An animal model of chronic tympanic membrane perforation.

Previous investigations into the healing and reconstruction of tympanic membrane (TM) perforations have involved animal models with acute TM perforations. A problem with the acute TM perforation model is that most acute TM perforations will heal spontaneously, both in animals and human beings. A second inadequacy of acute perforation models is that they are not analogous to the salient problem in human beings: long-standing TM perforation. The ideal animal model must have a TM perforation that is permanent, well-epithelialized, and free from infection. The perforation must also be subtotal to preserve a rim of membrane for experimental manipulations. In the chinchilla, we have identified a hardy animal with a short, wide ear canal and relatively large tympanic membranes. Thermal myringectomy, followed by medial infolding of TM microflaps, has resulted in permanent, subtotal chronic TM perforations in the chinchilla animal model. Of the 19 chinchillas (38 TMs) perforated, chronic subtotal perforations were created in 32 ears, 6 to 8 weeks after the initial procedure (84% success). Persistent infection or TM regeneration despite reperforation was recorded in 6 ears (16%) failure). This model is currently being used to assess various biomembrane scaffolds impregnated with growth-promoting substances in the regeneration of a physiologically sound TM, initially in our animal model and then in human beings. We envision the development of a biomembrane disc impregnated with biorecombinant growth factors that may provide a simple office technique for the repair of chronic, non-infected TM perforations.     

Carcinoid tumors and inflammatory bowel disease.

Three cases are described in which carcinoid tumors arose in previously established inflammatory bowel disease: two were in the ileum in cases of Crohn's disease, and one was in the rectum in a case of ulcerative colitis. Review of this association in the literature suggests that it may be more than fortuitous.     

Update on the Interaction of Rifampin and Warfarin

A 79-year-old man with a history of deep vein thrombosis and pulmonary embolism received anticoagulation therapy with warfarin 5 mg daily for 8 months. He was diagnosed with osteomyelitis and underwent partial metatarsal resection of his right foot. After surgery, antibiotics were initiated including ertapenem sodium 1 g intravenously every 24 hours, vancomycin 1400 mg intravenously every 24 hours, and rifampin 300 mg by mouth twice daily. Achieving a therapeutic level of anticoagulation was difficult despite escalating doses of warfarin, because of the interaction with rifampin. A 5- to 6-fold increase in warfarin dose was prescribed to reach therapeutic international normalized ratios (INRs), but even these increases were insufficient to maintain his INR in the therapeutic range. After rifampin was discontinued, warfarin doses were gradually reduced over the next 2 months. When concurrent warfarin-rifampin therapy is necessary, vigilant monitoring is imperative and significant increases in warfarin doses are likely.     

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.     

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.