Thyroid disorders induced by checkpoint inhibitors.

Immune checkpoint inhibitors are drugs that inhibit the "checkpoint molecules". Different types of cancer immune checkpoint inhibitors have been approved recently: CTLA-4 monoclonal antibodies (as ipilimumab); anti-PD-1 monoclonal antibodies (as pembrolizumab and nivolumab); and anti-PD-L1 monoclonal antibodies (as atezolizumab, avelumab, and durmalumab). The increased immune response induced by these agents leads to immune-related adverse events (irAEs), that can vary from mild to fatal, according to the organ system and severity. Immune-related endocrine toxicities are thyroid dysfunctions, hypophysitis, adrenal insufficiency, and type 1 diabetes mellitus, and are usually irreversible in 50%. In particular, hypophysitis is the most frequent anti-CTLA-4-antibodies-related irAE, while thyroid abnormalities (as hypothyroidism, thyrotoxicosis, painless thyroiditis, or even "thyroid storm") are more frequently associated with anti-PD-1-antibodies. The combination of anti-CTLA-4-antibodies, with anti-PD-1-antibodies, is associated with about 30% of irAEs. Clinical signs and symptoms vary according to the influenced target organ. Endocrinopathies can often be managed by the treating oncologist. However in more severe cases (i.e. in the presence of insulin-dependent diabetes, adrenal insufficiency, or disorders of gonadal hormones, or severe hyperthyroidism, or hypothyroidism, or long-lasting management of hypophysitis) an endocrinological evaluation, and a prompt therapy, are needed.

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.

High circulating levels of N-terminal pro-brain natriuretic peptide and interleukin 6 in patients with mixed cryoglobulinemia.

Many patients with mixed cryoglobulinemia and chronic HCV infection experience symptoms, such as dyspnea, which sometimes do not seem to indicate the involvement of the liver but rather the symptoms of heart failure. To our knowledge, there has been no other study evaluating the serum levels of N-terminal pro-brain natriuretic peptide (NTproBNP) and Interleukin 6 (IL-6) in such patients. Serum NTproBNP and IL-6 were assayed in 54 patients with mixed cryoglobulinemia and chronic HCV infection, and in 54 sex- and age-matched controls. Cryoglobulinemic-patients showed significantly higher mean NTproBNP and IL-6 levels than the controls (P = 0.005). By defining a high NTproBNP level as a value higher than 125 pg/ml (the single cut-off point for patients under 75 years of age), 30% of patients with mixed cryoglobulinemia and chronic HCV infection and 7% of controls had high NTproBNP (chi-square; P < 0.003). With a cut-off point of 300 pg/ml (used to rule out heart failure in patients under 75 years of age), 5/49 patients with mixed cryoglobulinemia and chronic HCV infection and 0/54 controls had high NTproBNP (chi-square; P < 0.04). With a cut-off point of 900 pg/ml (used for including heart failure in patients aged between 50 and 75, such as the patients in this study) 3/51 of patients with mixed cryoglobulinemia and chronic HCV infection and 0/54 controls had high NTproBNP (chi-square; P = 0.07). The study revealed high levels of circulating NTproBNP and IL-6 in patients with mixed cryoglobulinemia and chronic HCV infection. The increase in NTproBNP could indicate the presence of a subclinical cardiac dysfunction.

Role of matrix metalloproteinases and their tissue inhibitors as potential biomarkers of left ventricular remodelling in the athlete's heart.

The aim of the present study was to verify whether plasma MMPs (matrix metalloproteinases) and TIMPs (tissue inhibitors of MMPs) could be used as potential markers of paraphysiological remodelling in the athlete's heart, and to correlate these matrix parameters with echocardiographic signs of LV (left ventricular) remodelling. Plasma MMP-2 and MMP-9 were measured by zymography, and TIMP-1 and TIMP-2 were measured by ELISA in 42 veteran marathoners with AH (athlete's heart), and in 25 sedentary healthy subjects (CTL). All subjects were submitted to a clinical examination and two-dimensional colour Doppler echocardiography together with the measurement of circulating NT-proBNP (N-terminal pro-B-type natriuretic peptide); GGT (gamma-glutamyl transpeptidase) was evaluated as a marker of cardiovascular disease. Veteran athletes had a significant elevation in LV dimensions and calculated LV mass index. Diastolic and systolic functions were normal for both groups. MMP-9 levels were significantly lower in AH than in CTL subjects (56.9+/-4.3 compared with 119.4+/-21.5 m-units/l, P<0.01). There were significant differences in MMP-2 between the two groups, with a down-regulation in the AH subjects (182.5+/-16.8 units/ml in CTL compared with 117.1+/-9.1 units/ml in AH, P<0.01). MMP-2 and MMP-2/TIMP-2 were inversely correlated with myocardial indices of hypertrophy in AH and CTL subjects. AH and CTL subjects showed similar TIMP values. The results of the present study indicate that MMPs and TIMPs could represent potential biomarkers of adaptive heart remodelling in the athletes. In addition, the inverse correlation of the MMP-2/TIMP-2 system with echocardiographic signs of myocardial hypertrophy could represent a new diagnostic and prognostic indicator useful in the evaluation of cardiovascular risk in athletes.

High values of CXCL10 serum levels in mixed cryoglobulinemia associated with hepatitis C infection.

OBJECTIVES: No study has evaluated circulating CXCL10 in patients with mixed cryoglobulinemia (MC) and hepatitis C virus (HCV) chronic infection. The aim of this study is to measure inteferon-inducible protein 10 (CXCL10/IP-10), interferon-gamma (IFN-gamma), and tumor necrosis factor alpha (TNF-alpha) (Th1 cytokines) in a series of cryoglobulinemic patients and to correlate this parameter to the clinical phenotype. METHODS: Serum CXCL10, IFN-gamma, and TNF-alpha were assayed in 102 patients with hepatitis C-associated cryoglobulinemia (MC + HCV), in 102 sex- and age-matched patients with type C chronic hepatitis without cryoglobulinemia (HCV+), and in 102 sex- and age-matched controls. RESULTS: Cryoglobulinemic patients showed significantly higher mean CXCL10 serum levels than controls (P < 0.0001) or HCV+ patients (P < 0.0001) (397 +/- 132 pg/mL, 92 +/- 53 pg/mL, 280 +/- 149 pg/mL, respectively). Moreover, CXCL10 was significantly increased in 30 cryoglobulinemic patients with active vasculitis compared to those without it (460 +/- 104 pg/mL vs 369 +/- 139 pg/mL, respectively; P < 0.001). Both groups of MC + HCV patients with or without active vasculitis had serum CXCL10 significantly higher than HCV+ patients (P < 0.001, P= 0.02, respectively). IFN-gamma levels were not significantly different in MC + HCV than in HCV+ patients or controls. Serum TNF-alpha levels were significantly higher in MC + HCV than in HCV+ patients or controls (median [interquartile range]: 12.0 [9.8], 5.7 [5.4], 1.3 [2.1] pg/mL, respectively; P < 0.0001). CONCLUSIONS: The study demonstrates high CXCL10 and TNF-alpha serum levels in patients with hepatitis C-associated cryoglobulinemia. Moreover, in MC + HCV patients, increased CXCL10 levels were significantly associated with the presence of active vasculitis.

Arterial stiffness, intima-media thickness and carotid artery fibrosis in patients with primary aldosteronism.

OBJECTIVES: To evaluate vascular wall structure and conduit artery stiffness in patients with primary aldosteronism. METHODS: This observational study, conducted in a University Hypertension Center, evaluated the carotid wall by 2-D ultrasonography and ultrasonic tissue characterization, and analyzed arterial stiffness by applanation tonometer. Twenty-three consecutive patients with primary aldosteronism, 24 matched patients with essential hypertension and 15 controls were studied. Intima-media thickness and corrected integrated backscatter signal of the carotid arteries were evaluated. Radial and femoral pulse wave velocity and aortic augmentation index were also investigated. RESULTS: Intima-media thickness in patients with essential hypertension (0.69 +/- 0.03 mm) was higher (P < 0.04) than that in controls (0.59 +/- 0.02 mm). This finding was more evident in primary aldosteronism patients (0.84 +/- 0.03 mm), in whom intima-media thickness was greater than that in controls (P < 0.0001) or in patients with essential hypertension (P < 0.01). Similarly, corrected integrated backscatter signal in patients with essential hypertension (-23.6 +/- 0.35 dB) was higher (P < 0.0001) than that in controls (-26.2 +/- 0.44 dB), but it was even more elevated in patients with primary aldosteronism (-22.1 +/- 0.46 dB), who showed greater corrected integrated backscatter signal than was the case in patients with essential hypertension (P < 0.009) or in controls (P < 0.0001). Femoral pulse wave velocity was higher in primary aldosteronism patients (10.8 +/- 0.57 m/s) than in patients with essential hypertension (9.1 +/- 0.34 m/s, P < 0.03) or in controls (7.1 +/- 0.51 m/s, P < 0.0001). Femoral pulse wave velocity was lower in controls than in patients with essential hypertension (P < 0.0001). The same pattern was observed for radial pulse wave velocity. Aortic augmentation index was higher in primary aldosteronism patients (28.2 +/- 2.1%) than in patients with essential hypertension (26.0 +/- 1.8%) or in controls (16.8 +/- 2.0%, P < 0.001). Patients with essential hypertension likewise exhibited higher aortic augmentation index than controls (P < 0.001). CONCLUSION: Aldosterone excess is responsible per se for vascular morphological (wall thickening and carotid artery fibrosis) and functional (central stiffness) damage.

Preclinical cardiac involvement in phaeochromocytoma: a study with integrated backscatter.

OBJECTIVE: It is well known that vascular and cardiac structure may be influenced by circulating neurohormonal factors. Our aim was to study the myocardial wall texture by integrated backscatter (IBS) analysis in patients with phaeochromocytoma (PHEO). DESIGN: Fourteen patients with PHEO, 15 matched high-normal blood pressure (BP) subjects, 15 mild essential hypertensives and 15 normotensive controls underwent two-dimensional conventional ultrasonography and ultrasonic IBS of the myocardial wall. IBS analysis was performed at both interventricular septum and posterior wall levels. IBS values were expressed in decibels and corrected for the IBS values obtained within the pericardium (C-IBS). The systo-diastolic cyclical variations in IBS (CV-IBS), an index of myocardial contractile performance, were also evaluated. RESULTS: Patients with PHEO showed C-IBS values comparable to those of hypertensive patients, and significantly higher than those of high-normal BP subjects and controls at both septum and posterior wall levels (P < 0.001 for all). In PHEO patients, CV-IBS was lower than that of normotensive, high-normal BP subjects and hypertensive patients, at both septum and posterior wall levels (P < 0.001 for all). An inverse relationship was found in the PHEO group between 24-h urinary normetanephrine and CV-IBS of both septum (r(2) = -0.29, P < 0.05) and posterior wall (r(2) = -0.46, P < 0.05). CONCLUSIONS: Our results show that patients with PHEO have myocardial remodelling characterized by increased myocardial fibrosis, confirmed by an increase in the overall myocardial backscatter level measured. The observed decrease in the magnitude of CV-IBS suggests an impairment of myocardial contractile performance. These results may provide insights into the role of catecholamines in left ventricular (LV) structure and function in PHEO.

Carotid integrated backscatter analysis in patients with subclinical hypothyroidism.

OBJECTIVE: The aim of the present study was to determine whether integrated backscatter (IBS) analysis combined with conventional ultrasonography could differentiate the tissue characteristics of carotid artery intimal hyperplasia in patients with subclinical hypothyroidism (SH). METHODS: Forty-one patients with SH, as judged by elevated serum TSH levels and free thyroid hormones within the normal range, and 31 sex- and age-matched euthyroid volunteers underwent two-dimensional conventional ultrasonography and IBS analysis of the carotid wall. Carotid intima-media thickness (IMT) and corrected IBS (C-IBS), an index of arterial wall degeneration and fibrosis, were evaluated. RESULTS: Mean IMT as well C-IBS values were higher in SH than in controls (P < 0.0001 for both), whereas the carotid diameter was not significantly different between the two groups. The distribution of C-IBS values in each group showed that regions with higher C-IBS values were found more frequently in SH patients than in control subjects. The percentage of regions that could be considered as fibromatous (C-IBS value from -18 to -21 dB) was 28% in SH and 9% in euthyroid subjects (P < 0.0001). In the SH group, C-IBS values were significantly and positively associated with plasma TSH (r = 0.32, P < 0.05 and r = 0.59, P < 0.0001, respectively) and with both total cholesterol (r = 0.46, P = 0.01) and low density lipoprotein (LDL)-cholesterol (r = 0.55, P = 0.001). CONCLUSIONS: Carotid IMT in subclinically hypothyroid patients is higher than that in euthyroid controls. This is characterized by increased IBS values, which are related to the collagen content of the arterial wall. The severity of this remodelling process seems to be related to TSH and cholesterol levels.

High values of CXCL10 serum levels in patients with hepatitis C associated mixed cryoglobulinemia in presence or absence of autoimmune thyroiditis.

The aim of this study was to evaluate CXCL10 serum levels in patients with hepatitis C virus chronic infection (HCV) associated mixed cyoglobulinemia (MC), in the presence or absence of autoimmune thyroiditis (AT). CXCL10 was assayed in 50 MC patients without AT, in 40 MC patients with AT (MC+AT), in 2 gender- and age-matched control groups [50 healthy controls (without HCV or AT; control); 40 controls with AT (without HCV and MC; control+AT)]. CXCL10 was significantly higher: (1) in control+AT than in control (p<0.001); (2) in MC patients than in control (p<0.001); (3) in MC+AT patients than in control (p<0.001), control+AT (p<0.001), or in MC (p=0.002). CXCL10 was significantly increased in MC+AT patients with thyroid hypoechogenicity (388+/-147 vs 302+/-112; p=0.03), or hypothyroidism (391+/-142 vs 307+/-118; p=0.04), compared to those without. By defining a high CXCL10 level as a value at least 2 SD above the mean value of the control (>167 pg/ml), 8% of control, 22% of control+AT, 47% of MC and 80% of MC+AT had high CXCL10 (p<0.0001). In conclusion, our study is the first to demonstrate high serum levels of CXCL10 in MC and that CXCL10 in MC+AT patients are significantly higher compared to MC patients.

An in vitro comparative study of the antioxidant activity and SIRT1 modulation of natural compounds.

Oxidative stress arises from an imbalance between the production of free radicals and antioxidant defences. Several studies have suggested that dietary antioxidants (such as polyphenols and berberine) may counteract oxidative stress through the involvement of the Sirtuin 1/Adenosine Monophosphate-Activated Protein Kinase (SIRT1/AMPK) pathway. The aim of this study was to evaluate the direct and specific antioxidant activity of some natural compounds, as well as their ability to modulate the expression of SIRT1 and the activation of AMPK. Quercetin, tyrosol, ferulic acid, catechin, berberine and curcumin were evaluated for their specific and direct antioxidant activity with TOSC assay. Their ability to modulate SIRT1 and AMPK was assessed by immunoblotting assay, while their cytotoxicity by CellTiter-Blue Cell Viability Assay. No statistically significant decrease (p > 0.05) in the number of viable cells was found upon challenging with the natural compounds. Quercetin exhibited the highest antioxidant activity against peroxyl radical and peroxinitrate derivates, while curcumin showed the best anti-hydroxyl activity with respect to the other compounds and, most importantly, respect to the reference antioxidants. Finally, all the tested compounds significantly increased the SIRT1 expression and the activation of AMPK. Our results clearly disclose the specific antioxidant activity of these natural compounds and their ability to increase SIRT1 expression and AMPK activation.

Three-Dimensional Echographic Evaluation of Carotid Artery Disease.

The introduction of three-dimensional echography (3D echo) in vascular field is not recent, but it still remains a seldom-used technique because of the costs of ultrasound probe and the need of dedicated laboratories. Therefore, despite significant prognostic implications, the high diagnostic accuracy in plaque definition, and the relative ease of use, 3D echo in vascular field is a niche technique. The purpose of this review is mainly clinical and intends to demonstrate the potential strength of a 3D approach, including technical aspects, in order to present to clinicians and imagers the appealing aspects of a noninvasive and radiation-free methodology with relevant diagnostic and prognostic correlates in the assessment of carotid atherosclerosis. A comprehensive literature search (since 1990s to date) using the PubMed, MEDLINE, and Cochrane libraries databases has been conducted. Articles written in English have been assessed, including reviews, clinical trials, meta-analyses, and interventional/observational studies. Manual cross-referencing was also performed, and relevant references from selected articles were reviewed. The search was limited to studies conducted in humans. Search terms, retrieved also with PubMed Advanced search and AND/OR Boolean operators (mainly in title and abstract), included three-dimensional, echo, stroke/transient ischemic attack, predictors, carotid, imaging, and biomarkers.

α-Synuclein Aggregates with ß-Amyloid or Tau in Human Red Blood Cells: Correlation with Antioxidant Capability and Physical Exercise in Human Healthy Subjects.

Neurodegenerative disorders (NDs) are characterized by abnormal accumulation/misfolding of specific proteins, primarily α-synuclein (α-syn), ß-amyloid1-42 (Aß), and tau, in both brain and peripheral tissue. In addition to homo-oligomers, the role of α-syn interactions with Aß or tau has gradually emerged. The altered protein accumulation has been related to both oxidative stress and physical activity; nevertheless, no correlation among the presence of peripheral α-syn hetero-aggregates, antioxidant capacity, and physical exercise has been discovered as of yet. Herein, the content of α-syn, Aß, tau, and of their heterocomplexes was determined in red blood cells (RBCs) of healthy subjects (sedentary and athletes). Such parameters were related to the extent of the antioxidant capability (AOC), a key marker of oxidative stress in aging-related pathologies, and to physical exercise, which is known to play an important preventive role in NDs and to modulate oxidative stress. Tau content and plasma AOC toward hydroxyl radicals were both reduced in older or sedentary subjects; in contrast, α-syn and Aß accumulated in elderly subjects and showed an inverse correlation with both hydroxyl AOC and the level of physical activity. For the first time, α-syn heterocomplexes with Aß or tau were quantified and demonstrated to be inversely related to hydroxyl AOC. Furthermore, α-syn/Aß aggregates were significantly reduced in athletes and inversely correlated with physical activity level, independent of age. The positive correlation between antioxidant capability/physical activity and reduced protein accumulation was confirmed by these data and suggested that peripheral α-syn heterocomplexes may represent new indicators of ND-related protein misfolding.

α-Synuclein Aggregated with Tau and ß-Amyloid in Human Platelets from Healthy Subjects: Correlation with Physical Exercise.

The loss of protein homeostasis that has been associated with aging leads to altered levels and conformational instability of proteins, which tend to form toxic aggregates. In particular, brain aging presents characteristic patterns of misfolded oligomers, primarily constituted of ß-amyloid (Aß), tau, and α-synuclein (α-syn), which can accumulate in neuronal membranes or extracellular compartments. Such aging-related proteins can also reach peripheral compartments, thus suggesting the possibility to monitor their accumulation in more accessible fluids. In this respect, we have demonstrated that α-syn forms detectable hetero-aggregates with Aß or tau in red blood cells (RBCs) of healthy subjects. In particular, α-syn levels and its heteromeric interactions are modulated by plasma antioxidant capability (AOC), which increases in turn with physical activity. In order to understand if a specific distribution of misfolded proteins can occur in other blood cells, a cohort of human subjects was enrolled to establish a correlation among AOC, the level of physical exercise and the concentrations of aging-related proteins in platelets. The healthy subjects were divided depending on their level of physical exercise (i.e., athletes and sedentary subjects) and their age (young and older subjects). Herein, aging-related proteins (i.e., α-syn, tau and Aß) were confirmed to be present in human platelets. Among such proteins, platelet tau concentration was demonstrated to decrease in athletes, while α-syn and Aß did not correlate with physical exercise. For the first time, α-syn was shown to directly interact with Aß and tau in platelets, forming detectable hetero-complexes. Interestingly, α-syn interaction with tau was inversely related to plasma AOC and to the level of physical activity. These results suggested that α-syn heterocomplexes, particularly with tau, could represent novel indicators to monitor aging-related proteins in platelets.

Epicardial coronary artery size in hypertensive and physiologic left ventricular hypertrophy.

BACKGROUND: In the hypertensive heart, epicardial arteries are not enlarged, despite increased total coronary flow related to augmented cardiac workload, wall stress, and left ventricular (LV) mass. The aims of this study were to assess the impact of different hemodynamic factors and LV mass on baseline left main coronary artery (LMA) size in hypertensive LV hypertrophy (LVH) and physiologic LVH, used as a pressure-independent model of hypertrophy. METHODS: In 104 subjects without coronary disease (26 normotensive subjects without LVH, 15 athletes with physiologic LVH, and 63 untreated hypertensive subjects [28 without and 35 with LVH]), LMA size and coronary flow reserve (CFR) were measured by transesophageal echocardiography, and LV mass, volumes, stroke work, and wall stress were measured by transthoracic echocardiography. RESULTS: The LMA area in normotensive control subjects, athletes, and hypertensive subjects without and with LVH was 13.2 +/- 4.2, 17.5 +/- 2.9, 10.1 +/- 3.2 and 13.1 +/- 3.9 mm(2). In normotensive control subjects, LMA size increased with body surface area, rate-pressure product, stroke work, and LV mass or wall thickness (r = 0.39, 0.39, 0.47 and 0.67 or 0.62, P < .05-0.01). In athletes with physiologic LVH, LMA area increased with CFR (0.65, P < .01). In the whole hypertensive population, LMA lumen increased with LV mass (r = 0.40, P < .01), and decreased with office systolic blood pressure (r = -0.48, P < .01). CONCLUSIONS: In the hypertensive LVH, baseline LMA area is not increased and is inversely related to office systolic blood pressure. In the physiologic LVH, increase in baseline LMA size seems to reflect effect of high-flow stimuli.

Carotid vascular remodeling in patients with pheochromocytoma.

CONTEXT: The influence of catecholamines on vascular remodeling in humans was investigated. OBJECTIVE: The objective was to study the carotid vascular wall in patients with pheochromocytoma (PHEO). DESIGN AND SETTING: An observational study was conducted in a university referral center for blood pressure diseases. PATIENTS: Fourteen patients with PHEO, 15 matched high-normal essential hypertensives, 15 mild essential hypertensives, and 15 controls underwent two-dimensional conventional ultrasonography and ultrasonic tissue characterization of the carotid wall. MAIN OUTCOME MEASURES: Intimal media thickness (IMT), diameter, and corrected ultrasonic integrated backscatter signal (C-IBS) of carotid arteries were evaluated. RESULTS: IMT in PHEOs (0.844 +/- 0.18 mm, mean +/- sd) was greater than not only controls (0.596 +/- 0.09 mm, P < 0.0002) but also high-normal (0.710 +/- 0.17 mm, P < 0.03), and even mild (0.727 +/- 0.20 mm, P = 0.06) hypertensives. IMT in the latter was higher than in controls (P < 0.03), without difference in comparison with high-normal hypertensives. C-IBS values in PHEOs (-21.71 +/- 2.0 dB, mean +/- sd) were greater than in controls (-26.20 +/- 1.73 dB, P < 0.0001) but also than in high-normal (-23.84 +/- 1.16 dB, P < 0.002) and mild (-23.37 +/- 1.99 dB, P < 0.01) hypertensives. C-IBS values in controls were lower than in high-normal (P < 0.0005) and mild (P < 0.0001) hypertensives. Carotid diameter was not significantly different in the four groups. In PHEOs, C-IBS was associated with urinary noradrenaline (r = 0.640, P < 0.01) and normethanephrine (r = 0.737, P < 0.009). CONCLUSIONS: Carotid IMT of PHEOs is higher than in controls and matched groups of hypertensives with comparable or even higher blood pressure. This vascular rearrangement is characterized by increased IBS values due to collagen deposition and vascular fibrosis. Therefore, our data show that abnormal catecholamine levels take part per se in carotid wall remodeling of patients with PHEO.

Endothelium-dependent vasodilation and carotid artery wall remodeling in athletes and sedentary subjects.

In this study, the relationship between age, carotid artery remodeling, and endothelium-dependent vasodilation is investigated in sedentary subjects and athletes. Thirty-two young and old healthy sedentary subjects and 32 age-matched endurance athletes underwent ultrasonography of the carotid wall for measuring intima-media thickness (IMT) and corrected integrated backscatter (C-IBS), two early indicators of the atherosclerosis process. Endothelium-dependent vasodilation was assessed by intra-brachial acetylcholine (strain-gauge plethysmography), at baseline and during NO sythase inhibitor NG-monomethyl-L-arginine (L-NMMA), and the antioxidant Vitamin C. Response to sodium nitroprusside (SNP) was also evaluated. Independently of trained status, IMT and C-IBS were higher in older than in young individuals (p<0.0001), while response to acetylcholine, but not to SNP, was lower (p<0.0001). Older athletes showed lower IMT, lower C-IBS (p<0.0001), greater response to acetylcholine (p<0.0001), and greater inhibition of acetylcholine by L-NMMA (p<0.001) than older controls. Only in older sedentary individuals, Vitamin C increased response to acetylcholine (p<0.001) and restored the inhibiting effect of L-NMMA (p<0.01). In the whole population maximal acetylcholine-induced vasodilation was inversely related to IMT (r=-0.60, p<0.0001) and to C-IBS (r=-0.56, p<0.0001). In conclusion, regular physical training can attenuate the age-related impairment of endothelium-dependent vasodilation, which is related to an attenuation of the age-induced remodeling of the carotid wall.

Acute effects of hemodialysis on left ventricular function evaluated by tissue Doppler imaging.

Evidence exists that left ventricular function is impaired in chronic uremic patients. During hemodialysis (HD) treatment, myocardium undergoes electrolyte, hemodynamic and neuro-humoral stress; however, data about the acute changes on ventricular function are controversial. Aim of the present study was to evaluate the effect of a single hemodialysis session on left ventricular (LV) systolic and diastolic function using pulsed tissue Doppler imaging (TDI) sampled by echocardiography. The study group included 20 uremic patients (17 males, aged 51+/-13 yrs) on maintenance HD, free from clinically overt cardiac dysfunction who underwent echocardiography with pulsed TDI 30 min prior and 30 min after a HD session. TDI was performed by placing the sample volume in the center of the basal lateral segment and the basal interventricular septum in the apical four-chamber view. Myocardial systolic wave (S(m)) and early (E(m)) and atrial (A(m)) diastolic waves were measured. On standard sonography examination, no significant changes in LV systolic function parameters were observed after HD, but the indices for LV diastolic function deteriorated significantly (peak E, 75.4+/-11.2 vs. 58.8+/-12.5 cm/s, P<0.01; E/A ratio, 1.0+/-0.3 vs. 0.8+/-0.2, P<0.01). However, regarding TDI measures following HD, the patients exhibited a lower S(m) peak (septum: 7.6+/-1.1 vs. 5.9+/-0.8 cm/s; lateral wall: 7.7+/-1.7 vs. 6.8+/-1.2 cm/s, P<0.001), a lower E(m) peak (septum: 8.3+/-1.6 vs. 6.3+/-1.7 cm/s; lateral wall: 10.2+/-2.4 vs. 7.1+/-1.9 cm/s, P<0.001), and a reduced E(m)/A(m) ratio (septum: 1.0+/-0.4 vs. 0.7+/-0.2; lateral wall: 1.2+/-0.5 vs. 0.7+/-0.2, P<0.001, respectively), as compared to pre-HD parameters. Of interest, peak E(m), and E(m)/A(m) ratio of the lateral wall were negatively related to ultrafiltration rate (r = -0.60, P<0.05 and -0.69, P<0.01, respectively). Our data indicate that a single hemodialysis session is associated with acute deterioration of diastolic and systolic parameters of myocardial function, as assessed by TDI. These reversible changes could be considered as a cardiac stunning that seems to be related to the ultrafiltration rate and then to the interdialysis weight gain. These findings suggest that low ultrafiltration volume and/or limited interdialytic weight gain are cardioprotective measures in hemodialysis patients.

"Effects of recombinant human erythropoietin high mimicking abuse doses on oxidative stress processes in rats".

Although many studies highlight how long-term moderate dose of Recombinant Human Erythropoietin (rHuEPO) treatments result in beneficial and antioxidants effects, few studies take into account the effects that short-term high doses of rHuEPO (mimicking abuse conditions) might have on the oxidative stress processes. Thus, the aim of this study was to investigate the in vivo antioxidant activity of rHuEPO, administered for a short time and at high doses to mimic its sports abuse as doping. Male Wistar healthy rats (n=36) were recruited for the study and were treated with three different concentrations of rHuEPO: 7.5, 15, 30µg/kg. Plasma concentrations of erythropoietin, 8-epi Prostaglandin F2α, plasma and urinary concentrations of NOx were evaluated with specific assay kit, while hematocrit levels were analyzed with an automated cell counter. Antioxidant activity of rHuEPO was assessed analyzing the possible variation of the plasma scavenger capacity against hydroxylic and peroxylic radicals by TOSC (Total Oxyradical Scavenging Capacity) assay. Statistical analyses showed higher hematocrit values, confirmed by a statistically significant increase of plasmatic EPO concentration. An increase in plasma scavenging capacity against peroxyl and hydroxyl radicals, in 8-isoprostane plasmatic concentrations and in plasmatic and urinary levels of NOX were also found in all the treated animals, though not always statistically significant. Our results confirm the literature data regarding the antioxidant action of erythropoietin administered at low doses and for short times, whereas they showed an opposite incremental oxidative stress action when erythropoietin is administered at high doses.

Subclinical cardiac involvement in patients with facioscapulohumeral muscular dystrophy.

Myocardial involvement is a common finding in certain myopathies, while it has not been extensively investigated in facioscapulohumeral muscular dystrophy (FSHD1A). Aim of this study was to assess in FSHD1A patients the electrical and functional properties of the myocardium. Twenty-four patients with FSHD1A (mean age 41.2+/-14.5 years) and 24 matched healthy subjects were studied. Standard- and signal-averaged electrocardiography were recorded to determine QT dispersion and the presence of ventricular late potentials (VLPs). Standard echocardiography with systo-diastolic variations of integrated backscatter signal (CV-IBS) were performed to assess functional properties of the myocardium. Compared with control subjects, patients with FSHD1A had significantly lower CV-IBS and higher QT dispersion. Nine patients had positive VLPs. QT and QTc dispersion were inversely related to CV-IBS at both septum and posterior wall levels. Moreover, septal CV-IBS was inversely related to the Kpnl-BinI4q fragment size. These results suggest a subclinical cardiac involvement in FSHD1A patients, which can represent a substrate for ventricular arrhythmias and heart failure.

Physical activity, plasma antioxidant capacity, and endothelium-dependent vasodilation in young and older men.

BACKGROUND: Sedentary aging is associated with oxidative stress and endothelial dysfunction. The aim of this study was to evaluate the relationship between long-term physical activity, plasma antioxidant status, and conduit artery endothelial function in young and older healthy men. METHODS: In young (n = 16) and older athletes (n = 16) and in matched healthy sedentary subjects, endothelium-dependent flow-mediated dilation (FMD) and endothelium-independent response to glyceryl trinitrate (GTN), 400 microg, were measured in the brachial artery from high-resolution ultrasonography. Plasma malondialdehyde (MDA) and antioxidant capacity as total oxyradical scavenging capacity (TOSC) were also evaluated. RESULTS: We found that FMD was lower (< or =0.01) in sedentary older subjects (2.3% +/- 1.0%) as compared with older athletes (5.3% +/- 3.2%) and both sedentary (5.4% +/- 2.0%) and athletically trained (6.1% +/- 3.2%) young subjects. Sedentary older subjects showed higher (P < or = .05) MDA levels and lower (P < .0001) plasma antioxidant capacity as compared with the other subgroups, whereas in older athletes MDA levels and antioxidant capacity were similar to those observed in the young subgroups. In the whole group, FMD, but not GTN, was negatively related to age (r = -0.31, P < .05) and directly related (P < or = .01) to VO2max (r = 0.49) and TOSC against peroxyl (r = 0.69) and hydroxyl radicals (r = 0.53). In the multivariate analysis, TOSC against peroxyl radicals resulted as the most significant predictor of FMD (R2 = 0.60; P = .003). CONCLUSIONS: These results suggest that regular physical activity is associated with preserved antioxidant defenses and endothelial function in older individuals.