A Comparison Between Recipients Receiving Matched Kidney and Those Receiving Mismatched Kidney from the Same Cadaver Donor

The optimal allocation of cadaveric kidneys for transplantation with reference to human leukocyte antigen (HLA) match and sharing these organs to a distant center remains controversial. The current analysis was performed using the United Network for Organ Sharing (UNOS) database for cadaveric kidney transplants (Tx) between 1988 and 1997. The graft survivals of zero-mismatch (matched) kidneys with the mate (mismatched) kidneys were compared. There were 2385 donors and 4770 Tx. Significant differences in recipient demographics between matched and mismatched Tx were: fewer African-American race (AA) in the matched group (9.0% vs. 21.9%), higher number of previous Tx (25.5% vs. 14.8%) and elevated mean cold ischemia time (24.0 vs. 22.2 h). Post-Tx dialysis requirements were similar (22.8% vs. 24.1%, p = 0.62) and matched kidneys had to travel more distance (920 vs. 232 miles). Using a Cox model, the matched group had a decreased relative hazard of graft failure of 23.0% (p = 0.0002) or 35% (p < 0.0001) with and without censoring for death. There was significantly better graft survival in the matched recipients in all pairs except AA (matched) and non-AA (mismatched). For older donors (> or = 50 years, n = 1508), the matched grafts survival was marginally significant (p =0.05). Matched kidneys have improved survival compared with the mismatched kidneys despite the longer distance traveled. The benefit of mismatched transplants was predominantly seen in non-AA.     

Immunologic and pharmacologic concepts of monoclonal antibodies

While monoclonal antibodies have solved many of the difficulties of using immunologic reagents for radioimmunodiagnosis and therapy, in the 13 years since their introduction a number of persistent problems remain, most notably a low yield of antibody-producing cells from the fusion process, difficulty in obtaining high-affinity antibodies, and the potential immunogenicity of murine immunoglobulins (Igs). Several solutions are under development, including fusion techniques that enrich for cells producing desired antibodies, production of human-mouse chimeric antibodies by recombinant DNA technology, and the generation of human monoclonal antibodies by promising new approaches. Until these upcoming methodologies are established, and to better direct their development and application, a sound understanding of the pharmacology of presently available native and modified monoclonal antibodies is crucial. Although much has been already determined in this area, a great deal of further clarification remains necessary.     

Assessment of caffeine exposure: caffeine content of beverages, caffeine intake, and plasma concentrations of methylxanthines

The caffeine content of all tea or coffee beverages consumed by 17 healthy adults over 24 hours was measured. Plasma caffeine, theophylline, theobromine, and paraxanthine concentrations were determined over the same 24 hours. The average caffeine content per drink was 60.4 +/- 21.8 mg for instant coffee (14-fold range), 80.1 +/- 19.2 mg for brewed coffee (2.8-fold range), and 28.8 +/- 13.7 mg for tea (5.5-fold range). The number of drinks of coffee and tea consumed was a poor index of actual caffeine intake (r2 = 0.42). Caffeine intake correlated poorly with the 24-hour average caffeine concentration (r2 = 0.41), but there was a very good correlation between a single plasma caffeine concentration measured at 5 PM and the 24-hour average concentration (r2 = 0.94). The same was true for paraxanthine (r2 = 0.86). Paraxanthine accounted for 67.3% of the total dimethylxanthines in plasma, while theobromine and theophylline accounted for 24.4% and 8.3%, respectively. Mean caffeine clearance was 1.2 +/- 0.3 ml/min/kg. Plasma caffeine concentration before the first drink in the morning correlated very poorly with caffeine clearance (r2 = 0.07), even when adjusted for caffeine intake (r2 = 0.21).     

CAR2 displays unique ligand binding and RXRalpha heterodimerization characteristics.

The constitutive androstane receptor (CAR; NR1I3) regulates the expression of genes involved in xenobiotic metabolism. Alternative splicing of the human CAR gene yields an array of mRNAs that encode structurally diverse proteins. One form of CAR, termed CAR2, contains an additional four amino acids (SPTV) that are predicted to reshape the ligand-binding pocket. The current studies show a marked, ligand-independent, CAR2-mediated transactivation of reporters containing optimal DR-3, DR-4, and DR-5 response elements, and reporters derived from the natural CYP2B6 and CYP3A4 gene promoters. Overexpression of the RXRalpha ligand binding domain was critical for achieving these effects. CAR2 interaction with SRC-1 was similarly dependent on the coexpression of RXRalpha. Mutagenesis of Ser233 (SPTV) to an alanine residue yielded a receptor possessing higher constitutive activity. Alternatively, mutating Ser233 to an aspartate residue drastically reduced the transactivation capacity of CAR2. The respective abilities of these mutagenized forms of CAR2 to transactivate a DR-4 x 3 reporter element correlated with their ability to interact with RxRalpha and to recruit SRC-1 in a ligand-regulated manner. Together, these results demonstrate a robust RXRalpha-dependent recruitment of coactivators and transactivation by CAR2. In addition, CAR2 displays novel dose responses to clotrimazole and androstanol compared with the reference form of the receptor while at the same time retaining the ability to bind CITCO. This result supports a hypothesis whereby the four-amino-acid insertion in CAR2 structurally modifies its ligand binding pocket, suggesting that CAR2 is regulated by a set of ligands distinct from those governing the activity of reference CAR.     

FDA’S Perspectives on Cardiovascular Devices

The Food and Drug Administration (FDA) decision process for approving or clearing medical devices is often determined by a review of robust clinical data and extensive preclinical testing of the device. The mission statement for the Center for Devices and Radiological Health (CDRH) is to review the information provided by manufacturers so that it can promote and protect the health of the public by ensuring the safety and effectiveness of medical devices deemed appropriate for human use (Food, Drug & Cosmetic Act, §903(b)(1, 2(C)), December 31, 2004; accessed December 17, 2008 ). For high-risk devices, such as ventricular assist devices (VADs), mechanical heart valves, stents, cardiac resynchronization therapy (CRT) devices, pacemakers, and defibrillators, the determination is based on FDA’s review of extensive preclinical bench and animal testing followed by use of the device in a clinical trial in humans. These clinical trials allow the manufacturer to evaluate a device in the intended use population. FDA reviews the data from the clinical trial to determine if the device performed as predicted and the clinical benefits outweigh the risks. This article reviews the regulatory framework for different marketing applications related to cardiovascular devices and describes the process of obtaining approval to study a cardiovascular device in a U.S. clinical trial.     

Localized bullous pemphigoid in a patient with primary lymphoedema tarda

We report a case of localized bullous pemphigoid (BP) in a woman patient with primary lymphoedema tarda. There is only one previous case reported of localized pemphigoid in an area of lymphoedema, this being of the cicatricial variant. Slow circulation in the lymphatic vessels, increased capillary permeability with preferential localization of antibodies in the area, and potential cleavage of the epidermal junction due to increased hydrostatic pressure leading to autoimmunity, have all been advocated as possible pathogenic mechanisms. Nevertheless, we consider that the mechanism by which localized pemphigoid arises on lymphoedema remains elusive, based on a previous case of generalized BP sparing an area of postsurgical lymphoedema.     

Evaluation of gastric emptying in familial and sporadic Parkinson disease

ObjectiveTo assess for the presence of gastric dysmotility in familial and sporadic Parkinson disease (PD).Methods10 subjects with familial Parkinson disease (fPD), 35 subjects with sporadic Parkinson disease (sPD), and 15 controls, all from academic tertiary care movement disorders centers, were studied. fPD was defined as the presence of at least 2 affected individuals within 2–3 consecutive generations in a family. Molecular genetic analysis has not revealed, thus far, any known genomic abnormality in these families. Gastric emptying was assessed by dynamic abdominal scintigraphy over 92 min following ingestion of a solid meal containing 99mTc-labeled colloid of 40 MBq activity. The main outcome measures were gastric emptying half-time and radiotracer activity over the gastric area at 46 and at 92 min.ResultsGastric emptying time was delayed in 60% of subjects with PD. In comparison to mean t_1/2 of 38 ± 7 min in controls, mean t_1/2 was 58 ± 25 min in fPD (p = 0.02) and 46 ± 25 min in sPD (p = 0.10). Both fPD and sPD groups included subjects with delayed gastric emptying at an early stage of disease.ConclusionsPatients with fPD showed significantly delayed gastric emptying in comparison to normal age-matched individuals. Further studies of gastrointestinal dysfunction in PD, particularly fPD, are warranted.