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Background: the lack of standardized pathways for patients with gastrointestinal bleeding may have led to differences in their management and inequity to medical care access. The "Hub & Spoke" model was adopted to fill this gap in many disciplines, but, to our knowledge, no data exist on its efficacy on mortality in GI bleeding. We aimed to evaluate if the "Hub & Spoke" organizational model has an impact on mortality risk from UGIB. Methods: from January 2014 to December 2015, 3324 consecutive patients admitted for UGIB in 50 Italian hospitals were enrolled (1977 patients in hospitals within the "Hub & Spoke" network for digestive hemorrhagic emergency and 1347 in hospitals outside the "Hub & Spoke" network). Clinical, endoscopic and organizational data were recorded. Results: we observed no differences in mortality between patients admitted to hospitals included or not included in the "Hub & Spoke" network (5.2% vs 6.1%, p = 0.3). On multivariate analysis, admission in gastroenterology wards (OR 0.61, p = 0.001) or an academic hospital (OR 0.65, p < 0.056) were independent protective factors while being in "Hub & Spoke" organization system did not affect mortality (OR 1.09, p = 0.57). Conclusion: the "Hub & Spoke" model per sé does not impact on mortality while being treated in academic hospital or gastroenterology wards improved survival.

This study aims to analyze the early and late outcomes of our 30-year experience with mycotic aneurysms of the abdominal aorta and iliac arteries.This retrospective cohort study compared the outcomes of all the patients with mycotic aneurysm, by analyzing prospectively collected data between September 1989 and October 2019 from the Unit of Vascular Surgery of Fondazione Policlinico Universitario Gemelli - IRCCS in Rome, Italy.Twenty-three patients with mycotic aneurysm were included. Twenty-two patients underwent surgery; one patient arrived at the emergency room with unstable clinical conditions and died before being treated. Fourteen cases (60.9%) were located at the infrarenal aorta, while three cases (13.0%) were pararenal aortic aneurysms. Six cases (26.1%) had an iliac arteries localization. Seventeen patients (77.3%) underwent open surgical repair aneurysmectomy with in situ reconstruction, while three cases (13.6%) underwent extra-anatomic revascularization. Three patients (13.6%) underwent the placement of an endoprosthesis, of whom two underwent hybrid procedures, and one EVAR. The latter underwent an early conversion to open repair due to a type I endoleak. The mean length of hospital stay was 35 ± 18.7 days. Five patients (22.7%) died in the immediate postoperative period. In the follow-up of 45.5 ± 41.3 months (range 2-156), we documented six deaths (35.3%), of whom two (11.8%) were aortic-related for a 34.8% overall aortic-related mortality. Eleven patients were alive, with an overall survival of 47.8%.Mycotic aneurysm is an extremely rare and varied pathology. Open surgical repair showed to be a safe approach because of a complete and aggressive debridement of local infected tissues, with an acceptable long-term mortality rate.

We used subtractive library screening to identify the changes that occur in gene expression during thyroid cell neoplastic transformation. Complementary DNA from normal thyroid cells (HTC 2) was subtracted from a complementary DNA library constructed from a human thyroid papillary carcinoma cell line. The library was screened for genes upregulated in human thyroid papillary carcinoma cell line cells, and several cDNA clones were isolated. One of these clones has a sirtuin core and high homology with the human silent information regulator protein family. This clone, designated ‘SIR-T8’, was overexpressed in human thyroid carcinoma cell lines and tissues, but not in adenomas. The human SIR-T8 protein has a molecular weight of 39 kDa and is primarily located in the cytoplasm under the nuclear membrane. The SIR-T8 gene is located on chromosome 17q25-1. British Journal of Cancer (2002) 86, 917–923. DOI: 10.1038/sj/bjc/6600156 www.bjcancer.com © 2002 Cancer Research UK

We show that human osteosarcoma cells (Saos-2) have downregulation of alpha3beta1-integrin compared to normal bone cells; this was further described in human osteosarcomas and in a primary murine sarcoma. The alpha3 gene was silenced in Saos-2 cells causing a low expression of alpha3beta1-integrin and reduction in collagen attachment with increasing migratory capacity. Chromatin immunoprecipitation assay performed on alpha3 promoter established that Myc and Yin Yang protein (YY1) cooperate in tandem to downregulate the alpha3 gene. This silencing mechanism involves the binding of Myc and YY1 to DNA and formation of complexes among Myc/Max, YY1, CREB-binding protein and deacetylation activity. The promoter containing deletions of E-boxes or YY1 cassettes failed to downregulate the transcription of a reporter gene as well as the inhibition of deacetylation activity. Overexpression of both Myc and YY1 was necessary to determine the alpha3-integrin promoter downregulation in normal osteoblasts. This downregulation of alpha3beta1-integrin can contribute to the acquisition of a more aggressive phenotype. YY1 regulated negatively the Myc activity through a direct interaction with the Myc/Max and deacetylase complexes. This represents a novel silencing mechanism with broad implications in the transcription machinery of tumours.

The aetiology of Crohn's disease is unknown and therefore no curative treatments are available for the disease. The natural history of Crohn's disease is characterized by recurrent flare-ups of symptoms. Several drug treatments are effective in inducing clinical remission. However, no drug treatments are available in order to prevent clinical relapses, although several drug regimens may delay clinical flare-ups. Crohn's disease treatment for maintaining clinical remission needs to be tailored in relation to specific characteristics of each patient. The frequency of clinical relapse indeed shows marked variations in subgroups of patients, as the likelyhood of relapse is higher in patients in clinical remission for less than 6 months. Treatment strategies for maintaining remission may therefore differ among inactive patients. In chronically active, steroid-dependent or steroid-refractory Crohn's disease patients immunomodulatory drugs (azathioprine 2-2.5 mg/kg by mouth, 6-mercaptopurine 1-1.5 mg/kg by mouth, or methotrexate 15-25 mg/i.m./week) should be added to oral mesalazine (2.4 g/day), while in long-term inactive Crohn's disease patients mesalazine alone may be effective in delaying relapse. Recently, treatment with anti-tumour necrosis factor-alpha monoclonal antibodies (Infliximab or CDP571) has shown efficacy in delaying relapse in responsive patients. One other issue which needs to be considered before selecting drug treatments for maintaining remission in Crohn's disease, is that Crohn's disease activity is currently assessed on the basis of standard clinical scores which may not appropriately reflect the biological activity of the disease. Clinical remission as defined by standardized scores may include heterogeneous subgroups of patients showing different endoscopic and histological activity or persistence of activated immunocompetent cells within the gut. Several sub-clinical markers of relapse have indeed been reported in quiescent Crohn's disease, although their usefulness in clinical practice in currently uncertain.

Oxygen radical species can influence vascular tone, and antioxidants may have hemodynamic and vascular effects. To date, the vascular effects of chronic intervention with a combination of antioxidant vitamins E and C on renal blood flow (RBF) in hypercholesterolemia (which increases oxidative stress) have not been fully defined. The aim of this intervention study was to explore the involvement of increased oxidative stress in pig RBF disturbance by using chronic dietary antioxidant vitamin intervention. Responses of RBF to the acetylcholine (Ach) were measured in vivo using electron beam computed tomography (EBCT). Acetylcholine significantly increased RBF in normal and hypercholesterolemic + vitamins (P < 0.05 for both), but not in hypercholesterolemic pigs (P=0.1). In normocholesterolemic + vitamins pigs, Ach infusion did not induce any further increase in RBF, but RBF was similar to that observed in normal and hypercholesterolemic + vitamins under the same conditions, and tended to be higher than in hypercholesterolemic pigs (P=0.06). Thus, antioxidants improve RBF in hypercholesterolemic pigs and this effect may help to prevent renal diseases and hypertension in animals.

Crohn's disease is characterized by a chronic inflammation of the intestine of unknown aetiology. One of the main problems when treating patients with Crohn's disease, is the identification of patients undergoing early clinical relapse, for timely treatment and the possible prevention of complications. No sub-clinical markers are currently available that predict relapse during remission. Several parameters have been proposed for this purpose. Although none have proven useful, growing evidence suggests a possible benefit in the clinical management of Crohn's disease. Among these, we may identify: clinical behaviour, the characteristics of the host, clinical activity, markers of intestinal inflammation and markers of immune activation. In particular, the possible relationship between cytokine pattern and the clinical behaviour of Crohn's disease has been addressed. Overall, these observations suggest that mucosal immune activation is a feature of Crohn's disease, and may persist in the form of activated immunocompetent cells during remission. On the basis of this evidence, studies are currently investigating whether the down-regulation of immune activation markers is associated with clinical remission in Crohn's disease. It has been shown that higher mucosal levels of TNF-alpha and an increased state of activation of lamina propria mononuclear cells in patients with inactive Crohn's disease, are significantly associated with an earlier clinical relapse of the disease. These observations suggest that a persistent local immune activation during remission may represent a marker of early clinical relapse of Crohn's disease.

Different rehabilitation models for persons diagnosed with disorders of consciousness have been proposed in Europe during the last decade. In Italy, the Ministry of Health has defined a national healthcare model, although, to date, there is a lack of information on how this has been implemented at regional level. The INCARICO project collected information on different regional regulations, analysing ethical aspects and mapping care facilities (numbers of beds and medical units) in eleven regional territories.The researchers found a total of 106 laws; differences emerged both between regions and versus the national model, showing that patients with the same diagnosis may follow different pathways of care. An ongoing cultural shift from a treatment-oriented medicalapproach towards a care-oriented integrated biopsychosocial approach was found in all the welfare and healthcare systems analysed. Future studies are needed to explore the relationship between healthcare systems and the quality of services provided.

The effects of chronic treatment with the new sulfhydryl angiotensin-converting enzyme (ACE)-inhibitor, zofenopril, in comparison with the classical sulfhydryl ACE-inhibitor captopril or enalapril or placebo on the development of atherosclerosis were determined in apolipoprotein-E knockout (apoE(-/-)) mice. Groups of 2-month-old male mice received either placebo (N=10), 0.05 mg/kg/day of zofenopril (N=10), 1 mg/kg/day of zofenopril (N=10), 5 mg/kg/day of captopril (N=10) or 0.5 mg/kg/day of enalapril (N=8). After 29 weeks of treatment, computer-assisted imaging analysis revealed that zofenopril reduced the aortic cumulative lesion area by 78% at 0.05 mg/kg/day and by 89% at 1 mg/ml/day of zofenopril compared to that of the placebo (P

Background and Purpose — Atherosclerosis occurs later and is less extensive in intracranial arteries than in extracranial arteries. However, the mechanisms responsible are poorly understood. A previous study has suggested a better antioxidant protection of intracranial arteries. Methods — To assess the influence of age on arterial activity of antioxidant enzymes and atherogenesis, we compared intracranial and extracranial arteries of humans of different ages who retrospectively lacked confounding classic risk factors (48 premature fetuses aged 6.4±0.8 months [mean±SD], 58 children aged 7.9±3.8 years, 42 adults aged 42.5±5.1 years, and 40 elderly subjects aged 71.8±3.4 years; all males). Lesions were quantified by computer-assisted imaging analysis of sections of the middle cerebral and basilar arteries, the left anterior descending coronary artery, the common carotid artery, and the abdominal aorta. Macrophages, apolipoprotein B, oxidized LDL, and matrix metalloproteinase-9 in lesions were determined by immunocytochemistry. The effect of aging on atherogenesis was then compared with that on the activity of 4 antioxidant enzymes in the arterial wall. Results — Atherosclerosis was 6- to 19-fold greater ( P

The prodromal stage of atherosclerotic lesions (known as lipidotic fatty streak accumulation) is already formed during human fetal development.1 Fatty streaks containing characteristic accumulations of lipids, lipid peroxidation products, and macrophages occur in the aorta of premature fetuses. Intimal thickening is also observed in fetal coronary arteries.2,3 During infancy, fatty streaks become increasingly prevalent, and some of them progress to advanced stages of atherosclerotic lesions.4–7 Once initiated, the progression of atherosclerosis is influenced by classic risk factors that promote vascular inflammation and plaque rupture. The observation that maternal hypercholesterolemia is associated with greatly enhanced fatty streak formation in fetal arteries1 indicates that hypercholesterolemia may play a pathogenic role in early fetal atherosclerotic lesions. Maternal hypercholesterolemia is also able to influence fetal sterol metabolism during pregnancy in animal models.8,9 Consistently, direct evidence for a causal role of maternal hypercholesterolemia and the involvement of oxidative stress has been obtained in a rabbit model10,11 and in LDL receptor–deficient mice.12 From a molecular standpoint, many signaling pathways are affected by increased oxidation of LDL or the intracellular formation of reactive oxygen species, and this phenomenon can be exacerbated by concomitant hypercholesterolemia.13 Interestingly, deletion of the p66 shc longevity gene reduces systemic and tissue oxidative stress, vascular cell apoptosis, and early atherogenesis in mice fed a very highly hypercholesterolemic diet.14 Finally, growing evidence in the literature suggests that vascular damage occurs early and is mediated by …

Objective Maternal hypercholesterolaemia during pregnancy increases lipid peroxidation in mothers and fetuses and programs increased susceptibility to atherosclerosis later in life. The objective of this study was to elucidate the role of the placenta in mediating oxidative stress from mother to offspring. Design Comparison between normo- and hypercholesterolaemic mothers (n = 36 each) and their children. Setting Obstetric wards, hospitals of the University of Naples and Regione Campania. Population Healthy primiparas delivering by caesarean section. Methods Biochemical measurements of oxidative stress and serum leptin in cord plasma and placenta, immunochemistry of placenta microvessels, and vasoreactivity studies were performed. Main outcome measures Oxidative status (i.e. lipid composition and content of oxidised fatty acids, activity of pro- and antioxidant enzymes, immunohistochemical presence of oxidation-specific epitopes) in maternal and cord blood and in placental tissue, as well as vascular reactivity in omental arteries. Results Hypercholesterolaemia during pregnancy was associated with extensive changes in fatty acid composition of both maternal and cord blood lipids, sufficient to alter vasoreactivity of omental vessels. Results also indicated that the placenta is not only subject to substantial oxidative stress, but that it may further increase fetal oxidative stress through changes of pro- and antioxidant enzyme activities. Conclusions The placenta plays an important role in both transmitting and enhancing pathogenic effects of gestational hypercholesterolaemia.

Introduction Crucial advances in our understanding of atherogenesis have been achieved during the past two decades. The historical hypothesis of pathogenesis (‘lipid accumulation’) has evolved to integrate several pathogenic mechanisms contributing to the initiation and evolution of atherogenesis. Vascular inflammation and apoptosis may play pivotal roles in its progression and onset. Endothelial dysfunction is considered to be one of the earliest events in atherogenesis. This chapter will discuss emerging concepts in the pathogenesis of, and therapeutic approaches to, atherosclerosis. Some novel risk factors, including impaired fasting glucose, triglycerides and triglyceride-rich lipoprotein remnants, lipoprotein (a), homocysteine, and high-sensitivity C-reactive protein, might contribute to an increased risk of atherosclerosis (Fruchart et al . 2004). Moreover, hypercholesterolaemia and hypertension have synergistic deleterious effects on coronary endothelial function (Rodriguez-Porcel et al . 2003). The pathogenesis of atherosclerosis has been related also to infiltration of immune cells, which are involved in systemic and local, innate as well as adaptive, immune responses (Zhou and Hansson 2004). As some inflammatory and autoimmune diseases could be treated by immunologically based therapy, it is of particular interest to consider whether such principles could also be applied to prevent or treat atherosclerosis. Atherosclerosis is ultimately responsible for myocardial infarction, peripheral arterial disease and ischaemic stroke, and is characterised by a long lag-time between onset and clinical manifestation. The prodromal stages of human atherosclerotic lesions are already formed during fetal development (Napoli et al . 1997a, 1999a, Palinski and Napoli 2002a). Intimal thickening is also observed in fetal coronary arteries (Ikari et al . 1999).

New approaches to atherosclerosis-related diseases include novel uses of proven treatments and development of innovative agents. Several commonly used cardiovascular drugs such as dihydropyridine calcium antagonists, ACE inhibitors containing the sulphydryl group, or highly lipophilic beta-blockers have some anti-atherosclerotic activities. Moreover, new clinical trials suggesting that additional reduction of low-density lipoprotein cholesterol levels with statin therapy results in additional benefit in coronary heart disease prevention. Notably, new cholesterol transport or bile acid transport inhibitors have been found to produce significant reductions in intestinal cholesterol absorption and experimental atherosclerosis. Inhibitors of acyl coenzyme A:cholesterol acyltransferase, which can reduce cholesterol storage in macrophages and in arterial lesions, have also been developed. Finally, newer therapeutical strategies against atherogenesis may include the use of antioxidants and cholestyramine during pregnancy or the development of metalloproteinase inhibitors.

AIM: To investigate protease activated receptor 2 (PAR-2) expression in human coronary atherosclerotic lesions because PAR-2 is involved in the modulation of inflammatory events and vascular function. METHODS: An immunohistochemical analysis was performed on serial arterial sections, using the following antibodies: MDA2, a murine monoclonal antibody against malondialdehyde lysine epitopes of oxidised low density lipoprotein (oxLDL); HAM-56, a monoclonal antibody against human macrophages/foam cells; B5, a rabbit polyclonal antibody against PAR-2; and SAM11, a mouse monoclonal antibody against human PAR-2. Sections containing at least one lesion showing substantial immunostaining were counted as positive, and results were expressed as per cent of all sections of the same artery. RESULTS: PAR-2 expression was enhanced in human coronary atherosclerotic lesions. This phenomenon correlated with an increase in oxLDL epitopes in the coronary artery. CONCLUSION: This study shows for the first time that PAR-2 expression is enhanced in human coronary atherosclerotic lesions, and suggests that PAR-2 dependent cellular trafficking may be one of the regulatory signalling responses to vascular injury. Further pharmacological studies will establish whether modulation (and in which direction) of PAR-2 represents a possible therapeutic target for controlling the vascular response to injury.

Oxygen radical species can influence vascular tone, and antioxidants may have hemodynamic and vascular effects. To date, the vascular effects of chronic intervention with a combination of antioxidant vitamins E and C on renal blood flow (RBF) in hypercholesterolemia (which increases oxidative stress) have not been fully defined. The aim of this intervention study was to explore the involvement of increased oxidative stress in pig RBF disturbance by using chronic dietary antioxidant vitamin intervention. Responses of RBF to the acetylcholine (Ach) were measured in vivo using electron beam computed tomography (EBCT). Acetylcholine significantly increased RBF in normal and hypercholesterolemic + vitamins (P0.05 for both), but not in hypercholesterolemic pigs (P=0.1). In normocholesterolemic + vitamins pigs, Ach infusion did not induce any further increase in RBF, but RBF was similar to that observed in normal and hypercholesterolemic + vitamins under the same conditions, and tended to be higher than in hypercholesterolemic pigs (P=0.06). Thus, antioxidants improve RBF in hypercholesterolemic pigs and this effect may help to prevent renal diseases and hypertension in animals.

Crohn's disease is characterized by a chronic inflammation of the intestine of unknown aetiology. One of the main problems when treating patients with Crohn's disease, is the identification of patients undergoing early clinical relapse, for timely treatment and the possible prevention of complications. No sub-clinical markers are currently available that predict relapse during remission. Several parameters have been proposed for this purpose. Although none have proven useful, growing evidence suggests a possible benefit in the clinical management of Crohn's disease. Among these, we may identify: clinical behaviour, the characteristics of the host, clinical activity, markers of intestinal inflammation and markers of immune activation. In particular, the possible relationship between cytokine pattern and the clinical behaviour of Crohn's disease has been addressed. Overall, these observations suggest that mucosal immune activation is a feature of Crohn's disease, and may persist in the form of activated immunocompetent cells during remission. On the basis of this evidence, studies are currently investigating whether the down-regulation of immune activation markers is associated with clinical remission in Crohn's disease. It has been shown that higher mucosal levels of TNF-alpha and an increased state of activation of lamina propria mononuclear cells in patients with inactive Crohn's disease, are significantly associated with an earlier clinical relapse of the disease. These observations suggest that a persistent local immune activation during remission may represent a marker of early clinical relapse of Crohn's disease.

The paper describes a patented proposal to use jets of air in the cooling system of heavy trucks. Preliminary tests have been carried out, in the Heat Transfer Laboratory of the University of Rome “Tor Vergata”, to evaluate the heat transfer characteristics of a jet flow of air, impinging onto an externally finned cylinder. The cylinder is internally heated with an electric system. Thermocouples, located inside the cylinder, allow to measure the wall temperatures, in order to calculate the local and average convective heat transfer coefficients. A preliminary design of the practical apparatus, applied to heavy trucks, has been done in cooperation with Iveco. Nozzles are designed to be put after the fan of heavy trucks to converge air, in the form of jets, onto the tube where the charged air is flowing from the outlet of the turbo-compressor. The efficiency of the jet flow increases the cooling performances but, due to the high temperature at the outlet of the turbo-compressor, it may not be enough. The heat transfer cooling performances are enhanced if the tube to be cooled is externally finned. Some preliminary experiments have been carried out in a real scale bank test of an heavy truck engine at the Engineering Testing Laboratories Department of Iveco. Comparisons are done between the experiments and a simple theoretical model. Some conclusions are drawn about the cooling at different fluid dynamics conditions of the impinging jets.

This study tested the hypothesis that c-Myc activation, an oxidation-sensitive transcription factor, and its binding partner Max occurs in coronary arteries of hypercholesterolemic (HC) pigs, and can be attenuated by chronic antioxidant intervention. Coronary arteries were isolated from normal, HC pigs, or HC supplemented with antioxidant vitamins (HC + vitamins). The expression of the c-Myc/Max complex, and its target genes GADD45 and p53, was studied in nonatherosclerotic, early lesions (LL), positively staining for oil-red-O, in adjacent lesion-prone regions (PL), and in healthy segments (HV). The expression of c-Myc and Max in HC was 2- to 3-fold greater in PL, and 4-fold in LL, compared to normal vessels (P < 0.01). The expression of GADD45 was down-regulated, and of p53 increased, in the same regions. These alterations were attenuated in the HC + vitamins. Thus, c-Myc activation is an early atherosclerosis, in both PL and LL coronary arterial regions, and can be blunted by chronic dietary antioxidant intervention.

Background —Atherosclerotic lesions in intracranial arteries occur later and are less extensive than in extracranial arteries. To investigate potential mechanisms responsible for this difference, in particular the atherogenic response to hypercholesterolemia and LDL oxidation, we compared the extent of fatty streak formation and the composition of these very early lesions in intracranial arteries of human fetuses from normocholesterolemic and hypercholesterolemic mothers with those in extracranial arteries. Methods and Results —Lesions were quantified by computer-assisted image analysis of 30 oil red O–stained sections, each from the middle cerebral, basilar, and common carotid arteries and the abdominal aorta of human fetuses (spontaneous abortions and premature newborns who died within 12 hours of birth; both of fetal age 6.2±1.3 months) from 43 hypercholesterolemic mothers and 34 normocholesterolemic mothers. Macrophages, apolipoprotein B, and 2 epitopes of oxidized LDL in lesions were determined immunocytochemically. Activities of superoxide dismutase, catalase, and glutathione peroxidase in the arterial wall were also determined. Lesion numbers and sizes were dramatically greater in the abdominal aorta (area of the largest lesion per section: 66.5±10.9 ×10 3 μm 2 ) and the carotid (11.6±5.3 ×10 3 μm 2 ) than in the basilar and middle cerebral artery (0.4±0.1 and 0.8±0.2 ×10 3 μm 2 , respectively; P Conclusions —Exposure to hypercholesterolemia during fetal development results in extensive formation of fatty streaks in extracranial but not intracranial arteries. The fact that such a difference in lesion formation occurs in the absence of many other atherogenic risk factors found later in life suggests that differences in the atherogenic response to hypercholesterolemia are an important contributor to the slower onset of the disease in intracranial vessels in adults. Fetal arteries may allow elucidation of the mechanisms responsible, for example, better protection of intracranial arteries against free radical–mediated atherogenic processes.

We have recently reported that neoplastic transformation of two rat thyroid epithelial cell lines by retroviruses carrying the v-mos and v-ras Ki oncogenes is associated with a drastic increase of AP-1 activity. The most important effects were represented by the dramatic junB and fra-1 gene induction, which was abolished by the block of the transformation-induced HMGI-C protein synthesis. Here, we have further characterized the transformation-dependent AP-1 activity, by analysing the expression of different jun- and fos-related components, in rat thyroid cell lines transformed by several oncogenes, in human thyroid carcinoma cell lines, and in naturally occurring human thyroid tumours. A significant increase of Fra-1 and JunB protein levels was detected in all oncogene transformed rat thyroid cell lines. Fra-1 gene induction was demonstrated to occur also in human thyroid carcinoma cell lines and tissues. Conversely, c-Jun and JunD proteins, rather than JunB, accumulated in human thyroid carcinoma cell lines. An induction of AP-1 target genes was also detected both in rat and human thyroid transformed cell lines. Therefore, in vivo and in vitro thyroid cell transformation is associated with important compositional changes in the AP-1 complex and an increased transcriptional activity.

Background and purpose: It is well established that human vascular lesions begin very early stage in life with the development of fatty streak lesions in the arteries of fetuses. Although several studies have demonstrated that maternal cholesterol may exert detrimental effects on the number and degree of vascular lesions in fetuses, however, how cholesterol affects in utero programming is still unclear. Epigenetics migh promote pathogenic mechanisms by which gene-environment interactions could occurr. The aim of this study was to verify whether maternal hypercholesterolemia during pregnancy affects epigenetic signature in fetal aortic tissues. Methods: Human fetal aortas (n=42) were analyzed by immunohistochemistry and dichotomized in their respective high and low maternal cholesterol during pregnancy. Immunohistochemistry in fetal arteries was performed with the following antibodies: Anti-trimethyl-Histone H3, (Lys4, Lys9, Lys27), and Anti-CD68 antibody. Methyl DNA immunoprecipitation was performed by MeDIP kit (DIAGENODE). Results: The data indicated a strong signal >75% of positive cells with histone trimethyl lys 27 antibody present in 27% of the biggest fetal aortic lesion area (>120mm2/section) (p>0.039). Molecular analysis of specific cholesterol regulatory circuit gene expression revealed hypermethylation in promoter and 3' UTR of SREBP2 and LDL receptor gene in aortas from hypercholesterolemic mothers compared to normocholesterolemic group (p

Background: Elevated Maternal Cholesterol during Pregnancy (MCP) enhances atherogenesis in childhood, but its impact on acute myocardial infarction (AMI) in adults is unknown. Methods: 89 AMI patients meeting narrow criteria (born after 1945, typical chest pain, transmural infarction Q-waves, elevated creatinine kinase, no cerebrovascular or terminal disease) were identified among patients admitted to coronary care unit in Naples, Italy. Patients were classified by MI severity (severe=involving 3 arteries, left ventricle ejection fraction ≤35, CK-peak >1200 mg/dl, or CK-MB >200 mg/dl). The association of MCP with AMI severity was tested by linear and multiple regression analysis that included conventional cardiovascular risk factors, gender, age, and treatment. Associations of MCP with BMI was assessed by linear correlation. Results: MCP correlated with four measures of AMI severity: number of vessels (β=0.382, p=0.001), ejection fraction (β=-0.315, p=0.003), CK (β=0.260, p=0.014) and CK-MB (β=0.334, p=0.001), as well as survival time (β=-0.252, p=0.031). In multivariate analysis of patients stratified by AMI severity, MCP predicted AMI severity independently of age, gender, and CHD risk factors (OR=1.304, 95% CI 1.107-1.559; p=0.004). Screening for point mutations ruled out that this was due to certain inherited differences in lipid metabolism. Survival was affected mainly by AMI severity. Conclusions: MCP is associated with adult BMI, atherosclerosis-related risk and severity of AMI.

Background Essential hypertension is associated with enhanced LDL oxidation and impaired endothelium-dependent vasodilation. The antioxidant status is linked to the nitric oxide (NO) pathway. Sulfhydryl angiotensin-converting enzyme (ACE) inhibitors inhibit oxidative stress and atherogenesis in experimental models; therefore we tested whether this beneficial antioxidant activity could be also clinically relevant in patients with essential hypertension. Methods Plasma LDL oxidizability was investigated initially in untreated normocholesterolemic patients with moderate essential hypertension without clinically evident target organ damage (n 96) and in control normotensive subjects (n 46). Patients were then randomly assigned into two age- and sex-matched groups to receive the new sulfhydryl ACE inhibitor zofenopril (15 to 30 mg/d; n 48) or enalapril (20 mg/d, n 48). LDL oxidizability was evaluated (generation of malondialdehyde, MDA) and systemic oxidative stress was evaluated by isoprostanes (8-isoPGF2). Asymmetrical dimethyl-L-arginine (ADMA), a competitive inhibitor of endothelial NO synthase, and plasma nitrite and nitrates (NOx) were also measured. Results LDL from hypertensive subjects had enhanced susceptibility to oxidation in vitro compared with that in control subjects (P .05). Similarly, isoprostanes were significantly increased (P .01) in hypertensive subjects versus control subjects. After 12-week treatment, MDA levels were significantly reduced by zofenopril (P .05) but not enalapril treatment (P not significant). Isoprostanes were normalized after zofenopril treatment (P .03), whereas enalapril was ineffective. After treatment with both ACE inhibitors, plasma NOx concentrations were significantly reduced (P .05). Similarly, hypertension increased ADMA concentration compared with the normotensive state, whereas ACE inihibition elicited a significant decrease. However, the reduction of ADMA concentration was significantly higher in patients receiving sulfhydryl ACE inhibition (P .05 vs enalapril). Conclusions The sulfhydryl ACE inhibitor zofenopril reduces oxidative stress and improves the NO pathway in patients with essential hypertension. If confirmed in a large multicenter clinical trial, our data suggest a possible vasculoprotective effect of the compound in retarding vascular dysfunction and atherogenesis that often develops rapidly in hypertensive patients. (Am Heart J 2004;148:e5.) Low