Coexpression of microsomal prostaglandin E synthase with cyclooxygenase-2 in human rheumatoid synovial cells

OBJECTIVE: Recently, microsomal prostaglandin (PG) E synthase (mPGES) was cloned as a terminal enzyme catalyzing PGH2 to PGE2. We investigated mPGES as well as cyclooxygenase (COX)-2, catalyzing arachidonic acid to PGH2, in synovial cells from patients with rheumatoid arthritis (RA). The effect of dexamethasone on mPGES expression was also studied. METHODS: Synovial cells were treated with interleukin 1beta (IL-1beta) and dexamethasone under various conditions, and expression of mPGES mRNA and protein was analyzed by Northern blot and Western blot, respectively. Conversions of arachidonic acid or PGH2 to PGE2 were measured by ELISA. Subcellular localization of mPGES and COX-2 was determined by immunofluorescent microscopic analysis. RESULTS: mPGES mRNA and protein expression were significantly upregulated by IL-1beta in synovial cells. COX-2 mRNA and protein were also upregulated by IL-1beta, but with a different time course from that of mPGES. Conversion of PGH2 to PGE2 increased by IL-1beta and was correlated with mPGES expression. Increased conversion of arachidonic acid to PGE2 was maintained when mPGES and COX-2 were coexpressed. Subcellular localization of mPGES and COX-2 overlapped in the perinuclear region in IL-1beta stimulated synovial cells. Dexamethasone inhibited mRNA and protein expression for mPGES and increased conversion of arachidonic acid to PGE2, but inhibition of mPGES was weaker compared with that of COX-2 in IL-1beta stimulated cells. CONCLUSION: The results suggest that abundant PGE2 production at inflammation sites such as rheumatoid synovia is caused by the coordinated upregulation of mPGES and COX-2. Thus mPGES might be a potential new target for therapeutic strategies to control PGE2 synthesis specifically in patients with RA and other inflammatory diseases.     

Elastofibroma Dorsi

(Received for publication on Oct. 26, 1998; accepted on July 13, 1999)     

Randomized trial of 8-week versus 12-week VNCOP-B plus G-CSF regimens as front-line treatment in elderly aggressive non-Hodgkin's lymphoma patients.

BACKGROUND: Among the third-generation chemotherapy regimens specifically adapted in the last decade for elderly aggressive non-Hodgkin's lymphoma (NHL) patients, we designed an 8-week cyclophosphamide, mitoxantrone, vincristine, etoposide, bleomycin and prednisone (VNCOP-B) plus granulocyte colony-stimulating factor (G-CSF) regimen which, in a national multicenter trial, induced good complete response (CR) and relapse-free survival rates with only moderate toxic effects. Here we report a prospective, multicenter, randomized trial comparing the efficacy and toxicity of 8- and 12-week regimens of VNCOP-B plus G-CSF. PATIENTS AND METHODS: From February 1996 to June 2001, 306 consecutive previously untreated stage II-IV aggressive NHL patients > or =60 years of age were enrolled from 12 Italian cooperative institutions. Of the 297 evaluable patients, 149 and 148 received 8- and 12-week regimens, respectively, of VNCOP-B. RESULTS: The CR rates were 63% and 56% in the 8- and 12-week groups; at a median of 32 months (range 3-62 months), relapse-free survival rates were 59% and 55%, respectively. Hematological and non-hematological toxicities were similar in both treatment groups. CONCLUSIONS: Our data show that extending induction treatment with the VNCOP-B plus G-CSF regimen from 8 to 12 weeks does not raise the CR rate or provide a more durable remission.     

Hepatitis C virus, hepatitis B virus and human immunodeficiency virus infection in pregnant women in North-East Italy: A seroepidemiological study

Background: Pregnant women can be considered a sentinel population, because they are a relatively unselected population whose prevalence data may be extended to the general population. Methods: A seroepidemiological study was carried out in Padua (North-East Italy) to assess the epidemiological aspects of HCV, HBV and HIV infection in 2059 pregnant women consecutively seen at the Department of Obstetrics and Gynaecology during 1996. Out of them, 1804 (87.2%) were indigenous and 255 (12.8%) immigrants. Sociodemographical and sanitary data were collected for each woman. Results: The overall prevalence of anti-HCV was 1.9% (42.5% with detectable HCV-RNA); HBsAg was found in 1.0%; the prevalence of anti-HIV was 0.3%. Findings are substantially consistent with the epidemiological picture of such infections in the general population of our geographic area. A parenteral risk factor for HCV infection was found in 19 subjects (47.5%): 18 were intravenous drug users and 1 a blood transfusion recipient. HBsAg seroprevalence was higher in immigrants than in autochthonous (3.1% vs. 0.7% respectively, p < 0.01). One of the 6 anti-HIV positive women was intravenous drug user. Logistic regression analysis was carried out for each viral agent to determine which characteristics were independently associated with infection: anti-HCV prevalence resulted independently associated to Italian origin (OR: 3.7), unmarried status (OR: 2.7), unemployed condition (OR: 6.1) and history of previous abortion (OR: 2.8). HBsAg prevalence was independently associated to unemployed condition (OR: 10.8), whereas HIV positivity was significantly related to the unmarried status (OR: 18.5). Conclusion: Our study pinpoints the need of screening all pregnant women for HCV and HIV infection, in addition to the HBsAg screening which is compulsory in Italy.     

The surgeon's approach to preoperative evaluation of esophageal cancer: recent developments

Esophageal resection for cancer is still associated with high morbidity and mortality. Postoperative complications may be either patient- or surgeon-related. Patient-related factors include age, malnutrition, immunodepression and associated diseases. Surgeon-related factors are surgical experience, hospital volume and multidisciplinary approach. In the last 20 years major improvements and new technologies have been proposed and applied in esophageal surgery: its evolution depended on a thorough knowledge of surgical anatomy and technique, as well as on important developments in pre- and postoperative care. Preoperative evaluation is defined as the process of clinical assessment that precedes the induction of anesthesia. The principle is to gain information about the patient that could lead to modify his/her management, and improve outcome.     

Primary breast lymphoma: outcome of 7 patients and a review of the literature

Primary breast lymphomas (PBL) are uncommon neoplasms. Seven PBL were diagnosed between March 1993 and October 2002. A lumpectomy (n = 4) or radical mastectomy (n = 3) was performed; 5 patients were in clinical stage (CS) II and 2 in CS IV; 6 patients received the CEOP regimen (cyclophosphamide, vincristine, epirubicin and prednisone) after surgery and 4 also had additional radiotherapy; 1 patient did not receive any treatment after local excision. Five patients (71%) achieved complete remission and 2 (29%) partial remission, with an overall response rate of 100%. All remitter patients are alive and well after a median follow-up of 75 months (range 10 - 121 months). Two patients in partial remission died of progressive disease. After a median follow-up of 99 months (range 84 - 111 months) for surviving patients, the 10 year overall and disease-free survival rates are both 71%, with 5 patients well and still free of disease. We conclude that the optimal sequence of full-dose anthracycline-containing regimens and radiation therapy should be the treatment of choice for patients with PBL.     

Mediators involved in decreasing peripheral vascular resistance with carbachol in the rat hind limb perfusion model

We examined the involvement of nitric oxide (NO) and/or endothelium-derived hyperpolarizing factor (EDHF) in decreasing peripheral vascular resistance in the rat hind limb perfusion model and analyzed the identity of EDHF in this model. The potency of carbachol (CCh) to produce relaxation was quantitatively similar to sodium nitroprusside (SNP). CCh-induced relaxation was abolished after endothelial denudation, but resistant to nitroarginine and indomethacin. The relaxation was inhibited by tetraethylammonium, ouabain, charybdotoxin plus apamin, and under depolarization. SNP-induced relaxation was accompanied by increased cGMP production, which was inhibited by ODQ (1H-[1,2,4]oxadiazolo[4,3-a]quinoxaline-l-one). Although CCh produced a similar extent of relaxation to SNP, the cGMP level was 24 times lower than that with SNP. Low KCl produced a definite relaxation, which was inhibited by ouabain, but independent of NO, prostacyclin, and endothelium. 1-EBIO (1-ethyl-2-benzimidazolinone) as an activator of IK(Ca) channel also produced a concentration-dependent relaxation, which was inhibited by charybdotoxin, ouabain, and depolarization, but independent of NO and prostacyclin. Clotrimazole and 17-octadecynoic acid as inhibitors of P(450) monooxygenase inhibited the CCh-induced relaxation. Meanwhile, catalase at a concentration sufficient to inhibit H(2)O(2)-induced relaxation did not exert definite inhibition of the CCh-induced relaxation. These results suggest that CCh produces an endothelium-dependent, EDHF-dependent, and NO-cGMP-independent relaxation and that K(+) and metabolite(s) of P(450) monooxygenase possibly play an important role for this relaxation.