Enhanced de novo alloantibody and antibody-mediated injury in rhesus macaques.

Chronic allograft rejection is a major impediment to long-term transplant success. Humoral immune responses to alloantigens are a growing clinical problem in transplantation, with mounting evidence associating alloantibodies with the development of chronic rejection. Nearly a third of transplant recipients develop de novo antibodies, for which no established therapies are effective at preventing or eliminating, highlighting the need for a nonhuman primate model of antibody-mediated rejection. In this report, we demonstrate that depletion using anti-CD3 immunotoxin (IT) combined with maintenance immunosuppression that included tacrolimus with or without alefacept reliably prolonged renal allograft survival in rhesus monkeys. In these animals, a preferential skewing toward CD4 repopulation and proliferation was observed, particularly with the addition of alefacept. Furthermore, alefacept-treated animals demonstrated increased alloantibody production (100%) and morphologic features of antibody-mediated injury. In vitro, alefacept was found to enhance CD4 effector memory T cell proliferation. In conclusion, alefacept administration after depletion and with tacrolimus promotes a CD4+memory T cell and alloantibody response, with morphologic changes reflecting antibody-mediated allograft injury. Early and consistent de novo alloantibody production with associated histological changes makes this nonhuman primate model an attractive candidate for evaluating targeted therapeutics.

Primary vascularization of the graft determines the immunodominance of murine minor H antigens during organ transplantation.

Grafts can be rejected even when matched for MHC because of differences in the minor histocompatibility Ags (mH-Ags). H4- and H60-derived epitopes are known as immunodominant mH-Ags in H2(b)-compatible BALB.B to C57BL/6 transplantation settings. Although multiple explanations have been provided to explain immunodominance of Ags, the role of vascularization of the graft is yet to be determined. In this study, we used heart (vascularized) and skin (nonvascularized) transplantations to determine the role of primary vascularization of the graft. A higher IFN-γ response toward H60 peptide occurs in heart recipients. In contrast, a higher IFN-γ response was generated against H4 peptide in skin transplant recipients. Peptide-loaded tetramer staining revealed a distinct antigenic hierarchy between heart and skin transplantation: H60-specific CD8(+) T cells were the most abundant after heart transplantation, whereas H4-specific CD8(+) T cells were more abundant after skin graft. Neither the tissue-specific distribution of mH-Ags nor the draining lymph node-derived dendritic cells correlated with the observed immunodominance. Interestingly, non-primarily vascularized cardiac allografts mimicked skin grafts in the observed immunodominance, and H60 immunodominance was observed in primarily vascularized skin grafts. However, T cell depletion from the BALB.B donor prior to cardiac allograft induces H4 immunodominance in vascularized cardiac allograft. Collectively, our data suggest that immediate transmigration of donor T cells via primary vascularization is responsible for the immunodominance of H60 mH-Ag in organ and tissue transplantation.

Interleukin-15 receptor blockade in non-human primate kidney transplantation.

BACKGROUND: Interleukin (IL)-15 is a chemotactic factor to T cells. It induces proliferation and promotes survival of activated T cells. IL-15 receptor blockade in mouse cardiac and islet allotransplant models has led to long-term engraftment and a regulatory T-cell environment. This study investigated the efficacy of IL-15 receptor blockade using Mut-IL-15/Fc in an outbred non-human primate model of renal allotransplantation. METHODS: Male cynomolgus macaque donor-recipient pairs were selected based on ABO typing, major histocompatibility complex class I typing, and carboxy-fluorescein diacetate succinimidyl ester-based mixed lymphocyte responses. Once animals were assigned to one of six treatment groups, they underwent renal transplantation and bilateral native nephrectomy. Serum creatinine level was monitored twice weekly and as indicated, and protocol biopsies were performed. Rejection was defined as a increase in serum creatinine to 1.5 mg/dL or higher and was confirmed histologically. Complete blood counts and flow cytometric analyses were performed periodically posttransplant; pharmacokinetic parameters of Mut-IL-15/Fc were assessed. RESULTS: Compared with control animals, Mut-IL-15/Fc-treated animals did not demonstrate increased graft survival despite adequate serum levels of Mut-IL-15/Fc. Flow cytometric analysis of white blood cell subgroups demonstrated a decrease in CD8 T-cell and natural killer cell numbers, although this did not reach statistical significance. Interestingly, two animals receiving Mut-IL-15/Fc developed infectious complications, but no infection was seen in control animals. Renal pathology varied widely. CONCLUSIONS: Peritransplant IL-15 receptor blockade does not prolong allograft survival in non-human primate renal transplantation; however, it reduces the number of CD8 T cells and natural killer cells in the peripheral blood.

Impact of Leukocyte Function-Associated Antigen-1 Blockade on Endogenous Allospecific T Cells to Multiple Minor Histocompatibility Antigen Mismatched Cardiac Allograft.

BACKGROUND: Blocking leukocyte function-associated antigen (LFA)-1 in organ transplant recipients prolongs allograft survival. However, the precise mechanisms underlying the therapeutic potential of LFA-1 blockade in preventing chronic rejection are not fully elucidated. Cardiac allograft vasculopathy (CAV) is the preeminent cause of late cardiac allograft failure characterized histologically by concentric intimal hyperplasia. METHODS: Anti-LFA-1 monoclonal antibody was used in a multiple minor antigen-mismatched, BALB.B (H-2B) to C57BL/6 (H-2B), cardiac allograft model. Endogenous donor-specific CD8 T cells were tracked down using major histocompatibility complex multimers against the immunodominant H4, H7, H13, H28, and H60 minor Ags. RESULTS: The LFA-1 blockade prevented acute rejection and preserved palpable beating quality with reduced CD8 T-cell graft infiltration. Interestingly, less CD8 T cell infiltration was secondary to reduction of T-cell expansion rather than less trafficking. The LFA-1 blockade significantly suppressed the clonal expansion of minor histocompatibility antigen-specific CD8 T cells during the expansion and contraction phase. The CAV development was evaluated with morphometric analysis at postoperation day 100. The LFA-1 blockade profoundly attenuated neointimal hyperplasia (61.6 vs 23.8%; P < 0.05), CAV-affected vessel number (55.3 vs 15.9%; P < 0.05), and myocardial fibrosis (grade 3.29 vs 1.8; P < 0.05). Finally, short-term LFA-1 blockade promoted long-term donor-specific regulation, which resulted in attenuated transplant arteriosclerosis. CONCLUSIONS: Taken together, LFA-1 blockade inhibits initial endogenous alloreactive T-cell expansion and induces more regulation. Such a mechanism supports a pulse tolerance induction strategy with anti-LFA-1 rather than long-term treatment.

A model of sequential heart and composite tissue allotransplant in rats.

BACKGROUND: Some of the 600,000 patients with solid organ allotransplants need reconstruction with a composite tissue allotransplant, such as the hand, abdominal wall, or face. The aim of this study was to develop a rat model for assessing the effects of a secondary composite tissue allotransplant on a primary heart allotransplant. METHODS: Hearts of Wistar Kyoto rats were harvested and transplanted heterotopically to the neck of recipient Fisher 344 rats. The anastomoses were performed between the donor brachiocephalic artery and the recipient left common carotid artery, and between the donor pulmonary artery and the recipient external jugular vein. Recipients received cyclosporine A for 10 days only. Heart rate was assessed noninvasively. The sequential composite tissue allotransplant consisted of a 3 x 3-cm abdominal musculocutaneous flap harvested from Lewis rats and transplanted to the abdomen of the heart allotransplant recipients. The abdominal flap vessels were connected to the femoral vessels. No further immunosuppression was administered following the composite tissue allotransplant. Ten days after composite tissue allotransplantation, rejection of the heart and abdominal flap was assessed histologically. RESULTS: The rat survival rate of the two-stage transplant surgery was 80 percent. The transplanted heart rate decreased from 150 +/- 22 beats per minute immediately after transplant to 83 +/- 12 beats per minute on day 20 (10 days after stopping immunosuppression). CONCLUSIONS: This sequential allotransplant model is technically demanding. It will facilitate investigation of the effects of a secondary composite tissue allotransplant following primary solid organ transplantation and could be useful in developing future immunotherapeutic strategies.

Employment discrimination against transgender people and self-esteem.

The evocation of gender identity in company anti-discrimination policies is still very rare. This observation is also true forscientific studies. Very few researches have focused exclusively on transgender employees. Transgender are neither sick nor lesscompetent, and yet, the feeling of being strongly discriminated is shared by many transgender people. Such discrimination and thetype of causal attribution do not remain without any effect on the well-being of the concerned individuals. According to Crocker &Quinn (1998), the attribution of the discrimination to the existing prejudices may be a way to protect one-self from the negativeimpact on self-esteem. In this theoretical scope, the "rejection-identification" model (Branscombe, Schmitt & Harvey, 1999) has beenhighly mobilized. It emphasizes the importance of ingroup identification in the causal relationship between perceived discriminationsituation and well-being. Previous studies which did test this model show that the identification to a certain group can counteract thenegative effects on well-being. Following this theoretical frame, the presented study examines the impact of different types of causalattributions on self-esteem: internal causes (e.g. lack of skills), external causes (e.g. economic crisis), and gender identity relatedissues. For that purpose, an online survey has been created and fulfilled by 110 transgender people. Different scales were used to testthe model: the Rosenberg self-esteem scale, a causal attribution scale, the perceived discrimination of the transgender population inthe workplace scale and a group identification scale. The results show that transgender people feel still highly stigmatized today andattribute, significantly, the causes of their situation to the prejudices they are victim of. Also, in accordance with the “rejectionidentification”model, three links are observed: (1) a negative link between perceived discrimination and self-esteem; (2) a positivelink between perceived discrimination and ingroup identification; and (3) a positive link between ingroup identification and selfesteem.This situation reflects a lack in diversity considerations. Nevertheless, the attribution made to group stigmatization seems toplay a protective role towards transgender people self-esteem.

Rapamycin Interferes With Postdepletion Regulatory T Cell Homeostasis and Enhances DSA Formation Corrected by CTLA4-Ig.

Previously, we demonstrated that alemtuzumab induction with rapamycin as sole maintenance therapy is associated with an increased incidence of humoral rejection in human kidney transplant patients. To investigate the role of rapamycin in posttransplant humoral responses after T cell depletion, fully MHC mismatched hearts were transplanted into hCD52Tg mice, followed by alemtuzumab treatment with or without a short course of rapamycin. While untreated hCD52Tg recipients acutely rejected B6 hearts (n = 12), hCD52Tg recipients treated with alemtuzumab alone or in conjunction with rapamycin showed a lack of acute rejection (MST > 100). However, additional rapamycin showed a reduced beating quality over time and increased incidence of vasculopathy. Furthermore, rapamycin supplementation showed an increased serum donor-specific antibodies (DSA) level compared to alemtuzumab alone at postoperation days 50 and 100. Surprisingly, additional rapamycin treatment significantly reduced CD4(+) CD25(+) FoxP3(+) T reg cell numbers during treatment. On the contrary, ICOS(+) PD-1(+) CD4 follicular helper T cells in the lymph nodes were significantly increased. Interestingly, CTLA4-Ig supplementation in conjunction with rapamycin corrected rapamycin-induced accelerated posttransplant humoral response by directly modulating Tfh cells but not Treg cells. This suggests that rapamycin after T cell depletion could affect Treg cells leading to an increase of Tfh cells and DSA production that can be reversed by CTLA4-Ig.

Adult personality inconsistency and problems with parents: uncovering the roots of the false self

Research has established that individuals who tend to vary their personality depending on who they are with, show a variety of signs of psychological maladjustment in comparison to those who do not; they show more negative affect (Baird, Le and Lucas, 2006), lower life satisfaction (Suh, 2002), lower self-esteem (Sheldon et al., 1997), lower role-satisfaction (Donahue et al., 1993), higher rates of depression (Lutz and Ross, 2003), more anxiety (Diehl, Hastings and Stanton, 2001) and poorer physical health (Cross, Gore and Morris, 2003). It has also been shown that personality variability is positively related to the experience of inauthenticity and falsity (Sheldon et al., 1997). Donahue, Roberts, Robins and John (1993) found that personality inconsistency of this type is related to tension within the family. Psychoanalytic theory has also linked the operation of an adult false self to experiences with parents, particularly in early life (Winnicott, 1960). It was hypothesized that personality variability and the adult experience of falsity in social situations would be related to an emotionally unstable relationship with parents. The method to test this comprised a questionnaire-based survey given to a non-clinical population. The final sample comprised 305, with 193 women and 112 men, aged from 19 to 55. The first questionnaire asked participants to rate personality traits, including emotional stability, in three social contexts - with parents, with friends and with work colleagues. The second part involved 3 questions; participants were asked to select in which of the aforementioned three social contexts they felt “most themselves”; in which they were “most authentic” and in which they “put on a front”. It was found, consistent with predictions, that an index of overall personality variability calculated from the personality questionnaire correlated strongly with emotional instability around parents (r = 0.46, p<0.001), while not correlating with emotional instability in either of the other two contexts measured. This suggests a specific link between a person’s relationship with their parents and their overall personality integration. Furthermore, it was found that participants who cited one of the three social contexts (parents, friends, work colleagues) as being one in which they were “more themselves” or “more authentic” had significantly higher ratings of emotional instability with parents than those participants who found that they were equally authentic across settings (F = 9.8, p<0.005). The results suggest a clear link between a person’s relationships with their parents and their adult personality integration. An explanation is that individuals who experience an anxious or ambiguous attachment with their parents in childhood may fear rejection or abandonment in later life, and so habitually adapt their personality to fit in to social contexts as adults, in order to be accepted by others and to minimize the possibility of social rejection. These individuals meanwhile retain an emotionally unstable relationship with their parents in adulthood. This interpretation is speculative but is open to empirical testing. Clinicians should be aware that attachment problems with parents may underlie poor personality integration in adulthood.

Hemolymph Functions In Mytilus-Californianus - Cytochemistry Of Hemocytes And Their Responses To Foreign Implants And Hemolymph Factors In Phagocytosis

The hemocytes of Mytilus californianus are of three types: small and large basophils and large granular acidophils. The basophils contain lysosomal enzymes and phagocytose colloidal carbon. Agglutinins for yeast and human A Rh+ve erythrocytes are present in plasma, but are not needed for effective phagocytosis; in vitro both acidophilic and basophilic hemocytes rapidly phagocytose these particles. Plasma proteins, analyzed electrophoretically, are under strong homeostatic control. When Mya arenaria mantle is placed orthotopically on M. californianus mantle, the implant is invaded by host hemocytes in a manner consistent with that described in other published reports on molluscan graft rejection. Steady state is achieved by 26 days postimplant. Second- and third-set implants are rejected more rapidly than are first-set implants, but this is not a specific response. Third-set implants elicit a host cellular response that is more localized than the response to first-set implants. These data do not permit conclusions with respect to memory in these molluscan immune responses, but do imply a qualitative “improvement” in this quasi-immune response of M. californianus.

The Impact of Polystyrene Microplastics on Feeding, Function and Fecundity in the Marine CopepodCalanus helgolandicus

Microscopic plastic debris, termed “microplastics”, are of increasing environmental concern. Recent studies have demonstrated that a range of zooplankton, including copepods, can ingest microplastics. Copepods are a globally abundant class of zooplankton that form a key trophic link between primary producers and higher trophic marine organisms. Here we demonstrate that ingestion of microplastics can significantly alter the feeding capacity of the pelagic copepod Calanus helgolandicus. Exposed to 20 μm polystyrene beads (75 microplastics mL–1) and cultured algae ([250 μg C L–1) for 24 h, C. helgolandicus ingested 11% fewer algal cells (P = 0.33) and 40% less carbon biomass (P < 0.01). There was a net downward shift in the mean size of algal prey consumed (P < 0.001), with a 3.6 fold increase in ingestion rate for the smallest size class of algal prey (11.6–12.6 μm), suggestive of postcapture or postingestion rejection. Prolonged exposure to polystyrene microplastics significantly decreased reproductive output, but there were no significant differences in egg production rates, respiration or survival. We constructed a conceptual energetic (carbon) budget showing that microplastic-exposed copepods suffer energetic depletion over time. We conclude that microplastics impede feeding in copepods, which over time could lead to sustained reductions in ingested carbon biomass.

7. On the priority of "Genistion purgantis" Tüxen in Tüxen & Oberdorfer 1958 and "Senecioni-Genistetum purgantis" Tüxen & Oberdorfer 1958

In a recent review of which we were co-authors (Rivas-Martínez, Belmonte, Cantó, Fernández-González, Fuente, Moreno, Sánchez-Mata & Sancho, Lazaroa 7: 93-124. 1987), rejection of names Genistion purgantis Túxen in Túxen & Oberdorfer 1958 [Veróff. Geobot. Inst. Rúbel Zúrich 32: 228] and Senecio tournefortii-Genistapurgans Ass. Túxen & Oberdorfer 1958 [op. cit.: 229-230] versus Pino-Cytision purgantis Rivas-Martínez 1964 [Anales lnst. Bot. Cavanilles 22: 358] and Junipero nanae-Sarothamnetum purgantis Rivas-Martínez 1963 [Anales Inst. Bot. Cavanilles 21(1): 172-186] respectively, was proposed and adopted.

Historians and their duties

We need to specify what ethical responsibility historians, as historians, owe, and to whom. We should distinguish between natural duties and (non-natural) obligations, and recognize that historians' ethical responsibility is of the latter kind. We can discover this responsibility by using the concept of “accountability”. Historical knowledge is central. Historians' central ethical responsibility is that they ought to tell the objective truth. This is not a duty shared with everybody, for the right to truth varies with the audience. Being a historian is essentially a matter of searching for historical knowledge as part of an obligation voluntarily undertaken to give truth to those who have a right to it. On a democratic understanding, people need and are entitled to an objective understanding of the historical processes in which they live. Factual knowledge and judgments of value are both required, whatever philosophical view we might have of the possibility of a principled distinction between them. Historians owe historical truth not only to the living but to the dead. Historians should judge when that is called for, but they should not distort historical facts. The rejection of postmodernism's moralism does not free historians from moral duties. Historians and moral philosophers alike are able to make dispassionate moral judgments, but those who feel untrained should be educated in moral understanding. We must ensure the moral and social responsibility of historical knowledge. As philosophers of history, we need a rational reconstruction of moral judgments in history to help with this.

Validity, trustworthiness and rigour:reasserting realism in qualitative research

Aim The aim of this paper is to challenge recent sceptical approaches to the possibility of validating qualitative research and to underline the benefits of adopting a realist approach to validity. Background In recent discussion about the methodological bases for qualitative research it has been argued that, because different methodologies take different approaches to validity, attempts to develop a common set of validation criteria are futile. On the basis of this sceptical view, a number of strategies for judging qualitative research have been proposed. These include suggestions that: it should be judged according to aesthetic or rhetorical criteria, rather than epistemological validity; responsibility for appraisal should move from researchers to readers; each methodology should be assessed individually according to its own merits. Discussion None of these suggestions provide a viable alternative to validity, defined as the extent to which research reflects accurately that to which it refers. Because the form of research does not determine its content, replacement of epistemology by aesthetics is unsustainable. Because research reports mediate between writer and reader, a one-sided approach to this relationship constitutes a false dichotomy. If we accept the criterion of practitioner confidence as a means of judging methodological approaches, this involves rejection of judgement according to a methodology�s own merits. Conclusion If qualitative research is actually about something, and if it is required to provide beneficial information, then a realist approach to validity holds out greatest promise.

Sexual cannibalism and mate choice

Sexual cannibalism, where a female kills and consumes a courting male, represents an extreme form of sexual conflict and has been proposed as a mechanism of mate choice. We evaluate the evidence for mate choice through premating sexual cannibalism via mate rejection, other indirect mechanisms of mate 'choice' and choice in postmating sexual cannibalism. We highlight a paucity of investigations, particularly of field studies, and note gaps in our knowledge. There is empirical support for the size-dependent sexual cannibalism predicted by mate choice through premating sexual cannibalism. This may represent mate choice operating on absolute male size but it could be a by-product of female foraging behaviour and greater vulnerability of relatively smaller males. Thus, indirect mate choice is as plausible an explanation of size-dependent sexual cannibalism as is direct mate choice based on discrimination of male traits. Direct female choice, mediated through premating sexual cannibalism, has yet to be demonstrated. We suggest a framework for distinguishing direct and indirect choice and note an absence of information on which to test it. There is evidence for sequential mate choice in postmating sexual cannibalism, but the nature or basis of the female's discriminatory behaviour remains unclear. Costs and long-term fitness benefits of the putative mate choice have been largely ignored. Reversed sexual cannibalism, in which the male eats the female, presumably occurs when the gain from food is high and potential gain from mating low and probably has little to do with mate choice. (c) 2005 The Association for the Study of Animal Behaviour Published by Elsevier Ltd. All rights reserved.

Submillimeter wave frequency selective surface with polarisation independent spectral responses

This paper reports the design, construction and electromagnetic performance of a new freestanding frequency selective surface (FSS) structure which generates coincident spectral responses for dual polarisation excitation at oblique angles of incidence. The FSS is required to allow transmission of 316.5 - 325.5 GHz radiation with a loss = 0.6 dB and to achieve = 30 dB rejection from 349.5 - 358.5 GHz. It should also exhibit crosspolarisation levels below -25 dB, all criteria being satisfied simultaneously for TE and TM polarisations at 45° incidence. The filter consists of two identical, 30 mm diameter, 12.5 ?m thick, optically flat, perforated metal screens separated by 450 ?m. Each of the ˜5000 unit cells contains two nested, short circuited, rectangular loop slots and a rectangular dipole slot. The nested elements provide a passband spectral response centred at 320 GHz in the TE and TM planes; the dipole slot increases the filter roll-off above resonance. The FSS was fabricated from silicon-on-insulator wafers using precision micromachining and plating processes including the use of Deep Reactive Ion Etching (DRIE) to pattern the individual slots and remove the substrate under the periodic arrays. Quasi–optical transmission measurements in the 250 – 360 GHz range yielded virtually identical copolarised spectral responses, with the performance meeting or exceeding the above specifications. Experimental results are in excellent agreement with numerical predictions.