Red blood cell transfusions can induce proinflammatory cytokines in preterm infants.

BACKGROUND: The risk of developing red blood cell (RBC) transfusion-associated necrotizing enterocolitis (TANEC) in preterm infants has recently been emphasized. Our aim was to assess changes in cytokine serum levels after RBC transfusions in a cohort of very preterm infants to evaluate their possible proinflammatory effect. STUDY DESIGN AND METHODS: We carried out a prospective observational study. One transfusion event was studied in infants less than 32 weeks' gestation and more than 7 days old (n = 20) admitted to a tertiary neonatal intensive care unit. Interleukin (IL)-1ß, IL-6, IL-8, tumor necrosis factor-α, interferon-γ (IFN-γ), IL-17, monocyte chemoattractant protein-1 (MCP-1), interferon-γ-induced protein 10 (IP-10), intracellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule serum levels were measured in enrolled patients within 120 minutes before (T0 ) the RBC transfusion and then within 120 minutes (T1 ), 12 ± 3 hours (T2 ), 24 ± 6 hours (T3 ), and 48 ± 6 hours (T4 ) after the end of RBC transfusion. RESULTS: Infants received 19.8 ± 3.0 mL of RBCs at the mean age of 50 ± 18 days. Their hematocrit level increased from 24.1 ± 1.2% to 39.4 ± 2.9%. IL-1ß, IL-8, IFN-γ, IL-17, MCP-1, IP-10, and ICAM-1 increased significantly after RBC transfusions. CONCLUSION: Proinflammatory cytokines are increased after RBC transfusion. These findings may contribute to explaining the pathogenesis of TANEC and suggest the opportunity of adopting wise transfusion guidelines that would help to avoid detrimental risks of transfusion-related immunomodulation and of undertransfusion.

Vegetarian, vegan diets and multiple health outcomes: A systematic review with meta-analysis of observational studies.

BACKGROUND: Beneficial effects of vegetarian and vegan diets on health outcomes have been supposed in previous studies. OBJECTIVES: Aim of this study was to clarify the association between vegetarian, vegan diets, risk factors for chronic diseases, risk of all-cause mortality, incidence, and mortality from cardio-cerebrovascular diseases, total cancer and specific type of cancer (colorectal, breast, prostate and lung), through meta-analysis. METHODS: A comprehensive search of Medline, EMBASE, Scopus, The Cochrane Library, and Google Scholar was conducted. RESULTS: Eighty-six cross-sectional and 10 cohort prospective studies were included. The overall analysis among cross-sectional studies reported significant reduced levels of body mass index, total cholesterol, LDL-cholesterol, and glucose levels in vegetarians and vegans versus omnivores. With regard to prospective cohort studies, the analysis showed a significant reduced risk of incidence and/or mortality from ischemic heart disease (RR 0.75; 95% CI, 0.68 to 0.82) and incidence of total cancer (RR 0.92; 95% CI 0.87 to 0.98) but not of total cardiovascular and cerebrovascular diseases, all-cause mortality and mortality from cancer. No significant association was evidenced when specific types of cancer were analyzed. The analysis conducted among vegans reported significant association with the risk of incidence from total cancer (RR 0.85; 95% CI, 0.75 to 0.95), despite obtained only in a limited number of studies. CONCLUSIONS: This comprehensive meta-analysis reports a significant protective effect of a vegetarian diet versus the incidence and/or mortality from ischemic heart disease (-25%) and incidence from total cancer (-8%). Vegan diet conferred a significant reduced risk (-15%) of incidence from total cancer.

Increased homocysteine and lipoprotein(a) levels highlight systemic atherosclerotic burden in patients with a history of acute coronary syndromes.

BACKGROUND: Strong evidence supports an association between high levels of homocysteine (Hcy) and lipoprotein(a) [Lp(a)] and an increased rate of ischemic vascular events. METHODS: The study population comprised 162 patients (50 women [30.9%]; age, 66.71 ± 12.76 years) having a history of acute coronary syndrome within 1 year who underwent fasting blood sampling, measurement of intima-media thickness and pulse wave velocity at the common carotid and femoral arteries by Doppler ultrasound, and ankle-brachial index measurement. Cutoff values were considered 0.9 mm and 1.2 mm for carotid and femoral intima-media thickness, respectively; 12 m/s for pulse wave velocity; and <0.9 for ankle-brachial index. We included hypertension, dyslipidemia, diabetes, overweight/obesity, smoking, and family history of cardiovascular disease in the count of traditional risk factors (CRFs). Adding Hcy ≥15 µmol/L and Lp(a) ≥500 mg/L to CRFs, we obtained a new score, named TOTAL. RESULTS: On univariate analysis, Hcy and Lp(a) were significantly associated with presence of atherosclerotic extracoronary lesions (for Hcy: ß = .934; standard error = 0.178; P < .0001; for Lp(a): ß = .961; standard error = 0.177; P < .0001) and compliance alterations (for Hcy: odds ratio, 13.3; 95% confidence interval, 3.9-45.3; P < .0001; for Lp(a): odds ratio, 14.6; 95% confidence interval, 5.69-37.62; P < .0001). On multivariate analysis, Lp(a) and Hcy were significantly associated with extracoronary atherosclerosis, even after correction for CRFs. The area under the curve of the TOTAL score for both atherosclerosis and vascular compliance alterations was significantly higher than the area under the curve of traditional CRFs plus only Hcy ≥15 µmol/L or plus Lp(a) ≥500 mg/L, separately added. CONCLUSIONS: The addition of evaluation of Hcy ≥15 µmol/L and Lp(a) ≥500 mg/L to the traditional CRF count does improve detection of systemic atherosclerotic burden of patients with acute coronary syndrome and can offer a new opportunity to optimize secondary prevention.

Autoantibodies against ß1-Adrenergic Receptors: Response to Cardiac Resynchronization Therapy and Renal Function.

BACKGROUND: Cardiac resynchronization therapy (CRT) nonresponse remains a major clinical problem. Autoantibodies specific for the ß1-adrenergic (ß1-AAbs) and muscarinic (M2-AAbs) receptors are found in patients with chronic heart failure (HF) of various etiologies. MATERIALS AND METHODS: We retrospectively analyzed 73 HF patients (median age 67 years, 84% males, New York Heart Association II-IV, in sinus rhythm, left ventricular ejection fraction <35%) who received CRT defibrillator (CRT-D) from 2010 to 2013. ß1-AAbs and M2-AAbs were measured by enzyme-linked immunosorbent assay. Echocardiography was used to assess CRT response (reduction >15% in left ventricular end-systolic volume at 6 months follow-up). Renal function (RF) parameters (creatinine [Cr], blood urea nitrogen [BUN], estimated glomerular filtration rate [eGFR Modified Diet in Renal Disease], cystatin C [Cys-C], and neutrophil gelatinase-associated lipocalin [NGAL]) were also evaluated. RESULTS: A significantly higher percentage of patients positive for ß1-AAbs (OD sample/OD reference ratio >2.1) in nonresponders than in responder patients was observed (57% vs 27%, P = 0.004). No influence of M2-AAbs on CRT-D response was demonstrated. ß1-AAbs were predictive of a poor CRT-D response (odds ratio [OR] [95% confidence interval (CI)] 3.64 [1.49-8.88], P = 0.005), also after adjustment for RF parameters (OR [95% CI] 4.95 [1.51-16.26], P = 0.008) observed to influence CRT-D response (Cr P = 0.03, BUN P = 0.009, Cys-C P = 0.02). The positive rates of ß1-AABs in patients with abnormal blood level of Cr, eGFR, Cys-C, and NGAL were significantly higher than those with normal levels (P = 0.03, P = 0.02, P = 0.001, P = 0.007, respectively). CONCLUSIONS: Our study suggests that (1) the evaluation of ß1-AAb is useful to identify responders to CRT-D; (2) the presence of ß1-AAbs is in relationship with elevated renal function parameters.

Prasugrel in Clopidogrel Nonresponders Undergoing Percutaneous Coronary Intervention: The RECLOSE-3 Study (REsponsiveness to CLOpidogrel and StEnt Thrombosis).

OBJECTIVES: This study sought to investigate the efficacy of prasugrel compared with clopidogrel in clopidogrel nonresponders. BACKGROUND: Clopidogrel nonresponsiveness is a strong marker of the risk of cardiac death and stent thrombosis after a percutaneous coronary intervention (PCI). It is unknown whether clopidogrel nonresponsiveness is a nonmodifiable risk factor or whether prasugrel with more potent and predictable platelet inhibition as measured by ex vivo techniques is associated with a positive effect on clinical outcome. METHODS: The RECLOSE-3 (REsponsiveness to CLOpidogrel and StEnt thrombosis) study screened clopidogrel nonresponders after a 600-mg loading dose of clopidogrel. Clopidogrel nonresponders switched to prasugrel (10 mg/day) the day of the PCI, and an adenosine diphosphate (ADP) test (10 µmol/l of ADP) was performed 6 days after the PCI. The primary endpoint was 2-year cardiac mortality. Patient outcome was compared with the RECLOSE-2-ACS study. RESULTS: We screened 1,550 patients, of whom 302 were clopidogrel nonresponders. The result of the ADP test was 77.6 ± 6.2%. After switching to prasugrel, the ADP test result decreased to 47.1 ± 16.8%. The 2-year cardiac mortality rate was 4% in the RECLOSE-3 study and 9.7% in nonresponders of the RECLOSE-2-ACS study (p = 0.007). The definite and probable stent thrombosis rates were 0.7% and 4.4%, respectively (p = 0.004). On multivariable analysis, prasugrel treatment was related to the risk of 2-year cardiac death (hazard ratio: 0.32, p = 0.036). CONCLUSIONS: Clopidogrel nonresponsiveness can be overcome by prasugrel (10 mg/day), and optimal platelet aggregation inhibition on prasugrel treatment is associated with a low rate of long-term cardiac mortality and stent thrombosis.

Genetic Contributions to the Development of Complications in Preterm Newborns.

AIM: We aimed to identify specific polymorphisms of genes encoding for vascular endothelial growth factor A (VEGFA), endothelial nitric oxide synthase (eNOS), renin-angiotensin system (angiotensinogen gene [AGT], angiotensinogen type 1 receptor [AGTR1], angiotensin-converting enzyme [ACE]), and heme oxygenase-1 (HMOX-1) in a cohort of preterm infants and correlate their presence with the development of respiratory distress syndrome (RDS) requiring mechanical ventilation (MV), bronchopulmonary dysplasia (BPD), intraventricular hemorrhage (IVH) and retinopathy of prematurity (ROP). STUDY DESIGN: We carried out a retrospective study to evaluate the allele frequency and genotype distribution of polymorphisms of VEGFA, eNOS, AGT, AGTR1, ACE, and HMOX-1 in a population of preterm neonates (n=342) with a gestational age ≤28 weeks according to the presence or absence of RDS requiring MV, BPD, IVH, or ROP. Moreover, we evaluated through the haplotype reconstruction analysis whether combinations of the selected polymorphisms are related to the occurrence of RDS, BPD, IVH and ROP. RESULTS: In our population 157 infants developed RDS requiring MV, 71 BPD, 70 IVH, and 43 ROP. We found that TC+CC rs2070744 eNOS (41.7 vs. 25.4%, p=0.01) and GT+TT rs1799983 eNOS (51.8 vs. 35.2%, p=0.01) polymorphisms are independent risk factors for BPD. Haplotype reconstruction showed that haplotypes in VEGF and eNOS are significantly associated with different effects on RDS, BPD, IVH, and ROP in our population. CONCLUSIONS: We found that TC+CC rs2070744 eNOS and GT+TT rs1799983 eNOS polymorphisms are independent predictors of an increased risk of developing BPD. Haplotypes of VEGFA and eNOS may be independent protective or risk markers for prematurity complications.

Dual antiplatelet therapy tailored on platelet function test after coronary stent implantation: a real-world experience.

Patients' response to dual antiplatelet therapy (DAPT) is subject to variations and its monitoring allows to individualize this therapy. In this study, we evaluated if a strategy of tailored DAPT after platelet function testing could reduce high on-treatment platelet reactivity (HPR) and improve outcome of patients treated with stent implantation. In 257 patients undergoing percutaneous angioplasty, platelet function was measured by light transmittance aggregometry (LTA) using 10 µM/L adenosine-diphosphate (ADP) and 1 mM arachidonic acid (AA) as agonists. Patients with HPR by ADP (≥70%) were switched to double-dose clopidogrel, ticlopidine, prasugrel or ticagrelor; in patients with HPR by AA (≥20%) acetylsalicylic acid dose was increased if not contraindicated. Platelet function analysis was repeated 48 hours after therapy variation. At 20-month follow-up major adverse cardiovascular events (MACE) and bleedings were assessed. HPR was detected in 97/257 (37.7%) patients: 69/257 (26.8%) had HPR by ADP and 71/257 (27.6%) had HPR by AA. In patients with HPR by ADP or by AA, tailored DAPT determined a significant reduction in residual platelet reactivity. No significant difference in MACE or bleeding occurrence was documented in HPR patients treated with tailored DAPT vs. those without HPR. HPR patients treated with tailored DAPT had significant lower follow-up MACE and deaths vs. 139 HPR patients not switched, even after propensity score analysis. These results suggest that a DAPT tailored on platelet testing can improve antiplatelet response in HPR patients, possibly reducing their thrombotic events to a level similar to non-HPR patients, without increasing the risk of bleeding.

An organic khorasan wheat-based replacement diet improves risk profile of patients with acute coronary syndrome: a randomized crossover trial.

Khorasan wheat is an ancient grain with previously reported health benefits in clinically healthy subjects. The aim of this study was to examine whether a replacement diet, thereby substituting all other cereal grains, with products made with organic khorasan wheat could provide additive protective effects in reducing lipid, oxidative and inflammatory risk factors, in patients with Acute Coronary Syndromes (ACS) in comparison to a similar replacement diet using products made from organic modern wheat. A randomized double-blinded crossover trial with two intervention phases was conducted on 22 ACS patients (9 F; 13 M). The patients were assigned to consume products (bread, pasta, biscuits and crackers) made either from organic semi-whole khorasan wheat or organic semi-whole control wheat for eight weeks in a random order. On average, patients ingested 62.0 g dry weight (DW) day-1 khorasan or control semolina; and 140.5 g DW day-1 khorasan or control flour, respectively. An eight-week washout period was implemented between the respective interventions. Blood analyses were performed both at the beginning and end of each intervention phase; thereby permitting a comparison of both the khorasan and control intervention phases, respectively, on circulatory risk factors for the same patient. Consumption of products made with khorasan wheat resulted in a significant amelioration in total cholesterol (-6.8%), low-density lipoprotein cholesterol (LDL-C) (-8.1%) glucose (-8%) and insulin (-24.6%) from baseline levels, independently of age, sex, traditional risk factors, medication and diet quality. Moreover, there was a significant reduction in reactive oxygen species (ROS), lipoperoxidation of circulating monocytes and lymphocytes, as well as in the levels of Tumor Necrosis Factor-alpha. No significant differences from baseline in the same patients were observed after the conventional control wheat intervention phase. The present results suggest that a replacement diet with cereal products made from organic khorasan wheat provides additional protection in patients with ACS. Circulating cardiovascular risk factors, including lipid parameters, and markers of both oxidative stress and inflammatory status, were reduced, irrespective of the number and combination of medicinal therapies with proven efficacy in secondary prevention.

Characterization and identification of hidden rare variants in the human genome.

BACKGROUND: By examining the genotype calls generated by the 1000 Genomes Project we discovered that the human reference genome GRCh37 contains almost 20,000 loci in which the reference allele has never been observed in healthy individuals and around 70,000 loci in which it has been observed only in the heterozygous state. RESULTS: We show that a large fraction of this rare reference allele (RRA) loci belongs to coding, functional and regulatory elements of the genome and could be linked to rare Mendelian disorders as well as cancer. We also demonstrate that classical germline and somatic variant calling tools are not capable to recognize the rare allele when present in these loci. To overcome such limitations, we developed a novel tool, named RAREVATOR, that is able to identify and call the rare allele in these genomic positions. By using a small cancer dataset we compared our tool with two state-of-the-art callers and we found that RAREVATOR identified more than 1,500 germline and 22 somatic RRA variants missed by the two methods and which belong to significantly mutated pathways. CONCLUSIONS: These results show that, to date, the investigation of around 100,000 loci of the human genome has been missed by re-sequencing experiments based on the GRCh37 assembly and that our tool can fill the gap left by other methods. Moreover, the investigation of the latest version of the human reference genome, GRCh38, showed that although the GRC corrected almost all insertions and a small part of SNVs and deletions, a large number of functionally relevant RRAs still remain unchanged. For this reason, also future resequencing experiments, based on GRCh38, will benefit from RAREVATOR analysis results. RAREVATOR is freely available at http://sourceforge.net/projects/rarevator .

Inflammatory and antioxidant pattern unbalance in "clopidogrel-resistant" patients during acute coronary syndrome.

BACKGROUND: In acute coronary syndrome (ACS), inflammation and redox response are associated with increased residual platelet reactivity (RPR) on clopidogrel therapy. We investigated whether clopidogrel interaction affects platelet function and modulates factors related to inflammation and oxidation in ACS patients differently responding to clopidogrel. MATERIAL AND METHODS: Platelet aggregation was measured in 29 ACS patients on dual (aspirin/clopidogrel) antiplatelet therapy. Nonresponders (NR) were defined as RPR ≥70% by ADP. Several inflammatory and redox parameters were assayed and platelet proteome was determined. RESULTS: Eight (28%) out of 29 ACS patients resulted NR to clopidogrel. At 24 hours, the levels of Th2-type cytokines IL-4, IFNγ, and MCP-1 were higher in NR, while blood GSH (r-GSHbl) levels were lower in NR than responders (R). Proteomic analysis evidenced an upregulated level of platelet adhesion molecule, CD226, and a downregulation of the antioxidant peroxiredoxin-4. In R patients the proinflammatory cytokine IL-6 decreased, while the anti-inflammatory cytokine IL-1Ra increased. CONCLUSIONS: In patients with high RPR on clopidogrel therapy, an unbalance of inflammatory factors, platelet adhesion molecules, and circulatory and platelet antioxidant molecules was observed during the acute phase. Proinflammatory milieu persists in nonresponders for a long time after the acute event while antioxidant blood factors tend to conform to normal responsiveness.

Association of rs1466535 LRP1 but not rs3019885 SLC30A8 and rs6674171 TDRD10 gene polymorphisms with abdominal aortic aneurysm in Italian patients.

OBJECTIVE: Recently, a large genome-wide association study in patients with abdominal aortic aneurysm (AAA) and control subjects identified nine loci associated with AAA. Besides the significant association of the rs1466535 single nucleotide polymorphism in the low-density lipoprotein receptor-related protein 1 gene (LRP1), two of eight remaining loci, rs6674171 in the tudor domain containing protein 10 (TDRD10) and rs3019885 in solute carrier family 30 zinc transporter member 8 (SLC30A8) gene, showed a weakly significant association with AAA requiring further attention. Therefore, the aim of our study was to evaluate the role of these three polymorphisms in conferring AAA genetic susceptibility. METHODS: We studied these three polymorphisms in 423 patients and 423 sex- and age-comparable control subjects from Italy. All subjects were genotyped with the use of the real-time TaqMan approach. Multiple logistic regression analysis adjusted for traditional cardiovascular risk factor and chronic obstructive pulmonary disease was used to estimated odds ratios and 95% confidence intervals for AAA risk. RESULTS: The prevalence of carriers of the rs3019885 SLC30A8 G allele was higher in control subjects (67.8%) than in patients (60.3%, P = .022), suggesting a protective effect for AAA. The prevalence of carriers of the rs1466535 LRP1 T allele was higher in patients (51.8%) than in control subjects (39.7%, P = .0004), suggesting a risk effect for AAA. rs6674171 polymorphism genotype distribution did not differ between AAA patients and control subjects. In the multiple logistic regression analysis adjusted for traditional AAA risk factors, only the rs1466535 polymorphism remained significantly associated with AAA (odds ratio, 1.85; 95% confidence interval, 1.2-2.84; P = .01). CONCLUSIONS: Our findings confirm the role as significant and independent susceptibility factor for AAA of the rs1466535 LRP1 polymorphism (T allele) in an Italian population. Nevertheless, our findings consistently differed from previous published data because in the genome-wide association study, the risk allele was the most frequent rs1466535 C allele. Our findings are consistent with literature data of LRP1 knock-out mice developing atherosclerotic lesions and aortic dilatation and association of the T allele with reduced LRP1 gene expression in humans. CLINICAL RELEVANCE: Our work supports the evidence that the T allele of the rs1466535 LRP1 polymorphism is an independent risk factor for abdominal aortic aneurysm. Our findings are consistent with literature data of Lrp1 knock-out mice developing atherosclerotic lesions and aortic dilatation, and association of the T allele with reduced LRP1 gene expression in humans. These data could have a crucial role for developing future diagnostic or prognostic scores based on biohumoral, clinical, genetic, proteomic, and imaging data to be applied in everyday clinical practice in order to improve the management of these high-risk patients in consideration of their characteristics and pathophysiological complexity.

Residual platelet reactivity and outcomes with 5 mg prasugrel therapy in elderly patients undergoing percutaneous coronary intervention.

BACKGROUND: In acute coronary syndrome (ACS) patients older than 75 years old, prasugrel 10 mg maintenance therapy has shown less clinical efficacy and higher risk of bleeding. In patients older than 75 years, a prasugrel dose of 5 mg should be used if treatment is deemed necessary. OBJECTIVE: The aim of this study was to compare platelet reactivity and outcomes in elderly patients receiving prasugrel 5mg therapy with non-elderly patients receiving prasugrel 10 mg therapy. METHODS AND RESULTS: Consecutive ACS patients undergoing percutaneous coronary intervention (PCI) treated with prasugrel were included. Of 718 patients, 228 (32%) had ≥75 years and received prasugrel 5 mg/day. Residual platelet reactivity (RPR) was 47±18% and 36±16% in the elderly and non-elderly group, respectively (p=0.001). High RPR (≥70%) was found in 9% and 2% (p=0.0001) in elderly and non-elderly patients, respectively. In the 6-month follow-up, there was no difference in mortality, stent thrombosis, and reinfarction rates between the 2 groups but a higher rate of TIMI minor bleeding (7.9% vs 2.4%; p=0.001) in elderly as compared with younger patients. Age≥75 years was independently associated with bleeding events (HR 2.162 [1.105-4.229]; p=0.024). CONCLUSIONS: Elderly patients receiving prasugrel 5mg are more likely to experience high RPR than younger patients treated by prasugrel 10 mg. Despite the use of a reduced prasugrel maintenance dose and a higher level of RPR, elderly patients show increased risk of bleeding during prasugrel therapy as compared to younger patients.

Global platelet hyperreactivity and elevated C-reactive protein levels predict long term mortality in STEMI patients.

BACKGROUND: Data on long term - more than 1-year - prognostic value of global platelet reactivity (G-HPR) - by adenosine diphosphate (ADP) and arachidonic acid (AA) - in patients with STEMI undergoing PCI are limited. High C-reactive protein (CRP) levels have been suggested to be associated with post-PCI atherothrombotic events. Our aim was to evaluate the long-term prognostic impact of G-HPR and CRP levels in STEMI patients. METHODS AND RESULTS: We evaluated 494 STEMI patients (366 M/128 F; age: 65.8 ± 12.4 yrs) undergoing PCI with stent implantation. At a median follow-up of 2.3 years (1.09-4.06), in 58 patients we documented cardiovascular death (11.7%). Platelet reactivity was assessed by light transmission aggregometry by 1mM AA (AA-LTA) and 10 microM ADP (ADP-LTA). By the ROC curve analysis, 17%, 52% and 12 mg/L were found to be the values of AA-LTA, ADP-LTA and CRP associated with the highest specificity and sensitivity for death. G-HPR was defined as the presence of both AA-LTA ≥ 17% and ADP-LTA ≥ 52%. At Cox regression analysis adjusted for age, sex, cardiovascular risk factors, multivessel disease, ejection fraction, renal insufficiency, G-HPR and elevated CRP levels were associated with long-term mortality [HR=1.78 (95%CI 1.04-3.03), p=0.036 and HR=2.91 (1.54-5.52, p=0.001), respectively]. The contemporary presence of G-HPR and elevated CRP levels was associated with the highest risk of death [HR=5.1 (95%CI 1.9-13.4), p=0.001]. CONCLUSION: G-HPR and CRP are independent long-term prognostic markers in STEMI patients. The contemporary presence of G-HPR and CRP identifies a subgroup of patients at significantly higher risk of cardiovascular death.

Comparison of double (360 mg) ticagrelor loading dose with standard (60 mg) prasugrel loading dose in ST-elevation myocardial infarction patients: the Rapid Activity of Platelet Inhibitor Drugs (RAPID) primary PCI 2 study.

UNLABELLED: In ST-elevation myocardial infarction (STEMI) patients, residual platelet reactivity soon after a loading dose (LD) of prasugrel or ticagrelor is higher than that reported for healthy volunteers or subjects with stable coronary artery disease; and the majority of primary percutaneous coronary intervention (PPCI) procedures with bivalirudin monotherapy are performed without proper platelet inhibition. However, ticagrelor LD is just the daily dose, whereas prasugrel LD is 6-fold the long-term daily dose. We hypothesized that an increased ticagrelor LD may result in a faster and more effective platelet inhibition as compared with the standard prasugrel LD. METHODS: Fifty patients with STEMI, pretreated with intravenous aspirin, undergoing PPCI were randomized to receive prasugrel 60-mg LD (n = 25) or ticagrelor 360-mg LD (n = 25). Residual platelet reactivity was assessed by VerifyNow at baseline and 1, 2, 4, and 12 hours after drug LD. RESULTS: At the time of LD, 90% of enrolled patients had an aspirin reactivity unit value <550. P2Y12 reaction units 1 hour after the LD (study primary end point) were 236 (129-289) and 248 (115-304) in the prasugrel and ticagrelor group, respectively (P = .899). High residual platelet reactivity (P2Y12 reaction units ≥240) was found in 43% and 56% of patients (P = .386) at 1 hour and in 30% and 32% of patients (P = .907) at 2 hours, respectively. There was no significant difference in bleeding, arrhythmias, or dyspnea episodes in the 2 groups. CONCLUSIONS: In patients with STEMI undergoing PPCI, double (360 mg) ticagrelor LD failed to achieve a faster and more intense platelet inhibition as compared with the standard prasugrel LD. Intravenously administered aspirin allowed to achieve a very early inhibition of acid arachidonic pathway.

Effects of cryoablation and radiofrequency ablation on endothelial and blood clotting activation.

Cryoablation (CA) emerged as an alternative procedure to radiofrequency (RF). The aim of this study was to compare haemostatic system alterations in patients undergoing RF or CA for atrioventricular nodal reentrant tachycardia ablation. von Willebrand factor (vWF), spontaneous whole blood platelet aggregation, prothrombin fragment F1 + 2 (F1 + 2), thrombin-antithrombin complex (TAT), plasminogen activator inhibitor type-1 (PAI-1), and clot lysis time (CLT) were determined in 48 patients (27 CA; 21 RF; 19M/29F, mean age 49.6 ± 17.6 years). Blood samples were obtained before the procedure (T0), immediately after (T1), and 24 h later (T2). At T1 both procedures were associated with a significant increase in levels of the endothelial activation marker vWF. At T2 vWF levels were lower in CA than in RF group. No changes in whole blood platelet aggregation before and after ablation procedures were observed. At T1 both groups determined an increase in blood clotting activation markers, F1 + 2, TAT, and DD. At T2 F1 + 2, TAT and DD levels were similar to baseline values. The comparison between RF and CA showed no significant differences in F1 + 2 and TAT levels, whereas at T1 DD levels were higher in CA group than in RF group. Both procedures induced a significant decrease in CLT, whereas no changes in PAI-1 levels were found. There were no significant differences in CLT and PAI-1 levels. The fibrinolytic efficiency analysis showed that at T1 DD/TAT and DD/F1 + 2 ratios were lower in RF group and remained lower in RF than in CA group at T2. CA procedure may be associated with a lower degree of endothelial damage and with a higher fibrinolytic capacity respect to RF.

Switching from clopidogrel to prasugrel in patients having coronary stent implantation.

There are very few clinical data concerning the safety of switching from clopidogrel to prasugrel in patients undergoing coronary stenting. However, in the daily activity, clinicians face the decision of switching patients at high-risk of thrombotic events from clopidogrel to prasugrel. Thus, we sought to evaluate clinical events in patients undergoing coronary stent implantation and prasugrel therapy with (SWITCH group) or without (NAÏVE group) prior clopidogrel therapy. A total of 454 patients with stable or unstable coronary artery disease, aged 70 ± 10 years, underwent non-emergent stent implantation and received prasugrel therapy. Of these, 315 (69 %) patients received clopidogrel before switching to prasugrel therapy. In 239 patients with high residual platelet reactivity (HRPR) on clopidogrel, prasugrel decreased platelet aggregation from 72 ± 11 to 43 ± 16 % (p < 0.001). There was no difference in in-hospital major or minor TIMI bleeding (2.8 vs. 4.3 %; p = 0.411) between the SWITCH and NAÏVE groups as well as in mortality, acute stent thrombosis, reinfarction and stroke rates. At multivariable analysis, independent predictors of bleeding were female gender (OR 5.56 [1.41-19.88] p = 0.014) and chronic renal failure (OR 6.27 [1.59-21.65] p = 0.009), but switching therapy did not. This result was confirmed after switching propensity score adjustment (c-statistic 0.81; Hosmer-Lemeshow test p = 860). Switching from clopidogrel to prasugrel in patients undergoing non-emergent coronary stent implantation seems to be tolerated with no overt signs of increased bleeding.

Effect of Triticum turgidum subsp. turanicum wheat on irritable bowel syndrome: a double-blinded randomised dietary intervention trial.

The aim of the present study was to examine the effect of a replacement diet with organic, semi-whole-grain products derived from Triticum turgidum subsp. turanicum (ancient) wheat on irritable bowel syndrome (IBS) symptoms and inflammatory/biochemical parameters. A double-blinded randomised cross-over trial was performed using twenty participants (thirteen females and seven males, aged 18-59 years) classified as having moderate IBS. Participants received products (bread, pasta, biscuits and crackers) made either from ancient or modern wheat for 6 weeks in a random order. Symptoms due to IBS were evaluated using two questionnaires, which were compiled both at baseline and on a weekly basis during the intervention period. Blood analyses were carried out at the beginning and end of each respective intervention period. During the intervention period with ancient wheat products, patients experienced a significant decrease in the severity of IBS symptoms, such as abdominal pain (P< 0·0001), bloating (P= 0·004), satisfaction with stool consistency (P< 0·001) and tiredness (P< 0·0001). No significant difference was observed after the intervention period with modern wheat products. Similarly, patients reported significant amelioration in the severity of gastrointestinal symptoms only after the ancient wheat intervention period, as measured by the intensity of pain (P= 0·001), the frequency of pain (P< 0·0001), bloating (P< 0·0001), abdominal distension (P< 0·001) and the quality of life (P< 0·0001). Interestingly, the inflammatory profile showed a significant reduction in the circulating levels of pro-inflammatory cytokines, including IL-6, IL-17, interferon-γ, monocyte chemotactic protein-1 and vascular endothelial growth factor after the intervention period with ancient wheat products, but not after the control period. In conclusion, significant improvements in both IBS symptoms and the inflammatory profile were reported after the ingestion of ancient wheat products.

Mediterranean diet and health status: an updated meta-analysis and a proposal for a literature-based adherence score.

OBJECTIVE: To update previous meta-analyses of cohort studies that investigated the association between the Mediterranean diet and health status and to utilize data coming from all of the cohort studies for proposing a literature-based adherence score to the Mediterranean diet. DESIGN: We conducted a comprehensive literature search through all electronic databases up to June 2013. SETTING: Cohort prospective studies investigating adherence to the Mediterranean diet and health outcomes. Cut-off values of food groups used to compute the adherence score were obtained. SUBJECTS: The updated search was performed in an overall population of 4 172 412 subjects, with eighteen recent studies that were not present in the previous meta-analyses. RESULTS: A 2-point increase in adherence score to the Mediterranean diet was reported to determine an 8 % reduction of overall mortality (relative risk = 0·92; 95 % CI 0·91, 0·93), a 10 % reduced risk of CVD (relative risk = 0·90; 95 % CI 0·87, 0·92) and a 4 % reduction of neoplastic disease (relative risk = 0·96; 95 % CI 0·95, 0·97). We utilized data coming from all cohort studies available in the literature for proposing a literature-based adherence score. Such a score ranges from 0 (minimal adherence) to 18 (maximal adherence) points and includes three different categories of consumption for each food group composing the Mediterranean diet. CONCLUSIONS: The Mediterranean diet was found to be a healthy dietary pattern in terms of morbidity and mortality. By using data from the cohort studies we proposed a literature-based adherence score that can represent an easy tool for the estimation of adherence to the Mediterranean diet also at the individual level.

EXCAVATOR: detecting copy number variants from whole-exome sequencing data.

We developed a novel software tool, EXCAVATOR, for the detection of copy number variants (CNVs) from whole-exome sequencing data. EXCAVATOR combines a three-step normalization procedure with a novel heterogeneous hidden Markov model algorithm and a calling method that classifies genomic regions into five copy number states. We validate EXCAVATOR on three datasets and compare the results with three other methods. These analyses show that EXCAVATOR outperforms the other methods and is therefore a valuable tool for the investigation of CNVs in largescale projects, as well as in clinical research and diagnostics. EXCAVATOR is freely available at http://sourceforge.net/projects/excavatortool/.