The Role of the Cumulative Illness Rating Scale (CIRS) in Estimating the Impact of Comorbidities on Chronic Obstructive Pulmonary Disease (COPD) Outcomes: A Pilot Study of the MACH (Multidimensional Approach for COPD and High Complexity) Study.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a heterogeneous systemic syndrome that often coexists with multiple comorbidities. In highly complex COPD patients, the role of the Cumulative Illness Rating Scale (CIRS) as a risk predictor of COPD exacerbation is not known. OBJECTIVE: The objective of this study was determine the effectiveness of the CIRS score in detecting the association of comorbidities and disease severity with the risk of acute exacerbations in COPD patients. METHODS: In total, 105 adults with COPD (mean age 72.1 ± 9.0 years) were included in this prospective study. All participants at baseline had at least two moderate exacerbations or one leading to hospitalization. The primary outcome was a composite of moderate or severe COPD exacerbation during the 12 months of follow-up. RESULTS: The CIRS indices (CIRS total score, Severity Index and Comorbidity Index) showed a positive correlation with modified Medical Research Council (mMRC), COPD assessment test (CAT) and a negative correlation with forced expiratory volume in the first second (FEV1), Forced Vital Capacity (FVC), and FEV1/FVC. The three CIRS indices were able to predict the 12-month rate of moderate or severe exacerbation (CIRS Total Score: Hazard Ratio (HR) = 1.12 (95% CI: 1.08-1.21); CIRS Severity Index: HR = 1.21 (95% CI: 1.12-1.31); CIRS Comorbidity Index = 1.58 (95% CI: 1.33-1.89)). CONCLUSIONS: Among patients with COPD, the comorbidity number and severity, as assessed by the CIRS score, influence the risk in moderate-to-severe exacerbations. The CIRS score also correlates with the severity of respiratory symptoms and lung function.

Echocardiographic Evaluation of the Cardiac Chambers in Asthmatic Patients: The BADA (Blood Pressure Levels, Clinical Features and Markers of Subclinical Cardiovascular Damage of Asthma Patients) Study-ECO.

The "Blood pressure levels, clinical features and markers of subclinical cardiovascular Damage of Asthma patients" (BADA) study is aimed at defining the cardiovascular risk profile and the markers of subclinical and clinical vascular and cardiac damage in asthmatic patients. Very few studies have assessed asthmatic patients without concomitant heart disease through a transthoracic echocardiogram. The goal of the present study is to investigate the prevalence of morphology and/or function changes in the cardiac chambers of a sample of 86 patients with chronic asthma, referred to the dedicated outpatient unit of the Division of Respiratory Diseases of the AOUP "P. Giaccone" of the University of Palermo, and the results obtained were compared with those of a control group without respiratory or cardiovascular diseases. Patients with asthma showed a marked and widespread involvement of the four cardiac chambers compared with the controls: enlargement of the two atria, greater left ventricular remodeling with interventricular septal thickening, increased indexed left ventricular mass with a significantly greater percentage of patients with overt left ventricular hypertrophy, worse left ventricular diastolic function proven by the significant difference in the E/A ratio, and worse right ventricular systolic function with global right ventricular dysfunction estimated by the Myocardial Performance Index (Tei Index). Multivariate regression analysis, after adjustment for essential hypertension, hypertension severity, diabetes, Body Mass Index, and creatinine clearance, seems to indicate that the indexed left ventricular mass, right atrial volume, and right ventricular Tei index (but not left ventricular hypertrophy) correlate significantly with asthma, severe asthma, and FEV1 (and to a lesser extent with asthma duration). No correlation is apparent between inhaled therapy (ICS, SABA) and myocardial involvement. These results seem to confirm that a more in-depth cardiovascular evaluation in patients with chronic respiratory disease allows the identification of unrecognized cardiovascular involvement. A transthoracic echocardiogram performed in asthmatic patients without clinically overt signs or symptoms of cardiovascular impairment has identified some features indicative of an early subclinical cardiac impairment not found in the control group. These findings, considering also the higher frequency of hypertension in the asthma group, deserve further validation in the future.

Effects of Mediterranean Diet Combined with CrossFit Training on Trained Adults' Performance and Body Composition.

CrossFit is a high-intensity training discipline increasingly practiced in recent years. Specific nutritional approaches are usually recommended to maximize performance and improve body composition in high-intensity training regimens; notwithstanding, to date there are no targeted nutritional recommendations for CrossFit athletes. The Mediterranean Diet (MD) is a diet approach with a well-designed proportion of macronutrients, using only available/seasonal food of the Mediterranean area, whose health benefits are well demonstrated. No studies have evaluated this dietary strategy among CrossFit athletes and practitioners; for this reason, we tested the effects of 8 weeks of MD on CrossFit athletes' performance and body composition. Participants were assigned to two groups: a diet group (DG) in which participants performed CrossFit training plus MD, and a control group (CG) in which participants partook in the CrossFit training, continuing their habitual diet. Participants were tested before and after the 8 weeks of intervention. At the end of the study, no significant difference was noted in participants' body composition, whereas improvements in anaerobic power, explosive strength of the lower limbs, and CrossFit-specific performance were observed only in the DG. Our results suggest that adopting a MD in CrossFit athletes/practitioners could be a useful strategy to improve specific strength, endurance, and anaerobic capacity while maintaining overall body composition.

Non-Coding RNA Networks as Potential Novel Biomarker and Therapeutic Target for Sepsis and Sepsis-Related Multi-Organ Failure.

According to "Sepsis-3" consensus, sepsis is a life-threatening clinical syndrome caused by a dysregulated inflammatory host response to infection. A rapid identification of sepsis is mandatory, as the extent of the organ damage triggered by both the pathogen itself and the host's immune response could abruptly evolve to multiple organ failure and ultimately lead to the death of the patient. The most commonly used therapeutic strategy is to provide hemodynamic and global support to the patient and to rapidly initiate broad-spectrum empiric antibiotic therapy. To date, there is no gold standard diagnostic test that can ascertain the diagnosis of sepsis. Therefore, once sepsis is suspected, the presence of organ dysfunction can be assessed using the Sepsis-related Organ Failure Assessment (SOFA) score, although the diagnosis continues to depend primarily on clinical judgment. Clinicians can now rely on several serum biomarkers for the diagnosis of sepsis (e.g., procalcitonin), and promising new biomarkers have been evaluated, e.g., presepsin and adrenomedullin, although their clinical relevance in the hospital setting is still under discussion. Non-codingRNA, including long non-codingRNAs (lncRNAs), circularRNAs (circRNAs) and microRNAs (miRNAs), take part in a complex chain of events playing a pivotal role in several important regulatory processes in humans. In this narrative review we summarize and then analyze the function of circRNAs-miRNA-mRNA networks as putative novel biomarkers and therapeutic targets for sepsis, focusing only on data collected in clinical settings in humans.

New Insights in Prevention and Treatment of Cardiovascular Disease.

Cardiovascular (CV) disease (CVD) is still a major cause of morbidity and mortality in many countries in Europe although considerable efforts have been made in recent decades to address this disease in an even more "comprehensive" approach [...].

Cardiac Remodeling According to the Nocturnal Fall of Blood Pressure in Hypertensive Subjects: The Whole Assessment of Cardiac Abnormalities in Non-Dipper Subjects with Arterial Hypertension (Wacanda) Study.

OBJECTIVE: Several epidemiological studies suggest that the preservation of the physiological circadian rhythm of blood pressure or its disruption affects the extent of the organ damage developed by the patient. If we classify the circadian rhythm of blood pressure into four nocturnal profiles, significant differences emerge in terms of organ damage burden and prognosis: reverse dippers have the worst prognosis while dippers and mild dippers fall into an intermediate risk range. The risk profile of extreme dippers is still debated, and the available data are very conflicting and inconclusive. Starting from this gap of knowledge, we aimed to evaluate, retrospectively, in a cohort of hypertensive subjects, the degree of cardiac involvement in relation to the different nocturnal blood pressure profiles. METHODS: We retrospectively evaluated 900 patients with essential hypertension, of whom 510 met our study criteria. We graded the 510 patients in relation to the percentage of reduction in mean systolic blood pressure (SBP) at night-time compared with day-time, considering this as a continuous variable, and then compared the extreme quintiles with each other and with the middle quintile (considered as reference). RESULTS: Patients with less (or no) reduction in nocturnal SBP (reverse dipper) showed a higher level of organ damage and comorbidities. With regard to echocardiographic indexes, patients with maximum nocturnal pressure reduction (extreme dipper) showed a lower level of remodeling and/or impairment of E/e' ratio, Right Atrium Area, Basal Right Ventricular Diameter, Inferior Vena Cava Average Diameter, and Tricuspidal Anular Plane Systolic Excursion compared also with hypertensive patients with a physiological nocturnal pressure reduction, even after correction for the main confounders. CONCLUSIONS: These data suggest that extreme dippers may constitute the subgroup of hypertensive patients with the lowest 24-h pressure load and, therefore, less cardiac remodeling.

Ketogenic Diet, Physical Activity, and Hypertension-A Narrative Review.

Several studies link cardiovascular diseases (CVD) with unhealthy lifestyles (unhealthy dietary habits, alcohol consumption, smoking, and low levels of physical activity). Therefore, the strong need for CVD prevention may be pursued through an improved control of CVD risk factors (impaired lipid and glycemic profiles, high blood pressure, and obesity), which is achievable through an overall intervention aimed to favor a healthy lifestyle. Focusing on diet, different recommendations emphasize the need to increase or avoid consumption of entire classes of food, with only partly known and only partly foreseeable consequences on the overall level of health. In recent years, the ketogenic diet (KD) has been proposed to be an effective lifestyle intervention for metabolic syndrome, and although the beneficial effects on weight loss and glucose metabolism seems to be well established, the effects of a prolonged KD on the ability to perform different types of exercise and the influence of KD on blood pressure (BP) levels, both in normotensives and in hypertensives, are not so well understood. The objective of this review is to analyze, on the basis of current evidence, the relationship between KD, regular physical activity, and BP.

Role of Regular Physical Activity in Neuroprotection against Acute Ischemia.

One of the major obstacles that prevents an effective therapeutic intervention against ischemic stroke is the lack of neuroprotective agents able to reduce neuronal damage; this results in frequent evolution towards a long-term disability with limited alternatives available to aid in recovery. Nevertheless, various treatment options have shown clinical efficacy. Neurotrophins such as brain-derived neurotrophic factor (BDNF), widely produced throughout the brain, but also in distant tissues such as the muscle, have demonstrated regenerative properties with the potential to restore damaged neural tissue. Neurotrophins play a significant role in both protection and recovery of function following neurological diseases such as ischemic stroke or traumatic brain injury. Unfortunately, the efficacy of exogenous administration of these neurotrophins is limited by rapid degradation with subsequent poor half-life and a lack of blood-brain-barrier permeability. Regular exercise seems to be a therapeutic approach able to induce the activation of several pathways related to the neurotrophins release. Exercise, furthermore, reduces the infarct volume in the ischemic brain and ameliorates motor function in animal models increasing astrocyte proliferation, inducing angiogenesis and reducing neuronal apoptosis and oxidative stress. One of the most critical issues is to identify the relationship between neurotrophins and myokines, newly discovered skeletal muscle-derived factors released during and after exercise able to exert several biological functions. Various myokines (e.g., Insulin-Like Growth Factor 1, Irisin) have recently shown their ability to protects against neuronal injury in cerebral ischemia models, suggesting that these substances may influence the degree of neuronal damage in part via inhibiting inflammatory signaling pathways. The aim of this narrative review is to examine the main experimental data available to date on the neuroprotective and anti-ischemic role of regular exercise, analyzing also the possible role played by neurotrophins and myokines.

Prevalence of Arterial Hypertension and Characteristics of Nocturnal Blood Pressure Profile of Asthma Patients According to Therapy and Severity of the Disease: The BADA Study.

BACKGROUND: several studies report an increased risk for asthmatic subjects to develop arterial hypertension and the relationship between these two diseases, frequently co-existing, still has some unclear aspects. METHODS: The BADA (blood pressure levels, clinical features and markers of subclinical cardiovascular damage of asthma patients) study is aimed to evaluate the prevalence of the cardiovascular comorbidities of asthma and their impact on the clinical outcome. The main exclusion criteria were the presence of other respiratory diseases, current smoking, any contraindication to ambulatory blood pressure monitoring (ABPM). RESULTS: The overall percentage of asthmatics having also hypertension was 75% (30 patients) vs. 45% (18 patients) of the control group (p: 0.012). Reduced level of FEV1 (but not inhaled steroid therapy) was associated to newly-diagnosed hypertension (p: 0.0002), higher day SBP levels (p: 0.003), higher day DBP levels (p: 0.03), higher 24 h-SBP levels (p: 0.005) and higher 24h-DBP levels (p: 0.03). The regression analysis performed taking into account sex, age, diabetes, fasting glucose, and body mass index confirms the independent role played by asthma: odds ratio (OR): 3.66 (CI: 1.29-11.1). CONCLUSIONS: hypertension is highly prevalent in asthma; the use of ABPM has allowed the detection of a considerable number of unrecognized hypertensives.

New insights about the putative role of myokines in the context of cardiac rehabilitation and secondary cardiovascular prevention.

Exercise training prevents the onset and the development of many chronic diseases, acting as an effective tool both for primary and for secondary prevention. Various mechanisms that may be the effectors of these beneficial effects have been proposed during the past decades: some of these are well recognized, others less. Muscular myokines, released during and after muscular contraction, have been proposed as key mediators of the systemic effects of the exercise. Nevertheless the availability of an impressive amount of evidence regarding the systemic effects of muscle-derived factors, few studies have examined key issues: (I) if skeletal muscle cells themselves are the main source of cytokine during exercise; (II) if the release of myokines into the systemic circulation reach an adequate concentration to provide significant effects in tissues far from skeletal muscle; (III) what may be the role carried out by muscular cytokine regarding the well-known benefits induced by regular exercise, first of all the anti-inflammatory effect of exercise. Furthermore, a greater part of our knowledge regarding myokines derives from the muscle of healthy subjects. This knowledge may not necessarily be transferred per se to subjects with chronic diseases implicating a direct or indirect muscular dysfunction and/or a chronic state of inflammation with persistent immune-inflammatory activation (and therefore increased circulating levels of some cytokines): cachexia, sarcopenia due to multiple factors, disability caused by neurological damage, chronic congestive heart failure (CHF) or coronary artery disease (CAD). A key point of future studies is to ascertain how is modified the muscular release of myokines in different categories of unhealthy subjects, both at baseline and after rehabilitation. The purpose of this review is to discuss the main findings on the role of myokines as putative mediators of the therapeutic benefits obtained through regular exercise in the context of secondary cardiovascular prevention.

The "Neurocentric" Approach to Essential Hypertension: How Reliable is the Paradigm of Hyperkinetic Hypertension? A Focus on the Sympathetic Nervous System Dysregulation in Essential Hypertensive Patients with Elevated Resting Heart Rate.

BACKGROUND: Clinic resting heart rate (RHR), is one of the cardiovascular parameters more easily measurable. In the general population RHR has been associated with total and cardiovascular mortality and higher rate of vascular events. OBJECTIVE: The case of essential hypertension is in some ways peculiar: in the past decades has often been attributed to hypertensive subjects higher values of RHR than healthy controls as a result of the effects of the different factors leading to the development of essential hypertension itself, first of all the presence of an increased tone of the sympathetic nervous system Methods: Several excellent articles debated the issue of autonomic dysfunction in essential hypertension; nevertheless of this, after various decades of debate, this issue is to-date unresolved. The aim of this review is to discuss the reliability of the hypothesis that elevated resting heart rate in hypertensive subjects is associated to high blood pressure and both to elevated sympathetic nervous system activity or rather if these three phenomena coexist in a limited portion of subjects being not necessarily linked each other with a causal relationship. RESULTS: The ascertainment of the exact proportion of the hypertensive subjects having sympathetic overdrive appears to be hard, not only due to the multiple interferences and the constant interplay between the various determinants of the sympathetic tone, but also because a significant uncertainty remains with regard to the validity of the methods used for assessing the sympathetic tone. CONCLUSIONS: To date, any threshold used to define tachycardia is arbitrary. The percentage of hypertensive patients with elevated RHR varies considerably between the various studies, first of all because the modality of assessment influences the results. The "white coat tachycardia" is a clinical entity that must be taken into account. Ambulatory heart rate represents a good diagnostic alternative, since nocturnal mean heart rate appears to be the parameter with the highest prognostic value, probably because is less conditioned by external factors, being more representative of the "real" heart rate of the subject.

Ambulatory Arterial Stiffness Index (AASI) is Unable to Estimate Arterial Stiffness of Hypertensive Subjects: Role of Nocturnal Dipping of Blood Pressure.

BACKGROUND: Ambulatory Arterial Stiffness Index (AASI) has been proposed as an indirect and simpler method to estimate the Arterial Stiffness (AS). AASI, calculated from a set of data collected during a 24-hours ambulatory blood pressure monitoring (ABPM), is defined as 1 minus the regression slope of diastolic on systolic blood pressure (BP) values. For a given increase in diastolic BP, the increase in systolic BP is smaller in a compliant compared to a stiff artery; the stiffer the arterial tree, the closer AASI is to 1. AASI was demonstrated to predict cardiovascular mortality, cerebrovascular events and to be associated with target organ damage. Taking into account the almost complete absence of data regarding the ability of AASI to predict the different degree of AS when hypertensives are divided into four classes of dipping in relation to the extent of the nocturnal reduction of BP (extreme dippers, dippers, mild dippers and reverse dippers) aim to clarify the ability of AASI to estimate the different degree of AS of hypertensive subjects with different nocturnal BP profile and resulting in different extent of organ damage. MATERIALS AND METHODS: We enrolled 816 subjects (403 men and 413 women) with essential hypertension, referred to the U.O.C of Medicina Interna e Cardioangiologia of the University of Palermo; 173 subjects (71 men and 102 women, mean age 44.4 ± 14.6 years) without a history of hypertension were enrolled as controls. RESULTS: The analysis of data was performed by dividing the population into four categories in relation to the extent of the nocturnal decline of BP: 124 extreme dipper (mean age 54,8 ± 12,4 years, men 46.8 %); 287 dipper (mean age 55,9 ± 14,2 years, men 54,0 %); 271 mild dipper (mean age 61,5 ± 14,7 years, men 52,0 %); 134 reverse dipper (mean age 61,5 ± 14,7 years, men 33.6 %). The mean value of AASI was significantly higher for mild and reverse dippers versus control patients and versus the other categories of dipping. The multiple regression analysis with AASI as the dependent variable confirmed the significant association between AASI and nocturnal dip (p: 0.015). The Multinomial Logistic Regression Analysis, in which AASI values were adjusted for the main confounders (age, sex, Body Mass Index, 24h SBP, 24h DBP) showed that the association between AASI and dipping is maintained only for dipper and extreme dipper hypertensives, missing the significance for mild and reverse subjects. CONCLUSION: 1) AASI levels are associated with night-to-day BP ratio; 2) Lower levels of AASI are significantly associated to extreme dipper and dipper BP nocturnal profile when compared to healthy controls. 3) After correction for the major confounding factors, the association between AASI and the high-damaged class of hypertensive subjects with lower or no nocturnal fall of BP is lost. Our findings support the hypothesis that AASI is unable to estimate AS of older hypertensive subjects with a high burden of organ and vascular damage and several comorbidities, probably because the nocturnal reduction of BP is the main determinant of AASI, being more powerful than AS itself.

Preventive and Therapeutic Role of Muscle Contraction Against Chronic Diseases.

BACKGROUND: Due to the continuing increase of the elderly population in the western countries, the prevalence of the main chronic diseases (obesity, type 2 diabetes and related metabolic disorders, arterial hypertension, vascular damage due to atherosclerotic process, cancer, chronic obstructive pulmonary disease, neurodegenerative diseases, chronic kidney disease, immune-mediated diseases) is increasing. There is incontrovertible evidence that regular physical activity contributes to the primary and secondary prevention of several chronic diseases and is associated with a reduced risk of premature death. METHODS: In this review the most prevalent chronic pathologic conditions are discussed, how regular exercise may provide benefits for prevention and/or treatment of these diseases and are graphically described by means of various figures the main biological mechanisms through which exercise exerts its beneficial effects known to date. RESULTS: Specific interventions aimed to implement physical activity levels of the general population are of certain efficacy both for primary and secondary prevention of the major chronic diseases and constitutes an excellent cost/effective tool to improve the health status of different categories of patients. CONCLUSION: Exercise represents a unique case in which a single intervention is useful against a broad range of diseases and risk factors, this knowledge should lead to an ever-increasing use of this lifestyle change.

Are the Myokines the Mediators of Physical Activity-Induced Health Benefits?

BACKGROUND: The concept of the muscle as a secretory organ, developed during the last decades, partially answers to the issue of how the crosstalk between skeletal muscle and distant tissues happens. The beneficial effects of exercise transcend the simple improved skeletal muscle functionality: systemic responses to exercise have been observed in distal organs like heart, kidney, brain and liver. Increasing data have accumulated regarding the synthesis, the kinetics of release and the biological roles of muscular cytokines, now called myokines. The most recent techniques have meaningfully improved the identification of the muscle cell secretome, but several issues regarding the extent of secretion from the muscle as well as the actions of the myokines remain unexplained. METHODS: The goal of this review is to provide an update about the secretory properties of skeletal muscle during and after an acute bout of exercise and after exercise training, showing the main experimental evidences, but also speculate about the possible therapeutic use of the physical training-induced circulating factors, especially in some categories of patients in which the baseline conditions are heavily damaged by one or more pathological conditions. RESULTS: studies on myokines are relatively recent, and to date most of the evidence available in humans has focused on the biological role of Il-6 during muscle contraction. Regarding to the myokines more recently identified, for example myostatin, fibroblast growth factor 21 (FGF21), secreted protein acidic and rich in cysteine (SPARC) or follistatin-like 1 some of these seem to be promising therapeutic agents, but our awareness about their potential benefits towards human health is only at the beginning. CONCLUSION: for many of the myokines identified to date, the information available is limited and not enough to characterize precise functions and activities carried out by those in man. Several issues need to be addressed by future studies, tailored to ascertain accurately and surely the biological role and the therapeutic potential of some myokines.

Does sympathetic overactivation feature all hypertensives? Differences of sympathovagal balance according to night/day blood pressure ratio in patients with essential hypertension.

When evaluating the 'night/day BP ratio', both hypertensives and normotensives can be arbitrarily classified into four groups: extreme dippers (ratio ⩽0.8), dippers (0.8