Search

Aims/hypothesis: We aimed to analyse TrialNet Anti-CD3 Prevention (TN10) data using oral minimal model (OMM)-derived indices to characterise the natural history of stage 2 type 1 diabetes in placebo-treated individuals, to describe early metabolic responses to teplizumab and to explore the predictive capacity of OMM measures for disease-free survival rate. Methods: OMM-estimated insulin secretion, sensitivity and clearance and the disposition index were evaluated at baseline and at 3, 6 and 12 months post randomisation in placebo- and teplizumab-treated groups, and, within each group, in slow- and rapid-progressors (time to stage 3 disease >2 or ≤ 2 years). OMM metrics were also compared with the standard AUC C-peptide. Percentage changes in CD8+ T memory cell and programmed death-1 (PD-1) expression were evaluated in each group. Results: Baseline metabolic characteristics were similar between 28 placebo- and 39 teplizumab-treated participants. Over 12 months, insulin secretion declined in placebo-treated and rose in teplizumab-treated participants. Within groups, placebo slow-progressors (n=14) maintained insulin secretion and sensitivity, while both declined in placebo rapid-progressors (n=14). Teplizumab slow-progressors (n=28) maintained elevated insulin secretion, while teplizumab rapid-progressors (n=11) experienced mild metabolic decline. Compared with rapid-progressor groups, insulin clearance significantly decreased between baseline and 3, 6 and 12 months in the slow-progressor groups in both treatment arms. In aggregate, both higher baseline insulin secretion (p=0.027) and reduced 12 month insulin clearance (p=0.045) predicted slower progression. A >25% loss of insulin secretion at 3 months had specificity of 0.95 (95% CI 0.86, 1.00) to identify rapid-progressors and correctly classified the 2 year risk for progression in 92% of participants, with a sensitivity of 0.19 (95% CI 0.08, 0.30). OMM-estimated insulin secretion outperformed AUC C-peptide to differentiate groups by treatment or to predict progression. Metabolic changes were paralleled by relative frequency of change in PD-1+ CD8+ T effector memory cells. Conclusions/interpretation: OMM measures characterise the metabolic heterogeneity in stage 2 diabetes, identifying differences between rapid- and slow-progressors, and heterogeneous impacts of immunotherapy, suggesting the need to account for these differences when designing and interpreting clinical trials. [ABSTRACT FROM AUTHOR]

The Cognitive Assessment Interview (CAI) is an interview-based scale measuring cognitive impairment and its impact on functioning in subjects with schizophrenia (SCZ). The present study aimed at assessing, in a large sample of SCZ (n = 601), the agreement between patients and their informants on CAI ratings, to explore patients' insight in their cognitive deficits and its relationships with clinical and functional indices. Agreement between patient- and informant-based ratings was assessed by the Gwet's agreement coefficient. Predictors of insight in cognitive deficits were explored by stepwise multiple regression analyses. Patients reported lower severity of cognitive impairment vs. informants. A substantial to almost perfect agreement was observed between patients' and informants' ratings. Lower insight in cognitive deficits was associated to greater severity of neurocognitive impairment and positive symptoms, lower severity of depressive symptoms, and older age. Worse real-life functioning was associated to lower insight in cognitive deficit, worse neurocognitive performance, and worse functional capacity. Our findings indicate that the CAI is a valid co-primary measure with the interview to patients providing a reliable assessment of their cognitive deficits. In the absence of informants with good knowledge of the subject, the interview to the patient may represent a valid alternative. [ABSTRACT FROM AUTHOR]

The current study aimed to investigate alterations of event-related potentials (ERPs) microstate during reward anticipation in subjects with schizophrenia (SCZ), and their association with hedonic experience and negative symptoms. EEG data were recorded in thirty SCZ and twenty-three healthy controls (HC) during the monetary incentive delay task in which reward, loss and neutral cues were presented. Microstate analysis and standardized low-resolution electromagnetic tomography (sLORETA) were applied to EEG data. Furthermore, analyses correlating a topographic index (the ERPs score), calculated to quantify brain activation in relationship to the microstate maps, and scales assessing hedonic experience and negative symptoms were performed. Alterations in the first (125.0–187.5 ms) and second (261.7–414.1 ms) anticipatory cue-related microstate classes were observed. In SCZ, reward cues were associated to shorter duration and earlier offset of the first microstate class as compared to the neutral condition. In the second microstate class, the area under the curve was smaller for both reward and loss anticipation cues in SCZ as compared to HC. Furthermore, significant correlations between ERPs scores and the anticipation of pleasure scores were detected, while no significant association was found with negative symptoms. sLORETA analysis showed that hypo-activation of the cingulate cortex, insula, orbitofrontal and parietal cortex was detected in SCZ as compared to HC. Abnormalities in ERPs could be traced already during the early stages of reward processing and were associated with the anticipation of pleasure, suggesting that these dysfunctions might impair effective evaluation of incoming pleasant experiences. Negative symptoms and anhedonia are partially independent results. [ABSTRACT FROM AUTHOR]

Nutritional intake could influence the blood glucose profile during early life of preterm infants. We investigated the impact of macronutrient intake on glycemic homeostasis using continuous glucose monitoring (CGM). We analyzed macronutrient intake in infants born ≤ 32 weeks gestational age (GA) and/or with birth weight ≤ 1500 g. CGM was started within 48 h of birth and maintained for 5 days. Mild and severe hypoglycemia were defined as sensor glucose (SG) < 72 mg/dL and <47 mg/dL, respectively, while mild and severe hyperglycemia were SG > 144 mg/dL and >180 mg/dL. Data from 30 participants were included (age 29.9 weeks (29.1; 31.2), birthweight 1230.5 g (1040.0; 1458.6)). A reduced time in mild hypoglycemia was associated to higher amino acids intake (p = 0.011) while increased exposure to hyperglycemia was observed in the presence of higher lipids intake (p = 0.031). The birthweight was the strongest predictor of neonatal glucose profile with an inverse relationship between the time spent in hyperglycemia and birthweight (p = 0.007). Conclusions: Macronutrient intakes influence neonatal glucose profile as described by continuous glucose monitoring. CGM might contribute to adjust nutritional intakes in preterm infants. What is Known: • Parenteral nutrition may affect glucose profile during the first days of life of preterm infants. What is New: • Continuous glucose monitoring describes the relationship between daily parenteral nutrient intakes and time spent in hypo and hyperglycemic ranges. [ABSTRACT FROM AUTHOR]

Less than 2% of physicians complete a research training (PhD) after the residency with a declining trend in those pursuing a clinical scientist pathway in pediatrics. The exposure to research methodology during the clinical training may play a role in engaging the next generations of pediatric physician scientist. Herein, we describe the experience of the Padova Physician Scientist Research Training (PPSRT) of the pediatric residency program at the University of Padova. The PPSRT was addressed to residents attending PGY2 to PGY4 of the pediatric program and consisted of two cores: a general one including in person or virtual lectures about research methodology in pediatrics including design of a clinical trial, writing of a scientific paper and statistical methods, and a subspecialties core for the discussion of research challenges in each area and the scientific writing activities. The perceived barriers to a research training and an evaluation of the program were assessed by an anonymized questionnaire. Sixty-four out 150 residents registered for the research training with 62/64 completing the two cores. The major perceived barrier to research during clinical training was the absence of protected time (89%) followed by the lack of specific funds (37%). The group activities lead to the publication of 24 papers. Conclusion: This is the first experience in the Italian pediatric training of a dedicated research program within the frame of postgraduate medical education. Our report highlights the need for protected time to promote research interest and nurture a new generation of physician scientists. What is Known: • Training to medical research is not part of residency program. • The declining trend of physician scientists might be reverted by early exposure to research methodology and challenges during residency. What is New: • An early exposure to research training during pediatric residency increases the research engagement of pediatric residents. • The lack of protected time for research is perceived as the major barrier to research training during residency. [ABSTRACT FROM AUTHOR]

Clinically symptomatic type 1 diabetes (stage 3 type 1 diabetes) is preceded by a pre-symptomatic phase, characterised by progressive loss of functional beta cell mass after the onset of islet autoimmunity, with (stage 2) or without (stage 1) measurable changes in glucose profile during an OGTT. Identifying metabolic tests that can longitudinally track changes in beta cell function is of pivotal importance to track disease progression and measure the effect of disease-modifying interventions. In this review we describe the metabolic changes that occur in the early pre-symptomatic stages of type 1 diabetes with respect to both insulin secretion and insulin sensitivity, as well as the measurable outcomes that can be derived from the available tests. We also discuss the use of metabolic modelling to identify insulin secretion and sensitivity, and the measurable changes during dynamic tests such as the OGTT. Finally, we review the role of risk indices and minimally invasive measures such as those derived from the use of continuous glucose monitoring. [ABSTRACT FROM AUTHOR]

We aimed to assess the glucose and lactate kinetics during therapeutic hypothermia (TH) in infants with hypoxic-ischemic encephalopathy and its relationship with longitudinal neurodevelopment. We measured glucose and lactate concentrations before TH and on days 2 and 3 in infants with mild, moderate, and severe hypoxic-ischemic encephalopathy (HIE). Neurodevelopment was assessed at 2 years. Participants were grouped according to the neurodevelopmental outcome into favorable (FO) or unfavorable (UFO). Eighty-eight infants were evaluated at follow-up, 34 for the FO and 54 for the UFO group. Severe hypo- (< 2.6 mmol/L) and hyperglycemia (> 10 mmol/L) occurred in 18% and 36% from the FO and UFO groups, respectively. Glucose-to-lactate ratio on day 1 was the strongest predictor of unfavorable metabolic outcome (OR 3.27 ± 1.81, p = 0.032) when adjusted for other clinical and metabolic variables, including Sarnat score. Conclusion: Glucose-to-lactate ratio on day 1 may represent a new risk marker for infants with HIE undergoing TH. What is Known: • Glucose and lactate are key metabolic fuels during neonatal hypoglycemia. This suggests that their concentrations may influence the neurodevelopmental outcome of neonates experiencing hypoxic-hischemic encephalopathy (HIE). What is New: • We describe the relative availbility of glucose and lactate before and during theraputic hypothermia in neonates with HIE. [ABSTRACT FROM AUTHOR]

The objective of this study is to assess the effect of neonatal procedures on glucose variability in very preterm infants. Preterm infants (≤ 32 weeks gestation and/or birthweight ≤ 1500 g) were started on continuous glucose monitoring (CGM) on day 2 of birth and monitored for 5 days. Minimally invasive (heel stick, venipunctures) and non-invasive (nappy change, parental presence) procedures were recorded. CGM data were analyzed 30 min before and after each procedure. The primary outcome was the coefficient of glucose variation (CV = SD/mean) before and after the procedure; SD and median glucose were also evaluated. We analyzed 496 procedures in 22 neonates (GA 30.5 weeks [29–31]; birthweight 1300 g [950–1476]). Median glucose did not change before and after each procedure, while CV and SD increased after heel prick (p = 0.017 and 0.030), venipuncture (p = 0.010 and 0.030), and nappy change (p < 0.001 and < 0.001), in the absence of a difference during parental presence. Conclusions: Non-invasive and minimally invasive procedures increase glucose variability in the absence of changes of mean glucose. What is Known: • Minimally invasive procedures - including nappy change - may increase neonatal stress in preterm infants. What is New: • Continuous glucose monitoring provides a quantitative measure of neonatal stress during neonatal care procedures demonstrating an increase of glucose variability. [ABSTRACT FROM AUTHOR]

Mesenchymal stromal cells (MSCs), present in the stromal component of several tissues, include multipotent stem cells, progenitors, and differentiated cells. MSCs have quickly attracted considerable attention in the clinical field for their regenerative properties and their ability to promote tissue homeostasis following injury. In recent years, MSCs mainly isolated from bone marrow, adipose tissue, and umbilical cord—have been utilized in hundreds of clinical trials for the treatment of various diseases. However, in addition to some successes, MSC-based therapies have experienced several failures. The number of new trials with MSCs is exponentially growing; still, complete results are only available for a limited number of trials. This dearth does not help prevent potentially inefficacious and unnecessary clinical trials. Results from unsuccessful studies may be useful in planning new therapeutic approaches to improve clinical outcomes. In order to bolster critical analysis of trial results, we reviewed the state of art of MSC clinical trials that have been published in the last six years. Most of the 416 published trials evaluated MSCs' effectiveness in treating cardiovascular diseases, GvHD, and brain and neurological disorders, although some trials sought to treat immune system diseases and wounds and to restore tissue. We also report some unorthodox clinical trials that include unusual studies. [ABSTRACT FROM AUTHOR]

Heart failure (HF) is a highly prevalent clinical syndrome characterized by considerable phenotypic heterogeneity. The traditional classification based on left ventricular ejection fraction (LVEF) is widely accepted by the guidelines and represents the grounds for patient enrollment in clinical trials, even though it shows several limitations. Ejection fraction (EF) is affected by preload, afterload, and contractility, it being problematic to express LV function in several conditions, such as HF with preserved EF (HFpEF), valvular heart disease, and subclinical HF, and in athletes. Over the last two decades, developments in diagnostic techniques have provided useful tools to overcome EF limitations. Strain imaging analysis (particularly global longitudinal strain (GLS)) has emerged as a useful echocardiographic technique in patients with HF, as it is able to simultaneously supply information on both systolic and diastolic functions, depending on cardiac anatomy and physiology/pathophysiology. The use of GLS has proved helpful in terms of diagnostic performance and prognostic value in several HF studies. Universally accepted cutoff values and variability across vendors remain an area to be fully explored, hence limiting routine application of this technique in clinical practice. In the present review, the current role of GLS in the diagnosis and management of patients with HF will be discussed. We describe, by critical analysis of the pros and cons, various clinical settings in HF, and how the appropriate use and interpretation of GLS can provide important clues. [ABSTRACT FROM AUTHOR]

Psoriasis in adults is associated with an increased risk of metabolic disease. Various cardiometabolic comorbidities have been reported in childhood psoriasis, but only a few studies have analyzed the prevalence of metabolic syndrome. We performed a single-center prospective study investigating the prevalence of metabolic syndrome and insulin resistance in children with psoriasis. The prevalence of metabolic syndrome was evaluated in 60 pre-pubertal children with psoriasis (age: 3–10 years), accordingly to recently established criteria for the diagnosis of metabolic syndrome in children. Insulin resistance was considered altered when the homeostatic model assessment (HOMA-IR) for insulin resistance was ≥ 90th sex- and age-specific percentile and HOMA 2-IR was > 1.8. Eighteen (30%) children with psoriasis were found to have metabolic syndrome. Sixteen (27%) children were found to have insulin resistance. Conclusion: Our data underline the importance of assessing metabolic syndrome not only in adults and adolescents but also in young children with psoriasis. What is Known: • Psoriasis in adults is strongly associated with metabolic disease and insulin resistance. • Very limited data are available on the prevalence of metabolic syndrome and insulin resistance in pre-pubertal children with psoriasis. What is New: • This study reports that in pre-pubertal children with psoriasis, there is a high prevalence of metabolic syndrome and insulin resistance. • In children with psoriasis metabolic syndrome risk factors should be assessed. [ABSTRACT FROM AUTHOR]

In the aftermath of the SARS-CoV-2 pandemic, we revised the cost-effectiveness of the exploited interventions in neonatal intensive care unit, to redefine future strategies for hospital management. Costs were revised with respect to the lockdown R0 or under different R0 scenarios to estimate the cost-effectiveness of the screening program adopted. Weekly nasopharyngeal swabs for parents, neonates, and personnel were the major cost during the pandemic, although they effectively reduced the number of cases in our unit. Conclusion: Parents and healthcare personnel testing appears to be an effective strategy due to the high number of contact they have within the hospital environment and outside, able to minimize the cases within our unit. What is Known: • Costs of universal COVID-19 tests for parents, neonates, and NICU personnel have not been evaluated during the COVID-19 pandemic in neonatal intensive care unit in Europe. What is New: • Weekly nasopharyngeal swabs for parents, neonates, and personnel were the major cost during the COVID-19 pandemic in NICU. • Parents and healthcare personnel testing was effective to reduce costs related to COVID-19 due to the high number of contact they have within the hospital environment and outside. [ABSTRACT FROM AUTHOR]

Cor pulmonale is the condition in which the right ventricle undergoes morphological and/or functional changes due to diseases that affect the lungs, the pulmonary circulation, or the breathing process. Depending on the speed of onset of the pathological condition and subsequent effects on the right ventricle, it is possible to distinguish the acute cor pulmonale from the chronic type of disease. Echocardiography plays a central role in the diagnostic and therapeutic work-up of these patients, because of its non-invasive nature and wide accessibility, providing its greatest usefulness in the acute setting. It also represents a valuable tool for tracking right ventricular function in patients with cor pulmonale, assessing its stability, deterioration, or improvement during follow-up. In fact, not only it provides parameters with prognostic value, but also it can be used to assess the efficacy of treatment. This review attempts to provide the current standards of an echocardiographic evaluation in both acute and chronic cor pulmonale, focusing also on the findings present in the most common pathologies causing this condition. [ABSTRACT FROM AUTHOR]

Advanced chronic heart failure (ACHF) is the last phase in the evolution of heart failure and is characterized by high hospitalization and mortality rates and is refractory to medical therapy, therefore requiring more aggressive therapies, such as mechanical circulatory support or heart transplantation. Over the last years, the incidence of ACHF was continuously growing, together with the increase in population survival rates. Therefore, the early recognition of the transition to ACHF is of crucial importance in HF patients, which also helps in prognostication of such patients, since advanced therapeutic options are limited to selected patients and they also have some important risk implications. Echocardiography is the gold standard tool for the evaluation of patients with HF; moreover, the recent technological advances provided new structural and functional indices of the four cardiac chambers that showed to be comparable to advanced imaging or invasive hemodynamic parameters. This allows us to operate an accurate study of ACHF with first- and second-level echocardiographic techniques, which are now being integrated in daily clinical practice. The present review presents an overview of the currently available tools for the echocardiographic examination of patients with ACHF, with its advantages and limitations, based on the latest supporting evidences. [ABSTRACT FROM AUTHOR]

Atrial fibrillation is the most common arrhythmia and its prevalence is expected to further increase. Patients with atrial fibrillation have an increased risk of stroke (fivefold increased risk), heart failure, and death. In patients with non-valvular atrial fibrillation, the most recent guidelines recommend the use of the CHA2DS2-VASc (congestive heart failure, arterial hypertension, age > 75 years, diabetes mellitus, stroke/transient ischemic attack, vascular disease, age 65–74 years, sex category) scoring system to identify those who may benefit from oral anticoagulant treatment. Guidelines recommend initiation of oral anticoagulation with vitamin K antagonists or direct oral anticoagulants in men with a score ≥ 2 and in women with a score ≥ 3, while oral anticoagulation in individuals with a score of 0 is not recommended. Accordingly, men with CHA2DS2VASc score = 1 (and women with CHA2DS2VASc = 2) represent a grey zone where guidelines do not provide a definite oral anticoagulant indication. Implementation of risk stratification with transthoracic echocardiography could be extremely useful. Both prospective and observational studies using transthoracic echocardiography prediction of events and studies utilizing transesophageal echocardiographic parameters as surrogate markers of thromboembolic events make sustainable the hypothesis that echocardiography could improve thromboembolism prediction in non-valvular atrial fibrillation. However, because of some controversial results of different studies, determination of the best echocardiographic parameter predicting thromboembolic events in atrial fibrillation remains uncertain. The combination of left atrial enlargement with left atrial function (in particular assessing left atrial strain) appears to be very valuable, but needs to be confirmed in large-scale multi-center trials. [ABSTRACT FROM AUTHOR]

To analyze left ventricular myocardial deformation and contractile reserve in endurance athletes at rest and during exercise, and their possible correlations with functional capacity. The athlete's heart in endurance training is characterized by physiologic eccentric remodeling, with left ventricle adaptation at rest and echocardiographic parameters at low end of normality. Assessment of left ventricle systolic function and contractile reserve has an important role in the decision-making and in differential diagnosis with cardiomyopathies. Standard echo, lung ultrasound, left ventricle 2D speckle-tracking strain and myocardial work were performed at rest and during exercise in endurance athletes and in age- and sex-comparable healthy controls. 350 endurance athletes (male sex 58.5%; 31.6 ± 4.2 years) and 150 healthy controls were enrolled. Left ventricular ejection fraction at baseline was comparable between the two groups. Resting left ventricular global longitudinal strain was reduced in endurance athletes (- 18.4 ± 2.6% vs. - 22.4 ± 3.3% in controls; p < 0.01). Myocardial work efficiency did not show significative difference between the two groups. At peak exertion during exercise stress echocardiography, endurance athletes showed better exercise capacity and peak VO2 consumption (58.6 ± 10.2 ml/kg/min vs 38.6 ± 3.3 ml/kg/min in controls, p < 0.0001), associated with a preserved contractile reserve and augmented pulmonary artery systolic pressure. By multivariable analysis myocardial work efficiency at rest was closely related to maximal watts (p < 0.0001), peak VO2, (p < 0.0001), left ventricular E/e' (p < 0.001) and number of B-lines (p < 0.001), all measured at peak effort. Myocardial work efficiency shows less load-dependency than global longitudinal strain. Normal resting values of myocardial work efficiency in endurance athletes suggest a physiological remodeling, associated with a better exercise capacity and preserved contractile reserve during physical effort. [ABSTRACT FROM AUTHOR]

Chronic myeloid leukemia (CML) is a myeloproliferative disorder characterized by neoplastic transformation of pluripotent cells due to a typical cytogenetic and molecular mutation known as Philadelphia (Ph) chromosome. In 2001, the introduction of the tyrosine kinasis inhibitor (TKI) imatinib as a therapeutic strategy for CML with PH chromosome mutation represented an important step towards treatment of these patients, and nowadays, this drug represents the gold therapeutic standard in this clinical setting. A second generation of TKIs (dasatinib, nilotinib, and bosutinib) showed an effective action in all patients with mutations resistant to imatinib. Ponatinib is a third-generation TKI and is the only inhibitor with activity against T3151 mutation. The impact of ponatinib on cardiovascular events was first evaluated in the PACE trial. We therefore report and discuss most relevant evidence currently available on cardiovascular events associated with the use of ponatinib. Though many exams can be used for diagnosis and follow-up of this kind of cardiotoxicity, echocardiography seems to have a pivotal role thanks to its feasibility, availability, and low cost. [ABSTRACT FROM AUTHOR]

The role of two dimensional (2D) echocardiography (ECHO) for the diagnosis and clinical decision making in infective endocarditis (IE) has been extensively studied and described in the medical literature. Some reports have demonstrated the incremental value of three dimensional (3D) transesophageal (TE) ECHO in the setting of IE. However, a systematic review focusing on the role of 3D imaging is lacking. In this manuscript, we examine the role of 3D TE ECHO in the diagnosis of IE. IE is a challenging disease in which 2D transthoracic (TT) and TE ECHO have complementary roles and are unequivocally the mainstay of diagnostic imaging. Still, 2D imaging has important limitations. Technological advances in 3D imaging allow for the reconstruction of real-time anatomical images of cardiac structure and function. 3D imaging has emerged as a diagnostic technique that overcame some of the limitations of 2D ECHO. Currently, both transthoracic and transesophageal echocardiography transducers are able to generate 3D images. However, 3D TE ECHO provides images of a higher quality in comparison to 3D TT ECHO, and is the best echocardiographic modality able to allow for a detailed anatomical imaging. 3D TE ECHO may represent the key adjunctive echocardiographic technique being able to positively impact on IE-related surgical planning and intervention and to facilitate the interaction between the surgeon and the imaging specialist. Importantly, 3D TE ECHO is not the recommended initial modality of choice for the diagnosis of IE; however, in highly specialized centers, it has become an important complementary technique when advanced surgical planning is required. Furthermore, anatomical imaging has become the link between the different techniques that play a role in IE imaging. In fact, both computed tomography and magnetic resonance allow three dimensional reconstruction. An important future goal should allow for the fusion among various imaging modalities. Our review highlights the role of 3D TE ECHO in IE imaging and emphasize where it offers incremental value. [ABSTRACT FROM AUTHOR]

We sought to investigate the relationship between phasic left atrial function (LA) and functional capacity in the patients with type 2 diabetes (DM). This cross-sectional investigation included 72 controls and 64 uncomplicated DM subjects. All participants underwent echocardiographic examination and cardiopulmonary exercise testing. Total and passive LA emptying fractions (EF), demonstrating LA reservoir and conduit function, were significantly lower in DM patients than in controls. Active LA EF, the parameter of LA booster pump function, was similar between DM and controls. Total and positive LA strains, corresponding with reservoir and conduit function, were also significantly reduced in DM subjects comparing with controls. However, negative LA strain-parameter of LA booster pump function, was significantly increased in DM patients in comparison with controls. Peak oxygen consumption was significantly reduced and ventilation/carbon dioxide slope was elevated in DM patients. In the whole study population LA global longitudinal strain was associated with heart rate recovery in the first minute, peak oxygen consumption and ventilation/carbon dioxide slope independently of other clinical parameters and LV hypertrophy and LV diastolic function. In conclusion, LA phasic function and functional capacity were significantly impaired in the patients with DM. LA longitudinal strain, but not LA volume index, was independently related with functional capacity in the whole study population. Our results suggest that evaluation of LA function and functional capacity could detect subclinical target organ damage and prevent development of further complications in uncomplicated DM patients. [ABSTRACT FROM AUTHOR]

Cardiac surgical techniques and circulatory supports have strongly evolved in the last years. Right ventricular (RV) function during the post-operatory period is still subject of study, although its relevant prognostic impact has been variably described in different papers. RV post-surgical dysfunction's underlying mechanisms are still not clear and include a different hypothesis. Echocardiography, with both first and second level parameters, offers the possibility to accurately analyze the right ventricle and optimize these patients' management. This paper describes the pathophysiology of the right ventricle, the most used echo indexes of RV function, whether they alter after surgery, the different supposed mechanisms of RV dysfunction and its role in the prognosis of patients undergoing cardiac surgery. [ABSTRACT FROM AUTHOR]

Base excision repair (BER) is a frontline repair mechanism that operates through the G1 phase of the cell cycle, which ensures the genome integrity by repairing thousands of DNA lesions due to endogenous and exogenous agents. Its correct functioning is fundamental for cell viability and the health of the organism. Uracil is one of the most prevalent lesions that appears in DNA arising by spontaneous or enzymatic deamination of cytosine or misincorporation of the deoxyuridine 5′-triphosphate nucleotide (dUTP) in place of deoxythymidine 5′-triphosphate (dTTP) during DNA replication. In the first pathway, the uracil will preferentially pair with adenine, leading to C:G → T:A transition. When uracil in DNA arises from misincorporation of dUTP instead of dTTP, this process will result in A:U pairs. Organisms counteract the mutagenic effects of uracil in DNA using the BER repair system, which is mediated by a member of the uracil-DNA glycosylase (UDG) superfamily. Several assays evaluating the in vitro BER enzyme activity have been described so far. Some of these measure the BER activity by an oligonucleotide incision assay using radiolabeled duplex oligo. Others use circular double-stranded DNA substrates containing a defined lesion. The novelty of our method resides in its rapidity and safety (radioactive free detection) as well as in the possibility of having a reliable quantitative determination of UDG activity in both cell and tissue extracts. We also demonstrated the effectiveness of our method in assessing UDG activity in cell lines with a reduced DNA repair capacity and in different kinds of tissues. Key messages: • Base excision repair is a fundamental repair mechanism ensuring the genome integrity. • Uracil is one of the most prevalent lesions that appears in DNA. • The mutagenic effects of uracil in DNA are mitigated by the uracil-DNA glycosylase. • Several assays evaluating the in vitro BER activity have been described so far. • A safe and quantitative assay evaluating the in vitro UDG activity is required. [ABSTRACT FROM AUTHOR]

Anabolic-androgenic steroids (AAS) are used by power athletes to improve performance. However, the real effects of the chronic consumption of AAS on cardiovascular structures are subjects of intense debate. To detect by speckle tracking echocardiography (STE) underlying left atrial (LA) dysfunction in athletes abusing AAS and assess possible correlation between LA myocardial function and exercise capacity during cardiopulmonary stress test. 65 top-level competitive bodybuilders were selected (45 males), including 35 athletes misusing AAS for at least 5 years (users), 30 anabolic-free bodybuilders (non-users), compared to 40 age- and sex-matched healthy sedentary controls. Standard Doppler echocardiography, STE analysis and bicycle ergometric test were performed to assess LA myocardial function and exercise capacity. Athletes showed increased left ventricular (LV) mass index, wall thickness and stroke volume compared with controls, whereas LV ejection fraction, LV end-diastolic diameter and transmitral Doppler indexes were comparable between the three groups. Conversely, LA volume index, LV and LA strain and LV E/Em were significantly increased in AAS users. By multivariate analyses, LV E/Em (beta = - 0.30, p < 0.01), LA volume index (- 0.42, p < 0.001) and number of weeks of AAS use per year (- 0.54, p < 0.001) emerged as the only independent determinants of LA lateral wall peak STE. In addition, a close association between LA myocardial function and VO2 peak during cardiopulmonary exercise testing was evidenced (p < 0.001), showing a powerful incremental value with respect to clinical and standard echocardiographic data. STE represents a promising technique to assess LA myocardial function in athletes abusing steroids. AAS users showed a more impaired LA deformation, associated with reduced functional capacity during physical effort. [ABSTRACT FROM AUTHOR]

Hypertension is a condition characterized by pressure and/or volume overloads and echocardiography is helpful and feasible to understand hemodynamic mechanisms. Echocardiographic information is sometimes critical and susceptible of modifying decision making. In this review, we provide detailed descriptions of the parameters that can be derived from a standard transthoracic echocardiogram, including some more recent techniques. We will also explain how each parameter might have impact in the evaluation of the hypertensive patient and give indications on when to refer patients to echo-labs, which parameters are critical and which ones might be redundant, and how to use the information obtained in the report. Cardiac geometry, LV systolic and diastolic function, LV pump performance, output impedance and left atrial function are parameters that might be altered in arterial hypertension, but not necessarily doctors need the whole information for decision making. The critical measures are provided. [ABSTRACT FROM AUTHOR]

Human mesenchymal stromal/stem cells (hMSCs) emerged as a promising therapeutic tool for ischemic disorders, due to their ability to regenerate damaged tissues, promote angiogenesis and reduce inflammation, leading to encouraging, but still limited results. The outcomes in clinical trials exploring hMSC therapy are influenced by low cell retention and survival in affected tissues, partially influenced by lesion's microenvironment, where low oxygen conditions (i.e. hypoxia) and inflammation coexist. Hypoxia and inflammation are pathophysiological stresses, sharing common activators, such as hypoxia-inducible factors (HIFs) and NF-κB. HIF1α and HIF2α respond essentially to hypoxia, activating pathways involved in tissue repair. Little is known about the regulation of HIF3α. Here we investigated the role of HIF3α in vitro and in vivo. Human MSCs expressed HIF3α, differentially regulated by pro-inflammatory cytokines in an oxygen-independent manner, a novel and still uncharacterized mechanism, where NF-κB is critical for its expression. We investigated if epigenetic modifications are involved in HIF3α expression by methylation-specific PCR and histone modifications. Robust hypermethylation of histone H3 was observed across HIF3A locus driven by pro-inflammatory cytokines. Experiments in a murine model of arteriotomy highlighted the activation of Hif3α expression in infiltrated inflammatory cells, suggesting a new role for Hif3α in inflammation in vivo. [ABSTRACT FROM AUTHOR]

ESC guidelines for management of arterial hypertension allow one to choose among five classes of antihypertensive drugs indiscriminately. They are based on the principle that in the management of hypertensive patients, it is fundamental to reduce blood pressure (BP), independently of the utilized drug. However, it has been demonstrated that the renin-angiotensin system (RAS) plays a relevant role in the hypertensive-derived development and progression of organ damage. Thus, antihypertensive drugs interfering with the RAS should be preferred in preventing and reducing target organ damage. The availability of two classes of drugs, ACE-inhibitors and angiotensin AT1 receptor blockers (ARBs), both interfering with the RAS, makes the choice between them difficult. Both pharmacological strategies offer an effective BP control, and a substantial improvement of prognosis in different associated pathologies. Regarding cardiovascular prevention, ACE-inhibitors have an extensive scientific literature regarding utility in high-risk patients. Nevertheless, there is evidence to support the concept that in the early phases of organ tissue damage, the RAS is activated, but the ACE pathway producing angiotensin II is not always employed. Accordingly, ACE-inhibitors appear to be less effective, whereas ARBs have a greater beneficial action in the initial stages of atherosclerotic disease. Moreover, patients undergoing ARBs therapy show a substantially lower risk of therapy discontinuation when compared to those treated with ACE-inhibitors, because of a better tolerability. In conclusion, ACE-inhibitors should be used in patients who have already developed organ damage, but tolerate this drug well, while ARBs should be the first choice in naïve hypertensive patients without organ damage or at the initial stages of disease. [ABSTRACT FROM AUTHOR]

Purpose Of Review: Decades after the invention of insulin pump, diabetes management has encountered a technology revolution with the introduction of continuous glucose monitoring, sensor-augmented insulin pump therapy and closed-loop/artificial pancreas systems. In this review, we discuss the significance of the 2016 Endocrine Society Guidelines for insulin pump therapy and continuous glucose monitoring and summarize findings from relevant diabetes technology studies that were conducted after the publication of the 2016 Endocrine Society Guidelines.Recent Findings: The 2016 Endocrine Society Guidelines have been a great resource for clinicians managing diabetes in this new era of diabetes technology. There is good body of evidence indicating that using diabetes technology systems safely tightens glycemic control while managing both type 1 and type 2 diabetes. The first-generation diabetes technology systems will evolve as we gain more experience and collaboratively work to improve them with an ultimate goal of keeping people with diabetes complication and burden-free until the cure for diabetes becomes a reality. [ABSTRACT FROM AUTHOR]

The relationships of personal resources with symptom severity and psychosocial functioning have never been tested systematically in a large sample of people with schizophrenia. We applied structural equation models to a sample of 921 patients with schizophrenia collected in a nationwide Italian study, with the aim to identify, among a large set of personal resources, those that may have an association with symptom severity or psychosocial functioning. Several relevant demographic and clinical variables were considered concurrently. Poor service engagement and poor recovery style, as well as older age and younger age at onset, were related to greater symptom severity and poorer social functioning. Higher resilience and higher education were related to better social functioning only. Poor problem-focused coping and internalized stigma, as well as male gender and depression, were related to symptom severity only. The explored variables showed distinctive and partially independent associations with symptom severity and psychosocial functioning. A deeper understanding of these relationships may inform treatment decisions. [ABSTRACT FROM AUTHOR]

MicroRNAs are able to modulate gene expression in a range of diseases. We focused on microRNAs as potential contributors to the pathogenesis of ascending aorta (AA) dilatation in patients with stenotic tricuspid (TAV) or bicuspid aortic valve (BAV). Aortic specimens were collected from the 'concavity' and the 'convexity' of mildly dilated AAs and of normal AAs from heart transplant donors. Aortic RNA was analyzed through PCR arrays, profiling the expression of 84 microRNAs involved in cardiovascular disease. An in silico analysis identified the potential microRNA-mRNA interactions and the enriched KEGG pathways potentially affected by microRNA changes in dilated AAs. Distinct signatures of differentially expressed microRNAs are evident in TAV and BAV patients vs. donors, as well as differences between aortic concavity and convexity in patients only. MicroRNA changes suggest a switch of SMC phenotype, with particular reference to TAV concavity. MicroRNA changes potentially affecting mechanotransduction pathways exhibit a higher prevalence in BAV convexity and in TAV concavity, with particular reference to TGF-β1, Hippo, and PI3K/Akt/FoxO pathways. Actin cytoskeleton emerges as potentially affected by microRNA changes in BAV convexity only. MicroRNAs could play distinct roles in BAV and TAV aortopathy, with possible implications in diagnosis and therapy. [ABSTRACT FROM AUTHOR]

The purpose of this trial was to evaluate the effects of fluvastatin on the lipid pro-file and on renal function, as measured by creatinine clearance, in dyslipidemic patients with chronic renal failure. In this 8-month prospective, open-label, randomized, parallel-group trial, 130 patients (70 men and 60 women), after a 2-month washout period following previous lipid-lowering treatments, were randomly assigned to fluvastatin XL 80 mg given once daily (80 patients) or to standard treatment (50 patients). Mean total cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, and triglyceride values after 3 and 6 months of treatment with fluvastatin showed statistically significant improvement compared with standard treatment. Improved renal function, as measured by creatinine clearance, was observed at the end of the 6-month treatment period in approximately 65% of patients treated with fluvastatin. The increase in creatinine clearance consistently reached 10% to 15% of baseline values. A statistically significant reduction in C-reactive protein (CRP) over baseline values was observed in approximately 75% of patients treated with fluvastatin. Furthermore, mean values of CRP for the fluvastatin standard treatment groups, respectively, were 6.78 and 10.19 at 3 months and 4.47 and 11 at 6 months. Both treatments were well tolerated. No major adverse events were noted. Results of this study suggest that fluvastatin treatment in patients with chronic renal failure is effective in improving the lipid profile, and it demonstrates good safety and tolerability. Furthermore, fluvastatin may contribute to improved nephroprotection in this patient population. [ABSTRACT FROM AUTHOR]

Silent myocardial ischemia (SMI) is frequently observed in patients with essential hypertension (EH). The major risk factor for SMI is uncontrolled blood pressure (BP), but SMI is also observed in patients with well-controlled BP. To evaluate the prevalence of SMI and the factors associated with SMI in EH patients with well-controlled BP. The medical records of 859 EH patients who underwent simultaneous 24-h ambulatory blood pressure monitoring (ABPM) and 24-h ambulatory electrocardiogram recording (AECG) were retrospectively evaluated. Each SMI episode was characterized by: (a) ST segment depression ≥0.5 mm; (b) duration of ST segment depression >60 s; and (c) reversibility of the ST segment depression. Overall 126 EH patients (14.7 %) had at least one episode of SMI. The SMI events were more frequent among patients with poorly controlled compared to those with well-controlled BP [86/479 (17.95 %) vs. 40/380 (10.52 %), p < 0.01]. Among EH patients with well-controlled BP, current and past smoking as well as the presence of an additional metabolic syndrome (MetS) constitutive element (obesity, impaired fasting glucose level or dyslipidemia) were significantly associated with the occurrence of SMI. In all EH patients with well-controlled BP and AECG evidence of SMI, there were one or more coronary artery stenotic lesions greater than 50 % found at coronary angiography. In EH patients who are current smokers, or have one or more additional components of a MetS there is markedly reduced benefit associated with good BP control with regard to the occurrence of myocardial ischemia: in this patient category, an AECG may help detect this condition. [ABSTRACT FROM AUTHOR]

Unlabelled: The coexistence of two diseases associated with different metabolic disorders is a very rare event. Some associations, although sporadic, can be particularly challenging both in terms of diagnostic and therapeutic management and in terms of theoretical perspective. Here, we report a child affected by type 1 diabetes mellitus (T1DM) and glutaric aciduria type 1 (GA1). The child was diagnosed with classical T1DM at 15 months of age, with a tendency toward hypoglycemia. A few months later, during an acute intercurrent infective episode, the child displayed acute hypotonia of the lower limbs and limbs dystonia. A brain MRI showed bilateral striatal necrosis, suggesting GA1 diagnosis. Treatment with a low-lysine dietary regimen and carnitine supplementation was started and resulted in an improvement in metabolic control and a reduction of hypoglycemic episodes along with an increasing in insulin daily dose. After 2 years, the neurological outcome consisted of a reduction in dystonic movements and a metabolic stability of both diseases.Conclusion: This case provides some insight into the reciprocal interconnections between the two metabolic disorders. Similar pathogenic mechanisms responsible for the neuronal injury might have impacted each other, and a strict relationship between a specific aspect of GA1-impaired metabolism and glucose homeostasis might explain how the tailored management of GA1 was not only effective in controlling the disease, but it also resulted in an improvement in the control of the glycemic profile. What in known: • Glutaric aciduria type 1 (GA1) usually presents in childhood with severe and possibly irreversible neuronal damage, triggered by a catabolic stress • The association of GA1 with other diseases, including type 1 diabetes mellitus (T1DM), is a rare event, complicating the treatment management What is new: • Insulin treatment has a role in preventing GA1 metabolic decompensation, even in the catabolic condition of hypoglycemia • Promoting GA1 metabolic equilibrium by tailoring drug and dietary treatment in our patient affect by T1DM has a positive impact also in improving glycemic balance. [ABSTRACT FROM AUTHOR]

Assessment of left ventricular (LV) systolic function is the cornerstone of the echocardiographic examination. There are many echocardiographic parameters that can be used for clinical and research purposes, each one with its pros and cons. The LV ejection fraction is the most used one due to its feasibility and predictability, but it also has many limits, related to both the imaging technique used for calculation and to the definition itself. LV longitudinal function is expression of subendocardial fibers contraction. Because the subendocardium is often involved early in many pathological processes, its analysis has been a fertile field for the development of sensitive parameters. Longitudinal function can be evaluated in many ways, such as M-mode echocardiography, tissue Doppler imaging, and speckle tracking echocardiography. This latter is a relatively new tool to assess LV function through measurement of myocardial strain, with a high temporal and spatial resolution and a better inter- and intra-observer reproducibility compared to Doppler strain. It is angle independent, not affected by translation cardiac movements, and can assess simultaneously the entire myocardium along all the three-dimensional geometrical (longitudinal, circumferential, and radial) axes. Speckle tracking echocardiography also allows the analysis of LV torsion. The aim of this paper was to review the main echocardiographic parameters of LV systolic function and to describe its pros and cons. [ABSTRACT FROM AUTHOR]

Studies investigating neurobiological bases of negative symptoms of schizophrenia failed to provide consistent findings, possibly due to the heterogeneity of this psychopathological construct. We tried to review the findings published to date investigating neurobiological abnormalities after reducing the heterogeneity of the negative symptoms construct. The literature in electronic databases as well as citations and major articles are reviewed with respect to the phenomenology, pathology, genetics and neurobiology of schizophrenia. We searched PubMed with the keywords 'negative symptoms,' 'deficit schizophrenia,' 'persistent negative symptoms,' 'neurotransmissions,' 'neuroimaging' and 'genetic.' Additional articles were identified by manually checking the reference lists of the relevant publications. Publications in English were considered, and unpublished studies, conference abstracts and poster presentations were not included. Structural and functional imaging studies addressed the issue of neurobiological background of negative symptoms from several perspectives (considering them as a unitary construct, focusing on primary and/or persistent negative symptoms and, more recently, clustering them into factors), but produced discrepant findings. The examined studies provided evidence suggesting that even primary and persistent negative symptoms include different psychopathological constructs, probably reflecting the dysfunction of different neurobiological substrates. Furthermore, they suggest that complex alterations in multiple neurotransmitter systems and genetic variants might influence the expression of negative symptoms in schizophrenia. On the whole, the reviewed findings, representing the distillation of a large body of disparate data, suggest that further deconstruction of negative symptomatology into more elementary components is needed to gain insight into underlying neurobiological mechanisms. [ABSTRACT FROM AUTHOR]

Patients with type 1 diabetes (T1D) suffer excess mortality from cardiovascular disease (CVD) that has persisted despite substantial reductions in microvascular complications. Although T1D and type 2 diabetes (T2D) are etiologically distinct, it has generally been assumed that CVD in T1D is 'the same disease' as that found in T2D. Here, we review the most recent epidemiological and clinical studies on heart disease in T1D, highlighting differences between CVD in T1D and T2D. In addition, we discuss experimental and clinical evidence for a post-myocardial infarction (MI) autoimmune heart syndrome in T1D, including the development of diagnostic assays which we believe can, for the first time, differentiate between heart disease in T1D and T2D. We postulate that a clinically unrecognized form of chronic myocardial inflammation ('myocarditis') triggered by MI contributes to the poor CVD outcomes in T1D. These findings provide a conceptual shift in our understanding of CVD in T1D and have important diagnostic and therapeutic implications. [ABSTRACT FROM AUTHOR]