Immunosuppression in liver transplantation: beyond calcineurin inhibitors.

Although calcineurin inhibitors (CNIs) remain the mainstay of immunosuppression in liver transplantation (LTX), their long-term toxicity significantly contributes to morbidity and mortality. The elucidation of mechanisms of alloimmunity and leukocyte migration have provided novel targets for immunosuppression development. The toxicities of these agents differ from that of the CNI and act additively or synergistically. CNI avoidance protocols in LTX have not been achieved routinely; however, pilot trials have begun to delineate the limitations and promises of such approaches. CNI-sparing protocols appear to be much more promising in balancing the early need for minimizing rejection while tapering doses and minimizing long-term toxicity.     

The effect of the referring dialysis center on renal transplant results

Between 1/1/76 and 12/31/86, 448 patients underwent transplantation (360 first transplants). Of these, 286 (230 first) were referred by 5 dialysis centers, each referring more than 40 recipients. The remainder were referred by a large number of centers. Using our 5 largest referral centers, we studied the effect of dialysis center on graft and patient survival. There was no difference between dialysis centers in patient survival. Actuarial graft survival differed significantly for all cadaver transplants and for first cadaver transplants (P less than 105). Significant differences persisted when groups were subdivided by type of immunosuppression (azathioprine vs cyclosporine). Demographic (age, race, cause of renal disease) and immunologic (transfusions, PRA, matching) differences between groups did not explain the difference in graft survival. We conclude that referring dialysis center is a previously unrecognized factor affecting transplant outcome. Further studies with larger numbers will be required to determine the underlying reasons for ths phenomenon.     

Magnet extraction of frontal sinus foreign body

We report a metallic foreign body that entered through the anterior table of the frontal sinus, and rolled down to lodge in the nasofrontal duct. An electromagnet was used to remove the foreign body through a trephination.     

Discovering genes: the use of microarrays and laser capture microdissection in pain research

The DNA microarray is a powerful, high throughput technique for assessing gene expression on a system-wide genomic scale. It has great potential in pain research for determining the network of gene regulation in different pain conditions, and also for producing detailed gene expression maps in anatomical areas that process nociceptive stimuli. However, for the potential of this high throughput technology to be realised in pain research, microarrays need to be combined with other technologies. Laser capture microdissection is capable of isolating small populations of homogenous cells, allowing distinct areas involved in nociceptive processing to be examined. In combination with sophisticated PCR-based amplification protocols this technique provides sufficient amounts of messenger RNA (mRNA) for application to microarrays. Aside from the technological issues, a difficult task in any microarray study is the analysis of the resulting enormous data set to reveal the key genes, whose regulation is central to the phenotypic changes observed. For this to be achieved, the methods of data analysis, pattern searching and feature recognition, and bioinformatics have to be properly deployed all within the context of an appropriate statistical design. These issues are especially relevant to pain research where interindividual and interpopulation variation is likely to be high, and where polymorphisms can greatly affect nociceptive sensitivity and susceptibility to pain conditions. Methods for assessing the function of new candidate genes identified in microarray screening experiments are also discussed.     

Suicide risk and symptom reduction in patients assigned to placebo in duloxetine and escitalopram clinical trials: analysis of the FDA summary basis of approval reports.

BACKGROUND: We assessed suicide and suicide attempt risk as well as symptom reduction among 3,282 depressed patients participating in duloxetine and escitalopram clinical trials assigned to either an antidepressant or placebo. METHODS: We reviewed the FDA Summary Basis of Approval reports for data regarding safety and efficacy for duloxetine and escitalopram. Furthermore, we compared suicide risk among antidepressant clinical trials in this study with our two previous analyses on seven antidepressant clinical trials. RESULTS: Suicide and suicide attempt risk varied considerably among the three analyses, showing up to ten fold differences. Interestingly, the variability exists across the three reports, rather than between treatments (antidepressants versus placebo). CONCLUSIONS: These findings suggest caution in generalizing suicide risk even from a relatively large number of participants and thus, firm conclusions can only be drawn if the number of participants is overwhelmingly large (approximately two million patients). We also noted similar magnitude of response to placebo and antidepressants among the three studies.     

Transplantation for myocarditis: a controversy revisited.

Myocarditis is a major cause of end-stage heart failure and is responsible for up to 10% of cases of idiopathic dilated cardiomyopathy (IDC). Worldwide, approximately 45% of all heart transplants are performed for IDC and up to 8% for myocarditis. Early reports suggested that survival after transplantation for myocarditis was poor and patients had an increased risk of rejection. More recently, larger case series suggest that overall survival after transplantation for myocarditis is similar to survival after transplantation for other causes. However, certain disorders, including cardiac sarcoidosis and giant cell myocarditis (GCM), require heightened surveillance for post-transplantation disease recurrence. We present the case of a 42-year-old man with recurrence of GCM 8 years after transplantation and review the literature on the role of cardiac transplantation for patients with myocarditis.     

Transdermal selegiline for the treatment of major depressive disorder

Non-selective inhibition of monoamine oxidase (MAO) enzymes (ie, isoforms A and B) in the brain are associated with clinically significant antidepressant effects. In the US, the selegiline transdermal system (STS; EMSAM) is the first antidepressant transdermal delivery system to receive Food and Drug Administration (FDA) approved labeling for the treatment of major depressive disorder (MDD). Currently, the use of orally administered MAO inhibitor antidepressants (eg, phenelzine, tranylcypromine) is limited by the risk of tyramine-provoked events (eg, acute hypertension and headache, also known as the “cheese reaction”) when combined with dietary tyramine. The selegiline transdermal system is the only MAOI available in the US for the treatment of MDD that does not require dietary restriction at the clinically effective dose of 6 mg/24 hours. Delivery of selegiline transdermally (EMSAM^®) bypasses hepatic first pass metabolism, thereby avoiding significant inhibition of gastrointestinal and hepatic MAO-A activity (ie, reduced risk of tyramine-provoked events) while still providing sufficient levels of selegiline in the brain to produce an antidepressant effect. At dosages of 6–12 mg/24 hours, EMSAM has been shown to improve symptoms of depression, have good tolerability, and have high rates of medication adherence. However, at higher doses of EMSAM (ie, 9 mg/24 hours or more), dietary restriction of tyramine intake is recommended. The introduction of EMSAM overcomes many of the safety concerns affiliated with the conventional oral MAO inhibitors and EMSAM may be considered another strategy for the treatment of MDD, especially in patients who cannot tolerate oral antidepressants, are poorly adherent, who present with atypical depressive symptoms, or have failed other antidepressants.