Platelets in Early Antibody-Mediated Rejection of Renal Transplants

Antibody-mediated rejection is a major complication in renal transplantation. The pathologic manifestations of acute antibody-mediated rejection that has progressed to functional impairment of a renal transplant have been defined in clinical biopsy specimens. However, the initial stages of the process are difficult to resolve with the unavoidable variables of clinical studies. We devised a model of renal transplantation to elucidate the initial stages of humoral rejection. Kidneys were orthotopically allografted to immunodeficient mice. After perioperative inflammation subsided, donor-specific alloantibodies were passively transferred to the recipient. Within 1 hour after a single transfer of antibodies, C4d was deposited diffusely on capillaries, and von Willebrand factor released from endothelial cells coated intravascular platelet aggregates. Platelet-transported inflammatory mediators platelet factor 4 and serotonin accumulated in the graft at 100- to 1000-fold higher concentrations compared with other platelet-transported chemokines. Activated platelets that expressed P-selectin attached to vascular endothelium and macrophages. These intragraft inflammatory changes were accompanied by evidence of acute endothelial injury. Repeated transfers of alloantibodies over 1 week sustained high levels of platelet factor 4 and serotonin. Platelet depletion decreased platelet mediators and altered the accumulation of macrophages. These data indicate that platelets augment early inflammation in response to donor-specific antibodies and that platelet-derived mediators may be markers of evolving alloantibody responses.     

Dishonesty in scientific research

Fraudulent business practices, such as those leading to the Enron scandal and the conviction of Bernard Madoff, evoke a strong sense of public outrage. But fraudulent or dishonest actions are not exclusive to the realm of big corporations or to evil individuals without consciences. Dishonest actions are all too prevalent in everyone’s daily lives, because people are constantly encountering situations in which they can gain advantages by cutting corners. Whether it’s adding a few dollars in value to the stolen items reported on an insurance claim form or dropping outlier data points from a figure to make a paper sound more interesting, dishonesty is part of the human condition. Here, we explore how people rationalize dishonesty, the implications for scientific research, and what can be done to foster a culture of research integrity.     

Nocardia infection in lung transplant recipients.

BACKGROUND: Nocardia is responsible for infection in both normal and immunocompromised hosts. Organ transplant recipients are increasingly recognized as a sub-group of immunocompromised patients in whom nocardia is an important pathogen. The frequency of nocardia in organ transplant recipients varies between 0.7% and 3%. Nocardia infection has largely been reported in heart, kidney and liver transplant recipients. Presentations of nocardia in lung transplant recipients have been restricted primarily to case reports. The present study reviews the clinical and epidemiologic characteristics of nocardia infection in lung transplant recipients at our institution. METHODS: A retrospective cohort study of 473 lung transplant recipients from January 1991 to November 2000 was done at a university hospital. Patient demographics, immunosuppressive regimen at the time of isolation of nocardia species, use of trimethoprim-sulfamethoxazole for Pneumocystis carinii prophylaxis, rejection episodes in the preceding 6 months, concurrent pathogens, site of infection, radiologic findings and treatment and outcome were recorded. RESULTS: Nocardia infection was found in 2.1% (10 of 473) of our lung transplant recipients. Median time of onset was 34.1 months after transplantation. Nocardia species included N farcinica in 30% (3 of 10), N nova in 30% (3 of 10), N asteroides complex in 30% (3 of 10) and N brasiliensis in 10% (1 of 10) of patients. Post-transplant diabetes was present in 50% (5 of 10) of patients. The primary indication for lung transplantation was emphysema in 40% (4 of 10). Native lung involvement was noted in 75% (3 of 4) of patients with single lung transplant. Breakthrough nocardia infection were noted in 6 patients who were receiving trimethoprim-sulfamethoxazole prophylaxis for P carinii pneumonia; all breakthrough isolates remained susceptible to trimethoprim-sulfamethoxazole. Overall mortality was 40% (4 of 10). All patients (3 of 3) with infection due to N farcinica, except 1 (1 of 7) with infection due to other nocardia species, died. Seventy-five percent (3 of 4) of deaths were attributable to nocardia infection. CONCLUSIONS: Nocardia infection tended to involve the native lung in single lung transplant recipients. Trimethoprim-sulfamethoxazole for P carinii prophylaxis at the doses given was not protective against nocardiosis in these patients. Infection with N farcinica was associated with poor outcome. Thus, species identification and extended courses of antibiotics based on antimicrobial susceptibility testing are important in management of these patients.     

Bleeding complications precipitated by unrecognized Gingko biloba use after liver transplantation

Because of its neurocognitive enhancing effects, Gingko biloba has emerged as amongst the most commonly used herbal products. We report a liver transplant recipient with potentially life-threatening toxicity resulting from Gingko biloba use. Seven days after a second liver transplantation for recurrent hepatitisB virus infection, subphrenic hematoma was documented in a 59-year-old Korean patient. Failure to control bleeding with CT-guided drainage necessitated exploratory laparotomy for the evacuation of a large subphrenic hematoma. Three weeks later, an episode of vitreous hemorrhage was documented. Unbeknownst to his care providers, the patient had been consuming Gingko biloba throughout the postoperative period. No further bleeding episodes occurred after the cessation of Gingko biloba use. Unrecognized use of herbal products may be associated with serious side effects and adverse clinical sequelae in transplant recipients. Given their increasing popularity, the use of herbal products should be routinely sought as part of the history in transplant recipients.     

Toxicity, inflammation, and anti-human immunodeficiency virus type 1 activity following exposure to chemical moieties of C31G.

C31G, which has potent activity against the human immunodeficiency virus type 1 (HIV-1) and an established record of safety in animal studies and human trials, is a microbicidal agent comprised of a buffered equimolar mixture of two amphoteric, surface-active agents: an alkyl amine oxide (C14AO) and an alkyl betaine (C16B). Studies of long-term in vitro exposure to C31G and its constituents have suggested that the components of C31G may contribute differentially to its toxicity and efficacy. In the present studies, in vitro assays of cytotoxicity and anti-HIV-1 activity demonstrated that C16B was slightly less cytotoxic compared to either C31G or C14AO, whereas the anti-HIV-1 activities of C31G and its individual constituents were similar. In the murine model of cervicovaginal microbicide toxicity, in vivo exposure to C14AO resulted in severe cervical inflammation followed by a delayed disruption of the columnar epithelium. In contrast, exposure to C16B caused severe cervical epithelial disruption and a secondary, less intense inflammatory response. These results demonstrate that (i) there are both mechanistic and temporal differences in toxicity associated with the components of C31G not necessarily predicted by in vitro assessments of cytotoxicity and (ii) contributions of each component to the anti-HIV-1 activity of C31G appear to be equal. In addition, these findings indicate that direct and indirect mechanisms of in vivo toxicity can be observed as separate but interrelated events. These results provide further insight into the activity of C31G, as well as mechanisms potentially associated with microbicide toxicity.