Consumer Advisory Bulletin, Door-to-Door Sales: Your Right to Cancel, June 2011

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Autoreactive T cells bypass negative selection and respond to self-antigen stimulation during infection.

Central and peripheral tolerance prevent autoimmunity by deleting the most aggressive CD8(+) T cells but they spare cells that react weakly to tissue-restricted antigen (TRA). To reveal the functional characteristics of these spared cells, we generated a transgenic mouse expressing the TCR of a TRA-specific T cell that had escaped negative selection. Interestingly, the isolated TCR matches the affinity/avidity threshold for negatively selecting T cells, and when developing transgenic cells are exposed to their TRA in the thymus, only a fraction of them are eliminated but significant numbers enter the periphery. In contrast to high avidity cells, low avidity T cells persist in the antigen-positive periphery with no signs of anergy, unresponsiveness, or prior activation. Upon activation during an infection they cause autoimmunity and form memory cells. Unexpectedly, peptide ligands that are weaker in stimulating the transgenic T cells than the thymic threshold ligand also induce profound activation in the periphery. Thus, the peripheral T cell activation threshold during an infection is below that of negative selection for TRA. These results demonstrate the existence of a level of self-reactivity to TRA to which the thymus confers no protection and illustrate that organ damage can occur without genetic predisposition to autoimmunity.

Hematopoietic stem cells reversibly switch from dormancy to self-renewal during homeostasis and repair.

Bone marrow hematopoietic stem cells (HSCs) are crucial to maintain lifelong production of all blood cells. Although HSCs divide infrequently, it is thought that the entire HSC pool turns over every few weeks, suggesting that HSCs regularly enter and exit cell cycle. Here, we combine flow cytometry with label-retaining assays (BrdU and histone H2B-GFP) to identify a population of dormant mouse HSCs (d-HSCs) within the lin(-)Sca1+cKit+CD150+CD48(-)CD34(-) population. Computational modeling suggests that d-HSCs divide about every 145 days, or five times per lifetime. d-HSCs harbor the vast majority of multilineage long-term self-renewal activity. While they form a silent reservoir of the most potent HSCs during homeostasis, they are efficiently activated to self-renew in response to bone marrow injury or G-CSF stimulation. After re-establishment of homeostasis, activated HSCs return to dormancy, suggesting that HSCs are not stochastically entering the cell cycle but reversibly switch from dormancy to self-renewal under conditions of hematopoietic stress.

Adaptations of Natural Killer Cells to Self-MHC Class I.

Natural Killer (NK) cells use germ line encoded receptors to detect diseased host cells. Despite the invariant recognition structures, NK cells have a significant ability to adapt to their surroundings, such as the presence or absence of MHC class I molecules. It has been assumed that this adaptation occurs during NK cell development, but recent findings show that mature NK cells can also adapt to the presence or absence of MHC class I molecules. Here, we summarize how NK cells adjust to changes in the expression of MHC class I molecules. We propose an extension of existing models, in which MHC class I recognition during NK cell development sequentially instructs and maintains NK cell function. The elucidation of the molecular basis of the two effects may identify ways to improve the fitness of NK cells and to prevent the loss of NK cell function due to persistent alterations in their environment.

Characteristics of non-responders to self-reported questionnaires in a large inflammatory bowel disease cohort study.

BACKGROUND: A major threat to the validity of longitudinal cohort studies is non-response to follow-up, which can lead to erroneous conclusions. The objective of this study was to evaluate the profile of non-responders to self-reported questionnaires in the Swiss inflammatory bowel disease (IBD) Cohort. METHODS: We used data from adult patients enrolled between November 2006 and June 2011. Responders versus non-responders were compared according to socio-demographic, clinical and psychosocial characteristics. Odds ratio for non-response to initial patient questionnaire (IPQ) compared to 1-year follow-up questionnaire (FPQ) were calculated. RESULTS: A total of 1943 patients received IPQ, in which 331 (17%) did not respond. Factors inversely associated with non-response to IPQ were age >50 and female gender (OR = 0.37; p < 0.001 respectively OR = 0.63; p = 0.003) among Crohn's disease (CD) patients, and disease duration >16 years (OR = 0.48; p = 0.025) among patients with ulcerative colitis (UC). FPQ was sent to 1586 patients who had completed the IPQ; 263 (17%) did not respond. Risk factors of non-response to FPQ were mild depression (OR = 2.17; p = 0.003) for CD, and mild anxiety (OR = 1.83; p = 0.024) for UC. Factors inversely associated with non-response to FPQ were: age >30 years, colonic only disease location, higher education and higher IBD-related quality of life for CD, and age >50 years or having a positive social support for UC. CONCLUSIONS: Characteristics of non-responders differed between UC and CD. The risk of non-response to repetitive solicitations (longitudinal versus transversal study) seemed to decrease with age. Assessing non-respondents' characteristics is important to document potential bias in longitudinal studies.

A novel approach to the determination of clinical decision thresholds

Our objective was to determine the test and treatment thresholds for common acute primary care conditions. We presented 200 clinicians with a series of web-based clinical vignettes, describing patients with possible influenza, acute coronary syndrome (ACS), pneumonia, deep vein thrombosis (DVT) and urinary tract infection (UTI). We randomly varied the probability of disease and asked whether the clinician wanted to rule out disease, order tests or rule in disease. By randomly varying the probability, we obtained clinical decisions across a broad range of disease probabilities that we used to create threshold curves. For influenza, the test (4.5% vs 32%, p<0.001) and treatment (55% vs 68%, p=0.11) thresholds were lower for US compared with Swiss physicians. US physicians had somewhat higher test (3.8% vs 0.7%, p=0.107) and treatment (76% vs 58%, p=0.005) thresholds for ACS than Swiss physicians. For both groups, the range between test and treatment thresholds was greater for ACS than for influenza (which is sensible, given the consequences of incorrect diagnosis). For pneumonia, US physicians had a trend towards higher test thresholds and lower treatment thresholds (48% vs 64%, p=0.076) than Swiss physicians. The DVT and UTI scenarios did not provide easily interpretable data, perhaps due to poor wording of the vignettes. We have developed a novel approach for determining decision thresholds. We found important differences in thresholds for US and Swiss physicians that may be a function of differences in healthcare systems. Our results can also guide development of clinical decision rules and guidelines.

High-density linkage maps fail to detect any genetic component to sex determination in a Rana temporaria family.

Sex chromosome differentiation in Rana temporaria varies strikingly among populations or families: whereas some males display well-differentiated Y haplotypes at microsatellite markers on linkage group 2 (LG2 ), others are genetically undistinguishable from females. We analysed with RADseq markers one family from a Swiss lowland population with no differentiated sex chromosomes, and where sibship analyses had failed to detect any association between the phenotypic sex of progeny and parental haplotypes. Offspring were reared in a common tank in outdoor conditions and sexed at the froglet stage. We could map a total of 2177 SNPs (1123 in the mother, 1054 in the father), recovering in both adults 13 linkage groups (= chromosome pairs) that were strongly syntenic to Xenopus tropicalis despite > 200 My divergence. Sexes differed strikingly in the localization of crossovers, which were uniformly distributed in the female but limited to chromosome ends in the male. None of the 2177 markers showed significant association with offspring sex. Considering the very high power of our analysis, we conclude that sex determination was not genetic in this family; which factors determined sex remain to be investigated.

Ligandless cloud point extraction of trace amounts of palladium and rhodium in road dust samples using Span 80 prior to their determination by flame atomic absorption spectrometry

In this study, a procedure is developed for cloud point extraction of Pd(II) and Rh(III) ions in aqueous solution using Span 80 (non-ionic surfactant) prior to their determination by flame atomic absorption spectroscopy. This method is based on the extraction of Pd(II) and Rh(III) ions at a pH of 10 using Span 80 with no chelating agent. We investigated the effect of various parameters on the recovery of the analyte ions, including pH, equilibration temperature and time, concentration of Span 80, and ionic strength. Under the best experimental conditions, the limits of detection based on 3Sb for Pd(II) and Rh(III) ions were 1.3 and 1.2 ng mL-1, respectively. Seven replicate determinations of a mixture of 0.5 µg mL-1 palladium and rhodium ions gave a mean absorbance of 0.058 and 0.053 with relative standard deviations of 1.8 and 1.6%, respectively. The developed method was successfully applied to the extraction and determination of the palladium and rhodium ions in road dust and standard samples and satisfactory results were obtained.

Preconcentration of copper from natural water samples using ligand-less in situ surfactant-based solid phase extraction prior to FAAS determination

In the present work, a simple and rapid ligand-less, in situ, surfactant-based solid phase extraction for the preconcentration of copper in water samples was developed. In this method, a cationic surfactant (n-dodecyltrimethylammonium bromide) was dissolved in an aqueous sample followed by the addition of an appropriate ion-pairing agent (ClO4-). Due to the interaction between the surfactant and ion-pairing agent, solid particles were formed and subsequently used for the adsorption of Cu(OH)2 and CuI. After centrifugation, the sediment was dissolved in 1.0 mL of 1 mol L-1 HNO3 in ethanol and aspirated directly into the flame atomic absorption spectrometer. In order to obtain the optimum conditions, several parameters affecting the performance of the LL-ISS-SPE, including the volumes of DTAB, KClO4, and KI, pH, and potentially interfering ions, were optimized. It was found that KI and phosphate buffer solution (pH = 9) could extract more than 95% of copper ions. The amount of copper ions in the water samples varied from 3.2 to 4.8 ng mL-1, with relative standard deviations of 98.5%-103%. The determination of copper in water samples was linear over a concentration range of 0.5-200.0 ng mL-1. The limit of detection (3Sb/m) was 0.1 ng mL-1 with an enrichment factor of 38.7. The accuracy of the developed method was verified by the determination of copper in two certified reference materials, producing satisfactory results.

Spectrophotometric flow injection procedure to indirect determination of paracetamol in pharmaceutical formulations using o-tolidine as reagent

A spectrophotometric flow injection method for the determination of paracetamol in pharmaceutical formulations is proposed. The procedure was based on the oxidation of paracetamol by sodium hypochloride and the determination of the excess of this oxidant using o-tolidine dichloride as chromogenic reagent at 430 nm. The analytical curve was linear in the paracetamol concentration range from 8.50 x 10-6 to 2.51 x 10-4 mol L-1 with a detection limit of 5.0 x 10-6 mol L-1. The relative standard deviation was smaller than 1.2% for 1.20 x 10-4 mol L-1 paracetamol solution (n = 10). The results obtained for paracetamol in pharmaceutical formulations using the proposed flow injection method and those obtained using a USP Pharmacopoeia method are in agreement at the 95% confidence level.

Steps towards more effective antitrust system in EU – The Damages Directive’s effect on victim’s right to compensation for antitrust harm

Kaikkien kansalaisten ja yritysten, jotka kärsivät vahinkoa Euroopan Unionin kilpailusääntöjen (SEUT 101 ja 102 artiklan) rikkomisen vuoksi, on voitava vaatia korvauksia vahingon aiheuttaneelta osapuolelta. Euroopan unionin tuomioistuin on ratkaisuillaan Courage ja Manfredi vahvistanut vahinkoa kärsineen oikeuden saada korvausta kärsimästään vahingosta. Suomessa kilpailuoikeudellista vahingonkorvausta koskeva oikeuskäytäntö on ollut vähäistä, vaikkakin viime aikoina on annettu muutama merkittävä vahingonkorvausratkaisu, näistä kenties tunnetuimpana asvalttikartelliratkaisu. Kilpailuoikeuden rikkomisesta vahinkoa kärsineet saavat kuitenkin vain harvoin korvausta kärsimästään vahingosta, mikä on ollut seurausta erilaisista lainsäädännöllisistä ja menettelyistä johtuvista esteistä jäsenvaltioiden säännöissä. Komission pitkään kestänyt lainsäädäntöhanke EU:n kilpailuoikeuden täytäntöönpanojärjestelmän selkeyttämiseksi päättyi marraskuussa 2014, kun Euroopan parlamentin ja neuvoston direktiivi tietyistä säännöistä, joita sovelletaan jäsenvaltioiden ja Euroopan unionin kilpailuoikeuden rikkomisen johdosta kansallisen lainsäädännön nojalla nostettuihin vahingonkorvauskanteisiin (2014/104/ EU) hyväksyttiin. Direktiivi julkaistiin Euroopan unionin virallisessa lehdessä 5. joulukuuta 2014, ja jäsenvaltioilla on 27.12.2016 asti aikaa implementoida direktiivi osaksi kansallista lainsäädäntöä. Direktiivin tavoitteena on EU:n kilpailusääntöjen tehokas täytäntöönpano sekä kilpailuoikeuden julkisoikeudellisen ja yksityisoikeudellisen täytäntöönpanon selkeyttäminen. Lisäksi direktiivi pyrkii varmistamaan, että vahingonkärsijät voivat saada täyden korvauksen kärsimästään vahingosta, sekä poistamaan esteitä ja pienentämään kustannuksia vahingon todistamisessa, samalla harmonisoiden eri jäsenmaissa toimivien yritysten oikeussuojan tasoa. Tarkastelen pro gradu –tutkielmassani kilpailuoikeudellisen vahingonkorvauksen kehitystä sekä uuden EU:n vahingonkorvausdirektiivin vaikutuksia erityisesti vahingonkärsijän näkökulmasta, eli sitä kuinka direktiivi vaikuttaa vahingonkärsijän mahdollisuuteen saada korvausta kärsimästään vahingosta, joka johtuu EU:n kilpailusääntöjen rikkomisesta. Lisäksi tarkastelen lyhyesti direktiivin tuomia muutoksia Suomen lainsäädäntöön. Tutkielmani loppupäätelmä on, että vaikka vahingonkorvausdirektiivi ei täydellisesti paranna vahingonkärsijän asemaa, se selkeyttää monella tavalla kilpailuoikeudellisten vahingonkorvauskanteiden nykyistä tilaa, ja saattaa tietyssä määrin rohkaista vahingonkärsijiä hakemaan korvausta kärsimästään vahingosta.

Foreign trained teachers : the emergence of the right to practise their profession in Ontario

The purpose of this thesis is to examine the impact of 2 recent legal events, specifically the Fair Access to Regulated Professions Act (2006) and Siadat v. Ontario College of Teachers (2007) decision, with regards to the opportunity of foreign trained teachers to practice their profession in Ontario. The emphasis is on the case of Fatima Siadat, who was a teacher in Iran but was unable to satisfy all the licensing requirements of the Ontario College of Teachers and consequently was unable to practise her profession in Ontario. When the Ontario College of Teachers Appeals Committee upheld the previous decision of the Ontario College of Teachers Registrar to refuse to issue her a teacher's certificate, Ms. Fatima Siadat decided to initiate a lawsuit. Ms. Fatima Siadat challenged the decision ofthe Ontario College of Teachers Appeals Committee by raising a question of applicability of human rights legislation (i.e., The Ontario Human Rights Code, 1990) on the Ontario College of Teachers' decisions. The Ontario Superior Court of Justice decided in January of2007 in favour of Ms. Fatima Siadat (Siadat v. Ontario College of Teachers , 2007) and ordered that her licensing application be reconsidered by the Ontario College of Teachers Appeals Committee. In this thesis the author argues that the Fatima Siadat decision, together with the Fair Access to Regulated Professions Act, 2006, will likely make a significant contribution to enhancing the access of foreign trained teachers and other professionals to practice their regulated professions in Ontario.