Immune cell regulation and cardiovascular effects of sphingosine 1-phosphate receptor agonists in rodents are mediated via distinct receptor subtypes

Sphingosine 1-phosphate (S1P) is a bioactive lysolipid with pleiotropic functions mediated through a family of G protein-coupled receptors, S1P(1,2,3,4,5). Physiological effects of S1P receptor agonists include regulation of cardiovascular function and immunosuppression via redistribution of lymphocytes from blood to secondary lymphoid organs. The phosphorylated metabolite of the immunosuppressant agent FTY720 (2-amino-2-(2-[4-octylphenyl]ethyl)-1,3-propanediol) and other phosphonate analogs with differential receptor selectivity were investigated. No significant species differences in compound potency or rank order of activity on receptors cloned from human, murine, and rat sources were observed. All synthetic analogs were high-affinity agonists on S1P(1), with IC(50) values for ligand binding between 0.3 and 14 nM. The correlation between S1P(1) receptor activation and the ED(50) for lymphocyte reduction was highly significant (p < 0.001) and lower for the other receptors. In contrast to S1P(1)-mediated effects on lymphocyte recirculation, three lines of evidence link S1P(3) receptor activity with acute toxicity and cardiovascular regulation: compound potency on S1P(3) correlated with toxicity and bradycardia; the shift in potency of phosphorylated-FTY720 for inducing lymphopenia versus bradycardia and hypertension was consistent with affinity for S1P(1) relative to S1P(3); and toxicity, bradycardia, and hypertension were absent in S1P(3)(-/-) mice. Blood pressure effects of agonists in anesthetized rats were complex, whereas hypertension was the predominant effect in conscious rats and mice. Immunolocalization of S1P(3) in rodent heart revealed abundant expression on myocytes and perivascular smooth muscle cells consistent with regulation of bradycardia and hypertension, whereas S1P(1) expression was restricted to the vascular endothelium.     

Leiomyosarcoma of the splenic vein

Leiomyosarcomas are smooth muscle-derived tumors generally found intra-abdominally in the retoperitoneum, mesentery, or omentum. Only approximately 5% of these tumors originate from vessel wall smooth muscle. Those derived from the splenic vein are exceedingly rare, with only one previously published case in the literature. We present a second case of leiomyosarcoma of the splenic vein in a 58-year-old woman with 2 months of epigastric pain. A distal pancreatectomy was performed to include the tumor found centered in the splenic vein at the splenic and portal vein confluence and growing into the pancreas in the body on the posterior aspect. A saphenous vein patch was used for reconstruction.     

Cytotoxicity of platelet activating factor and related alkyl-phospholipid analogs in human leukemia cells, polymorphonuclear neutrophils, and skin fibroblasts

A series of 11 alkyl-phospholipid analogs, structurally related to platelet activating factor (L-PAF), were analyzed for cytotoxic activity in human leukemic (HL-60) cells, human polymorphonuclear neutrophils, and Detroit 551 human skin fibroblasts. The order of selectiveness of the analogs in their cytotoxic response toward HL-60 cells in comparison to neutrophils is 1-alkyl-2-acetamide-GPC greater than 1-alkyl-2-methoxy-GPC greater than D-PAF greater than 1-acyl-2- lyso-GPC greater than 1-alkyl-2-lyso-GPC greater than L-PAF. A time- sequenced progression of events caused by the most potent cytotoxic alkyl-phospholipid analogs was characterized by (a) a rapid decrease in the cellular uptake and incorporation of 3H-thymidine into DNA that was detectable 4 hr after exposure to the analog, (b) a release of lactate dehydrogenase activity into the media at 8 hr after exposure, and (c) a decrease in cell number due to cell death that begins at 12 hr after exposure. Treatment of HL-60 cells with 1-alkyl-2-methoxy-GPC for 1 hr destroyed 40% of the cells after a subsequent 24-hr incubation period. The varied biologic activities of L-PAF, including how it affects serotonin release from platelets, blood pressure in rats, and cytotoxic responses in normal and leukemic cells, are discussed in relation to its D-enantiomer, 3-alkyl-2-acetyl-GPC, and the 2-acetamide analog. This report characterizes the kinetic events of the cellular responses in both normal and HL-60 cells in relation to the antineoplastic activities of unnatural ether-linked phospholipid analogs that are structurally related to L-PAF.     

Predictors of Nipple–Areolar Complex Involvement by Breast Carcinoma: Histopathologic Analysis of 787 Consecutive Therapeutic Mastectomy Specimens

Background  

Breast-conserving therapy (BCT) is an accepted therapeutic option for most breast cancer patients. However, mastectomy is still performed in 30–50% of patients undergoing surgeries. There is increasing interest in preservation of the nipple and/or areola in hopes of achieving improved cosmetic and functional outcomes; however, the oncologic safety of nipple–areolar complex (NAC) preservation is a major concern. We sought to identify the predictive factors for NAC involvement in breast cancer patients.     

Effects of antihypertensive therapy on mechanics of cerebral arterioles in rats.

The purpose of this study was to examine effects of antihypertensive treatment on structure and mechanics of cerebral arterioles and the incidence of stroke in stroke-prone spontaneously hypertensive rats (SHRSP). Treatment of hypertension was begun at 3 months of age with cilazapril (45 mg/kg/day), an angiotensin converting enzyme (ACE) inhibitor, or with hydralazine (18 mg/kg/day). Cilazapril and hydralazine reduced systolic arterial pressure (from 195 +/- 8 to 125 +/- 5 and 148 +/- 3 mm Hg, respectively [mean +/- SEM]; p less than 0.05). To examine structure and mechanics of cerebral arterioles, we measured pressure (servonull), external diameter, and cross-sectional area of the vessel wall (histologically) in pial arterioles of normotensive Wistar-Kyoto (WKY) rats and SHRSP that were untreated or that were treated for 3 months with cilazapril or with hydralazine. Arterioles were maximally dilated with EDTA. In WKY rats, cilazapril and hydralazine did not alter pial arteriolar pressure, external diameter, or cross-sectional area of the vessel wall. In SHRSP, both cilazapril and hydralazine reduced cross-sectional area of the vessel wall to levels not significantly different from WKY rats (from 1,911 +/- 155 to 1,244 +/- 101 and 1,388 +/- 59 microns 2, respectively, compared with 1,405 +/- 95 microns 2 for untreated WKY rats). Cilazapril was more effective than hydralazine in reducing pial arteriolar pressure (from 110 +/- 6 to 62 +/- 2 mm Hg with cilazapril versus 79 +/- 5 mm Hg for hydralazine compared with 60 +/- 4 mm Hg for untreated WKY rats). Cilazapril, but not hydralazine, attenuated reductions in external diameter of pial arterioles (from 91 +/- 4 to 100 +/- 4 microns for cilazapril versus 91 +/- 3 microns for hydralazine compared with 107 +/- 3 microns for untreated WKY rats).(ABSTRACT TRUNCATED AT 250 WORDS)     

Beneficial effects of theophylline infusions in surgical patients with intra-abdominal hypertension

Background  

Intra-abdominal hypertension (IAH) can cause high mortality. Recently, we found that IAH was associated with increased serum levels of adenosine and interleukin 10. Our present “hypothesis-generated study” was based on the abovementioned results.