412 research outputs found
The mechanism of unresponsiveness to allografts induced by rapamycin and rapamycin/cyclosporine treatment in rats
No full textThe mechanisms by which rapamycin (RAPA) and/or cyclosporine induce unresponsiveness to allografts were investigated in a rat model. Buffalo (BUF, RT-1b) heart allografts were rejected by Wistar-Furth (WFu, RT-1u) recipients at a mean survival time (MST) of 6.5 +/- 0.5 days. A 14-day course of RAPA (0.8 mg/kg) delivered intravenously by an osmotic pump prolonged BUF allograft survival to 76.1 +/- 23.4 days (P < 0.001). Adoptive transfer of 30-50 x 10(6) spleen and lymph node T cells that had been isolated on day 40 postgrafting from CsA- or RAPA/CsA-treated hosts into lightly irradiated (6 Gray) secondary WFu recipients prolonged BUF graft survival from 9.8 +/- 1.2 to 29.2 +/- 11.0 (P < 0.01) and 58.2 +/- 38.9 days (P < 0.004), respectively. T cells transferred from animals treated with RAPA alone failed to prolong graft survival. In contrast, sera isolated on day 40 postgrafting from WFu primary hosts treated with RAPA alone or with the RAPA/CsA combination, but not with CsA alone, extended the survival of BUF hearts: 3 ml serum from RAPA-treated hosts prolonged BUF heart survival to 76.6 +/- 31.3 days (P < 0.002) and from RAPA/CsA-treated hosts to 47.1 +/- 12.8 days (P < 0.001). The effect of serum was immunologically specific: it did not prolong the survival of third-party outbred Sprague Dawley heart allografts. Although the IgM fraction (0.2 mg) purified from the serum of RAPA-treated recipients was ineffective (10.6 +/- 0.8 days; NS), an equal amount of the IgG fraction significantly (P < 0.002) prolonged BUF heart allograft survival to 26 days (n = 4). Thus, hosts treated with RAPA or a RAPA/CsA combination develop IgG antibodies that mediate the unresponsive state toward allogeneic heart allograft
Rapamycin inhibits production of cytotoxic but not noncytotoxic antibodies and preferentially activates T helper 2 cells that mediate long-term survival of heart allografts in rats
No full textRapamycin (RAPA) induces unresponsiveness toward heart allografts by at least two mechanisms: selective production of noncytotoxic IgG2c-blocking Ab and preferential activation of Th2 cells. RAPA (0.8 mg/kg/day) delivered via a 14-day osmotic pump to Wistar Furth (WF; RT-1u) recipients prolongs Buffalo (BUF; RT-1b) heart allograft survival from a mean survival time (MST) of 6.5 +/- 0.5 days to 75.0 +/- 18.9 days (n = 18; p < 0.001), with 6 of 18 grafts beating for more than 100 days. Recipient sera or their IgG but not IgM fraction, obtained after postgrafting day 40, passively transfer the unresponsive state to sublethally irradiated secondary recipients in a dose-dependent and immunologically-specific fashion. Sera obtained after untreated WF hosts rejected BUF hearts contained IgG moieties of all subclasses that bound to class I MHC BUF epitopes. In contrast, the unresponsive sera contained predominantly non-C'-fixing IgG2c and only marginal amounts of activated (C') fixing IgG1, IgG2a, and IgG2b Ab. The transcription of IL-2, IL-4, and IL-10 mRNAs was assessed using a PCR method. There were similar increases in the levels of IL-2, IL-4, and IL-10 mRNA in heart allografts from both untreated and RAPA-treated recipients on day 5 postgrafting. In contrast, on days 60 and 300 postgrafting heart allografts from RAPA-treated unresponsive recipients showed increased levels of IL-10 and IL-4 but not of IL-2 mRNA, suggesting preferential activation of Th2 cells. Thus, RAPA treatment selectively inhibits the synthesis of C'-binding of IgG subclasses, spares the non C-binding blocking IgG2c Ab, and preferentially activates Th2 cells
Kinetics of in vitro immune responses of T and B cells during tolerance induction by sirolimus
No full textThe purpose of the study presented herein was to examine immune performances of rat heart allograft recipients immunosuppressed with sirolimus (SRL, rapamycin; Rapamune, Wyeth-Ayerst, Princeton, NJ)
Understanding patient preferences for intervention in precursor multiple myeloma: the preference study
No full textOBJECTIVES: The objectives of the PREFERENCE Study are to characterize preferences of MGUS and SMM patients for early intervention according to attributes of the intervention, and to identify patient characteristics that predict intervention preference patterns.
METHODS: We developed a survey instrument that contained a conjoint survey, a brief demographic survey, and validated survey instruments to assess numeracy, tolerance for uncertainty, and perceived risk of cancer. The survey was distributed to 301 patients with MGUS or SMM. We analyzed the conjoint data using conditional logistic regression models to investigate the attributes that drive patient decisions about early intervention. We next used latent profile analysis to investigate whether there are latent classes of patients defined by their choice preferences. We then estimated posterior probabilities to evaluate which patient characteristics predict class membership.
RESULTS: We found that for every 10% increase in the ability of a treatment to prevent myeloma, there was an 86% increase in selecting the treatment strategy, and for every $100 increase in monthly cost, there was a 11% decrease in selecting the strategy. High personal inconvenience led to a 38% decrease in selecting a treatment strategy, and a high risk of side effects led to a 91% decrease in selecting a strategy. Latent profile analysis revealed three classes of patients. A class of patients who were willing to accept less efficacious therapies with a higher monthly cost to prioritize avoiding side effects, a class of patients who were willing to accept less efficacious therapies and some risk of side effects to keep monthly cost low, and a class of patients who were willing to accept some risk of side effects and a higher monthly cost to prioritize efficacious therapy. The posterior probabilities did not show a significant difference in class membership based on age, and participants with higher education and higher income were less likely to fall into the latent class prioritizing low cost. Results also showed that choosing efficacious therapy is not perfectly coupled with risk of multiple myeloma.
CONCLUSION: These results emphasize that the “one-size-fits-all” approach in treatment of MM precursor conditions will not meet the needs and preferences of MGUS and SMM patients. In broad populations there are diverse preferences leading to a need for comprehensive intervention portfolios
A sacramental theology of the poor centred on the Eucharistic liturgy from Coptic and Latin American perspectives
No full textThe integral liberation of the poor, the oppressed, and the marginalised (henceforth ‘the poor’) can be conceived as a deep sacramental act that Christians are called to realise and experience in history. In light of this concept, this interdisciplinary study explores the sacramental dimension of the theology of the poor (TP) and its eucharistic and liturgical applications from Coptic Orthodox perspectives and Latin American Liberation Theology perspectives. The main purpose is to investigate the grounds on which a sacramental theology of the poor (STP) stands and analyse its liberationist features and dynamics.
The study is primarily based on a dialogue between Coptic theologians and Latin American liberation theologians. It brings their writings into a guided open-ended conversation on key topics regarding the TP, its sacramental foundations, and its eucharistic and liturgical expressions. More precisely, it delves into the Christo-pneumatological aspect of the STP, the expected holistic transformation, and the place of eschatological imagination.
This dialogue demonstrates that both theologies share numerous areas of agreement albeit using different terminologies. It also reveals distinct areas of emphasis and in some cases diversion for each theology. The study argues that both theologies can be complementary to constructing a comprehensive STP.
Towards the end of this project, the opinions of liturgiologists, sociologists, and anthropologists of religion are introduced to the conversation to build an image of a liberating eucharistic liturgy, a liturgy of the poor. This image is afterward used – and tested – to analyse the current Coptic liturgical text.
The study bridges two distinct rich theologies for the sake of the poor. It uncovers an intrinsic relationship between integral liberation and eucharistic liturgy. It also offers a vision for a liberating liturgy and a tool to analyse critically and constructively a given liturgy practiced in a certain context from the perspective of the poor
Embedding Behavioral and Social Sciences across the Medical Curriculum: (Auto) Ethnographic Insights from Medical Schools in the United Kingdom
No full textKey concepts and theories that are taught in order to develop cultural competency skills are often introduced to medical students throughout behavioral and social science (BSS) learning content. BSS represents a core component of medical education in the United Kingdom. In this paper, we examine, through (auto)ethnographic data and reflections, the experiences of BSS in medical education. The empirical data and insights have been collected in two ways: (1) through long-term ethnographic fieldwork among medical students and (2) via autoethnographic reflexive practice undertaken by the co-authors who studied, worked, examined, and collaborated with colleagues at different UK medical schools. Our findings indicate that despite BSS constituting a mandatory, essential component of the medical curriculum, medical students did not always perceive BSS as useful for their future practice as doctors, nor did they find it to be clinically relevant, in comparison to the biomedical learning content. We suggest that it is paramount for all stakeholders to commit to cultivating and developing cultural competency skills in medical education, through robustly embedding BSS learning content across the undergraduate medical curriculum. We conclude with recommendations for a wide range of educational practices that would ensure a full integration of BSS in the medical curriculum
La dynamique spatiale et temporelle des débâcles et embâcles de glace sur la rivière Chaudière
No full textLa rivière Chaudière, ce cours d'eau de la rive sud du Saint-Laurent à Québec, s'est vu être la source de multiples inondations dans l'histoire beauceronne. Une partie importante de ses colères est attribuable aux embâcles de glace et à l'inévitable débâcle qui les initie. La compréhension des causes de ces embâcles est nécessaire afin d'agir, pour le mieux, sur le phénomène d'embâcle et cette étude s'inscrit dans cette ligne de pensée. L'étude vise à décrire, caractériser et quantifier la dynamique spatio-temporelle de la débâcle et des embâcles de glace sur la rivière Chaudière par des observations de terrain au cours des hivers 2018-2019 et 2019-2020. Pendant ces hivers, des dizaines de caméras autonomes et de GPS-trackers ont été installés à des endroits stratégiques. Grâce à cette instrumentation, à l'emploi d'outils tiers (données hydrométriques; CEHQ et COBARIC, images satellites; Sentinel-HUB) et à sa présence sur le terrain, l'auteur a pu reconstruire en détail la chronologie spatio-temporelle des débâcles sur la rivière Chaudière. Les observations montrent que les débâcles printanières s'initient d'abord en Haute Chaudière, et ensuite en Moyenne et Basse Chaudière presque simultanément. La débâcle est d'abord complétée en Haute Chaudière, ensuite en Basse Chaudière et finalement vient la Moyenne Chaudière où des vestiges d'embâcles hivernaux ont retardé le départ des glaces entre Saint-Joseph et Beauceville. Dans le segment le plus amont, la Haute Chaudière, les glaces ont été mises en mouvement lorsque le débit a atteint entre 60 et 200 m³/s (station Saint-Georges) et à un indice de dégel entre 20 et 80 °C-J. Plus à l'aval, en Moyenne Chaudière, c'est entre 220 et 1000 m³/s (station Saint-Georges), lorsque l'indice de dégel se situait entre 110 et 180 °C-J, que la majorité des glaces se sont mises en mouvement. En Basse Chaudière, c'est plutôt entre 140 et 710 m³/s (station Saint-Georges), et lorsque l'indice de dégel variait autour de 125 °C-J, que les glaces ont été évacuées du cours d'eau. Lors de ces deux saisons d'observation seulement, 51 embâcles de glace ont été répertoriés, illustrant le caractère dynamique de la Chaudière. La forte majorité d'entre eux était contenue dans le segment de la Moyenne Chaudière, démontrant sa forte capacité pour la rétention des glaces. Les plus longs, et ceux ayant contribué à des inondations, se sont formés entre Beauceville et Saint-Georges, témoignant du risque élevé qui plane sur les riverains dans ce tronçon. Les îles, bifurcations du chenal et changements de pente représentent les styles géomorphologiques les plus susceptibles d'obstruer le passage des glaces. Les relâchements d'embâcles ont engendré des ondes d'eau voyageant à des célérités de l'ordre de 1.5 m/s à 7.0 m/s. Les plus élevées ont été estimées entre Beauceville et Saint-Georges. Plus en aval, dans la section des « eaux mortes » (Moyenne Chaudière), la plaine inondable amortit l'onde et tend à réduire sa vitesse de propagation. C'est dans cette section que les plus faibles valeurs ont été estimées. Les patrons spatio-temporels de la débâcle, les seuils hydrométéorologiques de mobilisations des glaces, les sites d'embâcles et les célérités d'ondes d'eau, tous identifiés dans ce mémoire, peuvent servir à la conception d'ouvrages du génie, ainsi que pour le développement d'un système d'alerte précoce.The Chaudière River, located on the south shore of the Saint Lawrence River, Quebec, is well known for its frequent flooding events. An important part of those floods is caused by ice jams associated with the inevitable breakup that precedes them. In order to eventually alleviate the impacts of ice jam flooding events, knowledge must be acquired from observations of the breakup dynamics, which is the aim of this study. The goal of this study is to describe, characterize and quantify the spatiotemporal dynamics of the breakup events and ice jams along the Chaudière river. During the winters 2018-2019 and 2019-2020, tens of autonomous cameras and GPS-trackers were installed at strategic locations along the river. With this instrumentation, the use of third-party tools (hydrometric data; CEHQ and COBARIC, satellite images; Sentinel-HUB) along with his presence on the field, the author was able to reconstruct the detail of each breakup events. The resulting observations showed that spring breakups are initiated in upper reach of the river, the Haute Chaudière, and then after, almost simultaneously, in the Moyenne and Basse Chaudière segments. The breakup is usually first completed in the Haute Chaudière, then in Basse Chaudière, and lastly in Moyenne Chaudière where mid-winter ice jams have been seen to delay the ice clearing between Saint-Joseph and Beauceville. In the Haute Chaudière, ice movements began when the flow rate was between 60 and 200 m³/s (Saint-Georges station) and when the ice decay index was between 20 and 80 °C-J. In Moyenne Chaudière, it is when the discharge varied from 220 to 1000 m³/s (Saint-Georges station) and when the ice decay index was between 110 to 180 °C-J that the ice moved and eventually cleared. In Basse Chaudière, ice movements were observed between 140 m³/s and 710 m³/s (station Saint-Georges), and when the ice decay index was about 125 °C-J. During these two winter seasons, 51 ice jams were observed. The vast majority of them was found in the Moyenne Chaudière reach, demonstrating its strong capacity for ice retention. The longest jams, and those that contributed to flooding, were found between Beauceville and Saint-Georges, which translates a higher risk for the riparian residents along this reach. Islands, channel bifurcations and slope changes were the most susceptible geomorphological features to initiate ice jamming. Ice jam generated water waves ('Javes') that travelled at a celerity ranging from 1.5 m/s to 7.0 m/s. In the "eaux mortes" reach (Moyenne Chaudière), the floodplains dampened the waves and therefore reduced the velocities. The highest velocities were observed between Beauceville and Saint-Georges. Breakup patterns, hydrometeorological thresholds of ice mobilization, ice jam sites and javes celerity, all identified in this thesis, can serve as basis for engineering design, including the implementation of an early warning system
Update on treatment recommendations from the Fourth International Workshop on Waldenstrom's Macroglobulinemia.
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