BID: a novel BH3 domain-only death agonist

The BCL-2 family of proteins consists of both antagonists (e.g., BCL-2) and agonists (e.g., BAX) that regulate apoptosis and compete through dimerization. The BH1 and BH2 domains of BCL-2 are required to heterodimerize with BAX and to repress cell death; conversely, the BH3 domain of BAX is required to heterodimerize with BCL-2 and to promote cell death. To extend this pathway, we used interactive cloning to identify Bid, which encodes a novel death agonist that heterodimerizes with either agonists (BAX) or antagonists (BCL-2). BID possesses only the BH3 domain, lacks a carboxy-terminal signal-anchor segment, and is found in both cytosolic and membrane locations. BID counters the protective effect of BCL-2. Moreover, expression of BID, without another death stimulus, induces ICE-like proteases and apoptosis. Mutagenesis revealed that an intact BH3 domain of BID was required to bind the BH1 domain of either BCL-2 or BAX. A BH3 mutant of BID that still heterodimerized with BCL-2 failed to promote apoptosis, dissociating these activities. In contrast, the only BID BH3 mutant that retained death promoting activity interacted with BAX, but not BCL-2. This BH3-only molecule supports BH3 as a death domain and favors a model in which BID represents a death ligand for the membrane-bound receptor BAX.     

Mechanism of suppression of cell-mediated immunity by measles virus

The mechanisms underlying the profound suppression of cell-mediated immunity (CMI) accompanying measles are unclear. Interleukin-12 (IL-12), derived principally from monocytes and macrophages, is critical for the generation of CMI. Measles virus (MV) infection of primary human monocytes specifically down-regulated IL-12 production. Cross-linking of CD46, a complement regulatory protein that is the cellular receptor for MV, with antibody or with the complement activation product C3b similarly inhibited monocyte IL-12 production, providing a plausible mechanism for MV-induced immunosuppression. CD46 provides a regulatory link between the complement system and cellular immune responses.     

Atypical retinal astrocytic hamartoma diagnosed by fine-needle biopsy

We report a case of priapism in an 11-year-old boy known to have Fabry's disease. High flow was confirmed by color flow Doppler ultrasound and intracorporal blood gas measurements. Successful treatment was achieved by unilateral percutaneous Gelfoam embolization of the left internal pudendal artery. Previously reported cases of priapism associated with Fabry's disease were identified through a MEDLINE search of the English literature and review of the publications. Five reported cases of priapism associated with Fabry's disease were found, including those of 3 children. A report of a child with high-flow priapism that did not respond to conventional treatment including cavernovenous shunting was noted. Priapsim associated with Fabry's disease may be caused by unregulated high arterial inflow. Early recognition of the underlying pathophysiology may identify those cases that would be amenable to percutaneous embolization therapy and may obviate the need to pursue other ineffective conventional treatments.     

Acquired tracheomalacia--a case report

Divalproex sodium is an effective drug for the treatment of migraine. Most adverse drug events are transient and not of great clinical concern. Although rare, well-documented examples of liver toxicity have been reported in children under 2 years of age on polypharmacy. Additional cases occur in children under 10 who are receiving polypharmacy, particularly those who have intractable seizures and degenerative central nervous system disease. Clinicians who treat migraineurs with divalproex sodium do not need to be overly preoccupied with monitoring of drug levels and liver function tests. The most valuable test is clinical observation of the patient.     

Decrease in the ratio of high- to low-affinity isozymes of (Na+ +K+)-ATPase during the development of rat cardiac ventricles

The ratio of (Na+ +K+)-ATPase (EC 3.6.1.3.)isoforms with high and low affinity for cardiac glycosides was studied in heart preparations from neonatal, 3-month and 6-month old Wistar rats. Biphasic ouabain inhibition curves of (Na+ +K+)-ATPase activity indicated that the relative contribution of the high-affinity process decreased from 34% at 9 days to 23% at 3 months and to 10% at 6 months. Scatchard plots for [3H]ouabain binding were curvilinear and indicated that the relative contribution of the high-affinity sites (Kd = 0.1-0.25 microM) decreased by about one-half between 3 months (19-24%, N = 2) and 6 months (9-11%, N = 2).     

CTLA4 mediates antigen-specific apoptosis of human T cells

The regulation of T cell-mediated immune responses requires a balance between amplification and generation of effector function and subsequent selective termination by clonal deletion. Although apoptosis of previously activated T cells can be induced by signaling of the tumor necrosis factor receptor family, these molecules do not appear to regulate T-cell clonal deletion in an antigen-specific fashion. We demonstrate that cross-linking of the inducible T-cell surface molecule CTLA4 can mediate apoptosis of previously activated human T lymphocytes. This function appears to be antigen-restricted, since a concomitant signal T-cell receptor signal is required. Regulation of this pathway may provide a novel therapeutic strategy to delete antigen-specific activated T cells.