitro generation of tumor-reactive CTL by stimulation of PBMC from HLA-A*0201 melanoma patients with this particular peptide analogue was much more efficient than that observed with either one of the two natural peptides. These results suggest that the Melan-A(26-35) peptide analogue ELAGIGILTV may be more immunogenic than the natural peptides in HLA-A*0201 melanoma patients and should thus be considered as a candidate for future peptide-based vaccine trials.

(Re-) Shaping hatred: Anti-Semitic attitudes in Germany, 1890-2006

In this paper, we assess the determinants of long-run persistence of localculture, and examine the success of policy interventions designed to change attitudes.We analyze anti-Semitic attitudes drawing on individual-level survey results fromGermany s social value survey in 1996 and 2006. On average, we find that historicalvoting patterns for anti-Semitic parties between 1890 and 1933 are powerfulpredictors of anti-Jewish attitudes today. There is evidence that transmission takesplace both vertically (parent to child) and horizontally (among peers). Policy modifiedGerman views on Jews in important ways: The cohort that grew up under the Naziregime shows significantly higher levels of anti-Semitism. After 1945, the victoriousAllies implemented denazification programs in their zones of occupation. We usedifferences in these policies between the occupying powers as a source of identifyingvariation. The US and French zones today still show high anti-Semitism, reflecting anambitious botched attempt at denazification. In contrast, the British and Soviet zones,register much lower levels of Jew-hatred.

Married to intolerance: Attitudes towards intermarriage in Germany, 1900-2006

Marriage is amongst the biggest decisions in life. In general, there is a tendency towards assortative matching people marry others who are relatively similar to themselves. Intermarriage between different social, religious and ethnic groups in most societies is relatively rare (Blossfeld and Timm 2003). Where it occurs, it is associated with more rapid assimilation (Meng and Gregory 2005). The frequency of intermarriage can therefore serve as a useful indicator of tolerant attitudes towards a minority, and of the desire to integrate (Bisin, Topa, and Verdier 2004).In this paper, we analyze under which conditions intermarriage can be used as an indicator of tolerance, and whether such tolerant attitudes persisted in Germany during the last century. We combine information on individual-level attitudes from the German social survey (GESIS) with historical data on marriage patterns.

Activation of human melanoma reactive CD8+ T cells by vaccination with an immunogenic peptide analog derived from Melan-A/melanoma antigen recognized by T cells-1.

PURPOSE: As compared with natural tumor peptide sequences, carefully selected analog peptides may be more immunogenic and thus better suited for vaccination. However, T cells in vivo activated by such altered analog peptides may not necessarily be tumor specific because sequence and structure of peptide analogs differ from corresponding natural peptides. EXPERIMENTAL DESIGN: Three melanoma patients were immunized with a Melan-A peptide analog that binds more strongly to HLA-A*0201 and is more immunogenic than the natural sequence. This peptide was injected together with a saponin-based adjuvant, followed by surgical removal of lymph node(s) draining the site of vaccination. RESULTS: Ex vivo analysis of vaccine site draining lymph nodes revealed antigen-specific CD8+ T cells, which had differentiated to memory cells. In vitro, these cells showed accelerated proliferation upon peptide stimulation. Nearly all (16 of 17) of Melan-A-specific CD8+ T-cell clones generated from these lymph nodes efficiently killed melanoma cells. CONCLUSIONS: Patient immunization with the analog peptide leads to in vivo activation of T cells that were specific for the natural tumor antigen, demonstrating the usefulness of the analog peptide for melanoma immunotherapy.

KINDERGARTEN TEACHERS’ ATTITUDES TOWARDS INCLUSIVE EDUCATION OF CHILDREN WITH DISABILITIES IN THE REGULAR CLASSROOM IN WUHAN, CHINA

After the international trends towards inclusive education, Chinese legislations mandate the inclusion of students with disabilities into the regular education classroom. The purpose of this study was to investigate the kindergarten teachers’ attitudes towards inclusive education of children with disabilities in the regular classroom, in Wuhan, China, as well their sense of responsibility to include children with disabilities in regular classroom. Ninety kindergarten teachers from public and private kindergartens in Wuhan participated in this study. Descriptive analysis demonstrated that, in general, kindergarten teachers we studied have negative or contradictory attitudes towards inclusive education of children with disabilities in regular classroom. Statistically non-significant differences were found between teachers’ attitudes towards inclusion and teachers’ demographic variables (age, education degree, teaching experience, experience teaching children with disabilities, time experience with children with disabilities and training in special education). Significant correlation was found between teachers’ attitudes towards inclusive education and their sense of responsibility to include children with disabilities in regular classroom. The results allowed the identification of some crucial aspects necessary to achieve the inclusive education

Preventing contagion with avian influenza: Disease salience, attitudes toward foreigners, and avoidance beliefs

Building on an evolutionary approach to outgroup avoidance, this study shows relations between perceived disease salience and beliefs in the efficacy of avoiding foreigners as protective measures, in the context of a real-life pandemic risk; i.e., avian influenza. People for whom avian influenza was salient and who held unfavourable attitudes toward foreigners were more likely to believe that avoiding contact with foreigners protects against infection. This finding suggests that individual differences in social attitudes moderate evolved mechanisms relating threat of disease to outgroup avoidance.

Attitudes towards morphine use among Swiss nurses and physicians

Background: There is little information regarding risk perception and attitudes on morphine use in Switzerland. Objectives: We aimed at assessing such attitudes in a sample of health professionals in the French-speaking part of Switzerland. Study design: Cross-sectional study. Setting: five non-university hospitals of the French-speaking canton of Valais, Switzerland. Methods: 431 nurses and 40 physicians (age range: 20-63). Risk perception and attitudes towards morphine use were assessed using a validated questionnaire. Results: Over half of participants showed a negative attitude regarding most adverse events related to morphine, while less than one third showed a similar attitude regarding other statements. On bivariate analyses, participants working in geriatrics showed a more negative attitude towards use of morphine than participants working in medicine and surgery. Non-Swiss participants also showed a more negative attitude than Swiss regarding use of morphine. Conversely, no differences were found between genders, profession (nurses or physicians), years of experience (<=14 and >14) and religion (catholic vs. others/no religion). These findings were further confirmed by multivariate adjustment. Limitations: possible selection bias due to responders only. Results limited to French speaking participants. Conclusion: Attitudes regarding morphine uses are mainly driven by its potential adverse effects and vary according to specialty and nationality. Educational measures directed at health professionals working in geriatrics or coming from abroad might reduce the high morphinophobia levels observed in these groups.

Superantigen-reactive CD4+ T cells are required to stimulate B cells after infection with mouse mammary tumor virus.

Superantigens are defined by their ability to stimulate a large fraction of T cells via interaction with the T cell receptor (TCR) V beta domain. Endogenous superantigens, classically termed minor lymphocyte-stimulating (Mls) antigens, were recently identified as products of open reading frames (ORF) in integrated proviral copies of mouse mammary tumor virus (MMTV). We have described an infectious MMTV homologue of the classical endogenous superantigen Mls-1a (Mtv-7). The ORF molecules of both the endogenous Mtv-7 and the infectious MMTV(SW) interact with T cells expressing the TCR V beta 6, 7, 8.1, and 9 domains. Furthermore, the COOH termini of their ORF molecules, thought to confer TCR specificity, are very similar. Since successful transport of MMTV from the site of infection in the gut to the mammary gland depends on a functional immune system, we were interested in determining the early events after and requirements for MMTV infection. We show that MMTV(SW) infection induces a massive response of V beta 6+ CDC4+ T cells, which interact with the viral ORF. Concomitantly, we observed a B cell response and differentiation that depends on both the presence and stimulation of the superantigen-reactive T cells. Furthermore, we show that B cells are the main target of the initial MMTV infection as judged by the presence of the reverse-transcribed viral genome and ORF transcripts. Thus, we suggest that MMTV infection of B cells leads to ORF-mediated B-T cell interaction, which maintains and possibly amplifies viral infection.

Clinical outcome after a reactive hypothermic EEG following cardiac arrest.

BACKGROUND: Reactive electroencephalography (EEG) background during therapeutic hypothermia (TH) is related to favorable prognosis after cardiac arrest (CA), but its predictive value is not 100 %. The aim of this study was to investigate outcome predictors after a first reactive EEG recorded during TH after CA. METHODS: We studied a cohort of consecutive comatose adults admitted between February 2008 and November 2012, after successful resuscitation from CA, selecting patients with reactive EEG during TH. Outcome was assessed at three months, and categorized as survivors and non-survivors (no patient was in vegetative state). Demographics, clinical variables, EEG features, serum neuron-specific enolase (NSE) and procalcitonin, were compared using uni- and multivariable analyses. RESULTS: A total of 290 patients were treated with TH after cardiac arrest; 146 had an EEG during TH, which proved reactive in 90 of them; 77 (86 %) survived and 13 (14 %) died (without recovery from coma). The group of non-survivors had a higher occurrence of discontinuous EEG (p = 0.006; multivariate analysis p = 0.026), and a higher serum NSE peak (p = 0.021; multivariate analysis p = 0.014); conversely, demographics, and other clinical variables including serum procalcitonin did not differ. CONCLUSIONS: A discontinuous EEG and high serum NSE are associated with mortality after CA in patients with poor outcome despite a reactive hypothermic EEG. This suggests more severe cerebral damage, but not to higher extent of systemic disease.

Comparison of C-reactive protein and white blood cell count with differential in neonates at risk for septicaemia.

We prospectively compared the diagnostic value of C-reactive protein (CRP) and white blood cell counts for detection of neonatal septicaemia. Sensitivity and specifity in receiver operating characteristics, and positive and negative predictive value of CRP and white blood cell count were compared in 195 critically ill preterm and term newborns clinically suspected of infection. Blood cultures were positive in 33 cases. During the first 3 days after birth CRP elevation (sensitivity 75%, specifity 86%), leukopenia (67%/90%), neutropenia (78%/80%) and immature to total neutrophil count (I/T) ratio (78%/73%) were good diagnostic parameters, as opposed to band forms with absolute count (84%/66%) or percentage (79%/71%), thrombocytopenia (65%/57%) and toxic granulations (44%/94%). Beyond 3 days of age elevated CRP (88%/87%) was the best parameter. Increased total (84%/66%) or percentage band count (79%/71%) were also useful. Leukocytosis (74%/56%), increased neutrophils (67%/65%), I/T ratio (79%/47%), thrombocytopenia (65%/57%) and toxic granulations had a low specifity. The positive predictive value of CRP was 32% before and 37% after 3 days of age, that of leukopenia was 37% in the first 3 days. CONCLUSION: During the first 3 days of life CRP, leukopenia and neutropenia were comparably good tests while after 3 days of life CRP was the best single test in early detection of neonatal septicaemia. Serial CRP estimations confirm the diagnosis, monitor the course of infection and the efficacy of antibiotic treatment.