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1.  Clinical significance of lactate in acute cardiac patients 
World Journal of Cardiology  2015;7(8):483-489.
Lactate, as a metabolite of easy and quick assessment, has been studied over time in critically ill patients in order to evaluate its prognostic ability. The present review is focused on the prognostic role of lactate levels in acute cardiac patients (that is with acute coronary syndrome, cardiogenic shock, cardiac arrest, non including post cardiac surgery patients). In patients with ST-elevation myocardial infarction treated with mechanical revascularization, hyperlactatemia identified a subset of patients at higher risk for early death and in-hospital complications, being strictly related mainly to hemodynamic derangement. The prognostic impact of hyperlactatemia on mortality has been documented in patients with cardiogenic shock and in those with cardiac arrest even if there is no cut-off value of lactate to be associated with worse outcome or to guide resuscitation or hemodynamic management. Therapeutic hypothermia seems to affect per se lactate values which have been shown to progressively decrease during hypothermia. The mechanism(s) accounting for lactate levels during hypothemia seem to be multiple ranging from the metabolic effects of reduced temperatures to the hemodynamic effects of hypothermia (i.e., reduced need of vasopressor agents). Serial lactate measurements over time, or lactate clearance, have been reported to be clinically more reliable than lactate absolute value also in acute cardiac patients. Despite differences in study design, timing of lactate measurements and type of acute cardiac conditions (i.e., cardiogenic shock, cardiac arrest, refractory cardiac arrest), available evidence strongly suggests that higher lactate levels can be observed on admission in non-survivors and that higher lactate clearance is associated with better outcome.
doi:10.4330/wjc.v7.i8.483
PMCID: PMC4549782  PMID: 26322188
Lactate; Acute coronary syndrome; Cardiogenic shock; Cardiac arrest; Therapeutic hypothermia; Extracorporeal membrane oxygenation; Prognosis
2.  Clinical significance of glycated hemoglobin in the acute phase of ST elevation myocardial infarction 
World Journal of Cardiology  2014;6(4):140-147.
In population-based studies, including diabetic and nondiabetic cohorts, glycated hemoglobin A1c (HbA1c) has been reported as an independent predictor of all-cause and cardiovascular disease mortality. Data on the prognostic role of HbA1c in patients with acute myocardial infarction (MI) are not univocal since they stem from studies which mainly differ in patients’ selection criteria, therapy (thrombolysis vs mechanical revascularization) and number consistency. The present review is focused on available evidence on the prognostic significance of HbA1c measured in the acute phase in patients with ST-elevation myocardial infarction (STEMI) submitted to primary percutaneous coronary intervention (PCI). We furthermore highlighted the role of HbA1c as a screening tool for glucose intolerance in patients with STEMI. According to available evidence, in contemporary cohorts of STEMI patients submitted to mechanical revascularization, HbA1c does not seem to be associated with short and long term mortality rates. However, HbA1c may represent a screening tool for glucose intolerance from the early phase on in STEMI patients. On a pragmatic ground, an HbA1c test has several advantages over fasting plasma glucose or an oral glucose tolerance test in an acute setting. The test can be performed in the non-fasting state and reflects average glucose concentration over the preceding 2-3 mo. We therefore proposed an algorithm based on pragmatic grounds which could be applied in STEMI patients without known diabetes in order to detect glucose intolerance abnormalities from the early phase. The main advantage of this algorithm is that it may help in tailoring the follow-up program, by helping in identifying patients at risk for the development of glucose intolerance after MI. Further validation of this algorithm in prospective studies may be required in the contemporary STEMI population to resolve some of these uncertainties around HbA1c screening cutoff points.
doi:10.4330/wjc.v6.i4.140
PMCID: PMC3999334  PMID: 24772254
Glycated hemoglobin; ST-elevation myocardial infarction; Prognosis; Hyperglycemia; Glucose intolerance
3.  Non invasive continuous hemodynamic evaluation of cirrhotic patients after postural challenge 
World Journal of Hepatology  2012;4(4):149-153.
AIM: To assess whether Most Care is able to detect the cardiovascular alterations in response to physiological stress (posture).
METHODS: Non invasive hemodynamic was assessed in 26 cirrhotic patients compared to healthy subjects, both in the supine and standing positions.
RESULTS: In baseline conditions, when compared to healthy subjects, cirrhotic patients showed significantly lower values of dicrotic and diastolic pressures and systemic vascular resistance. While in the standing position, cirrhotic patients showed higher values of cardiac index, stroke volume index and cardiac cycle efficiency. When returning to the supine position, cirrhotic patients exhibited lower values of dicrotic and diastolic pressures and systemic vascular resistance in the presence of higher values of cardiac index, stroke volume index and cardiac cycle efficiency.
CONCLUSION: Most Care proved to be able to detect cardiovascular abnormalities bedside in the resting state and after postural challenge in cirrhotic patients.
doi:10.4254/wjh.v4.i4.149
PMCID: PMC3345539  PMID: 22567187
Liver cirrhosis; Non-invasive hemodynamic; Pressure recording analytical method; Posture
4.  Academic Education in Complementary Medicine: a Tuscan Methodological Perspective 
The implementation of complementary medicine (CM) involves a large number of persons in Italy, and in the nineties, the percentage of Italian citizens adopting the most frequent and relevant practices of CM almost doubled. Appropriate academic education in CM is an important and fascinating challenge for current didactic systems in the Italian University. Already in 2004, the Joint Italian Conference of the Deans of the Faculties of Medicine and of the Presidents of Medical Degree Courses released an official statement regarding the relationship between CM and health area degree courses. The main teaching objectives embedded in the institutional framework proposed by the Joint Italian Conference are now finding specific implementation modalities in the University of Florence. For many years, the Florence Medical School has had strong and fruitful contacts with institutional bodies in Tuscany and, together with these institutions, has established a continuous dialogue with the world of CM. This exchange has given rise to various teaching activities within the academic setting. With specific reference to the undergraduate curriculum in Medicine and Surgery, a methodological course regarding CM has been designed and conducted, with selective attention being given to the CM practices having an enhanced rate of supportive scientific evidence, such as herbal medicine and acupuncture. With regard to the postgraduate curriculum, a Master degree in Acupuncture and Traditional Chinese Medicine and a Master in Clinical Phytotherapy are already active in the University of Florence and are having a remarkable success among the attending health professionals. This high degree of satisfaction well documents the importance, need and feasibility of structured academic education in CM and, in particular, of a methodological didactics such as those currently implemented in the Florence Medical School.
doi:10.1093/ecam/nem105
PMCID: PMC2206245  PMID: 18227930
complementary medicine; evidence based medicine; clinical methodology; medical education; history of medicine
5.  Bleeding events and maintenance dose of prasugrel: BLESS pilot study 
Open Heart  2016;3(2):e000460.
Objective
To evaluate changes in residual platelet reactivity (RPR) over time, and bleeding and ischaemic events rate using 5 vs 10 mg maintenance dose (MD) regimens of prasugrel 1 month after acute coronary syndrome (ACS).
Background
The optimal level of RPR with prasugrel may change over time after an ACS.
Methods
After 60 mg loading dose of prasugrel (T0) followed by 10 mg/day for 1 month, patients were randomised to receive prasugrel 10 mg/day (n=95, group A) or 5 mg/day MD (n=98, group B) up to 1 year. RPR was assessed at T0, 37 (T1) and 180 days (T2). The primary end point was Bleeding Academic Research Consortium (BARC) bleeding events ≥2 between 1 and 12 months, and the secondary composite end point was cardiac death, myocardial infarction, stroke and definite/probable stent thrombosis.
Results
From T0 to T1, RPR significantly increased in both groups A and B and the increase was higher for group B (δ ADP 10 µmol: 13.8%±14.7% vs 23.5%±19.2%, p=0.001). At T2 a lower rate of high RPR patients were found in group A (2.6% vs13.3%; p=0.014). The BARC type ≥2 bleeding occurred in 12.6% of group A versus 4.1% of group B (OR 0.29, 95% CI 0.09 to 0.94) and secondary end point in 2.1% vs 1.0% (p=0.542), respectively, without stent thrombosis.
Conclusions
RPR increases shifting from 60 mg loading dose to 10 mg/day prasugrel MD with a further increase of RPR reducing prasugrel MD to 5 mg 1 month after ACS. Clinical value of these pharmacodynamic findings should be proved in larger clinical trials.
Trial registration number
NCT01790854.
doi:10.1136/openhrt-2016-000460
PMCID: PMC5093371  PMID: 27843564
PHARMACOLOGY; PERCUTANEOUS CORONARY INTERVENTION
6.  Impaired Femoral Vascular Compliance and Endothelial Dysfunction in 30 Healthy Male Soccer Players 
Sports Health  2015;7(4):335-340.
Background:
Despite beneficial effects of physical activity on cardiovascular risk, discordant data on elite athletes (high atherosclerotic damage in activity comprising strenuous exertion) and retired sportsmen are reported in the literature.
Hypothesis:
We hypothesize that long-lasting daily physical activity could affect the morphology and function of the carotid and femoral vessel walls differently, as assessed in elite male athletes aged 20 to 30 years compared with age- and sex-matched healthy controls.
Study Design:
Retrospective case-control study.
Level of Evidence:
Level 3.
Methods:
Sixty male subjects (30 athletes and 30 controls) underwent medical examination for ankle brachial index, augmentation index (AIX) and AIX corrected for heart rate (AIXr), peripheral arterial tonometry (PAT), and intima media thickness and pulse wave velocity assay at common carotid (carotid–intima media thickness [c-IMT], carotid–pulse wave velocity [c-PWv]) and femoral arteries (femoral–intima media thickness [f-IMT], femoral–pulse wave velocity [f-PWv]) assessed by ultrasonography using Doppler ultrasound.
Results:
Athletes showed a significantly lower heart rate (HR) at rest and a better lipid profile than controls. In athletes, c-PWv (5.87 ± 0.80 vs 6.62 ± 1.02 m/s, P = 0.001) and f-PWv (8.96 ± 1.29 vs 7.89 ± 1.39, P = 0.002) were, respectively, significantly lower and higher than values found in controls; accordingly, carotid AIX (4.03 ± 6.21 vs 7.81 ± 5.21, P = 0.003) and femoral AIX (8.56 ± 10.21 vs 6.09 ± 7.95, P = 0.042) were lower and higher than control values, even after correction for heart rate (P = 0.03). On the other hand, IMT values were significantly higher in controls than in athletes (c-IMT, P < 0.0001; f-IMT, P < 0.0001). A positive significant correlation between HR and c-IMT and f-IMT (r = 0.527, P < 0.001 and r = 0.539, P < 0.0001, respectively) and between HR and c-PWv (r = 0.410, P = 0.01) was found when controls and athletes were considered as a whole group. Soccer players showed lower PAT values in comparison with controls (P = 0.002).
Conclusion:
Elite sports positively affect c-IMT, f-IMT, and carotid PWv and AIX but not femoral PWv, AIX, AIXr, or PAT.
Clinical Relevance:
Physical activity affects vascular beds in elite athletes differentially, depending on the rate of superior or inferior limb involvement in different sports. In soccer players, physical activity has a protective effect on carotid and femoral vessel walls but worsens femoral arterial and endothelial function. These findings highlight how different results can be shown on carotid and femoral districts, when these vascular districts are differently stressed during sport activity.
doi:10.1177/1941738115577931
PMCID: PMC4481678  PMID: 26137179
intima media thickness; arterial stiffness; peripheral arterial tonometry
7.  A Case Based Approach to Clinical Genetics of Thoracic Aortic Aneurysm/Dissection 
BioMed Research International  2016;2016:9579654.
Thoracic aortic aneurysm/dissection (TAAD) is a potential lethal condition with a rising incidence. This condition may occur sporadically; nevertheless, it displays familial clustering in >20% of the cases. Family history confers a six- to twentyfold increased risk of TAAD and has to be considered in the identification and evaluation of patients needing an adequate clinical follow-up. Familial TAAD recognizes a number of potential etiologies with a significant genetic heterogeneity, in either syndromic or nonsyndromic forms of the manifestation. The clinical impact and the management of patients with TAAD differ according to the syndromic and nonsyndromic forms of the manifestation. The clinical management of TAAD patients varies, depending on the different forms. Starting from the description of patient history, in this paper, we summarized the state of the art concerning assessment of clinical/genetic profile and therapeutic management of TAAD patients.
doi:10.1155/2016/9579654
PMCID: PMC4897665  PMID: 27314043
8.  Marfan syndrome: current perspectives 
Marfan syndrome (MFS) is a pleiotropic connective tissue disease inherited as an autosomal dominant trait, due to mutations in the FBN1 gene encoding fibrillin 1. It is an important protein of the extracellular matrix that contributes to the final structure of a microfibril. Few cases displaying an autosomal recessive transmission are reported in the world. The FBN1 gene, which is made of 66 exons, is located on chromosome 15q21.1. This review, after an introduction on the clinical manifestations that leads to the diagnosis of MFS, focuses on cardiovascular manifestations, pharmacological and surgical therapies of thoracic aortic aneurysm and/or dissection (TAAD), mechanisms underlying the progression of aneurysm or of acute dissection, and biomarkers associated with progression of TAADs. A Dutch group compared treatment with losartan, an angiotensin II receptor-1 blocker, vs no other additional treatment (COMPARE clinical trial). They observed that losartan reduces the aortic dilatation rate in patients with Marfan syndrome. Later on, they also reported that losartan exerts a beneficial effect on patients with Marfan syndrome carrying an FBN1 mutation that causes haploinsufficiency (quantitative mutation), while it has no significant effect on patients displaying dominant negative (qualitative) mutations. Moreover, a French group in a 3-year trial compared the administration of losartan vs placebo in patients with Marfan syndrome under treatment with beta-receptor blockers. They observed that losartan decreases blood pressure but has no effect on aortic diameter progression. Thus, beta-receptor blockers remain the gold standard therapy in patients with Marfan syndrome. Three potential biochemical markers are mentioned in this review: total homocysteine, serum transforming growth factor beta, and lysyl oxidase. Moreover, markers of oxidative stress measured in plasma, previously correlated with clinical features of Marfan syndrome, may be explored as potential biomarkers of clinical severity.
doi:10.2147/TACG.S96233
PMCID: PMC4869846  PMID: 27274304
Marfan syndrome; thoracic aortic aneurysm; fibrillin 1; cardiovascular manifestations; diagnosis; therapy
9.  Ndufc2 Gene Inhibition Is Associated With Mitochondrial Dysfunction and Increased Stroke Susceptibility in an Animal Model of Complex Human Disease 
Background
The genetic basis of stroke susceptibility remains to be elucidated. STR1 quantitative trait locus (STR1/QTL) was identified on rat chromosome 1 of stroke‐prone spontaneously hypertensive rat (SHRSP) upon Japanese‐style stroke‐permissive diet (JD), and it contributes to 20% of the stroke phenotype variance.
Methods and Results
Nine hundred eighty‐six probe sets mapping on STR1 were selected from the Rat RAE230A array and screened through a microarray differential expression analysis in brains of SHRSP and stroke‐resistant SHR (SHRSR) fed with either regular diet or JD. The gene encoding Ndufc2 (NADH dehydrogenase [ubiquinone] 1 subunit), mapping 8 Mb apart from STR1/QTL Lod score peak, was found significantly down‐regulated under JD in SHRSP compared to SHRSR. Ndufc2 disruption altered complex I assembly and activity, reduced mitochondrial membrane potential and ATP levels, and increased reactive oxygen species production and inflammation both in vitro and in vivo. SHRSR carrying heterozygous Ndufc2 deletion showed renal abnormalities and stroke occurrence under JD, similarly to SHRSP. In humans, T allele variant at NDUFC2/rs11237379 was associated with significant reduction in gene expression and with increased occurrence of early‐onset ischemic stroke by recessive mode of transmission (odds ratio [OR], 1.39; CI, 1.07–1.80; P=0.012). Subjects carrying TT/rs11237379 and A allele variant at NDUFC2/rs641836 had further increased risk of stroke (OR=1.56; CI, 1.14–2.13; P=0.006).
Conclusions
A significant reduction of Ndufc2 expression causes complex I dysfunction and contributes to stroke susceptibility in SHRSP. Moreover, our current evidence may suggest that Ndufc2 can contribute to an increased occurrence of early‐onset ischemic stroke in humans.
doi:10.1161/JAHA.115.002701
PMCID: PMC4802485  PMID: 26888427
complex I; early‐onset ischemic stroke; knockout rat model; mitochondria; Ndufc2; stroke‐prone spontaneously hypertensive rat; Basic Science Research; Gene Expression & Regulation; Cerebrovascular Disease/Stroke
10.  Contact forces during hybrid atrial fibrillation ablation: an in vitro evaluation 
Purpose
Data on epicardial contact force efficacy in dual epicardial–endocardial atrial fibrillation ablation procedures are lacking. We present an in vitro study on the importance of epicardial and endocardial contact forces during this procedure.
Methods
The in vitro setup consists of two separate chambers, mimicking the endocardial and epicardial sides of the heart. A circuit, including a pump and a heat exchanger, circulates porcine blood through the endocardial chamber. A septum, with a cut out, allows the placement of a magnetically fixed tissue holder, securing porcine atrial tissue, in the middle of both chambers. Two trocars provide access to the epicardium and endocardium. Force transducers mounted on both catheter holders allow real-time contact force monitoring, while a railing system allows controlled contact force adjustment. We histologically assessed different combinations of epi-endocardial radiofrequency ablation contact forces using porcine atria, evaluating the ablation’s diameters, area, and volume.
Results
An epicardial ablation with forces of 100 or 300 g, followed by an endocardial ablation with a force of 20 g did not achieve transmurality. Increasing endocardial forces to 30 and 40 g combined with an epicardial force ranging from 100 to 300 and 500 g led to transmurality with significant increases in lesion’s diameters, area, and volumes.
Conclusions
Increased endocardial contact forces led to larger ablation lesions regardless of standard epicardial pressure forces. In order to gain transmurality in a model of a combined epicardial–endocardial procedure, a minimal endocardial force of 30 g combined with an epicardial force of 100 g is necessary.
doi:10.1007/s10840-015-0089-y
PMCID: PMC4757611  PMID: 26728030
Atrial fibrillation; Catheter ablation; Atrial arrhythmias; Computer model simulation; Contact force
11.  Effect of the Interaction between Recanalization and Collateral Circulation on Functional Outcome in Acute Ischaemic Stroke 
Interventional Neuroradiology  null;20(6):704-714.
Summary
Identification of patients with acute ischaemic stroke who could most benefit from arterial recanalization after endovascular treatment remains an unsettled issue. Although several classifications of collateral circulation have been proposed, the clinical role of collaterals is still debated. We evaluated the effect of the collateral circulation in relation to recanalization as a predictor of clinical outcome.
Data were prospectively collected from 102 patients consecutively treated for proximal middle cerebral or internal carotid artery occlusion. The collateral circulation was evaluated with a novel semiquantitative-qualitative score, the Careggi collateral score (CCS), in six grades. Both CCS and recanalization grades (TICI) were analysed in relation to clinical outcome. A statistical analysis was performed to evaluate the effect of interaction between recanalization and collateral circulation on clinical outcome.
Out of the 102 patients, 37 (36.3%) had poor collaterals, and 65 (63.7%) had good collaterals. Patients with good collaterals had lower basal National Institute of Health Stroke Scale (NIHSS), more distal occlusion, smaller lesions at 24h CT scan and better functional outcome. After multivariate analysis, the interaction between recanalization and collateral grades was significantly stronger as a predictor of good outcome (OR 6.87, 95% CI 2.11 – 22.31) or death (OR 4.66, 95%CI 1.48 – 14.73) compared to the effect of the single variables.
Collaterals showed an effect of interaction with the recanalization grade in determining a favourable clinical outcome. Assessment of the collateral circulation might help predict clinical results after recanalization in patients undergoing endovascular treatment for acute ischaemic stroke.
doi:10.15274/INR-2014-10069
PMCID: PMC4295242  PMID: 25496680
acute stroke intervention; angiography; collaterals; endovascular treatment; acute stroke; outcome
12.  The impact of deep vein thrombosis in critically ill patients: a meta-analysis of major clinical outcomes 
Blood Transfusion  2015;13(4):559-568.
Background
Critically ill patients appear to be at high risk of developing deep vein thrombosis (DVT) and pulmonary embolism during their stay in the intensive care unit (ICU). However, little is known about the clinical course of venous thromboembolism in the ICU setting. We therefore evaluated, through a systematic review of the literature, the available data on the impact of a diagnosis of DVT on hospital and ICU stay, duration of mechanical ventilation and mortality in critically ill patients. We also tried to determine whether currently adopted prophylactic measures need to be revised and improved in the ICU setting.
Materials and methods
MEDLINE and EMBASE databases were searched up to week 4 of June 2012. Two reviewers selected studies and extracted data. Pooled results are reported as relative risks and weighted mean differences and are presented with 95% confidence intervals (CI).
Results
Seven studies for a total of 1,783 patients were included. A diagnosis of DVT was frequent in these patients with a mean rate of 12.7% (95% CI: 8.7–17.5%). DVT patients had longer ICU and hospital stays compared to those without DVT (7.28 days; 95% CI: 1.4–13.15; and 11.2 days; 95% CI: 3.82–18.63 days, respectively). The duration of mechanical ventilation was significantly increased in DVT patients (weighted mean difference: 4.85 days; 95% CI: 2.07–7.63). DVT patients had a marginally significant increase in the risk of hospital mortality (relative risk 1.31; 95% CI: 0.99–1.74; p=0.06), and a not statistically significant increase in the risk of ICU mortality (RR 1.64; 95% CI: 0.91–2.93; p=0.10).
Conclusions
A diagnosis of DVT upon ICU admission appears to affect clinically important outcomes including duration of ICU and hospital stay and hospital mortality. Larger, prospective studies are warranted.
doi:10.2450/2015.0277-14
PMCID: PMC4624530  PMID: 26513770
deep vein thrombosis; critically ill patients; outcomes; meta-analysis
13.  Urban-Hazard Risk Analysis: Mapping of Heat-Related Risks in the Elderly in Major Italian Cities 
PLoS ONE  2015;10(5):e0127277.
Background
Short-term impacts of high temperatures on the elderly are well known. Even though Italy has the highest proportion of elderly citizens in Europe, there is a lack of information on spatial heat-related elderly risks.
Objectives
Development of high-resolution, heat-related urban risk maps regarding the elderly population (≥65).
Methods
A long time-series (2001–2013) of remote sensing MODIS data, averaged over the summer period for eleven major Italian cities, were downscaled to obtain high spatial resolution (100 m) daytime and night-time land surface temperatures (LST). LST was estimated pixel-wise by applying two statistical model approaches: 1) the Linear Regression Model (LRM); 2) the Generalized Additive Model (GAM). Total and elderly population density data were extracted from the Joint Research Centre population grid (100 m) from the 2001 census (Eurostat source), and processed together using “Crichton’s Risk Triangle” hazard-risk methodology for obtaining a Heat-related Elderly Risk Index (HERI).
Results
The GAM procedure allowed for improved daytime and night-time LST estimations compared to the LRM approach. High-resolution maps of daytime and night-time HERI levels were developed for inland and coastal cities. Urban areas with the hazardous HERI level (very high risk) were not necessarily characterized by the highest temperatures. The hazardous HERI level was generally localized to encompass the city-centre in inland cities and the inner area in coastal cities. The two most dangerous HERI levels were greater in the coastal rather than inland cities.
Conclusions
This study shows the great potential of combining geospatial technologies and spatial demographic characteristics within a simple and flexible framework in order to provide high-resolution urban mapping of daytime and night-time HERI. In this way, potential areas for intervention are immediately identified with up-to-street level details. This information could support public health operators and facilitate coordination for heat-related emergencies.
doi:10.1371/journal.pone.0127277
PMCID: PMC4436225  PMID: 25985204
14.  An Organic Khorasan Wheat-Based Replacement Diet Improves Risk Profile of Patients with Acute Coronary Syndrome: A Randomized Crossover Trial 
Nutrients  2015;7(5):3401-3415.
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.
doi:10.3390/nu7053401
PMCID: PMC4446758  PMID: 25970146
khorasan wheat; conventional wheat; acute coronary syndrome; secondary prevention; diet
15.  Characterization and identification of hidden rare variants in the human genome 
BMC Genomics  2015;16(1):340.
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.
Electronic supplementary material
The online version of this article (doi:10.1186/s12864-015-1481-9) contains supplementary material, which is available to authorized users.
doi:10.1186/s12864-015-1481-9
PMCID: PMC4416239  PMID: 25903059
16.  Effect of Triticum turgidum subsp. turanicum wheat on irritable bowel syndrome: a double-blinded randomised dietary intervention trial 
The British Journal of Nutrition  2014;111(11):1992-1999.
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.
doi:10.1017/S000711451400018X
PMCID: PMC4405706  PMID: 24521561
Irritable bowel syndrome; Grains; Wheat; Diets; Cytokines
18.  Identification of fibrillin 1 gene mutations in patients with bicuspid aortic valve (BAV) without Marfan syndrome 
BMC Medical Genetics  2014;15:23.
Background
Bicuspid aortic valve (BAV) is the most frequent congenital heart disease with frequent involvement in thoracic aortic dilatation, aneurysm and dissection. Although BAV and Marfan syndrome (MFS) share some clinical features, and some MFS patients with BAV display mutations in FBN1, the gene encoding fibrillin-1, the genetic background of isolated BAV is poorly defined.
Methods
Ten consecutive BAV patients [8 men, age range 24–42 years] without MFS were clinically characterized. BAV phenotype and function, together with evaluation of aortic morphology, were comprehensively assessed by Doppler echocardiography. Direct sequencing of each FBN1 exon with flanking intron sequences was performed on eight patients.
Results
We detected three FBN1 mutations in two patients (aged 24 and 25 years) displaying aortic root aneurysm ≥50 mm and moderate aortic regurgitation. In particular, one patient had two mutations (p.Arg2726Trp and p.Arg636Gly) one of which has been previously associated with variable Marfanoid phenotypes. The other patient showed a pArg529Gln substitution reported to be associated with an incomplete MFS phenotype.
Conclusions
The present findings enlarge the clinical spectrum of isolated BAV to include patients with BAV without MFS who have involvement of FBN1 gene. These results underscore the importance of accurate phenotyping of BAV aortopathy and of clinical characterization of BAV patients, including investigation of systemic connective tissue manifestations and genetic testing.
doi:10.1186/1471-2350-15-23
PMCID: PMC3937520  PMID: 24564502
Bicuspid aortic valve; Aortic disease; Aneurysm; Marfan syndrome; Fibrillin-1
19.  Environmental Temperature and Thermal Indices: What Is the Most Effective Predictor of Heat-Related Mortality in Different Geographical Contexts? 
The Scientific World Journal  2014;2014:961750.
The aim of this study is to identify the most effective thermal predictor of heat-related very-elderly mortality in two cities located in different geographical contexts of central Italy. We tested the hypothesis that use of the state-of-the-art rational thermal indices, the Universal Thermal Climate Index (UTCI), might provide an improvement in predicting heat-related mortality with respect to other predictors. Data regarding very elderly people (≥75 years) who died in inland and coastal cities from 2006 to 2008 (May–October) and meteorological and air pollution were obtained from the regional mortality and environmental archives. Rational (UTCI) and direct thermal indices represented by a set of bivariate/multivariate apparent temperature indices were assessed. Correlation analyses and generalized additive models were applied. The Akaike weights were used for the best model selection. Direct multivariate indices showed the highest correlations with UTCI and were also selected as the best thermal predictors of heat-related mortality for both inland and coastal cities. Conversely, the UTCI was never identified as the best thermal predictor. The use of direct multivariate indices, which also account for the extra effect of wind speed and/or solar radiation, revealed the best fitting with all-cause, very-elderly mortality attributable to heat stress.
doi:10.1155/2014/961750
PMCID: PMC3910390  PMID: 24523657
20.  EXCAVATOR: detecting copy number variants from whole-exome sequencing data 
Genome Biology  2013;14(10):R120.
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/.
doi:10.1186/gb-2013-14-10-r120
PMCID: PMC4053953  PMID: 24172663
21.  A meta-analysis of potential risks of low levels of protein Z for diseases related to vascular thrombosis 
Thrombosis and haemostasis  2010;103(4):749-756.
Summary
The relationship between protein Z levels and thrombosis is controversial. We performed a systematic review and meta-analysis of the available studies to assess the association between protein Z and vascular thrombotic diseases. We conducted an electronic literature search through MedLine, Embase, Google Scholar, Web of Science, The Cochrane Library, bibliographies of retrieved articles and abstracts of congresses up to October, 2009. Studies were included if they analysed protein Z levels in patients with vascular thrombotic diseases. After the review process, 28 case-control studies (33 patient cohorts), including 4,218 patients with thrombotic diseases and 4,778 controls, were selected for analysis. The overall analysis using a random-effects model showed that low protein Z levels were associated with an increased risk of thrombosis (odds ratio [OR] 2.90, 95% confidence interval [CI] 2.05–4.12; p<0.00001). On subgroup analysis, a significant association was found between low protein Z levels and arterial vascular diseases (OR 2.67, 95%CI 1.60–4.48; p=0.0002), pregnancy complications (OR 4.17, 95%CI 2.31–7.52; p<0.00001), and venous thromboembolic diseases (OR 2.18, 95%CI 1.19–4.00; p=0.01). The results of this meta-analysis are consistent with a role for protein Z deficiency in thrombotic diseases, including arterial thrombosis, pregnancy complications and venous thromboembolism.
doi:10.1160/TH09-09-0645
PMCID: PMC3692349  PMID: 20076855
Protein Z; thrombosis; coagulation; meta-analysis
22.  Minimally invasive thoracoscopic hybrid treatment of lone atrial fibrillation: early results of monopolar versus bipolar radiofrequency source 
We compare results of a hybrid monopolar vs. a hybrid bipolar thoracoscopic approach employing radiofrequency (RF) sources for the surgical treatment of lone atrial fibrillation (LAF). From January 2008 to June 2010, 19 patients (35.1%) underwent RF monopolar/monolateral RF ablation, whereas 35 (64.9%) had RF bipolar/bilateral thoracoscopic ablation. One-year time-related prevalence of postoperative AF was 13.3 (11.0–17.4) and 5.2% (4.2–6.7), in monopolar and bipolar groups, respectively (P < 0.001). It was 21.1 (17.6–24.9) vs. 8.2% (5.1–11.6) in long standing persistent (P < 0.001), 13.2 (10.6–17.8) vs. 3.8% (1.4–6.9) in persistent (P < 0.001) and 5.6 (2.8–8.3) vs. 3.2% (1.0–6.5) in paroxysmal AF (P = 0.64). At 12 months, estimated prevalence of anti-arrhythmic drugs was 26 (22.4–30.1) and 18.0% (15.5–21.7, P = 0.04), whereas prevalence of Warfarin use was 48.2 (44.2–52.2) and 29.0% (26.2–33.1, P < 0.001) in the monopolar and bipolar groups, respectively. Left atrial (LA) reverse remodelling occurred in 47.3% of monopolar patients (n = 9) and in 77.1% of bipolar patients (P = 0.03). The hybrid bilateral approach with a bipolar device for the treatment of LAF showed a good 1-year success rate independently of the AF type and seems to be the better choice for longstanding persistent and persistent LAF.
doi:10.1093/icvts/ivr142
PMCID: PMC3309825  PMID: 22228287
Atrial fibrillation; Ablation; Minimally invasive; Catheter ablation; Surgical ablation
23.  Minimally Invasive Mitral Valve Surgery: A Systematic Review 
Minimally Invasive Surgery  2013;2013:179569.
In the recent years minimally invasive mitral valve surgery (MIMVS) has become a well-established and increasingly used option for managing patients with a mitral valve pathology. Nonetheless, whether the purported benefits of MIMVS translate into clinically important outcomes remains controversial. Therefore, in this paper we provide an overview of MIMVS and discuss results, morbidity, mortality, and quality of life following mitral minimally invasive procedures. MIMVS has been proven to be a feasible alternative to the conventional full sternotomy approach with low perioperative morbidity and short-term mortality. Reported benefits of MIMVS include also decreased postoperative pain, improved postoperative respiratory function, reduced surgical trauma, and greater patient satisfaction. Finally, compared to standard surgery, MIMVS demonstrated comparable efficacy across a range of long-term efficacy measures such as freedom from reoperation and long-term survival.
doi:10.1155/2013/179569
PMCID: PMC3625540  PMID: 23606959
24.  Early Hemodynamic and Biochemical Changes in Overloaded Swine Ventricle 
Texas Heart Institute Journal  2013;40(3):235-245.
The present study was undertaken to investigate, in an animal model, the relationship between sarcoplasmic reticulum Ca2+-ATPase (SERCA2a) activity, phospholamban phosphorylation, acylphosphatase activity, and hemodynamic changes that occur in the early phase of pressure overload.
In 54 study-group pigs, weighing 40 ± 5 kg each, an aortic stenosis was created with a band of umbilical tape tied around the aorta; 18 sham-operated pigs formed our control group. Eight animals (6 study and 2 control) were randomly assigned to each experimental time (0.5, 3, 6, 12, 24, 48, 72, 96, and 168 hr).
All indices of left ventricular function declined significantly, with a peak at 6 hr and a return to baseline at 168 hr. At each observational time, SERCA2a activity, Ca2+ uptake, and acylphosphatase activity rose significantly, with a maximum increase at 6 hr. These changes indicated a higher expression of these proteins; conversely, phospholamban did not show significant changes in its concentration or in its phosphorylation status. Nuclear proto-oncogene c-fos expression rose at 6 hr. A strong inverse correlation was found when Ca2+-ATPase activity, Ca2+-ATPase expression, Ca2+ uptake, and acylphosphatase were compared with indices of systolic function.
In our model of induced pressure overload, an initial phase of depressed myocardial contractility was accompanied by an increased sarcoplasmic reticulum function and by higher Ca2+-ATPase and Ca2+ uptake activities mediated by acylphosphatase. This new finding of Ca2+ homeostasis might indicate a compensatory mechanism for mechanical stress. Further studies are needed to confirm our findings.
PMCID: PMC3709230  PMID: 23914011
Aortic valve stenosis/pathology; calcium; calcium-transporting ATP-ases; disease models, animal; hemodynamics; myocardial contraction/physiology; sarcoplasmic reticulum/physiology; sarcoplasmic reticulum calcium-transporting ATPases; swine
25.  Impact of one or two visits strategy on hypertension burden estimation in HYDY, a population-based cross-sectional study: implications for healthcare resource allocation decision making 
BMJ Open  2012;2(4):e001062.
Context
The prevalence of hypertension in developing countries is coming closer to values found in developed countries. However, surveys usually rely on readings taken at a single visit, the option to implement the diagnosis on readings taken at multiple visits, being limited by costs.
Objective
To estimate more accurately the magnitude and extent of the resource that should be allocated to the prevention of hypertension.
Design
Population-based cross-sectional survey with triplicate blood pressure (BP) readings taken on two separate home-visits.
Setting
Rural and urban locations in three areas of Yemen (capital, inland and coast).
Participants
A nationally representative sample of the Yemen population aged 15–69 years (5063 men and 5179 women), with an overall response rate of 92% in urban and 94% in rural locations.
Main outcome measure
Hypertension diagnosed as systolic BP ≥140 mm Hg and/or diastolic BP ≥90 mm Hg and/or self-reported use of antihypertensive drugs.
Results
Hypertension prevalence (age-standardised to the WHO world population 2001) based on fulfilling the same criteria on both visits (11.3%; 95% Cl 10.7% to 11.9%), was 35% lower than estimation based on the first visit (17.3%; 16.5% to 18.0%). Advanced age, blood glucose ≥7 mmol/l or proteinuria ≥1+ at dipstick test at visit one were significant predictors of confirmation at visit 2. The 959 participants found to be hypertensive at visit 1 or at visit 2 only and thus excluded from the final diagnosis had a rate of proteinuria (5.0%; 3.8% to 6.5%) comparable to rates of the general population (6.1%; 5.6% to 6.6%), and of subjects normotensive at both visits (5.6%; 5.1% to 6.2%). Only 1.9% of Yemen population classified at high or very high cardiovascular (CV) risk at visit 1 moved to average, low or moderate CV risk categories after two visits.
Conclusions
Hypertension prevalence based on readings obtained after two visits is 35% lower than estimation based on the first visit, subjects were excluded from final diagnosis belonging to low CV risk classes.
doi:10.1136/bmjopen-2012-001062
PMCID: PMC3425947  PMID: 22874627
Cardiology; Hypertension; Epidemiology; Preventive Medicine; Public Health; Internal Medicine; Diabetes & endocrinology; Internal Medicine; Cardiology

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