Mouse mast cell gp49B1 contains two immunoreceptor tyrosine-based inhibition motifs and suppresses mast cell activation when coligated with the high-affinity Fc receptor for IgE.

Mouse mast cells express gp49B1, a cell-surface member of the Ig superfamily encoded by the gp49B gene. We now report that by ALIGN comparison of the amino acid sequence of gp49B1 with numerous receptors of the Ig superfamily, a newly recognized family has been established that includes gp49B1, the human myeloid cell Fc receptor for IgA, the bovine myeloid cell Fc receptor for IgG2, and the human killer cell inhibitory receptors expressed on natural killer cells and T lymphocyte subsets. Furthermore, the cytoplasmic domain of gp49B1 contains two immunoreceptor tyrosine-based inhibition motifs that are also present in killer cell inhibitory receptors; these motifs downregulate natural killer cell and T-cell activation signals that lead to cytotoxic activity. As assessed by flow cytometry with transfectants that express either gp49B1 or gp49A, which are 89% identical in the amino acid sequences of their extracellular domains, mAb B23.1 was shown to recognize only gp49B1. Coligation of mAb B23.1 bound to gp49B1 and IgE fixed to the high-affinity Fc receptor for IgE on the surface of mouse bone marrow-derived mast cells inhibited exocytosis in a dose-related manner, as defined by the release of the secretory granule constituent beta-hexosaminidase, as well as the generation of the membrane-derived lipid mediator, leukotriene C4. Thus, gp49B1 is an immunoreceptor tyrosine-based inhibition motif-containing integral cell-surface protein that downregulates the high-affinity Fc receptor for IgE-mediated release of proinflammatory mediators from mast cells. Our findings establish a novel counterregulatory transmembrane pathway by which mast cell activation can be inhibited.     

Uveitis and arthritis induced by adjuvant: clinical, immunologic and histologic characteristics

The intradermal administration of complete Freund's adjuvant (CFA) containing Mycobacterium butyricum to Sprague-Dawley (SD) and Lewis strain rats results in polyarthritis and uveitis. Over 90% of the eyes examined from the SD rats given CFA had histologic evidence of anterior uveitis, clinically evident in only 20 to 28%. Many rats developed arthritis without clinical uveitis, but uveitis was rare in the absence of arthritis. Histologically, the ocular inflammation was characterized by a polymorphonuclear, and later, a lymphocytic infiltration of the iris and ciliary body with cells and fibrinous exudate in the anterior chamber and cells in the vitreous. Antibodies and cellular immunity to ocular (S antigen, alpha crystallin), articular (type II collagen, proteoglycan) and bacterial components (MDP), were demonstrated in some rats, but positive tests did not correlate with either articular or ocular disease. Ten percent of rats given type II collagen in incomplete Freund's adjuvant developed uveitis. Thus, the pathogenesis of the arthritis and uveitis in the adjuvant model may be mediated by lymphocytes which exhibit crossreactivity with antigens in these structures, although the specificity of such antigens has not been identified in our studies.     

Use of aspirin, beta-blockers, and lipid-lowering medications before recurrent acute myocardial infarction: missed opportunities for prevention?

BACKGROUND: For patients who have had a previous myocardial infarction (MI), the use of aspirin, beta-blockers, and lipid-lowering agents reduces the risk of recurrent MI and death. OBJECTIVE: To examine trends in and determinants of receipt of these 3 medications before hospitalization for recurrent acute MI (AMI). METHODS: The study population consisted of 1710 patients with a previous history of MI hospitalized with a validated recurrent AMI in all hospitals in Worcester, Mass, during 1986, 1988, 1990, 1991, 1993, and 1995. Logistic regression analyses were used to assess the effect of demographic, clinical, and temporal factors on the receipt of aspirin, beta-blockers, and lipid-lowering medications before hospital admission for recurrent AMI. RESULTS: More than 47% of patients in each study year were not receiving each medication before admission, although significant increases in use were noted over time for aspirin (from 13.5% to 52.6%), beta-blockers (from 33.2% to 44.4%), and lipid-lowering medications (from 0.8% to 11.7%). In multivariate analyses, advancing age was associated with not receiving aspirin (odds ratio [OR], 0.67; 95% confidence interval [CI], 0.51-0.89), lipid-lowering medications (OR, 0.14; 95% CI, 0.08-0.25), and beta-blockers (OR, 0.75; 95% CI, 0.57-1.00), although this effect was of borderline significance for beta-blockers. Being a woman was associated with not receiving aspirin (OR, 0.78; 95% CI, 0.62-0.98) but was positively associated with receiving lipid-lowering medications (OR, 1.59; 95% CI, 1.04-2.43). Coexisting medical conditions and concurrent use of other cardiovascular medications were also associated with receipt of each medication. CONCLUSION: Despite encouraging increases over time, the low absolute levels of receipt of medications shown to be efficacious in the long-term treatment of patients after an MI, and their variation by age and sex, suggest that substantial opportunities may exist to prevent recurrent AMIs through the increased use of aspirin, beta-blockers, and lipid-lowering medications.     

Substrate for endothelial prostacyclin production in the presence of platelets exposed to collagen is derived from the platelets rather than the endothelium

Interactions between vascular endothelial cells and blood platelets have been investigated using a model microcirculation consisting of microcarrier beads colonized with human umbilical vein endothelial cells (HUVECs) and perfused with washed platelet suspensions. To simulate the effects of endothelial desquamation and exposure of subendothelium, fibrillar collagen in suspension was coinjected with the platelets. In this model, neither the passage of platelets alone nor collagen alone stimulated prostacyclin (PGI2) production by the HUVECs. Platelets activated by coinjection with collagen released thromboxane A2 (TXA2), and this was associated with the simultaneous production of PGI2 by the HUVECs. By means of double-isotope experiments with [3H]arachidonic acid (AA) incorporated into platelets and [14C]-AA into HUVECs, it was shown that all the PGI2 generated was derived from platelet AA and/or endoperoxides. This interpretation was strengthened by the finding that PGI2 production was not prevented by treatment of HUVECs with indomethacin followed by perfusion with collagen-stimulated platelets. AA metabolites in double-isotope label experiments were further characterized by reverse-phase chromatography, and it was shown that both cyclooxygenase and lipoxygenase products of the HUVECs were derived from platelet membrane lipid. Thrombin regularly produced transient PGI2 release, but showed rapid tachyphylaxis. Platelet-derived compounds including ADP, ATP, and platelet-activating factor (PAF) did not produce PGI2 release by HUVECs in this system. Thus, the transfer of AA and metabolites from collagen- stimulated platelets is likely to be the mechanism for PGI2 production in the context of minor degrees of endothelial desquamation.     

Risk of proximal colorectal neoplasia among asymptomatic patients with distal hyperplastic polyps

PURPOSE: Many guidelines on colorectal cancer screening do not consider distal hyperplastic polyps to be a marker for proximal neoplasia. However, 11 of 17 published studies have shown an increased risk of proximal neoplasia in patients with distal hyperplastic polyps. Our goal is to assess the risk of proximal neoplasia in asymptomatic patients with distal hyperplastic polyps, compared to those with distal tubular adenomas or no distal polyps. METHODS: We assessed proximal (cecum, ascending, transverse colon and splenic flexure) and distal polyps in patients undergoing screening colonoscopy, classifying them into 3 groups: distal hyperplastic polyps only; distal adenomas with or without hyperplastic polyps; no distal polyps. The prevalence of proximal neoplasia and advanced neoplasia (polyps > or =1 cm, villous adenomas, or cancer) was compared among these groups. RESULTS: Of 2357 patients, 427 (18%) had neoplasia, including 103 (4%) with advanced neoplasia. Proximal neoplasia occurred in 175 (9%) of 1896 patients with no distal polyps, compared with 28 (12%) of 237 with distal hyperplastic polyps (P = 0.20) and 64 (29%) of 224 with distal adenomas (P <0.0001). Proximal advanced neoplasia occurred in 39 (2%) patients with no distal polyps, compared with 4 (2%) with distal hyperplastic polyps (P = 0.70) and 9 (4%) with distal adenomas (P = 0.13). CONCLUSIONS: Patients with distal hyperplastic polyps, unlike those with distal adenomas, do not exhibit an increased risk for proximal neoplasia or proximal advanced neoplasia compared to those with no distal polyps. The discovery of hyperplastic polyps on screening sigmoidoscopy should not prompt colonoscopy.     

Adult “idiopathic” extrahepatic venous thrombosis

The etiology of extrahepatic venous obstruction (EHVO) is unknown in 50% of cases. Recently the presence of a latent myeloproliferative disorder has been reported in adults with idiopathic EHVO. We evaluated the course of these patients to establish if any putative latent myeloproliferative disorder influenced the clinical course compared to those with a known cause. Among 132 EHVO patients, 78 (59%) had a known etiology, 7 (5%) with an overt myeloproliferative disorder. The idiopathic group had 54 patients; 24 (13 men, 11 women) were diagnosed after 15 years of age, (median 38 years, range 17–70) with a median follow up of 96 months (19–372). Only 2 (8%) developed an overt myeloproliferative disorder. These 24 had a similar pattern of bleeding and onset of ascites as those with known cause. In EHVO failure to diagnose a latent myeloproliferative disorder does not influence the course of variceal bleeding, and thus has little prognostic significance.Supported by R Farini Foundation for Gastroenterology Research.