The impact of calcineurin inhibitors on graft survival

The discovery of the first calcineurin inhibitor (CNI), cyclosporine, represents a watershed event in the history of immunosuppression, as it was the first drug shown to reversibly inhibit T-lymphocyte function, therefore allowing for one of the major breakthroughs in modern medicine, that of organ transplantation.Calcineurin inhibitors remain the most effective and widely used immunosuppressive agents in organ transplantation today. The 2010 OPTN/SRTR Annual Report showed that 96% of renal transplant recipients were on CNI at the time of discharge from hospital.The prolonged use of CNI, however, may result in renal toxicity, renal dysfunction and eventual renal failure in both recipients of renal and other solid organ transplants, as well as in patients treated with these agents for autoimmune diseases.This brief review, while acknowledging that CNI toxicity does indeed exist, will focus on the successful use of CNI in renal transplant recipients, highlighting recent observations that provide alternative explanations for some of the adverse outcomes that have been attributed to CNI nephrotoxicity in the past.     

Smoking cessation in the emergency department: a qualitative exploration of staff attitudes

Background

Emergency departments see uniquely large numbers of patients across all demographic groups who are more likely to smoke and who attend with acute health concerns that can provide an impetus for behaviour change. Despite this potential opportunity, no smoking cessation programme in any UK emergency department yet exists. This study sought to identify perceived barriers and facilitators for emergency department smoking cessation activity, as well as potential modes of intervention, by exploring staff attitudes.

Donor‐specific anti‐HLA antibodies in pediatric renal transplant recipients with creeping creatinine: Prevalence,histological correlations,and impact on patient and graft survival

Donor‐specific anti‐HLA antibodies (DSA) causing CAMR are responsible for a high proportion of long‐term graft failures after RTX. We studied the prevalence of DSA in RTX children biopsied for creeping Cr, its relationship with NA, and patient and graft survival according to histopathology. Between 2008 and 2013, 92 children were biopsied at a median of 38 months post‐RTX. At biopsy, the prevalence of DSA was 49% and C4d 70%. NA rate was 45%, higher in adolescents (60%). Most frequent diagnoses were CAMR (72%) and interstitial fibrosis with tubular atrophy (IFTA) (28%). Forty‐five of 66 patients with CAMR (68%) had detectable DSA. Twenty‐one DSA‐negative patients with CAMR had histological damage (IFTA + C4d positivity). C4d was detected in 64 of 66 biopsies with CAMR. Recipients with IFTA alone had neither C4d, nor detectable DSA, and were adherent. Graft survival at five yr was 89% in patients with CAMR, 79% in those with CAMR + TCMR Banff I, 33% in those with CAMR + TCMR Banff II, and 96% in those with IFTA. ABMR and complement activation were frequent in children biopsied for creeping Cr. Recipients with DSA were more likely to be non‐adherent and have CAMR or CAMR + TCMR and worse graft survival.     

A comparison of psychotropic drug use between the general population and clients of health and social service agencies

The purpose of this research was to study the epidemiology of psychotropic drug use among the general population and to draw comparisons to drug use among clients of medical, mental health, and social services in the same jurisdiction. Results showed considerably higher percentages of users for all drug categories among agency clientele. Age and sex differences in drug use replicated previous research in the general population but were noticeably absent among the clients of local services. Notably, the proportion of long-term daily users of minor tranquilizers in the agency population was about three times that of the general population. However, tranquilizer users in the two populations were similar in many respects. Results of the study are discussed in terms of the need for screening for persons with psychotropic drug problems in health and social services.     

Epidermal growth factor receptor inhibition by tyrphostin 51 induces apoptosis in luteinized granulosa cells

Growth factors may be involved in the control of ovarian cell fate and could contribute to regulation of ovarian cell apoptosis. Our objective is to test the hypothesis that, in human luteinized granulosa cells, epidermal growth factor (EGF) works through the MAPK signaling pathway and inhibition of EGF receptor by a specific tyrosine kinase inhibitor, tyrphostin 51, will inhibit the activation of MAPK and induce apoptosis. Luteinized granulosa cells from human in vitro fertilization aspirates were treated as follows: 1) vehicle (dimethylsulfoxide:ethanol), 2) EGF, 3) tyrphostin 51, and 4) tyrphostin 51 plus EGF. Blockage of EGF receptor by tyrphostin 51 reduced the MAPK activity and inhibited phosphorylation and nuclear translocation of activated MAPK. Blockage of EGF receptor also induced apoptosis as demonstrated by the activation of caspase-3, an executioner protease of the apoptotic pathway, and by an increased percentage of subdiploid apoptotic nuclei. These results support the hypothesis that in human luteinized granulosa cells, EGF works through the MAPK signaling pathway and that its inhibition by tyrphostin 51 inhibits MAPK phosphorylation and induces apoptotic nuclear changes. Our data thus provide additional information regarding regulation of apoptosis in luteinized granulosa cells.     

DA1 receptor mediates dopamine-induced relaxation of opossum lower esophageal sphincter in vitro

The objective of the present experiments was to determine the specific receptor subtype through which dopamine (DA) receptor agonists relax the lower esophageal sphincter in vitro. Opossum lower esophageal sphincter smooth muscle strips were placed in oxygenated Krebs' solution containing propranolol and cocaine. The tissues were placed at a tension that gave maximum relaxation to electrical field stimulation and were then pretreated with phenoxybenzamine. The effects of DA, and the DA receptor agonists epinine and apomorphine were determined. In addition, agonist responses were studied in the presence of the selective DA2 receptor antagonist domperidone, a mixed DA1/DA2 receptor antagonist metoclopramide, and the selective DA1 receptor antagonists bulbocapnine and SK&F 83566. The DA agonists relaxed the smooth muscle strips in the following order of potency: DA greater than epinine greater than apomorphine. Domperidone did not antagonize DA- or apomorphine-induced relaxation. Metoclopramide failed to alter DA-induced relaxation. Bulbocapnine and SK&F 83566 significantly inhibited the relaxation induced by DA. These data indicate that DA-induced lower esophageal sphincter relaxation in vitro is mediated by DA1 receptors.