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OBJECTIVE--Diabetes is associated with oxidative stress and increased mortality, but a possible correlation between leukocyte-endothelium interactions, oxidative stress, and silent myocardial ischemia (SMI) is yet to be confirmed. RESEARCH DESIGN [...]

Two women in their late 20s present to you with histories of abdominal swelling, vomiting, and diarrhea. In both cases, CT scan reveals ascites. Is this ovarian cancer... or something [...]

Gastrin release is affected by gastric inflammatory conditions. Antral G cells respond to inflammatory mediators by increasing gastrin secretion. Accumulating experimental evidence suggests that gastrin exerts immunomodulatory and proinflammatory effects. Gastrin could be a contributing factor to these pathologies, which may constitute a new justification for pharmacological blockade of gastrin action.

Regulated adhesion of T cells by the integrins LFA-1 (lymphocyte function-associated antigen-1) and VLA-4 (very late antigen-4) is essential for T-cell trafficking. The small GTPase Rap1 is a critical activator of both integrins in murine lymphocytes and T-cell lines. Here we examined the contribution of the Rap1 regulatory pathway in integrin activation in primary CD3+ human T cells. We demonstrate that inactivation of Rap1 GTPase in human T cells by expression of SPA1 or Rap1GAP blocked stromal cell-derived factor-1α (SDF-1α)–stimulated LFA-1–ICAM-1 (intercellular adhesion molecule-1) interactions and LFA-1 affinity modulation but unexpectedly did not significantly affect binding of VLA-4 to its ligand VCAM-1 (vascular cell adhesion molecule 1). Importantly, silencing of the Rap1 guanine exchange factor CalDAG-GEFI inhibited SDF-1α- and phorbol 12-myristate 13-acetate (PMA)–induced adhesion to ICAM-1 while having no effect on adhesion to VCAM-1. Pharmacologic inhibition of Phospholipase C (PLC) blocked Rap1 activation and inhibited cell adhesion and polarization on ICAM-1 and VCAM-1. Protein kinase C (PKC) inhibition led to enhanced levels of active Rap1 concomitantly with increased T-cell binding to ICAM-1, whereas adhesion to VCAM-1 was reduced. Thus, PLC/CalDAG-GEFI regulation of Rap1 is selectively required for chemokine- and PMA-induced LFA-1 activation in human T cells, whereas alternate PLC- and PKC-dependent mechanisms are involved in the regulation of VLA-4.

Antisecretory drugs are effective antiulcer agents, but its chronic use generates hypergastrinemia and accelerates the development of atrophic gastritis in Helicobacter pylori-positive patients. We have recently shown that gastrin exerts a proinflammatory effect in rats through CCK-2 receptor activation that contributes to the inflammation induced by H. pylori. The present study was designed to examine whether gastrin hypersecretion in response to treatment with antisecretory drugs induces an inflammatory response that could promote mucosal atrophy. The effects of omeprazole or famotidine on leukocyte/endothelial cell interactions in vivo were analyzed in rat mesenteric venules using intravital microscopy. Administration of a single dose of omeprazole or famotidine acutely increased gastrinemia and leukocyte rolling and adhesion, but not emigration into the interstitium. Daily treatment with omeprazole for a short period (3 days) induced a similar response, but when this treatment was extended to 14 days and a steady hyper-gastrinemic state was established, increased leukocyte rolling, adhesion, and emigration was observed. Pretreatment with the CCK-2 receptor antagonist proglumide prevented these inflammatory events in all cases. Leukocytes from rats treated with omeprazole showed increased expression of CD11b/CD18 initially in granulocytes (3-day protocol) and later in monocytes and lymphocytes (14-day protocol). These changes were not observed in animals pretreated with proglumide, and they were not reproduced by incubation of leukocytes from untreated animals in vitro with gastrin. Thus, hypergastrinemia induced by chronic treatment with antisecretory drugs may promote inflammation, which could partly explain their worsening effect in corpus gastritis observed in H. pylori-infected patients.

AbstractUna perspectiva diacrónica nos muestra que desde 1521, con la conquista de México, se han llevado a cabo transformaciones en la tenencia de la tierra y en las politicas agrarias. Todas estas reformas parecen haber resultado inconc1usas ante los problemas que vive el agro mexicano, aunque los protagonistas, los objetivos, los procedimientos y los alcances hayan variado en su devenir histórico.

Objective.The aim of this study was to test the hypothesis that p53 mutations are less frequent in ovarian cancers with alterations in other genes that regulate G1 progression.

Chronically elevated angiotensin II (Ang‐II)‐induced hypertension is partly mediated by superoxide production. In this study, we have investigated whether the leukocyte‐endothelial cell interactions elicited by Ang‐II involve reactive oxygen species (ROS) generation. Intravital microscopy within the rat mesenteric microvessels was used. Superfusion (60 min) with Ang‐II (1 nM) induced significant increases in leukocyte rolling flux, adhesion, and emigration, which were inhibited by pretreatment with superoxide dismutase or catalase. Dihydrorhodamine‐123 oxidation indicated that ROS are primarily produced by the vessel wall. Administration of dimethylthiourea, desferrioxamine, or N‐acetylcisteine provoked significant reductions in Ang‐II‐induced leukocyte‐endothelial cell interactions. In addition, a blockade of platelet‐activating factor or leukotrienes also attenuated such responses significantly. The results presented indicate that in vivoAng‐II‐induced leukocyte recruitment is dependent on the generation of intra‐ and extracellular ROS. Therefore, the use of anti‐oxidants might constitute an alternative therapy for the control of the subendothelial leukocyte infiltration associated with hypertension and atherosclerosis.

Objective.The regulation of the metastatic process in epithelial ovarian cancer has not been well defined. Similar to other tumor types, the angiogenic phenotype in ovarian cancer strongly influences clinical outcome, suggesting that the acquisition of a pro-angiogenic environment is essential to the process of ovarian cancer proliferation and metastasis. Thrombospondin-1 (TSP-1) is a potent peptide shown in other tumor systems to be associated with angiogenesis and possibly regulated by p53, a gene which is mutated in as high as 50% of advanced ovarian cancers. The purpose of this study was to investigate TSP-1 expression in invasive epithelial ovarian cancer and to examine the relationship between TSP-1 expression and the degree of angiogenesis. In addition, we examined whether TSP-1 expression was associated with overexpression of p53.

Objectives.Prior studies have shown that allelic loss on chromosome 1p36 occurs frequently in ovarian as well as several other types of cancer. This suggests that inactivation of gene(s) in this region may play a role in the pathogenesis of these cancers. The aim of this study was to further delineate the region of loss on chromosome 1p36 in ovarian cancers and to identify associated patient or tumor characteristics.

Angiotensin (Ang‐II) is a key molecule in the development of cardiac ischaemic disorders and displays proinflammatory activity in vivo. Since intracellular cyclic nucleotides elevating agents have proved to be effective modulators of leukocyte recruitment, we have evaluated their effect on Ang‐II‐induced leukocyte‐endothelial cell interactions in vivousing intravital microscopy within the rat mesenteric microcirculation.Pretreatment with iloprost significantly inhibited (1 nM) Ang‐II‐induced increase in leukocyte rolling flux, adhesion and emigration at 60 min by 96, 92 and 90% respectively, and returned leukocyte rolling velocity to basal levels. Pretreatment with salbutamol or co‐superfusion with forskolin exerted similar effects.When theophylline was administered, leukocyte rolling flux, adhesion and emigration elicited by Ang‐II were significantly attenuated by 81, 89 and 71% respectively. Rolipram administration caused similar reduction of Ang‐II‐induced leukocyte responses.Co‐superfusion of Ang‐II with the NO‐donor, spermine‐NO, or 8‐Br‐cyclic GMP, or pretreatment with a transdermal nytroglycerin patch, resulted in a significant reduction of the leukocyte‐endothelial cell interactions elicited by Ang‐II.Salbutamol preadministration did not modify leukocyte‐endothelial cell interactions elicited by either L‐NAME or L‐NAME+Ang‐II, indicating that the inhibitory leukocyte effects caused by cyclic AMP‐elevating agents are mediated through NO release.In conclusion, we have provided evidence that cyclic AMP elevating agents and NO donors, are potent inhibitors of Ang‐II‐induced leukocyte‐endothelial cell interactions. Thus, they could constitute a powerful therapeutical tool in the control of the leukocyte recruitment characteristic of the vascular lesions that occur in cardiovascular disease states where Ang‐II plays a critical role.

Background.Cutaneous gastrointestinal (GI) fistulas are a challenging complication in the oncologic patient population. The fistulous effluent is difficult to manage and adversely alters quality of life. Nonsurgical management of enteric fistulas is successful in 30% of cases, requiring at least 4 to 6 weeks. Recently a new technology has been developed to expedite wound healing. The Vacuum-Assisted Closure (VAC) method is a subatmospheric pressure technique that has been demonstrated in laboratory and clinical studies to significantly improve wound healing. Here we report its use in the successful medical management of a cutaneous GI fistula.

Chronic inhibition of nitric oxide synthase (NOS) provokes a hypertensive state which has been shown to be angiotensin II (Ang‐II) dependent. In addition to raising blood pressure, NOS inhibition also causes leukocyte adhesion. The present study was designed to define the role of Ang‐II in hypertension and in the leukocyte‐endothelial cell interactions induced by acute NOS or cyclo‐oxygenase (COX) inhibition using intravital microscopy within the rat mesenteric microcirculation.While pretreatment with an Ang‐II AT1receptor antagonist (losartan) reversed the prompt increase in mean arterial blood pressure (MABP) caused by indomethacin, it had no effect on the increase evoked by systemic L‐NAME administration.Pretreatment with losartan inhibited the leukocyte rolling flux, adhesion and emigration which occurs after 60 min NOS inhibition by 83, 80 and 70% respectively, and returned leukocyte rolling velocity to basal levels.Losartan significantly reduced the leukocyte‐endothelial cell interaction elicited by COX inhibition. In contrast, leukocyte recruitment induced by acute mast cell activation was not inhibited by losartan.AT1receptor blockade also prevented the drop in haemodynamic parameters such as mean red blood cell velocity (Vmean) and shear rate caused by NOS and COX inhibition.In this study, we have demonstrated a clear role for Ang‐II in the leukocyte‐endothelial cell interactions and haemodynamic changes which arise in the absence of NO or prostacyclin (PGI2). This is of interest since leukocyte recruitment, which culminates in the vascular lesions that occur in hypertension, atherosclerosis and myocardial ischemia‐reperfusion injury, might be prevented using AT1Ang‐II receptor antagonists.

Objective.Müllerian inclusion cysts (MIC) are small benign appearing glands that are occasionally noted in lymph nodes and peritoneal biopsies. They occur most frequently in women with serous ovarian tumors, with borderline tumors (SBOT) having a higher incidence than invasive cancers. The aim of this study was to examine whether MIC and SBOT have identical K-rasmutations, which would suggest that they are related.

Objective: To determine whether microsatellite instability in endometrioid endometrial cancer is associated with favorable survival.

The red-green pigment gene arrays of 203 (101 from a previous study and 102 from this study) randomly selected men of Japanese ancestry from the Seattle area were screened for the abnormal molecular patterns (deletions and red/green or green/red hybrid genes) that are usually associated with defective color vision. Such molecular patterns were found in approximately 5% of these individuals, which is equivalent to the frequency of phenotypic color vision defects in Japanese males in Japan. Thus, the majority of hybrid genes carried by Japanese males appear to be associated with defective color vision. In contrast, the frequency of hybrid genes among Caucasians and African-Americans is approximately two and five times the frequency of color vision defects in these two ethnic groups, respectively. The coding sequences of 50 males of Japanese ancestry were determined. All the polymorphisms in the red and green pigment genes that were detected in the Japanese sample had been observed in Caucasians and African-Americans. The same polymorphisms of the red pigment gene were present in the green pigment gene, suggesting that gene conversion contributes to sequence homogenization between these pigment genes. As is the case for Caucasians, exon 3 of the red and green pigment genes was observed to be a hot spot for recombination and gene conversion. Fewer polymorphic sites (4 vs 11) and haplotypes (5 vs 14) of the red pigment gene were observed in Japanese than in Caucasians. The Japanese population was more uniform with respect to the red pigment gene, with 70% of individuals having the same haplotype, as compared with the 43% for the Caucasian population. This difference was largely due to the lower degree of polymorphism at position 180 of the red pigment gene in Japanese (84% Ser and 16% Ala vs 62% Ser and 38% Ala.) The number of polymorphic sites and haplotypes in the green pigment gene was similar in the two populations. Nevertheless, the Japanese population was more uniform with 65% having the same haplotype. The difference in the frequency of alleles at position 283 accounted for this difference in haplotype distribution.