INFLUENCE OF CHRONIC KIDNEY DISEASE ON THE HAEMOSTATIC PROPERTIES, THE PLATELET TRANSCRIPTOMIC AND PLASMA PROTEOMIC PROFILES OF CORONARY ARTERY DISEASE PATIENTS

BACKGROUND - Patients with CKD present a higher incidence of coronary artery disease (CAD) and increasing evidence indicates that these patients are more likely to die of cardiovascular disease than to develop kidney failure. CKD patients show a double haemostatic profile: thrombotic tendencies, but also a bleeding diathesis. Platelets and Tissue Factor (TF), the main activator of blood coagulation, play a key role in the pathogenesis and in the thrombotic complications of CAD. TF is expressed also by circulating platelets and, of interest, platelet-associated TF expression is higher in acute coronary syndrome (ACS) patients. However, there are no studies focused on platelet-associated TF expression in CAD patients with CKD. Moreover, although it is reported that platelet transcriptome may vary in pathological conditions, no information is still available on the changes that may occur in platelet transcriptome of CAD patients with CKD. Finally, patients with end-stage renal disease (ESRD) present changes in the expression of plasma proteins associated to atherosclerosis, but no data are so far available on the plasma proteomic profile of CAD patients with mild-to-moderate CKD. AIM - The aim of this project has been to further characterize the haemostatic tendencies (assessment of TF expression and of the global haemostatic function of whole blood), the platelet transcriptome and the plasma proteome of CAD patients with and without CKD. METHODS - 139 ACS patients with (n=31) and without CKD (n=108) and 217 SA patients with (n=49) and without CKD (n=168) were enrolled. The glomerular filtration rate (GFR) has been calculated with the MDRD CKD EPI Equation and CKD is defined by an estimated GFR value < 60 ml/min. Assessment of surface and intracellular platelet TF expression has been performed by whole blood flow cytometry; the global haemostatic function by thromboelastometry (ROTEM); platelet transcriptome profiles using Illumina BeadChip Human HT-12 v4 microarray; the plasma proteomic profile by the classical gel-based proteomic approach and the results confirmed by ELISA analysis. RESULTS - The percentage of TF expression on platelet surface is significantly lower in CKD patients compared to patients without CKD in resting condition (ACS: 4.07%\ub11.05 and 5.23%\ub10.82 respectively, p0,05; SA: 12.93%\ub12.73 and 16.54%\ub11.52 respectively, p>0.05). This result is also supported by the intracellular expression of platelet TF performed on a subgroup of ACS patients: intracellular TF is significantly lower in patients with CKD compared to those without CKD (19.49%\ub14.04 and 27.53%\ub15.16 respectively, p<0,001). The haemostatic function of blood, assessed by thromboelastometry, shows that, in physiological conditions, the presence of CKD exerts different effects on the global haemostatic potential in SA and ACS patients, but in the presence of a platelet inhibitor, the formation of a pure fibrin clot is similar between these two groups of patients. Moreover, there is differential gene expression among patients with and without CKD: in particular, in CKD patients, there is the over-expression of genes involved in platelet activation and in the defence against oxidative damage, but also the down-regulation of translational elongation genes that may affect the de novo protein synthesis capacity of platelets from CKD patients. The proteomic analysis shows significant differences among patients with and without CKD (both SA and ACS) in the expression of alpha-1-Microglobulin (A1M), an anti-oxidant protein, Retinol Binding Protein 4 (RBP4), involved in the early phases of inflammation and Haptoglobin (HPT), an anti-inflammatory protein: all these proteins have a positive correlation with the severity of the renal pathology. CONCLUSIONS - In conclusion, all these data shed new light on additional mechanisms involved in CKD-associated haemostatic (thrombotic and haemorrhagic) profile of CAD patients. The peculiar platelet phenotype (lower amount of TF expression), found in CKD patients, provides information on the bleeding risk due to the platelet dysfunction responsible for the haemostatic abnormalities. The evaluation of the global haemostatic capacity of whole blood has shown that ACS patients with CKD seem to have a platelet function more \u201ccompromised\u201d compared to SA patients with CKD, in terms of clotting time, that is slower in ACS patients. Furthermore, CKD patients present also a differential gene expression profile and differentially expressed proteins compared to patients without CKD: there is the concomitant presence of transcripts and proteins with a protective function (anti-inflammatory and anti-oxidant), but also with the role to promote the progression of CKD and the development of the thrombotic/haemorrhagic complications

Individual differences in responsivity to social rewards: insights from two eye-tracking tasks

Humans generally prefer social over nonsocial stimuli from an early age. Reduced preference for social rewards has been observed in individuals with autism spectrum conditions (ASC). This preference has typically been noted in separate tasks that measure orienting toward and engaging with social stimuli. In this experiment, we used two eye-tracking tasks to index both of these aspects of social preference in in 77 typical adults. We used two measures, global effect and preferential looking time. The global effect task measures saccadic deviation toward a social stimulus (related to 'orienting'), while the preferential looking task records gaze duration bias toward social stimuli (relating to 'engaging'). Social rewards were found to elicit greater saccadic deviation and greater gaze duration bias, suggesting that they have both greater salience and higher value compared to nonsocial rewards. Trait empathy was positively correlated with the measure of relative value of social rewards, but not with their salience. This study thus elucidates the relationship of empathy with social reward processing

Treatment of Recurrent Tracheocutaneous Fistulas in the Irradiated Neck with a Two Layers-Two Flaps Combined Technique

The development of a tracheocutaneous fistula (TCF) is a well-documented complication after tracheostomy, especially in chronic morbid patients, in whom tubes or cannulas are left in place over time, or in irradiated patients. Surgical treatments are therefore needed which range from simple curettage and dressings to local skin flaps, muscle flaps and, in the more complex cases, microsurgical free tissue transfers. We present a novel combined technique used to successfully treat recurrent TCFs in irradiated patients, involving a superiorly based turnover fistula flap and a sternocleidomastoid transposition flap

Psychiatric disorders and headache familial recurrence: a study on 200 children and their parents

The main aim of the study was to examine the relationship between headache and familial recurrence of psychiatric disorders in parents and their children. Headache history and symptomatology have been collected in a clinical sample of 200 patients and their families, using a semi-structured interview (ICHD-II criteria). Psychiatric comorbidity was assessed by DSM-IV criteria. Chi squares and a loglinear analysis were computed in order to evaluate the main effects and interactions between the following factors: frequency and headache subtypes (migraine/ not-migraine) in children, headache (migraine/not-migraine-absent/ present) in parents, headache (absent/present) in grandparents, and psychiatric comorbidity (absent/present) have been analyzed: 94 mothers (47%) and 51 fathers (25.5%) had at least one psychiatric disorder, mainly mood and anxiety disorders. Considering the significant prevalence of Psi-co in children (P < 0.0001), we compared it with the presence of familiarity to headache: a significant interaction has been found (P < 0.05) showing that migraineurs with high familial recurrence of headache had a higher percentage (74.65%) of psychiatric disorders, than no-migraineurs (52.17%). Absence of headache familial loading seems to be related to psi-co only in no-migraine headache (87.5 vs. 45.5%). The occurrence of psychiatric disorders is high in children with headache, but a very different pattern seems to characterize migraine (familial co-transmission of migraine and Psi-Co?) if compared with non-migraine headache

Association of Microvesicles With Graft Patency in Patients Undergoing CABG Surgery

Abstract Background Graft patency is one of the major determinants of long-term outcome following coronary artery bypass graft surgery (CABG). Biomarkers, if indicative of the underlying pathophysiological mechanisms, would suggest strategies to limit graft failure. The prognostic value of microvesicles (MVs) for midterm graft patency has never been tested. Objectives The aim of this study was to evaluate whether MV pre-operative signature (number, cellular origin, procoagulant phenotype) could predict midterm graft failure and to investigate potential functional role of MVs in graft occlusion. Methods This was a nested case-control substudy of the CAGE (CoronAry bypass grafting: factors related to late events and Graft patency) study that enrolled 330 patients undergoing elective CABG. Of these, 179 underwent coronary computed tomography angiography 18 months post-surgery showing 24% graft occlusion. Flow cytometry MV analysis was performed in 60 patients (30 per group with occluded [cases] and patent [control subjects] grafts) on plasma samples collected the day before surgery and at follow-up. Results Before surgery, cases had 2- and 4-fold more activated platelet-derived and tissue-factor positive MVs respectively than control subjects. The MV procoagulant capacity was also significantly greater. Altogether this MV signature properly classified graft occlusion (area under the curve 0.897 [95% confidence interval: 0.81 to 0.98]; p Conclusions The pre-operative signature of MVs is independently associated with midterm graft occlusion in CABG patients and a cumulative MV score stratifies patients' risk. Because the MV signature mirrors platelet activation, patients with a high MV score could benefit from a personalized antiplatelet therapy

Brain Dynamics of Action Monitoring in Higher-Order Motor Control Disorders: The Case of Apraxia

Limb apraxia (LA) refers to a high-order motor disorder characterized by the inability to reproduce transitive actions on commands or after observation. Studies demonstrate that action observation and action execution activate the same networks in the human brain, and provides an onlooker’s motor system with appropriate cognitive, motor and sensory-motor cues to flexibly implementing action-sequences and gestures. Tellingly, the temporal dynamics of action monitoring has never been explored in people suffering from LA. To fill this gap, we studied the electro-cortical signatures of error observation in human participants suffering from acquired left-brain lesions with (LA+) and without (LA–) LA, and in a group of healthy controls (H). EEG was acquired while participants observed from a first-person perspective (1PP) an avatar performing correct or incorrect reach-to-grasp a glass action in an immersive-virtual environment. Alterations of typical EEG signatures of error observation in time (early error positivity; Pe) and time-frequency domain (theta band-power) were found reduced in LA+ compared with H. Connectivity analyses showed that LA+ exhibited a decreased theta phase synchronization of both the frontoparietal and frontofrontal network, compared with H and LA–. Moreover, linear regression analysis revealed that the severity of LA [test of upper LA (TULIA) scores] was predicted by mid-frontal error-related theta activity, suggesting a link between error monitoring capacity and apraxic phenotypes. These results provide novel neurophysiological evidence of altered neurophysiological dynamics of action monitoring in individuals with LA and shed light on the performance monitoring changes occurring in this disorder