Faripour Forouhar

Broad immunocytochemical localization of the formylpeptide receptor in human organs, tissues, and cells

Abstract The formylpeptide receptor (FPR), previously found only on polymorphonuclear leukocytes and monocytes/macrophages, responds to both synthetic N-formyl oligopeptides and those produced by bacteria. The cDNA for human FPR has been cloned and a rabbit polyclonal antiserum directed against a synthetic 11-amino-acid peptide corresponding to the deduced carboxy-terminus has been produced. We have now extensively characterized and used the antibody to detect FPR on normal human tissues and cell types. The receptor antigen is present on some epithelial cells, especially those with a secretory function, and on some endocrine cells, e.g., follicular cells of the thyroid and cortical cells of the adrenal. Liver hepatocytes and Kupffer cells are positive. Smooth muscle and endothelial cells are also generally positive. In the brain and spinal cord, the neurons of the motor, sensory, and cerebellar systems, and those of the parasympathetic and sympathetic systems stain positively. These data suggest that the putative endogenous agonist for FPR or an antigenically similar receptor reacts with cellular targets in the neuromuscular, vascular, endocrine, and immune systems.

Monoclonal antibody DF3 correlates with tumor differentiation and hormone receptor status in breast cancer patients.

SummaryThe murine monoclonal antibody (MAb) designated DF3, reacts with a 300-kd human mammary epithelial antigen which is expressed on apical borders of secretory mammary epithelial cells and in the cytosol of less differentiated malignant cells. Human mammary tumors have been evaluated for the level of DF3 antigen as a correlate to clinicopathologic parameters related to degree of tumor differentiation: nuclear grade (NG), histologic grade (HG), and estrogen receptor status (ER). More DF3 antigen was present in breast carcinomas with NG 1 and 2 as compared to tumors with NG 3 (p = .002). Similarly DF3 antigen presence was greater in HG 1 and 2 tumors than in HG 3 (p<.001). The results also demonstrate that quantitative differences in the presence of the DF3 differentiation antigen correlate with estrogen receptor status. Twenty-two of 23 ER positive tumors were also DF3 positive. Only 6 of 23 ER negative tumors were reactive to MAb DF3 (p<.001). There was, however, no correlation between DF3 reactivity and absolute levels of estrogen or progesterone receptor.These findings confirm our hypothesis that MAb DF3 reacts to a differentiation antigen present in some human breast carcinomas. The DF3 antigen phenotype can serve as an independent phenotypic marker with correlations to standard indicators of degree of differentiation and estrogen receptor status of infiltrating ductal carcinomas of the breast, and should thus be evaluated as a prognostic indicator in breast cancer patients. The data also suggests that DF3 histochemistry may be a useful alternative in assessing estrogen receptor status of small breast cancers where there is an insufficient amount of tumor present for biochemical assay of hormone receptor levels.

Cytoplasmic Phospholipase A2 Levels Correlate with Apoptosis in Human Colon Tumorigenesis

Colon cancers often display perturbations in arachidonic acid metabolism, with elevated levels of cyclooxygenase (COX)-2 expression and prostaglandin E2 (PGE2) production frequently observed. Whereas COX-2 and PGE2 are associated with cancer cell survival and tumor angiogenesis, arachidonic acid itself is a strong apoptotic signal that may facilitate cancer cell death. To further explore how cancer cells exploit the progrowth actions of prostaglandins while suppressing the proapoptotic actions of intracellular arachidonic acid, we determined the cytoplasmic phospholipase A2 (cPLA2) and COX-2 expression levels in a panel of human colon tumors by immunohistochemistry. Although high levels of cPLA2 and COX-2 expression are predicted to facilitate maximal prostaglandin production, tumors frequently displayed a high-COX-2/low-cPLA2 phenotype. The least represented phenotype was the high expression of cPLA2, a characteristic predicted to generate the highest levels of intracellular arachidonic acid. The potential proapoptotic role of cPLA2 was supported by a higher frequency of terminal deoxynucleotidyl transferase–mediated nick end labeling staining in cPLA2-positive tumors. Moreover, analysis of preneoplastic aberrant crypt foci from high-risk patients suggests that acquisition of the high-COX-2/low-cPLA2 phenotype may arise at an early stage of colon carcinogenesis. We additionally inhibited cPLA2 in HT-29 cells using antisense oligonucleotides. Our results indicate that cPLA2 plays an important role in tumor necrosis factor α–induced apoptosis in human colon cancer cells. Our data further support the model in which colon cancer growth is favored when intracellular arachidonic acid levels are suppressed by inhibition of cPLA2 or by a high-COX-2/low-cPLA2 phenotype.

Granulomatous liver diseases: A review

Granulomas that consist of focal accumulations of macrophages are commonly found in the liver due to stimulation of the immune system by a number of agents. Manifestations are variable depending on whether the underlying cause is a systemic disease or a primary hepatic granulomatous reaction. This article describes the common causes, presentation, histopathology, and manifestations of granulomatous diseases as well as various diagnostic and management strategies.

Fatal air and bile embolism after percutaneous liver biopsy and ERCP.

The major causes of death after percutaneous liver biopsy and ERCP includemassive hemorrhage, perforation of a viscus, or, in the case of ERCP, necrotizing pancreatitis. The presence of gas in the hepatic venous system after ERCP and sphincterotomy is reported, albeit rarely with fatal outcome. The likely mechanism is intramural dissection of insufflated air to the portal venous system after endoscopic sphincterotomy. Air embolism is an extremely rare cause of death after ERCP. To our knowledge, the only reported case is that of a 63-year-old woman who suffered a cardiopulmonary arrest after sphincterotomy for removal of a bile-duct stone. Cholangiography demonstrated air in the portal and the hepatic venous systems, as well as the pulmonary vasculature and the right heart on postmortem radiographs. The air was thought to have entered the portal venous system via venous radicles close to the major duodenal papilla that were transected inadvertently during sphincterotomy. Reported here is the first case in which an unfortunate fatal air and bile pulmonary embolism was caused by percutaneous liver biopsy followed by ERCP.

Cbl-b−/− T Cells Demonstrate In Vivo Resistance to Regulatory T Cells but a Context-Dependent Resistance to TGF-β

Cbl-b is an E3 ubiquitin ligase that negatively regulates T cell activation. Cbl-b−/− mice develop spontaneous autoimmunity, and Cbl-b dysregulation has been described in both murine and human autoimmune diseases. Although the mechanisms underlying the development of autoimmunity in Cbl-b−/− mice are not yet clear, we have reported that Cbl-b−/− CD4+CD25− effector T cells (Teffs) are resistant to CD4+CD25+ regulatory T cell (Treg)-mediated suppression in vitro and have suggested that this may be an important mechanism in the development of autoimmunity. To confirm the relevance of this resistance to autoimmune disease, we now show that Cbl-b−/− Teffs are resistant to suppression by Tregs in vivo and that this involves a resistance of truly naive Cbl-b−/− Teffs. Additionally, we show that Cbl-b−/− Tregs are fully functional in vivo, further suggesting that the regulatory abnormalities in Cbl-b−/− mice are related to defects in Teff, not Treg, function. To characterize the relevance of TGF-β sensitivity in Treg resistance, we examined in vivo Th17 generation and report that Cbl-b−/− mice are able to mount a normal Th17 response in vivo. As Cbl-b−/− Teffs have been shown to be insensitive to the suppressive effects of TGF-β in other in vivo models, the present results suggest that Cbl-b−/− Teffs demonstrate a context-dependent sensitivity to TGF-β in vivo. Overall, our results suggest that resistance to Tregs may be a bona fide mechanism underlying autoimmunity and that Cbl-b−/− mice offer unique approaches for studying the interrelationships between Treg function, TGF-β–mediated responses, and the development of autoimmunity.

A review of methotrexate‐associated hepatotoxicity

Methotrexate is effective not only in treating psoriasis and rheumatoid arthritis but also various other disorders. The use of methotrexate has been somewhat limited by concerns regarding its adverse effects, including its potential for hepatotoxicity. The purpose of this article is to provide an overview of methotrexate‐associated hepatotoxicity, including risk factors, pathogenesis and recommendations for monitoring it by US, UK and European guidelines, as well as providing a brief overview of its mechanism of action and of high‐dose methotrexate.

Etanercept-Induced Lupus Erythematosus Presenting as a Unilateral Pleural Effusion

A 72-year-old man receiving etanercept for the treatment of psoriatic arthritis had an exudative pleural effusion with nonspecific fluid analysis and pleural biopsy findings. He was ultimately found to have drug-induced lupus erythematosus due to the etanercept. The spectrum of autoimmune disease due to the use of tumor necrosis factor inhibitors is reviewed.

Lymph node biopsy for early diagnosis in Kawasaki disease

Kawasaki disease or mucocutaneous lymph node syndrome is an acute exanthematous illness of childhood of unknown etiology with a recent marked increase in incidence. Occasional fatalities occur usually as a result of coronary thromboarteritis. Diagnosis is based on a spectrum of clinical signs and symptoms, some of which occur late in the acute phase of the illness. We recently examined cervical lymph node biopsies from two children during the early stage of illnesses which subsequently met the clinical criteria of Kawasaki disease and in which electron microscopy, cultures, serology, and other special studies failed to identify an etiologic agent. Both lymph node biopsies revealed multiple foci of necrosis and fibrin thrombi within the microvasculature, changes which have received little attention in the pathologic literature. These pathologic alterations are distinctive and probably characteristic. Early presumptive diagnosis of Kawasaki disease in our second case was based on the histopathologic findings and resulted in prompt institution of antithrombotic therapy. Lymph node biopsy has been underutilized in the diagnosis, and characteristic acute pathologic changes which may occur have been under-publicized.

Early colonic anastomotic edema - Evaluation of stapled vs. Hand-sewn anastomoses

Early dysfunction of intestinal anastomoses is sometimes blamed on anastomotic edema. This study compares stapled and hand-sewn anastomoses for the development of early anastomotic edema. After segmental colon resections, one group of dogs was reconstructed with two-layered handsewn anastomoses, and the other group had stapled anastomoses. Controls were untouched small bowel in each operated animal and untouched colon in a separate group of dogs. At 24 hours postoperatively, all animals were given125I albumin and at 28 hours the animals were killed, venous blood was obtained, and the anastomoses were harvested. Tissue levels of125I albumin were measured at 1-mm and 1-cm distances from each anastomosis and compared with controls. This quantitative measure of edema was compared with the histologic appearance of the tissue specimens. The results show significant edema formation in both stapled and handsewn anastomoses compared with control tissues (P<.05 for each animal). Although quantitative and histologic results demonstrate less edema in the stapled group, the difference is not significant by the Wilcoxin rank test. These and similar studies may allow improvement in surgical technique.