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Chronic rejection is a major barrier to long-term renal allograft survival. Cyclosporine, though effective at reducing graft loss to acute rejection, has had little impact on the incidence of chronic rejection. Between June 2, 1986 and January 22, 1991, 587 kidney-alone transplants (566 patients) were performed, and had been entered into our renal transplant database and had at least 1 year of follow-up: 103 with biopsy-proven chronic rejection (37 living-related donor, 66 cadaver) and 484 without chronic rejection (236 LRD 248 CAD). The 5-year patient survival was 84% for recipients with biopsy-proven chronic rejection vs. 89% without (P = .08). The 5-year graft survival was 31% for recipients with biopsy-proven chronic rejection vs. 81% without (P < .0001). Using multivariate analysis, we determined the impact on the incidence of chronic rejection of these variables: transplant number, age at transplant (< 18 years, 18 to 50 years, > 50 years), gender, human leukocyte antigen matching, peak and transplant panel-reactive antibody, acute rejection episodes, infections (including cytomegalovirus, viral, and bacterial), donor age, and CsA dosage at 1 year (< 5 mg/kg vs. > or = 5 mg/kg). Logistic regression models were fit to the data using a forward stepwise selection procedure. In this analysis, risk factors included an acute rejection episode (P < .001), CsA dosage < 5 mg/kg/day at 1 year (P = .007), infection (P = .023), female gender (P = .042), and retransplant (P = .103). Individual analyses were done for CAD and LRD recipients. For both groups, important variables were acute rejection, infection, CsA dosage at 1 year, and age at transplant. In conclusion, acute rejection, CsA dosage < 5 mg/kg/day at 1 year, and infection are the major risk factors for the development of chronic rejection, suggesting that chronic rejection may be the result of inadequate immunosuppression (acute rejection episodes and low CsA dosage) or the production of inflammatory cytokines (infections).

Mycophenolate mofetil (MMF), a new immunosup-pressant that selectively inhibits proliferation of T and B lymphocytes, may reduce the frequency and severity of acute graft rejection. Acute graft rejection is the leading cause of graft loss in cadaveric renal transplantation. The purpose of this randomized, double-blind, multicenter study was to evaluate the efficacy and safety of MMF for the prevention of acute rejection episodes in adult patients during the first 6 months after renal transplantation. A total of 499 patients who were to receive a primary cadaveric renal allograft as their first transplant were randomized to receive MMF 1.0 g b.i.d. (MMF 2 g treatment group), MMF 1.5 g b.i.d. (MMF 3 g treatment group), or azathioprine 1–2 mg/kg/day. CsA, corticosteroids, and antithymocyte globulin (ATGAM) were administered as part of a quadruple sequential induction protocol. The primary efficacy endpoint was biopsy-proven rejection or treatment failure (defined as graft loss, death, or premature withdrawal from the study for any reason) during the first 6 months after transplant. All enrolled patients were included in the primary analyses of efficacy on the basis of intent to treat. The 495 patients who received study drug were included in the safety and secondary efficacy analyses. Biopsy-proven acute rejection episodes or treatment failure occurred in 47.6% of patients in the azathioprine group compared with 31.1% (P=0.0015) and 31.3% (P=0.0021) of patients in the MMF 2 g and 3 g treatment groups, respectively. Time to first biopsy-proven rejection episode or treatment failure was significantly longer for MMF 2 g versus azathioprine (P=0.0036) and MMF 3 g versus azathioprine (P=0.0006). First biopsy-proven rejection alone occurred in 38.0% of patients who received azathioprine compared with 19.8% and 17.5% of patients who received MMF 2 g and 3 g, respectively. Patients in the azathioprine group received a greater number of full courses of antirejection treatment as compared with the MMF 2 g and MMF 3 g groups (44.5%, 24.8%, and 21.1%, respectively). The use of antilymphocyte agents to treat rejection was greater in the azathioprine group (20.1%) compared with the MMF 2 g group (10.3%) and the MMF 3 g group (5.4%). At 6 months after transplant, graft and patient survival were similar in all 3 treatment groups. The incidence and types of adverse events were similar among treatment groups, with the exception of a higher incidence of diarrhea, certain other infrequent gastrointestinal adverse events, clinically important leukopenia, and tissue-invasive CMV disease in the MMF groups, particularly in the MMF 3 g group. Three patients who received MMF developed lymphoma/lymphoproliferative disorder. This study demonstrated that MMF administered at a dosage of 2 g or 3 g daily, in combination with maintenance CsA and corticosteroids as triple therapy following ATGAM induction therapy, is more effective than an otherwise identical regimen that includes azathioprine instead of MMF in preventing acute allograft rejection in first cadaveric renal transplant patients. This regimen also has an acceptable adverse event profile. The MMF 3 g dosage was considered to be somewhat less well tolerated than the MMF 2 g dosage.

People who are sensitive to social rejection tend to anxiously expect, readily perceive, and overreact to it. This article shows that this cognitive-affective processing disposition undermines intimate relationships. Study 1 describes a measure that operationalizes the anxious-expectations component of rejection sensitivity. Study 2 provides experimental evidence that people who anxiously expect rejection readily perceive intentional rejection in the ambiguous behavior of others. Study 3 shows that people who enter romantic relationships with anxious expectations of rejection readily perceive intentional rejection in the insensitive behavior of their new partners. Study 4 demonstrates that rejection-sensitive people and their romantic partners are dissatisfied with their relationships. Rejection-sensitive men's jealousy and rejection-sensitive women's hostility and diminished supportiveness help explain their partners' dissatisfaction.

Acute rejection is known to have a strong impact on graft survival. Many studies suggest that very low acute rejection rates can be achieved with current immunosuppressive protocols. We wanted to investigate how acute rejection rates have evolved on a national level in the U.S. and how this has impacted graft survival in the most recent era of kidney transplantation. For this purpose, we analyzed data provided by the Scientific Registry of Transplant Recipients regarding all adult first renal transplants between 1995 and 2000. We noted a significant decrease in overall acute rejection rates during the first 6 months, during the first year, and also in late rejections during the second year after transplantation. Despite this decrease in the rate of acute rejection, there was no significant improvement in overall graft survival; furthermore, we noted a statistically significant trend towards worse death-censored graft survival. There was also a trend for a greater proportion of rejection episodes to fail to recover to previous baseline function after treatment. Our data suggest that decreasing acute rejection rates between 1995 and 2000 have not led to an increase in long-term graft survival. Part of this discordance might be related to a higher proportion of acute rejections which have not resolved with full functional recovery in more recent years. However, the etiology of this concerning trend for worse death censored graft survival in recent years will warrant further investigation.

We prospectively studied kidney transplants that progressed to failure after a biopsy for clinical indications, aiming to assign a cause to every failure. We followed 315 allograft recipients who underwent indication biopsies at 6 days to 32 years posttransplant. Sixty kidneys progressed to failure in the follow-up period (median 31.4 months). Failure was rare after T-cell-mediated rejection and acute kidney injury and common after antibody-mediated rejection or glomerulonephritis. We developed rules for using biopsy diagnoses, HLA antibody and clinical data to explain each failure. Excluding four with missing information, 56 failures were attributed to four causes: rejection 36 (64%), glomerulonephritis 10 (18%), polyoma virus nephropathy 4 (7%) and intercurrent events 6 (11%). Every rejection loss had evidence of antibody-mediated rejection by the time of failure. Among rejection losses, 17 of 36 (47%) had been independently identified as nonadherent by attending clinicians. Nonadherence was more frequent in patients who progressed to failure (32%) versus those who survived (3%). Pure T-cell-mediated rejection, acute kidney injury, drug toxicity and unexplained progressive fibrosis were not causes of loss. This prospective cohort indicates that many actual failures after indication biopsies manifest phenotypic features of antibody-mediated or mixed rejection and also underscores the major role of nonadherence.

Mycophenolate mofetil (MMF) is a powerful immunosuppressant that inhibits the proliferation of T and B lymphocytes by blocking the enzyme inosine monophosphate dehydrogenase. MMF has been shown to prevent acute graft rejection in animal experiments and may have an important role in clinical renal transplantation. We conducted a prospective, double-blind, multicenter trial to compare the efficacy and safety of MMF and azathioprine within a standard immunosuppressive regimen for patients receiving a first or second cadaveric renal graft. A total of 503 patients were randomized to groups receiving MMF 3 g (n=164), MMF 2 g (n=173), or azathioprine (AZA) 100-150 mg (n=166) daily. All were treated simultaneously with equivalent doses of cyclosporine and oral corticosteroids and followed for 12 months. The primary endpoint was treatment failure, defined as the occurrence of biopsyproven graft rejection, graft loss, patient death, or discontinuation of the study drug during the first 6 months after transplantation. Treatment failure occurred in 50.0% of patients in the AZA group by 6 months after transplantation, compared with 34.8% in the MMF 3 g group (P=0.0045) and 38.2% in the MMF 2 g group (P=0.0287). Biopsy-proven rejection occurred in 15.9% of patients in the MMF 3 g group and 19.7% in the MMF 2 g group, compared with 35.5% in the AZA group. Rejection of histologic severity grade II or more developed in 6.1%, 10.4%, and 19.9% of patients in the MMF 3 g, MMF 2 g, and AZA groups, respectively. Patients receiving MMF required less frequent and less intensive treatment for acute rejection: 24.4% of patients on MMF 3 g and 31.0% on MMF 2 g were treated for acute rejection, compared with 47.5% on AZA. Only 4.9% on MMF 3 g and 8.8% on MMF 2 g required antilymphocyte antibodies for treatment of severe or steroid-resistant rejection, compared with 15.4% of the patients on AZA. At 1 year afte transplantation, graft survival in the MMF groups was marginally superior to that in the AZA group, although this difference was not statistically significant. Gastrointestinal toxicity and tissue-invasive cytomegalovirus infection were more common in the MMF 3 g group. Noncutaneous malignancies occurred in six patients on MMF 3 g, three patients on MMF 2 g, and four patients on AZA. Lymphoproliferative disorders occurred in two patients per MMF group, compared with one patient receiving AZA. MMF appears to be an important advance in prophylaxis following renal transplantation. It is associated with a significantly lower rate of treatment failure compared with AZA during the first 6 months after renal transplantation and produces a clinically important reduction in the incidence, severity, and treatment of acute graft rejection. These differences persist throughout the first year of follow-up. Clinical benefit was greatest with a dose of MMF 3 g/day, but gastrointestinal effects, invasive cytomegalovirus infection, and malignancies were slightly more common at that dose. The appropriate dose may lie between 2 g and 3 g per day and may require individualization depending on clinical course or other factors.

This article reviews the literature on the relationship between interpersonal rejection and aggression. Four bodies of research are summarized: laboratory experiments that manipulate rejection, rejection among adults in everyday life, rejection in childhood, and individual differences that may moderate the relationship. The theoretical mechanisms behind the effect are then explored. Possible explanations for why rejection leads to anger and aggression include: rejection as a source of pain, rejection as a source of frustration, rejection as a threat to self-esteem, mood improvement following aggression, aggression as social influence, aggression as a means of reestablishing control, retribution, disinhibition, and loss of self-control.

Introduction 1. Recent advances in the study of peer rejection S. R. Asher Part I. Behavioural Characteristics of Peer Rejected Children: 2. Peer group behavior and social status J. D. Coie, K. A. Dodge and J. Kupersmidt 3. Children's entry behavior M. Putallaz and A. Wasserman 4. Preschooler's behavioral orientations and patterns of peer contact: predictive of peer status? G. R. Ladd, J. M. Price and C. H. Hart Part II. Parent-Child Relations and Peer Rejection: 5. Social withdrawal in childhood: developmental pathways to peer rejection K. H. Rubin, L. J. Lemare and S. Lollis 6. Parent-child interaction M. Putallaz and A. H. Heflin Part III. Social-Cognitive Process: 7. Issues in social cognition and sociometric status K. A. Dodge and E. Feldman 8. Reputational bias: view from the peer group S. Hymel, E. Wagner and L. J. Butler Part IV. Consequences of Peer Rejection: 9. Peer rejection and loneliness in childhood S. R. Asher, J. T. Parkhurst, S. Hymell and G. A. Williams 10. The role of poor peer relationships in the development of disorder J. Kupersmidt, J. D. Coie and K. A. Dodge Part V. Issues in Intervention Research: 11. Adapting intervention to the problems of aggressive and disruptive rejected children J. D. Coie and G. K. Koeppl 12. Toward the development of successful social skill training for preschool children J. Mize and G. W. Ladd Conclusion: 13. Toward a theory of peer rejection J. D. Coie.

Preliminary studies suggested that mycophenolate mofetil (MMF), which inhibits proliferation of T and B cells, may reduce the frequency of acute rejection after renal transplantation. Our randomised, double-blind, multicentre, placebo-controlled study compared the efficacy and safety of MMF with placebo for prevention of acute rejection episodes after first or second cadaveric renal allograft transplantation. 491 patients were enrolled; 166 were assigned placebo, 165 MMF 2 g, and 160 MMF 3 g. Patients also received cyclosporin and corticosteroids. Significantly fewer (p less than or equal to 0.001) patients had biopsy-proven rejection or withdrew early from the trial (for any reason) during the first 6 months after transplantation with MMF 2 g (30.3%) or 3 g (38.8%) than with placebo (56.0%). The corresponding percentages for biopsy-proven rejection were 17.0%, 13.8%, and 46.4%. 28.5% of MMF 2 g and 24.4% of MMF 3 g patients needed full courses of corticosteroids or antilymphocyte agents for treatment of rejection episodes in the first 6 months, compared with 51.8% of placebo recipients. By 6 months, 10.2%, 6.7%, and 8.8% of the patients in the placebo, MMF 2 g, and MMF 3 g groups, respectively, had died or lost the graft. Overall, the frequency of adverse events was similar in all treatment groups, although gastrointestinal problems, leucopenia, and opportunistic infections were more common in the MMF groups and there was a trend for more events in the 3 g than the 2 g group. MMF significantly reduced the rate of biopsy-proven rejection or other treatment failure during the first 6 months after transplantation and was well tolerated, The 3 g dose was somewhat less well tolerated.

This article describes a new model that provides a framework for understanding people's reactions to threats to social acceptance and belonging as they occur in the context of diverse phenomena such as rejection, discrimination, ostracism, betrayal, and stigmatization. People's immediate reactions are quite similar across different forms of rejection in terms of negative affect and lowered self-esteem. However, following these immediate responses, people's reactions are influenced by construals of the rejection experience that predict 3 distinct motives for prosocial, antisocial, and socially avoidant behavioral responses. The authors describe the relational, contextual, and dispositional factors that affect which motives determine people's reactions to a rejection experience and the ways in which these 3 motives may work at cross-purposes. The multimotive model accounts for the myriad ways in which responses to rejection unfold over time and offers a basis for the next generation of research on interpersonal rejection.

BACKGROUND: Among American Conservatives, but not Liberals, trust in science has been declining since the 1970's. Climate science has become particularly polarized, with Conservatives being more likely than Liberals to reject the notion that greenhouse gas emissions are warming the globe. Conversely, opposition to genetically-modified (GM) foods and vaccinations is often ascribed to the political Left although reliable data are lacking. There are also growing indications that rejection of science is suffused by conspiracist ideation, that is the general tendency to endorse conspiracy theories including the specific beliefs that inconvenient scientific findings constitute a "hoax." METHODOLOGY/PRINCIPAL FINDINGS: We conducted a propensity weighted internet-panel survey of the U.S. population and show that conservatism and free-market worldview strongly predict rejection of climate science, in contrast to their weaker and opposing effects on acceptance of vaccinations. The two worldview variables do not predict opposition to GM. Conspiracist ideation, by contrast, predicts rejection of all three scientific propositions, albeit to greatly varying extents. Greater endorsement of a diverse set of conspiracy theories predicts opposition to GM foods, vaccinations, and climate science. CONCLUSIONS: Free-market worldviews are an important predictor of the rejection of scientific findings that have potential regulatory implications, such as climate science, but not necessarily of other scientific issues. Conspiracist ideation, by contrast, is associated with the rejection of all scientific propositions tested. We highlight the manifold cognitive reasons why conspiracist ideation would stand in opposition to the scientific method. The involvement of conspiracist ideation in the rejection of science has implications for science communicators.

Selective inhibition of T cell costimulation using the B7-specific fusion protein CTLA4-Ig has been shown to induce long-term allograft survival in rodents. Antibodies preventing the interaction between CD40 and its T cell-based ligand CD154 (CD40L) have been shown in rodents to act synergistically with CTLA4-Ig. It has thus been hypothesized that these agents might be capable of inducing long-term acceptance of allografted tissues in primates. To test this hypothesis in a relevant preclinical model, CTLA4-Ig and the CD40L-specific monoclonal antibody 5C8 were tested in rhesus monkeys. Both agents effectively inhibited rhesus mixed lymphocyte reactions, but the combination was 100 times more effective than either drug alone. Renal allografts were transplanted into nephectomized rhesus monkeys shown to be disparate at major histocompatibility complex class I and class II loci. Control animals rejected in 5-8 days. Brief induction doses of CTLA4-Ig or 5C8 alone significantly prolonged rejection-free survival (20-98 days). Two of four animals treated with both agents experienced extended (>150 days) rejection-free allograft survival. Two animals treated with 5C8 alone and one animal treated with both 5C8 and CTLA4-Ig experienced late, biopsy-proven rejection, but a repeat course of their induction regimen successfully restored normal graft function. Neither drug affected peripheral T cell or B cell counts. There were no clinically evident side effects or rejections during treatment. We conclude that CTLA4-Ig and 5C8 can both prevent and reverse acute allograft rejection, significantly prolonging the survival of major histocompatibility complex-mismatched renal allografts in primates without the need for chronic immunosuppression.

The relation between social rejection and growth in antisocial behavior was investigated. In Study 1,259 boys and girls (34% African American) were followed from Grades 1 to 3 (ages 6-8 years) to Grades 5 to 7 (ages 10-12 years). Early peer rejection predicted growth in aggression. In Study 2,585 boys and girls (16% African American) were followed from kindergarten to Grade 3 (ages 5-8 years), and findings were replicated. Furthermore, early aggression moderated the effect of rejection, such that rejection exacerbated antisocial development only among children initially disposed toward aggression. In Study 3, social information-processing patterns measured in Study 1 were found to mediate partially the effect of early rejection on later aggression. In Study 4, processing patterns measured in Study 2 replicated the mediation effect. Findings are integrated into a recursive model of antisocial development.

How similar are the experiences of social rejection and physical pain? Extant research suggests that a network of brain regions that support the affective but not the sensory components of physical pain underlie both experiences. Here we demonstrate that when rejection is powerfully elicited--by having people who recently experienced an unwanted break-up view a photograph of their ex-partner as they think about being rejected--areas that support the sensory components of physical pain (secondary somatosensory cortex; dorsal posterior insula) become active. We demonstrate the overlap between social rejection and physical pain in these areas by comparing both conditions in the same individuals using functional MRI. We further demonstrate the specificity of the secondary somatosensory cortex and dorsal posterior insula activity to physical pain by comparing activated locations in our study with a database of over 500 published studies. Activation in these regions was highly diagnostic of physical pain, with positive predictive values up to 88%. These results give new meaning to the idea that rejection "hurts." They demonstrate that rejection and physical pain are similar not only in that they are both distressing--they share a common somatosensory representation as well.

If one reading is a long way from the rest in a series of replicate determinations, or if in a least-squares analysis one reading is found to have a much greater residual than the others, there is temptation to reject it as spurious. Numerous criteria for the rejection of outliers have been proposed and discussed during the past 100 years. They seem always to have been regarded as something like significance tests, and attention has been focussed on rejection rates. It is suggested that rejection rules are not significance tests but insurance policies, and attention would be better focussed on error variance. A detailed study is made of the effect of routine application of rejection criteria to replicate determinations of a single value. Determinations in triplicate and quadruplicate are especially considered. Complex patterns of observations are also considered, especially factorial arrangements with high symmetry, and there is a study of the correlations between residuals. Attention is focussed mainly on rejection rules appropriate when the population variance is known, but some consideration is also given to Studentieed rules.

We propose a method for rejection sampling from any univariate log‐concave probability density function. The method is adaptive: As sampling proceeds, the rejection envelope and the squeezing function converge to the density function. The rejection envelope and squeezing function are piece‐wise exponential functions, the rejection envelope touching the density at previously sampled points, and the squeezing function forming arcs between those points of contact. The technique is intended for situations where evaluation of the density is computationally expensive, in particular for applications of Gibbs sampling to Bayesian models with non‐conjugacy. We apply the technique to a Gibbs sampling analysis of monoclonal antibody reactivity.

BACKGROUND: Monoclonal antibodies that block the high-affinity interleukin-2 receptor expressed on alloantigen-reactive T lymphocytes may cause selective immunosuppression. Daclizumab is a genetically engineered human IgG1 monoclonal antibody that binds specifically to the alpha chain of the interleukin-2 receptor and may thus reduce the risk of rejection after renal transplantation. METHODS: We administered daclizumab (1.0 mg per kilogram of body weight) or placebo intravenously before transplantation and once every other week afterward, for a total of five doses, to 260 patients receiving first cadaveric kidney grafts and immunosuppressive therapy with cyclosporine, azathioprine, and prednisone. The patients were followed at regular intervals for 12 months. The primary end point was the incidence of biopsy-confirmed acute rejection within six months after transplantation. RESULTS: Of the 126 patients given daclizumab, 28 (22 percent) had biopsy-confirmed episodes of acute rejection, as compared with 47 of the 134 patients (35 percent) who received placebo (P=0.03). Graft survival at 12 months was 95 percent in the daclizumab-treated patients, as compared with 90 percent in the patients given placebo (P=0.08). The patients given daclizumab did not have any adverse reactions to the drug, and at six months, there were no significant differences between the two groups with respect to infectious complications or cancers. The serum half-life of daclizumab was 20 days, and its administration resulted in prolonged saturation of interleukin-2alpha receptors on circulating lymphocytes. CONCLUSIONS: Daclizumab reduces the frequency of acute rejection in kidney-transplant recipients.

The authors hypothesized a self-fulfilling prophecy wherein rejection expectancies lead people to behave in ways that elicit rejection from their dating partners. The hypothesis was tested in 2 studies of conflict in couples: (a) a longitudinal field study where couples provided daily-diary reports and (b) a lab study involving behavioral observations. Results from the field study showed that high rejection-sensitive (HRS) people's relationships were more likely to break up than those of low rejection-sensitive (LRS) people. Conflict processes that contribute to relationship erosion were revealed for HRS women but not for HRS men. Following naturally occurring relationship conflicts, HRS women's partners were more rejecting than were LRS women's partners. The lab study showed that HRS women's negative behavior during conflictual discussions helped explain their partners' more rejecting postconflict responses.