F. Cuccurullo

Incidental venous thromboembolism in ambulatory cancer patients receiving chemotherapy.

While the association between cancer and symptomatic venous thromboembolism (VTE) is well established, the incidence and risk factors for incidental VTE in cancer patients remain unclear. The medical records of 1,921 consecutive cancer patients starting chemotherapy from January 2003 up to March 2009 were identified. Patients with a positive history of VTE were excluded. Pre-existing signs of VTE, kind and stage of malignancy, first and subsequent lines of chemotherapy, and all follow-up computed tomography (CT) scans were analysed. The primary outcome was incidental VTE. Overall, there were 101 (5.3%) VTE, 62 (3.2%) incidental and 39 (2.0%) symptomatic during a median of eight months (range 3-72). The incidence on CT scans was 0.58% (95%CI: 0.44-0.74). Incidental VTE included 24 pulmonary embolism, 28 deep venous thrombosis of the extremities, and 10 thromboses of the cava or splanchnic veins. Half of the incidental VTE occurred in the first 3-6 months of chemotherapy with a relatively higher incidence in gynecological and lung cancers. The presence of metastases, high leukocyte count, and platin-based chemotherapy increased the risk up to three-fold. All patients with incidental VTE regardless the location received half to full therapeutic doses of low-molecular-weight heparin for a minimum of three months. In summary, incidental VTE is a relative common finding in patients with solid tumours, especially in the first months of chemotherapy. Further research is needed to understand the natural history of incidental thrombosis in order to develop adequate management guidelines.

H2‐receptor antagonists are scavengers of oxygen radicals

Abstract. Potential oxygen radical scavenging properties of the H2‐receptor antagonists cimetidine, ranitidine and famotidine were investigated. These drugs, although ineffective against superoxide anion and hydrogen peroxide, can scavenge hydroxyl radical (OH·) with a very high rate constant, which is about tenfold higher than that of the specific scavenger mannitol for famotidine (1·7 × 1010 mol−1 s−1) and cimetidine (1·6 × 1010 mol−1 s−1), ranitidine displaying a rate constant of 7·5 × 109 mol−1 s−1. These OH· scavenging effects are significant beginning from 10, 28 and 100 μmol 1−1 concentration for famotidine, cimetidine and ranitidine, respectively, thus suggesting that the drugs may effectively act as OH· scavengers in vivo especially in the gastric lumen. Only cimetidine can apparently bind and inactivate iron, which further emphasizes its antioxidant capacity. Moreover, all drugs, even at 10 μmol 1−1 concentration, show powerful scavenging effects on hypochlorous acid and monochloramine, which are cytotoxic oxidants arising from inflammatory cells, such as neutrophils. These data suggest that some therapeutical effects of H2‐receptor antagonists in peptic ulcer may also be related to their antiradical‐antioxidant capacity, and that these drugs could potentially be used in other disease entities characterized by free radical‐mediated oxidative stress in vivo.

Antiproliferative effect of desferrioxamine on vascular smooth muscle cells in vitro and in vivo.

Vascular smooth muscle cell (VSMC) growth is a primary component of accelerated and spontaneous atherosclerosis. Previous studies have shown that iron may be involved in the control of enzymatic activities that modulate DNA synthesis in human cells. In this study the effects of the iron chelator desferrioxamine on in vitro and in vivo VSMC proliferation were tested. Rat VSMCs in culture and a rabbit model of carotid artery balloon injury were used. Desferrioxamine showed a significant inhibitory effect on [3H]thymidine incorporation in cell cultures that was antagonized by iron supplementation. Desferrioxamine also provided effective preventive myointimal VSMC proliferation as assessed by bromodeoxyuridine labeling and morphometric analysis of endoluminal stenosis. These experiments suggested that iron may be involved in the control of VSMC proliferation and that desferrioxamine may have a role in preventing VSMC growth and myointimal proliferative lesions.

Sodium cromoglycate in the treatment of eosinophilic gastroenteritis

Two patients suffering from eosinophilic gastroenteritis (EG) were treated with sodium cromoglycate (SCG). Before treatment they showed enteric and cutaneous symptoms, such as abdominal pain, nausea, vomiting, diarrhoea and recurrent urticaria and angioedema. The histological findings were a notable amount of eosinophilic infiltration in the lamina propria and gastric glands, a villous shortening and thickening and weak eosinophilic inflammation in the duodenum. The patients were treated with 300 mg SCG, 4 times daily, for 4/5 months. During treatment, the clinical symptoms disappeared and at the end of treatment a reduced inflammation with an almost complete decrease of eosinophilic infiltration was observed. The results provide evidence of SCG efficacy in the treatment of EG and suggest its employment as an alternative to the steroids commonly used in EG.

Increased Transforming Growth Factor-β Production and Gene Expression by Peripheral Blood Monocytes of Hypertensive Patients

Cultured human peripheral blood monocytes are known to secrete and express transforming growth factor-beta (TGF-beta), a multifunctional cytokine that can be involved in myocardial and vascular remodeling. In addition, monocytes/macrophages have been demonstrated to be colocalized with fibrosis of hypertrophied heart and in the vascular wall of hypertensive vessels. In this study, we tested TGF-beta production and mRNA expression in peripheral blood monocytes from hypertensive patients with myocardial hypertrophy and increased carotid myointimal thickness with respect to healthy normotensive control subjects. We found an increased TGF-beta activity in the conditioned medium of monocytes from hypertensive patients compared with control subjects as evaluated by inhibition of [3H]thymidine incorporation by mink lung epithelial cells (-83% and -18% in hypertensive and normotensive subjects; P<.001). Western blot analysis confirmed a significant difference in the amount of TGF-beta protein secreted in the conditioned medium of hypertensive patients compared with that of normotensive subjects. Finally, we also observed a 4.2- and 5.5-fold increase in the amount of TGF-beta1 and TGF-beta2 transcripts, respectively. Our results indicate an upregulation of the TGF-beta system in the peripheral blood monocytes of hypertensive patients with cardiovascular structural changes, suggesting a possible role of TGF-beta monocyte production in hypertensive disease.

Glutathione peroxidase, glutathione reductase and glutathione transferase activities in the human artery, vein and heart

The continuous exposure to blood components, including prooxidants, makes the blood vessel wall susceptible to oxidative stress and free radical mediated reactions (Henning and Chow, 1988; Stamm et al., 1989; Halliwell and Gutteridge, 1984). Free radicals can be produced extracellularly via the respiratory bursts of activated neutrophils, or intracellularly, via oxidation of hypoxanthine by xanthine oxidase (Henning and Chow, 1988; Stamm et al., 1989; Rubanyi, 1988). Microsomal enzymes such as lipoxygenase and cyclooxygenase may also be a source of reactive species of oxygen (Henning and Chow, 1988; Stamm et al., 1989; Rubanyi, 1988; Mason et al., 1980). It has been proposed that free radicals are involved in the initiation and progression of various cardiovascular diseases including arteriosclerosis (Henning and Chow, 1988; Stamm et al., 1989; Yagi, 1988; Jürgens et al., 1987). Thus the adequacy of the defence systems against free radicals is critical for the susceptibility of blood vessel wall to oxidative damage. Among the enzymatic systems capable of protecting the cell against oxidative injury, selenium dependent glutathione peroxidase (Se-GSH-px), glutatione reductase (GSSG-rx) and glutathione transferase (GST) play a crucial role (Flohe et al., 1976; Mannervik and Danielson, 1988). Using glutathione (GSH) as a cofactor, Se-GSH-px reduces H2O2 to water and organic hydroperoxides to the corresponding alcohols (Flohe et al., 1976). This reaction leads to conversion of GSH into its oxidized form (GSSG). In the presence of NADPH, GSSG-rx is able to reduce the oxidized glutathione.(ABSTRACT TRUNCATED AT 250 WORDS)

Vascular changes in hypertensive patients with different left ventricular geometry

Objective To evaluate vascular structural changes in hypertensive patients with different patterns of left ventricular geometry. Design and methods From 250 untreated hypertensive patients who underwent ambulatory blood pressure monitoring and echocardiographic study, we selected four groups matched for sex, age, body mass index, smoking habits and serum lipid values: 25 hypertensive subjects with normal left ventricular geometry, 16 with concentric left ventricular remodeling, 26 with concentric left ventricular hypertrophy and 18 with eccentric non-dilated left ventricular hypertrophy. These patients underwent carotid ultrasonography to evaluate the intimal-medial thickness and lumen diameter, and venous occlusion plethysmography to record minimum forearm vascular resistance (an index of arteriolar structural changes). Results The intimal-medial thickness and minimum forearm vascular resistance were significantly higher (both P < 0.05) in hypertensive subjects with concentric left ventricular remodeling (0.95 mm, 2.68 RU) and concentric left ventricular hypertrophy (0.96 mm, 2.71 RU) than in those with eccentric non-dilated left ventricular hypertrophy (0.81 mm, 2.36 RU) and normal left ventricular geometry (0.71 mm, 2.15 RU). There was no difference between hypertensive patients with concentric left ventricular remodeling and concentric left ventricular hypertrophy. The intimal–medial thickness and minimum forearm vascular resistance tended to be higher in hypertensive subjects with eccentric non-dilated left ventricular hypertrophy than in those with normal left ventricular geometry, but this difference did not attain statistical significance. Conclusions This study shows that the spectrum of cardiac adaptation to hypertension is associated with a spectrum of vascular adaptation which might be related both to hemodynamic stimuli and differences in the expression or activity of vascular growth factors.

Modulation of rat vascular smooth muscle cell (VSMC) proliferation by cysteinyl leukotriene D4: a role for mediation of interleukin 1

Recent studies suggest the involvement of inflammatory mechanisms in the progression of atherosclerosis. Cysteinyl leukotrienes and cytokines could orchestrate this progression by acting on the proliferation of vascular smooth muscle cells (VSMC). In cultures of rat VSMC, proliferation was modulated by cysteinyl leukotriene C4 (LTC4) and LTD4, but not LTE4. Co-culturing LTD4 with VSMC produced an increased cell proliferation as assessed by [3H]thymidine incorporation studies (200%) as well as cell counts (70%), using LTD4 at 10(-6)M compared to controls. LTD4 exerted its effect through an interleukin 1 (IL-1)-dependent autocrine regulatory mechanism. When IL-1 was inhibited by using a receptor antagonist (IL-1ra) and a polyclonal antibody to IL-1, we found an inhibition of VSMC proliferation. The increase of VSMC proliferation was associated with the autocrine production of interleukin-1 (IL-1) concomitant to LTD4 stimulation (55.5 +/- 2.5 pg/ml in controls and 177 +/- 0.5 pg/ml in 10(-6)M LTD4). These results may shed new light on the mechanism of inflammatory involvement during atherogenesis, suggesting that the control of cysteinyl leukotrienes may be important in inflammatory processes involving IL-1.

High preprocedural non-HDL cholesterol is associated with enhanced oxidative stress and monocyte activation after coronary angioplasty: possible implications in restenosis

Objective: To investigate whether enhanced oxidant stress in patients undergoing percutaneous transluminal coronary angioplasty (PTCA) is associated with a higher concentration of non-high density lipoprotein (HDL) cholesterol at baseline, and whether this contributes to the inflammatory reaction and luminal renarrowing after PTCA. Design: An ex vivo and in vitro study of 46 patients who underwent PTCA and who had repeat angiograms after six months. Blood samples were collected immediately before PTCA, and at 24 hours, 48 hours, and 15 days after. Setting: Tertiary referral centre. Subjects: 46 patients (30 male, 16 female; mean (SD) age, 62 (5) years) with stable or unstable angina who underwent elective PTCA. Main outcome measures: Continuous variable luminal loss as defined by change in minimum lumen diameter during follow up, normalised for vessel size; lag phase of low density lipoprotein to in vitro oxidation; plasma fluorescent products of lipid peroxidation (FPLP); plasma vitamin C and E; interleukin (IL) 1β secretion from unstimulated monocytes; plasma C reactive protein (CRP). Results: Restenosis occurred in 12 patients (26%). Oxidant stress after PTCA was greater (p < 0.0001 at 15 days) in the patients with restenosis and showed a significant correlation with the preprocedural concentration of non-HDL cholesterol (p < 0.001). Inflammatory reaction (as reflected by IL-1β production and CRP) and late lumen loss were linearly correlated (p < 0.001) with lag phase and FPLP throughout the study, and inversely (p < 0.05) with vitamin C and E measured at two and 15 days after PTCA. Conclusions: This study provides evidence for the critical role of cholesterol dependent oxidant stress in the pathophysiology of restenosis after PTCA. The findings raise the possibility that drugs capable of modulating oxidant status might provide a novel form of adjuvant treatment in patients with hypercholesterolaemia undergoing PTCA.

Down-regulation of cyclooxygenase-2 (COX-2) by interleukin-1 receptor antagonist in human monocytes.

Cyclooxygenase (COX) is the key rate‐limiting enzyme in the synthesis of prostanoids from arachidonic acid. Two isoforms of COX have been described in mammalian cells, referred to as cyclooxygenase‐1 (COX‐1) and cyclooxygenase‐2 (COX‐2). COX‐1 is a constitutively expressed enzyme; COX‐2 is an inducible enzyme that appears to be expressed in inflamed tissue and following exposure to growth factors or cytokines, such as interleukin‐1 (IL‐1). The aim of the present study was to test if the antagonism on the binding of IL‐1 to its cell‐surface receptor by human recombinant IL‐1 receptor antagonist (hrIL‐1ra) may control the COX mRNA expression and prostaglandin E2 (PGE2) production by human monocyte cultures. Northern blot studies showed that hrIL‐ra (500u2003ng/ml) had a strong inhibitory effect on inducible COX activity. The effect was evident after 6u2003hr incubation (2.7‐fold decrease of mRNA COX‐2 transcripts); and about a threefold decrease at 24u2003hr incubation. A non‐significant effect was observed with COX‐1 transcripts. Induced PGE2 production by monocyte cultures treated with lipopolysaccharide (LPS) or interleukin‐1β (IL‐1β) was strongly inhibited in the presence of hrIL‐1ra (500u2003ng/ml). In addition, a significant inhibition of COX‐2 protein expression, as evaluated by Western blotting, was also observed. These data suggest that hrIL‐1ra may be the key mediator in the down‐regulation of the COX‐2 inducible pathway.