Structural and functional abnormality of systemic microvessels in cardiac syndrome X

BACKGROUND AND AIM: Microvascular damage of coronary bed has been considered the main pathogenetic factor of cardiac syndrome X (chest pain, exercise-induced ischemic ST-segment changes and angiographically normal coronary arteries). Previous studies have demonstrated that vascular abnormalities are not confined to the heart, suggesting a peripheral vascular dysfunction. On the hypothesis of a generalized microvascular disturbance in cardiac syndrome X, we performed a morphologic and functional study of systemic microcirculation in patients with syndrome X compared to normal subjects. METHODS AND RESULTS: Microvessels were evaluated with intravital videocapillaroscopy (VCP) executed in peripheral and conjunctival observation sites which explore micro and paramicrocirculation; biohumoral study included markers of inflammation and of endothelial function, coagulative-fibrinolytic system and lipid metabolism. Videocapillaroscopy showed several morphologic changes (present in high percent of patients with syndrome X and not in controls) and significant quantitative alterations (capillary density, granular flow score, alterations of vessel profile, length of capillary loop branches and of arteriole/venule diameter) which indicated a severe alteration of whole vessel structure and an important rearrangement of microvascular disposition. In a similar way, the humoral study showed some significant changes of endothelial (vWF, ICAM-1, E-sel, PAI-1), inflammatory (C-reactive protein (CRP), fibrinogen) and metabolic factors (HDL-chol) which are commonly associated with inflammatory response. CONCLUSIONS: We conclude that patients with cardiac syndrome X exhibited some structural and functional alterations of systemic microvasculature; the pattern is similar to that detected in systemic inflammatory diseases and suggests a vascular lesion of inflammatory type. The same changes could be operating also in coronary microvessels of patients with syndrome X.     

Effect of atorvastatin on different fibrinolyis mechanisms in hypercholesterolemic subjects

BACKGROUND: Hydroxymethyl-glutaryl-CoA-reductase inhibitors (statins) reduce cardiovascular events by cholesterol lowering as well as non-lipid related actions. Among them, the modulation of fibrinolysis could play a relevant role in vascular protection. Atorvastatin is able of reducing platelet activity and thrombin generation before low-density lipoprotein cholesterol (LDL-C) decrease in hypercholesterolemic subjects in which coagulation and fibrinolysis are linked by the activation of thrombin activable fibrinolysis inhibitor (TAFI). The aim of our study was to evaluate whether atorvastatin could modulate fibrinolysis by interactions with endothelial mechanisms and thrombin generation. METHODS: Forty-four pure hypercholesterolemic subjects (26 M, 18 F, mean age 52.7+/-13.7, LDL-C 194.8+/-9.3t mg/dl) were evaluated for plasmin-antiplasmin complexes (PAP), tissue-plasminogen acivator (t-PA) and its inhibitor (PAI-1) (ELISA), TAFI activity (HPLC), platelet P-selectin (P-sel) (cytofluorymetric detection), platelet-dependent thrombin generation (PDTG, coagulative-chromogenic method) and lipid profile at baseline and after 7, 14, 28 and 90 days of atorvastatin (10 mg/die) treatment. RESULTS: PAP were significantly reduced at baseline in hypercholesterolemic versus control subjects (P<0.05) and were related to P-sel (P<0.01), PDTG (P<0.01) and its inhibitor (PAI-1) after venous occlusion (VO) (P<0.05). Atorvastatin induced a significant increase of PAP at T(2) related to modifications of P-sel (P<0.01) and PDTG (P<0.01) before significant LDL-C reduction (P=0.132). PAI-1 was significantly changed at T(3) with relation to LDL-C (P<0.01), Von Willebrand factor (VWF) (P<0.01) and sE-sel (P<0.05). CONCLUSIONS: The profibrinolytic activity of atorvastatin in hypercholesterolemic subjects is related, initially, to the positive effects exerted on platelet function and thrombin generation which can modulate fibrinolysis by TAFI activity.     

Endoscopic implantation of a biopolymer in the lower esophageal sphincter for gastroesophageal reflux: a pilot study

BACKGROUND: GERD is the most frequent disorder of the esophagus. Endoscopic minimally invasive treatment is desirable. However, the results of injection techniques have been disappointing. METHODS: A pilot study was conducted in patients with GERD, who required continuous therapy with a proton pump inhibitor, in which ethylene-vinyl-alcohol was injected into the muscle of the gastric cardia. Primary endpoints were the safety of the procedure, the effect on lower esophageal sphincter pressure and the stability of the injected material. A secondary endpoint was the effect on heartburn score after discontinuation of treatment with a proton pump inhibitor. RESULTS: Ethylene-vinyl-alcohol injection into the cardia resulted in circular diffusion of the product in 10 of 15 cases, suggesting that implantation into the muscle is feasible. Lower esophageal sphincter pressure was increased in 13 of 15 cases at 1 month and was sustained at a median follow-up of 6 months (range 4-12 months). Mean plus minus SEM of lower esophageal sphincter pressures (15 patients) were 12.2 plus minus 0.9, 18.7 plus minus 1.5 (p = 0.001 at baseline), and 16.7 plus minus 1.3 mm Hg (p = 0.038 from baseline) at, respectively, baseline, 1 month follow-up, and final follow-up. There was also a sustained reduction in heartburn score (off proton pump inhibitor) (3.40 plus minus 0.13 vs. 1.53 plus minus 0.24 and 1.87 plus minus 0.26 at baseline vs. 1 month and final follow-up, respectively; p < 0.01). Nine of the 15 patients had more than 50% of the injected material in place at second follow-up (at 6 months for 8 patients; at 12 months for 1 patient). In only 2 patients was there loss of more than 75% of injected ethylene-vinyl-alcohol. Persistence of greater than 50% of the material was associated with achievement of a circular injection. Only 4 patients had to resume therapy with a proton pump inhibitor. Mild retrosternal discomfort was observed in 8 patients; this disappeared in all cases after a maximum of 3 days. CONCLUSIONS: Ethylene-vinyl-alcohol implantation in the muscle of the cardia is feasible and safe. It leads to a sustained increase in resting lower esophageal sphincter pressure. This is associated with a sustained improvement in heartburn score for patients who previously required continuous therapy with a proton pump inhibitor.     

Different effect of statins on platelet oxidized-LDL receptor (CD36 and LOX-1) expression in hypercholesterolemic subjects.

Hydroxymethyl-glutaryl-CoA-reductase inhibitors (statins) reduce cardiovascular mortality by decreasing cholesterol as well as by non-lipid-related actions. Oxidized low-density lipoproteins (ox-LDL) are pro-atherogenic molecules and potent platelet agonists. CD36 and lectin-like ox-LDL receptor-1 (LOX-1) are specific ox-LDL receptors also expressed in platelets. This study was planned to address whether treatment with atorvastatin 10 mg/day, pravastatin 40 mg/day or simvastatin 20 mg/day could affect platelet CD36 and LOX-1 expression. Twenty-four patients for each treatment were evaluated after 3, 6, and 9 days and at 6 weeks for complete lipid profile (chromogenic), ox-LDL (ELISA), platelet P-selectin (P-sel), CD36, LOX-1 (FACS), and intracellular citrullin recovery (iCit) (HPLC). Data show hyperactivated platelets (P-sel absolute values, percent variation in activated cells, all p < 0.001), and CD36 and LOX-1 overexpression (all p < 0.001) in patients at baseline. P-sel, CD36, and LOX-1 were significantly decreased by atorvastatin and simvastatin (all p < 0.01) and related with iCit increase (r = 0.58, p < 0.001) and platelet-associated ox-LDL (r = 0.51, p < 0.01) at 9 days. Pravastatin reduced LOX-1 and P-sel (p < 0.05) at 6 weeks in relation with decreased LDL and ox-LDL (r = 0.39, p < 0.01 and r = 0.37, p < 0.01, respectively). These data suggest that atorvastatin and simvastatin reduce platelet activity by exposure of CD36 and LOX-1 before significant LDL reduction, whereas pravastatin action is detected later and in relation with LDL and ox-LDL lowering. Rapid and consistent reduction of CD36 and LOX-1 could be considered a direct anti-atherothrombotic mechanism related to the role of ox-LDL in platelet activation, platelet-endothelium interactions, and NO synthase activity.     

Hostile attributional bias and aggressive behavior in global context

We tested a model that children’s tendency to attribute hostile intent to others in response to provocation is a key psychological process that statistically accounts for individual differences in reactive aggressive behavior and that this mechanism contributes to global group differences in children’s chronic aggressive behavior problems. Participants were 1,299 children (mean age at year 1 = 8.3 y; 51% girls) from 12 diverse ecological-context groups in nine countries worldwide, followed across 4 y. In year 3, each child was presented with each of 10 hypothetical vignettes depicting an ambiguous provocation toward the child and was asked to attribute the likely intent of the provocateur (coded as benign or hostile) and to predict his or her own behavioral response (coded as nonaggression or reactive aggression). Mothers and children independently rated the child’s chronic aggressive behavior problems in years 2, 3, and 4. In every ecological group, in those situations in which a child attributed hostile intent to a peer, that child was more likely to report that he or she would respond with reactive aggression than in situations when that same child attributed benign intent. Across children, hostile attributional bias scores predicted higher mother- and child-rated chronic aggressive behavior problems, even controlling for prior aggression. Ecological group differences in the tendency for children to attribute hostile intent statistically accounted for a significant portion of group differences in chronic aggressive behavior problems. The findings suggest a psychological mechanism for group differences in aggressive behavior and point to potential interventions to reduce aggressive behavior.Why do children in some ecological contexts and cultural groups across the world exhibit more chronic aggressive behavior problems than children in other contexts? We assert that groups differentially socialize a key psychological process of attribution of hostile intent, which mediates the display of aggression in response to threat (i.e., it statistically accounts for differences in reactive aggressive behavior), which, when repeated in interpersonal interactions over time, grows into chronic aggressive behavior problems.Some evolutionary theorists posit the adaptive function of deescalating aggressive conflict in response to ambiguous provocation or threat. Axelrod’s computer simulations and empirical tests of ambiguous conflicts in political science suggest (but do not prove) that the response strategy responsible for the containment of violence and the evolution of cooperation is a “tit for tat” tactic characterized by a benign interpretation of another’s ambiguous intentions (1). He asserts that an alternate two-step strategy of attributing hostile intent to another and retaliating with aggression leads to escalation of conflict and eventual mutual destruction.Despite Axelrod’s assertions that the long-term adaptiveness of reactive aggression is poor, certain ecological contexts have been found to encourage hostile attributions and reactive aggression in response to ambiguous provocations. For example, rhesus macaque mothers who hold high dominance ranks socialize their 9-mo-old infants to display a pattern of high vigilance to threatening faces, probably as a short-term adaptive strategy to enable the offspring to maintain high rank (2). In the US South, a unique “culture of honor” promotes vigilance toward provocateurs, perceptual readiness to attribute hostile intent to others, and retaliatory aggression in response to being dishonored (3). Qualitative accounts of urban violence among minority males also point toward the importance of retaliating against being “dissed,” as in disrespected (4). Recent “Stand Your Ground” laws in the United States excuse retaliation against a perceived provocateur.A pattern of hypervigilance to threat, hostile attribution of intent, and reactive aggression in response to provocation often comes at a cost to an individual within a society and to that society’s long-term health and well-being. A large body of psychological research in the United States indicates that, when an individual attributes hostile intent to a peer provocateur, the individual is likely to become anxious and escalate reactive aggression, leading in turn to chronic aggressive behavior problems (5). Children who consistently make hostile attributions about others have been shown to escalate aggression in response to provocation, to become chronically anxious, and to increase their aggressive behavior problems over time and grow into violent adults (6).How do we reconcile the universality of Axelrod’s tit for tat pattern of benign attributions and cooperation with known ecological group differences in chronic aggressive behavior rates? A social ecological model that embeds behavior in a widening circle of ecological contexts (e.g., family, community, culture) posits that a child’s cultural-ecological context of local norms, values, and affordances will influence that child’s attention and attribution processes, which, in turn, will account for that child’s aggressive behavior (ecological context → child hostile attribution bias → child aggression) (7). We assert that some environments socialize a pattern that consists of high vigilance to threat, hostile attributions of another’s intent, and reactive aggression. The reasons for group differences in socialization patterns are beyond the scope of this study but likely grow in response to local environmental challenges such as genuine threat from outside groups, political conflict, and relative economic disadvantage, and are perpetuated through transmission across generations.We propose a model of hostile attributional bias, depicted in Fig. 1, which builds on these ideas. We posit that Axelrod’s universal axiom that the psychological act of making a benign attribution about another’s provocation leads to the deescalation of conflict (and, reciprocally, that a hostile attribution leads to reactive aggression). We hypothesize that variation in a child’s reactive aggressive behaviors across the situations that a child experiences will co-occur within that child with the attribution of hostile intent toward a provocateur. We further hypothesize that individual differences across children in reactive aggression in response to provocation will be accounted for partially by individual differences across children in the tendency to make hostile attributions and that both hostile attributional biases and reactive aggressive responses to provocation will predict present and future individual differences in chronic aggressive behavior problems even controlling for prior individual differences in chronic aggression.Open in a separate windowFig. 1.Hypothesized model of how ecological context affects chronic aggressive behavior by influencing hostile attributional biases.Finally, and most importantly, we assert that ecological group differences in rates of chronic aggressive behavior problems are due in part to culturally socialized differences in how children are reared to become vigilant toward threat and to make hostile attributions about others under conditions of ambiguous provocation. If this model is supported, it suggests interventions to reduce a group’s rate of chronic aggressive problems, and it has implications for understanding some cross-group conflicts (e.g., Arab-Israeli conflict and racial conflict within the United States), which could be understood as a function of group differences in how attributions of outgroup intentions are socialized and used to justify cross-group violence. Study of antecedents of cross-group conflict is beyond the present scope and is not pursued further here.To test the tenets of this model, we used identical methods with large samples of children followed prospectively across diverse ecological socializing contexts around the world. The goal of the current study was to test three sets of hypotheses in a sample of 8-y-old boys and girls from 12 different groups around the world followed annually over 4 y.The first hypothesis (the within-child hypothesis) is that variation in reactive aggressive behavior in response to provocation situations within a child will be statistically accounted for by variation in the attributions that child makes across peer provocation situations. We hypothesize that this relation will hold universally in each ecological context and in each sex.The second hypothesis (the between-children hypothesis) asserts that measurements of a child’s attributions about peers’ intentions will yield internally consistent individual differences across children, called hostile attributional bias, which acts like an acquired personality trait to correlate with and predict chronic aggressive behavior. We hypothesize that variation across children in hostile attributional bias will be correlated with children’s chronic tendencies to assert that they would react aggressively in response to a provocation; furthermore, we hypothesize that children’s hostile attributional biases will predict their current and future chronic aggressive behavior problems as measured by themselves and their mothers even controlling for prior aggressive behavior problems, and these relations will hold in each ecological context and each sex.The third hypothesis (the between-context hypothesis) asserts that ecological-cultural group differences in children’s rates of mother-rated and self-rated chronic aggressive behavior problems will be partially statistically accounted for by group differences in children’s hostile attributional biases and self-predicted tendencies to react aggressively in response to ambiguous threat.     

Effectiveness of an educational intervention on the management of type 2 diabetic patients hospitalized in Internal Medicine: results from the FADOI-DIAMOND study

Appropriate management of hyperglycemia is crucial for patients with type 2 diabetes. Aim of the FADOI-DIAMOND study was to evaluate real-world management of type 2 diabetic patients hospitalized in Internal Medicine wards (IMW) and the effects of a standardized educational intervention for IMW staff. DIAMOND has been carried out in 53 Italian IMW, with two cross-sectional surveys interspersed with an educational program (PRE phase and POST phase). In PRE phase, each center reviewed the charts of the last 30 hospitalized patients with known type 2 diabetes. An educational program was conducted in each center by means of the “outreach visit,” a face-to-face meeting between IMW staff and a trained external expert. Six months after, each center repeated the data collection (POST phase), specular to the PRE. A total of 3,167 patients were enrolled (1,588 PRE and 1,579 POST). From PRE phase to POST, patients with registered anthropometric data (54.1 vs. 74.9 %, p < 0.001) and in-hospital/recent measurement of glycated hemoglobin (48.2 vs. 61.4 %, p < 0.005) increased significantly. After educational program, more patients received insulin during hospitalization (68.3 vs. 63.6 %, p = 0.005). A more relevant variation in glycemia during hospitalization was observed in POST phase than PRE (?22.2 vs. ?15.5 mg/dL, p < 0.001), without differences as for occurrence of hypoglycemia (12.3 vs. 11.9 %). A one-shot educational intervention led to persistent improvement in the management of hospitalized patients with type 2 diabetes and to significant better glycemic control. Further studies might evaluate the effectiveness of a more aggressive educational program, on both management and outcomes.     

Exploratory investigation on nitro- and phospho-proteome cerebellum changes in hyperammonemia and hepatic encephalopathy rat models

Hepatic encephalopathy (HE) is a neurological disease associated with hepatic dysfunction. Current knowledge suggests that hyperammonemia, related to liver failure, is a main factor contributing to the cerebral alterations in HE and that hyperammonemia might impair signal transduction associated with post-translational modification of proteins such as tyrosine-nitration and phosphorylation. However, the molecular bases of the HE remain unclear and very little is known about the occurrence of post-translational modification on in vivo proteins. In this exploratory study we look for evidence of post-translation modifications of proteins in the cerebellum of experimental HE rat models using a proteomic approach. For the first time we showed that hyperammonemia without liver failure (HA rats) and experimental HE with liver failure due to portacaval shunt (PCS rats) lead to a reduced protein nitration in rat cerebellum, where the undernitrated proteins were involved in energy metabolism and cytoskeleton remodelling. Moreover we showed that tyrosine nitration loss of these proteins was not necessarily associated to a change in their phosphorylation state as result of the disease. Interestingly the rat cerebellum phosphoproteome was mainly perturbed in PCS rats, whereas HA rats did not shown appreciable changes in their phosphoprotein profile. Since the protein nitration level decreased similarly in the cerebellum of both HA and PCS rats, this implies that the two disease models share common effects but also present some differential signalling effects in the cerebellum of the same animals. This study highlights the interest for studying the concerted action of multiple signalling pathways in HE development.     

Risk of COVID 19 in patients with inflammatory bowel diseases compared to a control population

BackgroundIt is unclear whether patients with inflammatory bowel disease (IBD) are at increased risk of COVID-19.ObjectivesThis observational study compared the prevalence of COVID-19 symptoms, diagnosis and hospitalization in IBD patients with a control population with non-inflammatory bowel disorders.MethodsThis multicentre study, included 2733 outpatients (1397 IBD patients and 1336 controls), from eight major gastrointestinal centres in Lombardy, Italy. Patients were invited to complete a web-based questionnaire regarding demographic, historical and clinical features over the previous 6 weeks. The prevalence of COVID-19 symptoms, diagnosis and hospitalization for COVID-19 was assessed.Results1810 patients (64%) responded to the questionnaire (941 IBD patients and 869 controls). IBD patients were significantly younger and of male sex than controls. NSAID use and smoking were more frequent in controls. IBD patients were more likely treated with vitamin-D and vaccinated for influenza. Highly probable COVID-19 on the basis of symptoms and signs was less frequent in the IBD group (3.8% vs 6.3%; OR:0.45, 95%CI:0.28–0.75). IBD patients had a lower rate of nasopharyngeal swab-PCR confirmed diagnosis (0.2% vs 1.2%; OR:0.14, 95%CI:0.03–0.67). There was no difference in hospitalization between the groups (0.1% vs 0.6%; OR:0.14, 95%CI:0.02–1.17).ConclusionIBD patients do not have an increased risk of COVID-19 specific symptoms or more severe disease compared with a control group of gastroenterology patients.