Oxidative Stress-Related Signaling Pathways Predict Oocytes' Fertilization In Vitro and Embryo Quality.

Oocyte development and fertilization are largely influenced by the microenvironment of the follicular fluid (FF), and the exploration of its molecular/metabolic composition may help in improving in vitro fertilization (IVF) outcomes. Here, the concentrations of molecules related to oxidative stress/inflammation were measured in FF from follicles at oocyte retrieval during IVF. Here, the FF antioxidant potential was correlated with the number of retrieved/mature oocytes and the number of fertilized ones. FF collected from the follicles of normal fertilized oocytes presented an elevated antioxidant capability, lower levels of pro-inflammatory molecules (i.e., IL-6, IL-8, IL-12, TGF-ß, and HIF-1α), and a higher IL-10 concentration. FF samples from follicles at oocyte retrieval that resulted in top-quality embryos displayed a peculiar antioxidant capability and a further decrease in proinflammatory molecules when compared with FF, giving rise to poor-quality embryos. Finally, pro-inflammatory molecules were lower and accompanied by a high antioxidant capability in samples giving rise to successful embryo implantation. The antioxidant capability and IL-10 displayed a good predictive ability for fertilization and embryo quality. Overall, our data showed the great influence of oxidative stress on the oocytes' fertilization, and shed light on the importance of controlling the inflammatory and oxidative status of FF to obtain good-quality embryos with significant implantation potential.

Fertility Impairment after Trekking at High Altitude: A Proof of Mechanisms on Redox and Metabolic Seminal Changes.

Many authors described negative but reversible effects of high-altitude hypoxic exposure on animal and human fertility in terms of sperm concentration, function, and biochemical alterations. The aim of this study was to evaluate the acute and chronic effects of high-altitude exposure on classical sperm parameters, redox status, and membrane composition in a group of travellers. Five healthy Italian males, all lowlanders not accustomed to the altitude, were evaluated after 19 days-trekking through low, moderate, and high altitudes in the Himalayas. Sperm samples were collected before (Pre), 10 days after (Post), and 70 days after the end of the expedition (Follow-up). Sperm concentration, cholesterol and oxysterol membrane content, and redox status were measured. Hypoxic trek led to a significant reduction in sperm concentration (p < 0.001, η2p = 0.91), with a reduction from Pre to Post (71.33 ± 38.81 to 60.65 ± 34.63 × 106/mL) and a further reduction at Follow-up (to 37.13 ± 39.17 × 106/mL). The seminal volume was significantly affected by the hypoxic trek (p = 0.001, η2p = 0.75) with a significant reduction from Pre to Post (2.86 ± 0.75 to 1.68 ± 0.49 mL) and with partial recovery at Follow-up (to 2.46 ± 0.45 mL). Moreover, subjects had an increase in ROS production (+86%), and a decrease in antioxidant capacity (−37%) in the Post period with partial recovery at Follow-up. These results integrated the hormonal response on thyroid function, hypothalamus−pituitary−gonadal axis, and the prolactin/cortisol pathways previously reported. An uncontrolled ROS production, rather than a compromised antioxidant activity, was likely the cause of impaired sperm quality. The reduction in fertility status observed in this study may lie in an evolutionary Darwinian explanation, i.e., limiting reproduction due to the "adaptive disadvantage" offered by the combined stressors of high-altitude hypoxia and daily physical exercise.

Energy cost and psychological impact of robotic-assisted gait training in people with spinal cord injury: effect of two different types of devices.

BACKGROUND: In the last years, there has been an intense technological development of robotic devices for gait rehabilitation in spinal cord injury (SCI) patients. The aim of the present study was to evaluate energy cost and psychological impact during a rehabilitation program with two different types of robotic rehabilitation systems (stationary system on a treadmill, Lokomat, and overground walking system, Ekso GT). METHODS: Fifteen SCI patients with different injury levels underwent robot-assisted gait training sessions, divided into 2 phases: in the first phase, all subjects completed 3 sessions both Lokomat and Ekso GT. Afterwards, participants were randomly assigned to Lokomat or the Ekso for 17 sessions. A questionnaire, investigating the subjective psychological impact (SPI) during gait training, was administered. The functional outcome measures were oxygen consumption (VO2), carbon dioxide production (VCO2), metabolic equivalent of task (MET), walking economy, and heart rate (HR). RESULTS: The metabolic responses (7.73 ± 1.02 mL/kg/min) and MET values (3.20 ± 1.01) during robotic overground walking resulted to be higher than those during robotic treadmill walking (3.91 ± 0.93 mL/kg/min and 1.58 ± 0.44; p < 0.01). Both devices showed high scores in emotion and satisfaction. Overground walking resulted in higher scores of fatigue, mental effort, and discomfort while walking with Lokomat showed a higher score in muscle relaxation. All patients showed improvements in walking economy due to a decrease in energy cost with increased speed and workload. CONCLUSIONS: Overground robotic-assisted gait training in rehabilitation program needs higher cognitive and cardiovascular efforts than robot-assisted gait training on a treadmill.

The level of physical training modulates cytokine levels through P2X7 receptor in healthy subjects.

INTRODUCTION: The P2X7 receptor-NLRP3 inflammasome complex (P2X7R-Infl) regulates inflammatory and immune responses. Physical exercise modulates heat-shock proteins (Hsps), influencing cytokine levels and oxidative stress; Hsp72 triggers P2X7R-Infl-dependent responses. SUBJECTS AND METHODS: We studied the effect of a single bout of maximal exercise on lymphomonocyte expression of P2X7R, NLRP3, caspase-1, NF-kB and Hsp72 and circulating levels of IL-1ß, IL-18 and MCP-1, all modulated by P2X7R-Infl, in healthy sedentary (SED), trained (ATH), endurance (END) male individuals. RESULTS: Baseline P2X7R, NLRP3 and Caspase-1 expression progressively increased from SED to ATH and END; NF-kß showed the same trend. Hsp72 did not differ among groups. Acute exercise strongly reduced P2X7R in all participants, irrespective of their degree of physical training. Inflammasome responses differed across groups: in SED, NLRP3 and Caspase-1 increased; in ATH, NLRP3 reduced and caspase-1 did not vary; in END, NLRP3 and Caspase-1 declined. Baseline IL-1ß, higher in END, was unmodified after exercise; IL-18 decreased; MCP-1 doubled in SED, did not vary in ATH, declined in END. In the whole study population, significant direct relationships emerged between P2X7R expression and IL-1ß, IL-18, MCP-1 levels, all P < .001; also Caspase-1 related with these markers. A multivariate analysis showed age, BMI and P2X7R as determinants of postexercise IL-1ß levels. CONCLUSION: Endurance show higher P2X7R-Infl expression and function vs SED and ATH; however, maximal exercise determines prevailing pro-inflammatory vs anti-inflammatory responses in untrained and trained participants, respectively, highlighting a likely cause-effect relationship between degree of physical activity and P2X7R-Infl-mediated responses.

Pharmacodynamic comparison of pitavastatin versus atorvastatin on platelet reactivity in patients with coronary artery disease treated with dual antiplatelet therapy.

BACKGROUND: Levels of platelet reactivity in patients on dual antiplatelet therapy (DAPT) can be influenced by concomitant treatment with statins. We verified if the pharmacodynamic effects of CYP3A4-metabolized statins (atorvastatin) and non-CYP3A4-metabolized statins (pitavastatin) differ in patients with coronary artery disease (CAD) treated with DAPT. METHODS AND RESULTS: A total of 155 CAD patients receiving DAPT (clopidogrel 75mg plus aspirin 100mg) entered the PORTO trial. Patients were randomly assigned to atorvastatin (20mg day) or pitavastatin (4mg day) for 30 days, and then switched to the other drug for 30 days. Platelet reactivity was expressed as VerifyNow P2Y12 platelet response units (PRU) before and after each 30-day treatment period. High platelet reactivity was defined as PRU >208. As compared with pretreatment (192±49), PRU was significantly higher after 30-day atorvastatin (210±56; P=0.003), but was unchanged after 30-day pitavastatin (199±47 PRU, NS). In the 48 patients with PRU >208 at baseline (232±44), PRU increased significantly after 30-day atorvastatin (258±41, P=0.004), but not after 30-day pitavastatin (237±43, NS). In the 107 patients with PRU <208 at baseline (174±52), PRU did not change significantly with respect to baseline either after 30-day atorvastatin (188±61, NS) or after 30-day pitavastatin (181±59, NS). CONCLUSIONS: Pitavastatin, a non-CYP3A4-metabolized statin, does not affect clopidogrel's response as compared with atorvastatin in patients who are borderline or poor responders to DAPT.

Exploring Neurocognitive Deterioration in Alzheimer's Disease.

Oxidative stress (OS) contributes to cerebral biochemical impairment and is defined as the imbalance between reactive oxygen species (ROS) and the antioxidant potential of neuronal cells pertaining brain activity [...].

Engagement in a structured physical activity program and its effects upon health-related quality of life in elderly women: An observational study.

Aging is a complex process associated with an impairment in functional capacity and low health-related quality of life (HRQoL) due to a high frequency of chronic diseases in the elderly population. Regular physical activity (PA) may limit some physiological effects of sedentary lifestyle and increase life expectancy. An observational was conducted to measure the HRQoL among older adults living in the community, by comparing a convenience sample of elderly females practicing a structured program of PA from 2 to 3 times per week in 60-min sessions (i.e., active females, AFs) to a sample of participants adopting lifestyle behaviors expending little energy (i.e., sedentary females, SFs). A validated questionnaire (the RAND 36-item) was used as outcome measure. All participants were assessed in terms of cognitive status (Montreal Cognitive Assessment, MoCA) to exclude mild cognitive impairment, divided attention/executive functioning (Trail Making Test, Stroop Test) and psychopathological dimensions of anxiety (Geriatric Anxiety Inventory, GAI), and depression (Geriatric Depression Scale, GDS). Non-parametric analysis revealed that AFs and SFs differed significantly in the RAND Energy/Fatigue (E/F), Emotional Wellbeing (EW), and Social Functioning (SoF), that was however influenced by education level. Moreover, E/F and EW were negatively associated to anxiety and depression, while SoF was influenced by divided attention. PA results in a healthful behavior for combating feelings of fatigue and low energy as well as emotional distress that can affect health status perception in older women.

Corrigendum: Engagement in a structured physical activity program and its effects upon health-related quality of life in elderly women: an observational study.

[This corrects the article DOI: 10.3389/fpsyg.2023.1135433.].

Ultrasound and Clinical Alterations in the Foot of Children with Obesity and Diabetes.

BACKGROUND: Alterations in plantar soft tissues are often reported in adults with diabetes, whereas data on children are conflicting. Also, the extent of foot damage caused by excess body fat in children has not been fully characterized yet. This study aimed to address the relationship between body mass and structural changes of the foot in children and adolescents with and without diabetes. METHODS: In a case-control study, 43 participants (age 13 ± 2.6 years) were recruited, 29 (67%) with type 1 diabetes (T1D) and 14 (33%) controls. Anthropometric parameters [body mass index (BMI), waist circumference (WC), and waist-to-height ratio (WHtR)], foot posture index-6 (FPI-6) for static foot posture, and navicular drop test (NDT) for medial longitudinal arch height (MLA) were measured in all participants. The thickness of the midfoot plantar fascia (MPF) and medial midfoot fat pad (MMFP) were quantified using ultrasound. RESULTS: No differences in clinical and ultrasonographical parameters were observed between the study groups. MMFP thickness was correlated with MPF thickness (p = 0.027). MMFP and MPF thicknesses were positively associated with BMI (p < 0.001 and p = 0.013, respectively), WC (p < 0.001 and p = 0.013), and WHtR (p < 0.001 and p = 0.026). The NDT measured on the right and left foot correlated with WHtR (p = 0.038 and p = 0.009, respectively), but not with WC and BMI. CONCLUSIONS: Children with T1D show structural alterations of plantar soft tissues which seem related to body mass increase rather than diabetes pathology. Ultrasound is a valuable tool to assess early structural changes of the foot in young people with an elevated BMI.

Regular exercise delays microvascular endothelial dysfunction by regulating antioxidant capacity and cellular metabolism.

Aging is the basis for several unfavorable conditions, including cardiovascular diseases (CVDs). In this sense, regular physical activity (regular PA) has been proven to delay cellular aging and prevent endothelial dysfunction related to CVDs. Despite numerous studies involving athletes, little is known about cellular and molecular mechanisms of regular PA among master athletes. The present study aimed at evaluating the effects of regular PA on local microcirculatory functions in elderly athletes as compared to age-matched sedentary controls. Moreover, molecular/epigenetic mechanisms (nitric oxide, oxidative stress, PGC-1α, SIRT1 and miR29) were also assessed. The results of the present study showed that regular PA significantly increased local blood flow in post-ischemia and post-heating conditions, as well as NO plasma concentrations, denoting a better endothelial function/microcirculatory efficiency. Moreover, athletes presented a greater plasma antioxidant and increased transcriptional levels of the metabolism regulator PGC-1α. Finally, regular PA enhanced plasma level of SIRT1 and miR29, suggested as epigenetic regulators of redox balance and cellular metabolism. In addition, stimulated local blood flow was directly related to plasma antioxidant capacity, and SIRT1 and miR29 levels. Overall, our data confirm the beneficial effects of regular PA on the cardiovascular profile in elderly athletes and shed light on molecular signals involved in the positive adaptations to exercise.

Increased finger skin vasoreactivity and stimulated vasomotion associated with simvastatin therapy in systemic sclerosis hypercholesterolemic patients.

We conducted an open-label trial to evaluate whether simvastatin therapy was, or was not, associated in systemic sclerosis hypercholesterolemic patients (SSc-Ps) with beneficial changes in finger skin microvascular function. 13 females SSc-Ps and 15 females healthy control subjects (CSs), age-matched with SSc-Ps, underwent finger skin post-occlusive reactive hyperaemia (PORH), using laser Doppler flowmetry (LDF). This test was repeated in SSc-Ps after about 10 weeks of simvastatin (20 mg/day) therapy (ST). At baseline and after ST, finger skin vasomotion was evaluated using spectral Fourier analysis of the LDF tracings. Endothelin-1 and cholesterol serum levels were also determined in SSc-Ps at baseline and after ST. At baseline, SSc-Ps had significantly lower basal finger skin blood flow (basal flow) and PORH, compared to CSs (18.9 ± 11.7 PU vs. 28.5 ± 17.5 PU, 58.6 ± 31.0 PU vs. 93. 1 ± 37.3; P < 0.05). After ST, SSc-Ps had a significant increase in basal flow and PORH compared to baseline (42.7 ± 35.7 PU vs. 18.9 ± 11.7 PU, 111.0 ± 66.6 PU vs. 58.6 ± 31.0 PU, respectively; P < 0.05), as well as a significant reduction in endothelin-1, total- and LDL-cholesterol serum levels. After ST, SSc-Ps also showed a partially restored post-ischaemic amplification in finger skin blood flow oscillations within 0.06-0.6 Hz, related to myogenic vasomotion. This study showed that a short time period of ST in hypercholesterolemic SSc-Ps resulted in increased finger skin vasoreactivity and in partially restored post-ischaemic amplification of finger skin vasomotion, suggesting that ST affects positively finger skin microvascular dysfunction in SSc-Ps.

Exploring the Role of Lipid-Binding Proteins and Oxidative Stress in Neurodegenerative Disorders: A Focus on the Neuroprotective Effects of Nutraceutical Supplementation and Physical Exercise.

The human brain is primarily composed of lipids, and their homeostasis is crucial to carry on normal neuronal functions. In order to provide an adequate amount of lipid transport in and out of the central nervous system, organisms need a set of proteins able to bind them. Therefore, alterations in the structure or function of lipid-binding proteins negatively affect brain homeostasis, as well as increase inflammation and oxidative stress with the consequent risk of neurodegeneration. In this regard, lifestyle changes seem to be protective against neurodegenerative processes. Nutraceutical supplementation with antioxidant molecules has proven to be useful in proving cognitive functions. Additionally, regular physical activity seems to protect neuronal vitality and increases antioxidant defenses. The aim of the present review was to investigate mechanisms that link lipid-binding protein dysfunction and oxidative stress to cognitive decline, also underlining the neuroprotective effects of diet and exercise.

A Minireview Exploring the Interplay of the Muscle-Gut-Brain (MGB) Axis to Improve Knowledge on Mental Disorders: Implications for Clinical Neuroscience Research and Therapeutics.

What benefit might emerge from connecting clinical neuroscience with microbiology and exercise science? What about the influence of the muscle-gut-brain (MGB) axis on mental health? The gut microbiota colonizes the intestinal tract and plays a pivotal role in digestion, production of vitamins and immune system development, but it is also able to exert a particular effect on psychological well-being and appears to play a critical role in regulating several muscle metabolic pathways. Endogenous and exogenous factors may cause dysbiosis, with relevant consequences on the composition and function of the gut microbiota that may also modulate muscle responses to exercise. The capacity of specific psychobiotics in ameliorating mental health as complementary strategies has been recently suggested as a novel treatment for some neuropsychiatric diseases. Moreover, physical exercise can modify qualitative and quantitative composition of the gut microbiota and alleviate certain psychopathological symptoms. In this minireview, we documented evidence about the impact of the MGB axis on mental health, which currently appears to be a possible target in the context of a multidimensional intervention mainly including pharmacological and psychotherapeutic treatments, especially for depressive mood.

Acute pericarditis in patients receiving coronavirus disease 2019 vaccines: a case series from the community.

BACKGROUND: International agencies reported that cases of pericarditis occur very rarely following the administration of coronavirus disease 2019 (COVID-19) vaccines. Herewith, we described a series of patients from the community diagnosed with acute pericarditis after vaccination. METHODS: We retrospectively included 28 patients (median age 51 years, 79% female) with or without a positive history of acute respiratory syndrome coronavirus 2 recovered infection who were diagnosed with acute pericarditis following the administration of COVID-19 vaccine. We excluded specific identifiable causes of pericarditis, including infectious, autoimmune, neoplastic and metabolic disease. Patients were referred for a complete cardiovascular evaluation. Transthoracic echocardiography (TTE) was performed and diagnosis of acute pericarditis was achieved according to current guidelines. RESULTS: There were 16 patients administered with Pfizer-BioNTech/Comirnaty vaccine, 8 with Moderna/Spikevax vaccine and 4 with Astra Zeneca/Vaxzevria vaccine. Nine patients had been previously diagnosed with COVID-19, while the others had no prior history of COVID-19. Eleven patients had no comorbidity while the others had between one and four comorbidities. Ten patients had a history of rheumatic or autoimmune diseases. Chest pain was present in 24 patients. Minor ECG abnormalities were detected in 10 patients, T-wave inversion in 6, and 7 patients had concave ST elevation. The majority of patients showed mild pericardial effusions at TTE. Only two patients exhibited large pericardial effusions. CONCLUSION: This case series shows a higher incidence of acute pericarditis in patients administered with COVID-19 vaccines than previously estimated, probably because of a more comprehensive assessment of clinical as well as echocardiographic parameters.

What Does the Brain Have to Keep Working at Its Best? Resilience Mechanisms Such as Antioxidants and Brain/Cognitive Reserve for Counteracting Alzheimer's Disease Degeneration.

Here we performed a narrative review highlighting the effect of brain/cognitive reserve and natural/synthetic antioxidants in exerting a neuroprotective effect against cognitive deterioration during physiological and pathological aging. Particularly, we discussed pathogenesis of Alzheimer's disease, brain and cognitive reserve as means of resilience towards deterioration, and evidence from the literature about antioxidants' role in sustaining cognitive functioning in the preclinical phase of dementia. During aging, the effects of disease-related brain changes upon cognition are reduced in individuals with higher cognitive reserve, which might lose its potential with emerging cognitive symptoms in the transitional phase over the continuum normal aging-dementia (i.e., Mild Cognitive Impairment). Starting from this assumption, MCI should represent a potential target of intervention in which antioxidants effects may contribute-in part-to counteract a more severe brain deterioration (alongside to cognitive stimulation) causing a rightward shift in the trajectory of cognitive decline, leading patients to cross the threshold for clinical dementia later.

Metabolic and Molecular Mechanisms of Diet and Physical Exercise in the Management of Polycystic Ovarian Syndrome.

Polycystic ovary syndrome (PCOS) is an endocrine systemic disorder mainly characterized by a hormonal and metabolic disbalance that leads to oligo/anovulation, hyperandrogenism and the formation of ovarian cysts. Despite the progress that has been reached in its diagnosis and management, little is known about the molecular mechanisms and signaling pathways underlying the pathogenic mechanisms. In this sense, recent research has suggested that the influence of multiple factors, including age, environment, lifestyle and the disease state environment can change the clinical presentation of PCOS via epigenetic modifications. Variants in the genes encoding for proteins involved in steroidogenesis and glucose homeostasis play a crucial role in the development of the disease. Other genes involved in inflammation and cell proliferation seem to undergo an epigenetic control. Moreover, lifestyle factors influence the PCOS course and prognosis, including diet and physical activity, which are fundamental in reducing oxidative stress, inflammation and in improving metabolic and hormonal parameters. In the present review, literature evidence on molecular and epigenetic mechanisms related to PCOS etiology will be discussed, with a particular attention on the positive influence of diet and physical activity as nonpharmacological ways of intervention in the management of the disease.

Endometrial Dysbiosis Is Related to Inflammatory Factors in Women with Repeated Implantation Failure: A Pilot Study.

An abnormal endometrial microbiota has been suggested to impair the process of embryo implantation, thus leading to repeated implantation failure (RIF) in women undergoing in vitro fertilization (IVF). However, the molecular mechanisms linking uterine microbiota and IVF out-comes are still an open question. The aim of this cohort study was to outline the relationship between endometrial microbiota, inflammation and IVF outcomes. To this purpose, endometrial microbiota and selected components of the "cytokine network" were analyzed in women presenting RIF and divided between eubiosis and dysbiosis groups, according to the percentage of endometrial lactobacilli (≥90% or <90%, respectively). The Dysbiosis group presented significantly higher tissue concentrations of the inflammatory markers (IL-6, IL-1ß, HIF-1α and COX-2) and significantly lower levels of the anti-inflammatory/well-being factors, IL-10 and IGF-1, with respect to women with eubiosis. Moreover, the Lactobacillus percentage was negatively related to the concentrations of the inflammatory molecules and positively related to IL-10/IGF-1. Interestingly, the number of IVF attempts was directly related to the levels of the inflammatory factors COX-2, IL-1ß and HIF-1α in the eubiosis group. Overall, endometrial dysbiosis was demonstrated to be associated with inflammation-related endometrial changes affecting the process of embryo implantation, underlining the importance of assessing uterine microbiota in patients undergoing IVF.

Effects of long-term vegan diet on breath composition.

The composition of exhaled breath derives from an intricate combination of normal and abnormal physiological processes that are modified by the consumption of food and beverages, circadian rhythms, bacterial infections, and genetics as well as exposure to xenobiotics. This complexity, which results wide intra- and inter-individual variability and is further influenced by sampling conditions, hinders the identification of specific biomarkers and makes it difficult to differentiate between pathological and nominally healthy subjects. The identification of a 'normal' breath composition and the relative influence of the aforementioned parameters would make breath analyses much faster for diagnostic applications. We thus compared, for the first time, the breath composition of age-matched volunteers following a vegan and a Mediterranean omnivorous diet in order to evaluate the impact of diet on breath composition. Mixed breath was collected from 38 nominally healthy volunteers who were asked to breathe into a 2 l handmade Nalophan bag. Exhalation flow rate and carbon dioxide values were monitored during breath sampling. An aliquot (100 ml) of breath was loaded into a sorbent tube (250 mg of Tenax GR, 60/80 mesh) before being analyzed by thermal desorption-gas chromatography-mass spectrometry (TD-GC-MS). Breath profiling using TD-GC-MS analysis identified five compounds (methanol, 1-propanol, pentane, hexane, and hexanal), thus enabling differentiation between samples collected from the different group members. Principal component analysis showed a clear separation between groups, suggesting that breath analysis could be used to study the influence of dietary habits in the fields of nutrition and metabolism. Surprisingly, one Italian woman and her brother showed extremely low breath isoprene levels (about 5 pbv), despite their normal lipidic profile and respiratory data, such as flow rate and pCO2. Further investigations to reveal the reasons behind low isoprene levels in breath would help reveal the origin of isoprene in breath.

Characterization of hemodynamic and metabolic abnormalities in the heart failure spectrum: the role of combined cardiopulmonary and exercise echocardiography stress test.

Heart failure (HF) is a complex clinical syndrome characterized by different etiologies and a broad spectrum of cardiac structural and functional abnormalities. Current guidelines suggest a classification based on left ventricular ejection fraction (LVEF), distinguishing HF with reduced (HFrEF) from preserved (HFpEF) LVEF. HF should also be thought of as a continuous range of conditions, from asymptomatic stages to clinically manifest syndrome. The transition from one stage to the next is associated with a worse prognosis. While the rate of HF-related hospitalization is similar in HFrEF and HFpEF once clinical manifestations occur, accurate knowledge of the steps and risk factors leading to HF progression is still lacking, especially in HFpEF. Precise hemodynamic and metabolic characterization of patients with or at risk of HF may help identify different disease trajectories and risk factors, with the potential to identify specific treatment targets that might offset the slippery slope towards overt clinical manifestations. Exercise can unravel early metabolic and hemodynamic alterations that might be silent at rest, potentially leading to improved risk stratification and more effective treatment strategies. Cardiopulmonary exercise testing (CPET) offers valuable aid to investigate functional alterations in subjects with or at risk of HF, while echocardiography can assess cardiac structure and function objectively, both at rest and during exercise (exercise stress echocardiography [ESE]). The purpose of this narrative review was to summarize the potential advantages of using an integrated CPET-ESE evaluation in the characterization of both subjects at risk of developing HF and patients with stable HF.

Circulating chemokine (CXC motif) ligand (CXCL)9 is increased in aggressive chronic autoimmune thyroiditis, in association with CXCL10.

Chemokine (CXC motif) ligand (CXCL)9 (CXCL9) has been shown to be involved in autoimmune thyroid disorders, however no data are present about CXCL9 circulating levels in chronic autoimmune thyroiditis (AT) vs controls. Serum CXCL9 (and for comparison CXCL10) has been measured in patients with AT vs normal control and nontoxic multinodular goiter, and this parameter has been related to the clinical phenotype. For this study we selected 189 consecutive patients with newly diagnosed AT, 63 euthyroid controls, 30 patients with nontoxic multinodular goiter. The three groups were similar in gender distribution and age; 26% of AT patients had subclinical hypothyroidism. Serum CXCL9 was significantly higher in AT (148±110 pg/mL) than in controls (71±34 pg/mL) or patients with multinodular goiter (87±35 pg/mL) (p<0.0001). Among AT patients, CXCL9 levels were significantly higher in patients older than 50 years, those with a hypoechoic ultrasonographic pattern or with hypothyroidism. Also CXCL10 was confirmed to be associated with AT, overall in presence of hypothyroidism. In a multiple linear regression model of CXCL9 (ln[pg/mL]) vs age, thyroid volume, TSH, AbTg, AbTPO, hypoechoic pattern, the presence of hypervascularity, and CXCL10 (ln[pg/mL]), only TSH and CXCL10 (ln[pg/mL]) were significantly related to serum CXCL9 levels. We show that circulating CXCL9 is increased in patients with aggressive thyroiditis and hypothyroidism. A strong relation between circulating CXCL9 and CXCL10 has been first shown, underlining the importance of a T helper 1 immune attack in the initiation of AT.