From Endothelium to Lipids, Through microRNAs and PCSK9: A Fascinating Travel Across Atherosclerosis.

Lipids and endothelium are pivotal players on the scene of atherosclerosis and their interaction is crucial for the establishment of the pathological processes. The endothelium is not only the border of the arterial wall: it plays a key role in regulating circulating fatty acids and lipoproteins and vice versa it is regulated by these lipidic molecules thereby promoting atherosclerosis. Inflammation is another important element in the relationship between lipids and endothelium. Recently, proprotein convertase subtilisin/kexin type 9 (PCSK9) has been recognized as a fundamental regulator of LDL-C and anti-PCSK9 monoclonal antibodies have been approved for therapeutic use in hypercholesterolemia, with the promise to subvert the natural history of the disease. Moreover, growing experimental and clinical evidence is enlarging our understanding of the mechanisms through which this protein may facilitate the genesis of atherosclerosis, independently of its impact on lipid metabolism. In addition, environmental stimuli may affect the post-transcriptional regulation of genes through micro-RNAs, which in turn play a key role in orchestrating the crosstalk between endothelium and cholesterol. Advances in experimental research, with development of high throughput techniques, have led, over the last century, to a tremendous progress in the understanding and fine tuning of the molecular mechanisms leading to atherosclerosis. Identification of pivotal keystone molecules bridging lipid metabolism, endothelial dysfunction and atherogenesis will provide the mechanistic substrate to test valuable targets for prediction, prevention and treatment of atherosclerosis-related disease.

Circulating CD40 ligand, Dickkopf-1 and P-selectin in HIV-infected patients.

OBJECTIVES: The aim of this study was to evaluate the circulating levels of CD40 ligand (CD40 L), Dickkopf-1 (DKK-1) and P-selectin, their relationships and their contributions to cardiovascular risk in subjects with HIV infection. METHODS: The study population included 80 HIV-infected patients, 14 (17.5%) of whom had diabetes mellitus (DM) and 32 (40.0%) of whom had arterial hypertension (AH). The HIV-infected patients were compared with a control group with similar demographic and clinical features. CD40L, DKK-1 and P-selectin levels were measured using an enzyme-linked immunosorbent assay. RESULTS: The HIV-infected patients showed higher levels of all the cardiovascular disease (CVD) markers. Both serum CD40L and DKK-1 were significantly higher in HIV-infected patients than in the HIV-negative controls (P < 0.001), while soluble P-selectin showed no significant between-group difference (P = 0.133), reflecting the role of HIV infection in CVD. In the HIV-infected group, patients with DM showed lower levels of CD40L and DKK-1 in comparison with the nondiabetic patients and patients with AH (P < 0.05, with Bonferroni correction). In contrast, patients with AH showed higher levels of CD40L and DKK-1 in comparison to patients without DM or AH (P < 0.05, with Bonferroni correction). Patients with AH showed higher levels of CD40L and DKK-1 than patients with DM (P < 0.05, with Bonferroni correction). CONCLUSIONS: In this study, we found that HIV-infected patients displayed significantly higher circulating levels of both CD40L and DKK-1, which were linearly and directly correlated, when compared to HIV-negative patients. The presence of diabetes was associated with lower levels of both CD40L and DKK-1, whereas the presence of hypertension was associated with higher levels of CD40L.

Cancer mortality in Rieti province (Latium Region, Italy) for the years 2006-2010: evaluation of temporal and spatial trends and comparison with the other Latium provinces.

BACKGROUND: The present research aims to obtain information on cancer deaths in the five Latium provinces in the years 2006-2010 and to highlight similarities and differences between them. METHODS: The survey was carried through statistical elaboration of cancer mortality data for the years 2006-2010 obtained from the National Institute of Statistics. RESULTS: The mortality due to oncological diseases in Rieti province showed a decreasing temporal trend for the years investigated. Among all the Latium provinces, Rieti presented the lowest standardized mortality rates. This phenomenon could be related to specific environmental conditions and low levels of air, water and soil pollution affecting the Rieti province. CONCLUSION: The results of the present study show that the "healthy" environment of Rieti province could be considered as a benchmark for studies in oncological diseases.

Aspirin, platelets, and cancer: The point of view of the internist.

Growing evidence suggests the beneficial effect of aspirin against some types of cancer, particularly of the gastrointestinal tract, and it has been provided for an effect both in cancer prevention as well as in survival improvement of cancer patients. Aspirin benefits increase with duration of treatment, especially after 10years of treatment. The inhibition of platelet activation at sites of gastrointestinal mucosal lesions could be the primary mechanism of action of low-dose aspirin. Indeed, the formation of tumor cell-induced platelet aggregates may favor immune evasion, by releasing angiogenic and growth factors, and also by promoting cancer cell dissemination. Moreover, platelets may contribute to aberrant COX-2 expression in colon carcinoma cells, thereby contributing to downregulation of oncosuppressor genes and upregulation of oncogenes, such as cyclin B1. Platelet adhesion to cancer cells leads also to an increased expression of genes involved in the EMT, such as the EMT-inducing transcription factors ZEB1 and TWIST1 and the mesenchymal marker vimentin. The aspirin-mediated inactivation of platelets may restore antitumor reactivity by blocking the release of paracrine lipid and protein mediators that induce COX-2 expression in adjacent nucleated cells at sites of mucosal injury. Thus, recent findings suggest interesting perspectives on "old" aspirin and NSAID treatment and/or "new" specific drugs to target the "evil" interactions between platelets and cancer for chemoprevention.

Epidemiological profile of cancer mortality in a province of central Italy for the years 2008 and 2009: preliminary analysis.

BACKGROUND: The aim of the study was to perform a preliminary analysis of the mortality data for cancer as widely as possible, in order to obtain useful information for planning specific public health interventions. For this purpose, data on cancer mortality in the province of Rieti (Latium, central Italy) have been collected and analysed. To date, in the Rieti province a Cancer Registry record is not available. METHODS: The study was conducted through statistical analysis of cancer mortality data related to the years 2008 and 2009, obtained from the National Institute of Statistics. Data were cumulative for the province of Rieti and specific for the five districts in which the province is divided. RESULTS: The standardized mortality rates obtained for Rieti province resulted lower than those reported for the other provinces of the Latium region, for Italy and for the European Community, both for 2008 and 2009. In these years, the anatomical areas more affected in terms of mortality were "trachea, bronchus and lung", "colorectal" and "stomach", but gender differences were evidenced. CONCLUSIONS: The present study, also considering the limitation of two years studied only, leads to some basic insights about the importance of updating mortality data to trace an epidemiological profile, to evaluate the presence of risk and protective factors, to program strategically health interventions, and to assess the effectiveness of these interventions.

Oxidative stress drivers and modulators in obesity and cardiovascular disease: from biomarkers to therapeutic approach.

This review article is intended to describe how oxidative stress regulates cardiovascular disease development and progression. Epigenetic mechanisms related to oxidative stress, as well as more reliable biomarkers of oxidative stress, are emerging over the last years as potentially useful tools to design therapeutic approaches aimed at modulating enhanced oxidative stress "in vivo", thereby mitigating the consequent atherosclerotic burden. As a paradigm, we describe the case of obesity, in which the intertwining among oxidative stress, due to caloric overload, chronic low-grade inflammation induced by adipose tissue dysfunction, and platelet activation represents a vicious cycle favoring the progression of atherothrombosis. Oxidative stress is a major player in the pathobiology of cardiovascular disease (CVD). Reactive oxygen species (ROS)- dependent signaling pathways prompt transcriptional and epigenetic dysregulation, inducing chronic low-grade inflammation, platelet activation and endothelial dysfunction. In addition, several oxidative biomarkers have been proposed with the potential to improve current understanding of the mechanisms underlying CVD. These include ROS-generating and/or quenching molecules, and ROS-modified compounds, such as F2-isoprostanes. There is also increasing evidence that noncoding micro- RNA (mi-RNA) are critically involved in post- transcriptional regulation of cell functions, including ROS generation, inflammation, regulation of cell proliferation, adipocyte differentiation, angiogenesis and apoptosis. These molecules have promising translational potential as both markers of disease and site of targeted interventions. Finally, oxidative stress is a critical target of several cardioprotective drugs and nutraceuticals, including antidiabetic agents, statins, renin-angiotensin system blockers, polyphenols and other antioxidants. Further understanding of ROS-generating mechanisms, their biological role as well as potential therapeutic implications would translate into consistent benefits for effective CV prevention.

The recovery of platelet cyclooxygenase activity explains interindividual variability in responsiveness to low-dose aspirin in patients with and without diabetes.

BACKGROUND: Interindividual variability in response to aspirin has been popularized as 'resistance'. We hypothesized that faster recovery of platelet cyclooxygenase-1 activity may explain incomplete thromboxane (TX) inhibition during the 24-h dosing interval. OBJECTIVE: To characterize the kinetics and determinants of platelet cyclooxygenase-1 recovery in aspirin-treated diabetic and non-diabetic patients. PATIENTS/METHODS: One hundred type 2 diabetic and 73 non-diabetic patients on chronic aspirin 100 mg daily were studied. Serum TXB(2) was measured every 3 h, between 12 and 24 h after a witnessed aspirin intake, to characterize the kinetics of platelet cyclooxygenase-1 recovery. Patients with the fastest TXB(2) recovery were randomized to aspirin 100 mg once daily, 200 mg once daily or 100 mg twice daily, for 28 days and TXB(2) recovery was reassessed. RESULTS AND CONCLUSIONS: Platelet TXB(2) production was profoundly suppressed at 12 h in both groups. Serum TXB(2) recovered linearly, with a large interindividual variability in slope. Diabetic patients in the third tertile of recovery slopes (≥ 0.10 ng mL(-1) h(-1) ) showed significantly higher mean platelet volume and body mass index, and younger age. Higher body weight was the only independent predictor of a faster recovery in non-diabetics. Aspirin 100 mg twice daily completely reversed the abnormal TXB(2) recovery in both groups. Interindividual variability in the recovery of platelet cyclooxygenase activity during the dosing interval may limit the duration of the antiplatelet effect of low-dose aspirin in patients with and without diabetes. Inadequate thromboxane inhibition can be easily measured and corrected by a twice daily regimen.

Platelet activation in obesity and metabolic syndrome.

Obesity is associated with increased cardiovascular disease. Metabolic syndrome (MS) identifies substantial additional cardiovascular risk beyond the individual risk factors, and is a powerful predictor of cardiovascular events even regardless of body mass index, thus suggesting a common downstream pathway conferring increased cardiovascular risk. Platelet hyper-reactivity/activation plays a central role to accelerate atherothrombosis and is the result of the interaction among the features clustering in obesity and MS: insulin resistance, inflammation, oxidative stress, endothelial dysfunction. Interestingly, the same pathogenic events largely account for the less-than-expected response to antiplatelet agents, namely low-dose aspirin. The proposed explanations for this phenomenon, besides underdosing of drug and/or reduced bioavailability, subsequent to excess of adipose tissue, include enhanced platelet turnover, leading to unacetylated COX-1 and COX-2 in newly formed platelets as a source of aspirin-escaping thromboxane formation; extraplatelet sources of thromboxane, driven by inflammatory triggers; and enhanced lipid peroxidation, activating platelets with a mechanism bypassing COX-1 acetylation or limiting COX-isozyme acetylation by aspirin. This review will address the complex interactions between platelets and the pathogenic events occurring in obesity and MS, trying to translate this body of mechanistic information into a clinically relevant read-out, in order to establish novel strategies in the prevention/treatment of atherothrombosis.

Determinants of increased cardiovascular disease in obesity and metabolic syndrome.

Obesity is associated with an increased mortality and morbidity for cardiovascular disease (CVD) and adipose tissue is recognised as an important player in obesity-mediated CVD. The diagnosis of the metabolic syndrome (MS) appears to identify substantial additional cardiovascular risk above and beyond the individual risk factors, even though the pathophysiology underlying this evidence is still unravelled. The inflammatory response related to fat accumulation may influence cardiovascular risk through its involvement not only in body weight homeostasis, but also in coagulation, fibrinolysis, endothelial dysfunction, insulin resistance (IR) and atherosclerosis. Moreover, there is evidence that oxidative stress may be a mechanistic link between several components of MS and CVD, through its role in inflammation and its ability to disrupt insulin-signaling. The cross-talk between impaired insulin-signaling and inflammatory pathways enhances both metabolic IR and endothelial dysfunction, which synergize to predispose to CVD. Persistent platelet hyperreactivity/activation emerges as the final pathway driven by intertwined interactions among IR, adipokine release, inflammation, dyslipidemia and oxidative stress and provides a pathophysiological explanation for the excess risk of atherothrombosis in this setting. Despite the availability of multiple interventions to counteract these metabolic changes, including appropriate diet, regular exercise, antiobesity drugs and bariatric surgery, relative failure to control the incidence of MS and its complications reflects both the multifactorial nature of these diseases as well as the scarce compliance of patients to established strategies. Evaluation of the impact of these therapeutic strategies on the pathobiology of atherothrombosis, as discussed in this review, will translate into an optimized approach for cardiovascular prevention.

Thromboxane and prostacyclin biosynthesis in heart failure of ischemic origin: effects of disease severity and aspirin treatment.

SUMMARY BACKGROUND: Thromboembolism is a relatively common complication of chronic heart failure (HF) and the place of antiplatelet therapy is uncertain. OBJECTIVES: We characterized the rate of thromboxane and prostacyclin biosynthesis in chronic HF of ischemic origin, with the aim of separating the influence of HF on platelet activation from that of the underlying ischemic heart disease (IHD). PATIENTS AND METHODS: We compared urinary 11-dehydro-thromboxane (TX)B(2), 2,3 dinor 6-keto-PGF(1alpha,) 8-iso-prostaglandin (PG)F(2alpha), and plasma N-terminal pro-brain natriuretic peptide (NT-pro-BNP), asymmetric dimethylarginine (ADMA), and soluble CD40 ligand (sCD40L), in 84 patients with HF secondary to IHD, 61 patients with IHD without HF and 42 healthy subjects. RESULTS: HF patients not on aspirin had significantly higher urinary 11-dehydro-TXB(2) as compared with healthy subjects (P < 0.0001) and IHD patients not on aspirin (P = 0.028). They also showed significantly higher 8-iso-PGF(2alpha) (P = 0.018), NT-pro-BNP (P = 0.021) and ADMA (P < 0.0001) than IHD patients not on aspirin. HF patients on low-dose aspirin had significantly lower 11-dehydro-TXB(2) (P < 0.0001), sCD40L (P = 0.007) and 2,3-dinor-6-keto-PGF(1alpha) (P = 0.005) than HF patients not treated with aspirin. HF patients in NYHA classes III and IV had significantly higher urinary 11-dehydro-TXB(2) than patients in classes I and II, independently of aspirin treatment (P < 0.05). On multiple linear regression analysis, higher NT-pro-BNP levels, lack of aspirin therapy and sCD40L, predicted 11-dehydro-TXB(2) excretion rate in HF patients (R(2) = 0.771). CONCLUSIONS: Persistent platelet activation characterizes HF patients. This phenomenon is related to disease severity and is largely suppressable by low-dose aspirin. The homeostatic increase in prostacyclin biosynthesis is impaired, possibly contributing to enhanced thrombotic risk in this setting.

Postprandial hyperglycemia is a determinant of platelet activation in early type 2 diabetes mellitus.

BACKGROUND: Chronic hyperglycemia is a major contributor to in vivo platelet activation in diabetes mellitus. OBJECTIVES: To evaluate the effects of acarbose, an alpha-glucosidase inhibitor, on platelet activation and its determinants in newly diagnosed type 2 diabetic patients. METHODS: Forty-eight subjects (26 males, aged 61 +/- 8 years) with early type 2 diabetes (baseline hemoglobin A(1c) < or = 7% and no previous hypoglycemic treatment) were randomly assigned to acarbose up to 100 mg three times a day or placebo, and evaluated every 4 weeks for 20 weeks. The main outcome measures were urinary 11-dehydro-thromboxane (TX)B(2) (marker of in vivo platelet activation) and 8-iso-prostaglandin (PG)F(2alpha) (marker of in vivo lipid peroxidation) excretion rate, 2-h postprandial plasma glucose (PPG) after a test meal, and assessment of glucose fluctuations by mean amplitude of glycemic excursions (MAGE). RESULTS: Baseline measurements revealed biochemical evidence of enhanced lipid peroxidation and platelet activation. As compared with the placebo group, patients treated with acarbose had statistically significant reductions in urinary 11-dehydro-TXB(2) and 8-iso-PGF(2alpha) excretion rate as early as after 8 weeks and at each subsequent time point (between-group P < 0.0001 at 12, 16 and 20 weeks), following earlier decreases in PPG and MAGE. Multiple regression analyses in the acarbose group revealed that PPG was the only significant predictor of 11-dehydro-TXB(2) urinary excretion rate (beta = 0.39, P = 0.002) and MAGE the only predictor of 8-iso-PGF(2alpha) urinary excretion rate (beta = 0.42, P = 0.001). CONCLUSIONS: Postprandial hyperglycemia is associated with enhanced lipid peroxidation and platelet activation in early type 2 diabetes. A moderate decrease in PPG achieved with acarbose causes time-dependent downregulation of these phenomena, suggesting a causal link between early metabolic abnormalities and platelet activation in this setting.

CD40/CD40L system and vascular disease.

Several distinct lines of investigation in the context of atherosclerosis dealing with low-grade inflammation, oxidative stress and platelet activation are now emerging, with CD40/CD40L system as the missing link. CD40 ligand is a transmembrane glycoprotein structurally related to tumour necrosis factor-alpha and more than 95% of the circulating CD40L derives from platelets. CD40L appears as a multiplayer of several cell types in the inflammatory network. The peculiarity of CD40L as an inflammatory mediator derived from platelets expands the functional repertoire of platelets from players of haemostasis and thrombosis to powerful amplifiers of inflammation by promoting the release of cytokines and chemokines, cell activation and cell-cell interactions. The multifunctional role of CD40L, as a simultaneous activator of all these systems, further blurs the intricate relationship between such events both in the physiological systems and the pathological derangement occurring in atherothrombosis.

Contribution of platelet-derived CD40 ligand to inflammation, thrombosis and neoangiogenesis.

CD40-CD40L interactions have been involved in inflammation and thrombosis. Several diseases are characterized by inflammation, hypercoagulability and increased prevalence of thromboembolic events. In the past decade, a series of preclinical and clinical studies has provided more insight into the pathogenetic mechanisms linking inflammatory mediators to the activation and regulation of the haemostatic system. In particular, the study of CD40-CD40L interactions has greatly contributed to understanding the role of platelets in a variety of pathophysiological conditions, including atherothrombosis, immuno-inflammatory diseases and, possibly, cancer. A wide variety of preclinical and clinical studies have generated clinical interest in the use of CD40L as a prognostic marker of thrombotic risk. However, the use of sCD40L in clinical studies requires reliable methods. For the correct interpretation of results, clinical and research laboratories and physicians must be aware of the limitations of immunoassays for this cytokine, which underlines the need for standardization of preanalytic conditions. This review will focus on biochemical evidence of CD40L involvement in platelet activation, contribution of platelet-derived CD40L to inflammation, thrombosis and neoangiogenesis, and possible methodological pitfalls regarding the appropriate specimen and preparation for laboratory evaluation of blood soluble CD40L as a biomarker in various human diseases characterized by underlying inflammation, such as atherothrombosis, cancer and immuno-inflammatory diseases.

Localized bacillary angiomatosis in the oral cavity: observations about a neoplasm with atypical behavior. Description of a case and review of the literature.

Bacillary angiomatosis is a rather frequent infectious pathology appearing mainly in the skin but can also affect the liver, spleen, heart, bones, lungs, muscles, central nervous system and other organs. The localization of the lesion in the oral cavity is rather rare, as it is evident in the literature. Bacillary angiomatosis can be clinically similar to the Kaposi's sarcoma and histologically confused with angiosarcoma, epitheloid hemangioma and pyogenic granuloma. A case of bacillary angiomatosis of the oral cavity in an immuno-competent patient is described. The high tendency to relapse, the capability in migration and to involve several localizations at the same time have induced the authors to deepen the research to exclude the possibility that it could be a Kaposi's sarcoma or a pyogenic granuloma and to get to an accurate diagnosis in order to resolve the disease.

Association between circulating adiponectin and interleukin-10 levels in android obesity: effects of weight loss.

OBJECTIVE: Adiponectin inhibits vascular inflammation and increases IL-10 mRNA expression in human macrophages. Thus, we investigated the possible relationship between plasma adiponectin and IL-10 levels and the effects of a diet-induced moderate weight loss on both cytokines. PATIENTS AND STUDY DESIGN: Plasma adiponectin and IL-10 levels were analyzed in 64 android [body mass index (BMI), > 28 kg/m2; waist to hip ratio (WHR), > or = 0.86] and 20 gynoid [BMI, > 28 kg/m2; WHR, < 0.86] obese healthy women. Android obese women (49 +/- 14 yr) had a mean BMI of 37.1 +/- 5.3 kg/m2, similar to that of gynoid obese women (49 +/- 11 yr; BMI, 33.4 +/- 2.6 kg/m2). Twenty nonobese control women (46 +/- 11 yr; BMI, 25.2 +/- 2.2 kg/m2) were also studied. In 15 android obese women, measurements were repeated after a 12-wk diet period (1200 kcal/d). RESULTS: Median adiponectin [5.2 (range, 3.3-7.8) vs. 12.1 (9.7-13.9) vs. 15.0 (12.6-18.2) microg/ml; P < 0.0001] and IL-10 [1.8 (1.2-3.3) vs. 3.5 (2.9-4.3) and vs. 4.1 (3.5-4.8) pg/ml; P < 0.0001] levels were lower in android vs. gynoid vs. nonobese women. Among android obese women, low adiponectin levels were independently related (P < 0.0001) to decreased IL-10 levels, independently of BMI, WHR, or insulin resistance. No significant change in either median adiponectin or IL-10 levels was observed after body weight reduction (8 +/- 4 kg; P < 0.01), although percent changes in adiponectin paralleled those in IL-10 (P < 0.05). CONCLUSIONS: Android obesity is associated with a concomitant reduction of IL-10 and adiponectin levels. However, the antiinflammatory status of obesity might require prolonged periods of energy-restricted diets to revert to normal.

Enhanced soluble CD40 ligand contributes to endothelial cell dysfunction in vitro and monocyte activation in patients with diabetes mellitus: effect of improved metabolic control.

AIMS/HYPOTHESIS: Inflammation plays a pathogenic role in the development of accelerated atherosclerosis in diabetes. Soluble CD40 ligand (sCD40L) is enhanced in diabetes; however, the molecular mechanisms linking sCD40L to accelerated atherosclerosis in diabetes are still unclear. We tested the hypothesis that sCD40L may be involved in the vascular complications in diabetes and exerts its effect by triggering inflammatory reactions on mononuclear and endothelial cells (ECs). METHODS: We studied 70 patients, 40 with type 2 and 30 with type 1 diabetes, with a history or physical examination negative for cardiovascular disease, and 40 non-diabetic and 30 healthy subjects, matched with the type 2 and type 1 diabetic patients, respectively. Plasma and serum sCD40L, and plasma soluble intercellular adhesion molecule-1, soluble vascular cell adhesion molecule-1, E-selectin and monocyte chemo-attractant protein-1 (MCP-1) were measured. Adhesion molecules and MCP-1 release, the ability to repair an injury in ECs, and O2- generation in monocytes were analysed in vitro after stimulation with serum from patients or controls. RESULTS: Type 2 and type 1 diabetic patients had significantly higher sCD40L levels than controls. Furthermore, high sCD40L was associated with in vitro adhesion molecules and MCP-1 release, impaired migration in ECs and enhanced O2- generation in monocytes. Improved metabolic control was associated with a reduction of plasma sCD40L by 37.5% in 12 type 1 diabetic patients. Furthermore, elevated sCD40L in diabetic patients was significantly correlated with HbA1c levels. CONCLUSIONS/INTERPRETATION: Upregulation of sCD40L as a consequence of persistent hyperglycaemia in diabetic patients results in EC activation and monocyte recruitment to the arterial wall, possibly contributing to accelerated atherosclerosis development in diabetes.

The role of nitric oxide in the development of diabetic angiopathy.

Diabetic angiopathy is the main cause of morbidity and mortality in patients with diabetes mellitus. Clinical manifestations and pathophysiological mechanisms of diabetic angiopathy can be traced back to the development of endothelial cell dysfunction with alterations in the eNOS/NO system production or availability as the primum movens in its natural history. Hyperglycemia per se or through the accumulation of AGEs, increased oxidative stress, leading to NOS uncoupling and NO-quenching by excess superoxide and peroxynitrite, and individual genetic background are thought to be responsible for this NO metabolism imbalance. The complex interplay of these mechanisms results in a perturbation of the physiological properties of NO in the maintenance of endothelial homeostasis, such as vasodilation, anticoagulation, leukocyte adhesion, smooth muscle cell proliferation, and antioxidant capacity. Hence, abnormality in NO availability results in generalized accelerated atherosclerosis, hyperfiltration, glomerulosclerosis, tubulointerstitial fibrosis and progressive decline in glomerular filtration rate, and apoptosis and neovascularization in the retina. Indeed, the parallel development of nephropathy, retinopathy, and macroangiopathy may be considered as manifestations of endothelial dysfunction at distinct vascular sites. Given this scenario, intervention targeting any of the pathways involved in the NOS/NO system cascade may prove potential therapeutic targets in the prevention of long-term diabetic complications.

[Enucleation of a pleomorphic adenoma of the palate: a conservative choice]. / Enucleazione di un adenoma pleomorfo del palato: una scelta conservativa.

The benign mixed tumor (pleomorphic adenoma) is the most common intraoral salivary gland tumor: more than 50% occurs on the hard and soft palate. The epidemiological data, histopathological and clinical features, preoperative diagnostic methodologies, treatment options, recurrence rates and prediction published in the literature for this neoplasm are discussed. A case of minor salivary gland tumor of the palate in a 26 year old man is reported. The therapy chosen was a surgical conservative enucleation of the lesion. Histological examination showed pleomorphic adenoma; there is no recurrence after 2 years.