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Mazzoccoli G.,Scientific Institute and Regional General Hospital Casa Sollievo della Sofferenza | Palumbo O.,Medical Genetics Unit | Carella M.,Medical Genetics Unit | Tavano F.,Scientific Institute and Regional General Hospital Casa Sollievo della Sofferenza | Di Sebastiano P.,Scientific Institute and Regional General Hospital Casa Sollievo della Sofferenza
Chronobiology International | Year: 2011

The clock gene machinery controls cellular metabolism, proliferation, and key functions, such as DNA damage recognition and repair. Dysfunction of the circadian clock is involved in tumorigenesis, and altered expression of some clock genes has been found in cancer patients. The aim of this study was to evaluate the expression levels of core clock genes in colorectal cancer (CRC). Quantitative real-time polymerase chain reaction (qPCR) was used to examine ARNTL1, CLOCK, PER1, PER2, PER3, CRY1, CRY2, Timeless (TIM), TIPIN, and CSNK1 expression levels in the tumor tissue and matched apparently healthy mucosa of CRC patients. In the tumor tissue of CRC patients, compared to their matched healthy mucosa, expression levels of ARNTL1 (p=.002), PER1 (p=.002), PER2 (p=.011), PER3 (p=.003), and CRY2 (p=.012) were lower, whereas the expression level of TIM (p=.044) was higher. No significant difference was observed in the expression levels of CLOCK (p=.778), CRY1 (p=.600), CSNK1 (p=.903), and TIPIN (p=.136). As to the clinical and pathological features, a significant association was found between low CRY1 expression levels in tumor mucosa and age (p=.026), and female sex (p=.005), whereas high CRY1 expression levels in tumor mucosa were associated with cancer location in the distal colon (p=.015). Moreover, high TIM mRNA levels in the tumor mucosa were prevalent whenever proximal lymph nodes were involved (p= .013) and associated with TNM stages IIIIV (p=.005) and microsatellite instability (p=.015). Significantly poorer survival rates were evidenced for CRC patients with lower expression in the tumor tissue of PER1 (p=.010), PER3 (p= .010), and CSNKIE (p=.024). In conclusion, abnormal expression levels of core clock genes in CRC tissue may be related to the process of tumorigenesis and exert an influence on host/tumor interactions. © Informa Healthcare USA, Inc.


Mazzoccoli G.,Scientific Institute and Regional General Hospital Casa Sollievo della Sofferenza | Copetti M.,Scientific Institute and Regional General Hospital Casa Sollievo della Sofferenza | Dagostino M.P.,Scientific Institute and Regional General Hospital Casa Sollievo della Sofferenza | Grilli M.,Scientific Institute and Regional General Hospital Casa Sollievo della Sofferenza | And 4 more authors.
Atherosclerosis | Year: 2012

Objective: Epicardial fat (EpiF) reflects abdominal visceral adiposity and visceral fat plays an important role in the development of an unfavorable metabolic and atherosclerosis risk profile. An increased cardiovascular risk has been evidenced in patients with deep venous thrombosis (DVT). Advancing age is characterized by alterations of body fat mass and function In this study we studied the association between EpiF, DVT, age, obesity and other atherosclerosis risk factors. Methods and results: 77 patients were recruited: 44 men and 33 women, 38 without DVT (65.9 ± 16.3 years, range 26-92 years) and 39 with DVT (65.4 ± 17.2 years, range 28-90 years). The study design was balanced for established atherosclerosis risk factors (gender, obesity, smoking habits, dyslipidemia, diabetes mellitus, arterial hypertension), for previous cardiovascular events, for use of statins and platelet anti-aggregating agents. Multivariate regression model and RECPAM regression tree were used to study the association between EpiF thickness and the other potential risk factors. Patients with DVT showed a thicker EpiF with respect to those without DVT (12 ± 2 mm vs. 9 ± 2 mm respectively, p < 0.001). Multivariate linear regression model showed that DVT, obesity and age were positively associated with EpiF thickness after adjusting for the established atherosclerosis risk factors. Furthermore, the RECPAM analysis was performed to evaluate interactions between DVT, age and obesity: four main distinct and homogeneous subgroups of patients in terms of EpiF thickness were identified. The most important variable in partitioning patients was represented, as expected, by DVT (p < 0.001) followed by age (p = 0.004), while obesity did not contribute to the model as well as the other atherosclerosis risk factors. Patients with DVT and older than 41 years of age had higher EpiF thickness in respect of patients with DVT and younger than 41 years of age. In patients without DVT the estimated cut-off age was 50 years, and older patients had thicker EpiF in respect of patients younger than 50 years of age. Conclusion: DVT should be considered as strongly associated with EpiF thickness. Advancing age (with or without spontaneous DVT) is significantly associated with an increased EpiF thickness. The measurement of EpiF thickness, a valuable marker of cardio-metabolic risk, may represent a useful and reliable method to evaluate cardiovascular risk in patients with idiopathic deep phlebothrombosis. © 2012 Elsevier Ireland Ltd.


Tarquini R.,University of Florence | Coletta D.,University of Florence | Mazzoccoli G.,Scientific Institute and Regional General Hospital Casa Sollievo della Sofferenza | Gensini G.F.,University of Florence
Internal and Emergency Medicine | Year: 2013

Recently, there is a growing interest in the concept of "continuity of care," since patients, being older and more complex, are increasingly seen by an array of providers in a wide variety of organizations and places. Different models of continuity of care have been proposed, yet no single model of care coordination has been proven to be universally applicable across patient (and disease) populations. In the present paper, we introduce a novel model of continuity of care, the Ospedale Santa Verdiana, in Castelfiorentino (Tuscany, Italy), and its first period (1 year) of implementation, since January 2010. There are two main cornerstones: (a) the clinical and urgent need to bridge the gap between primary care and hospital care; and (b) the development and implementation of a model of continuity and coordination of care, which target the so-called complex patient. It is not specific for a single disease but it works "across diseases." There are three driving forces: (a) "primary care" since one of the two Hospital Coordinators is a primary care physician; (b) "hospital care" since patients in the decompensated phase often require hospitalization; and (c) the "University of Florence", which is the "glue". The duties of the Hospital Coordinator, who is an assistant professor at University of Florence, are to guarantee an efficacious and dynamic communication between primary care physicians and hospitalists, and by creating a school for practitioners of the continuity and coordination of care, to make this model exportable. © 2012 SIMI.


Mazzoccoli G.,Scientific Institute and Regional General Hospital Casa Sollievo della Sofferenza | Notarsanto I.,Scientific Institute and Regional General Hospital Casa Sollievo della Sofferenza | de Pinto G.D.,Scientific Institute and Regional General Hospital Casa Sollievo della Sofferenza | Pia Dagostino M.,Scientific Institute and Regional General Hospital Casa Sollievo della Sofferenza | And 4 more authors.
Internal and Emergency Medicine | Year: 2010

For a long time, the endothelial covering of the vessels has been considered an inert surface. On the contrary, the endothelial cells are active and dynamic elements in the interaction between blood and tissues. The control of the vessel basal tone is obtained by the complex balance between the relaxing and contracting endothelial factors. Previous clinical studies show that patients suffering from rheumatoid arthritis and other autoimmune rheumatologic pathologies are at high risk of death being prematurely affected by atherosclerosis and cardiovascular diseases. Blocking tumor necrosis factor (TNF)-α by biological drugs improves the endothelial function. The aim of our study was to evaluate the effects of two anti-TNF-α drugs (infliximab and etanercept) on the endothelial function by evaluating the flow-mediated dilatation (FMD), which was measured in the brachial artery before and after treatment and after 8-12 weeks. We enrolled 36 patients (average age 52 ± 9.8 years, 12 men and 24 women), 25 of them were affected by rheumatoid arthritis (RA) and 11 were affected by psoriatic arthritis (PsA) and they were divided into three groups: 10 patients were treated with etanercept, 13 patients were treated with infliximab, 13 patients were treated with DMARDs. We measured the common carotid intimal-medial thickness (ccIMT) and the endothelial function was evaluated by FMD measurement in the brachial artery, before treatment, 1 h after the beginning of treatment and after 8-12 weeks. No statistically significant difference between the three groups was found for the ultrasonographic evaluation of the carotid IMT. On the contrary, the differences between FMD values before and after the treatment in the patients treated with etanercept (13.1 ± 0.01 vs. 18.8 ± 0.01%, p < 0.01) and in the patients treated with infliximab (11.8 ± 0.09 vs. 16.7 ± 0.09%, p < 0.01) were statistically significant. Long-term evaluation for infliximab and etanercept was performed by comparing the FMD values, respectively, 8 and 12 weeks after the first treatment. After 8 weeks, FMD value was similar to the value recorded at enrollment in the infliximab group (11.9 ± 0.03 vs. 13.54 ± 0.04%, p = 0.236) and the FMD values in the etanercept group after 12 weeks showed a not statistically significant reduction of vasodilatating effect (13.01 ± 0.03 vs. 15.67 ± 0.02%, p = 0.197). In conclusion, the use of biological drugs in patients affected by autoimmune arthritis can modify the endothelial function, as indicated by the induced FMD changes, but the long-term effect tends to be considerably reduced. © SIMI 2010.


Mazzoccoli G.,Scientific Institute and Regional General Hospital Casa Sollievo della Sofferenza | Fontana A.,Regional General Hospital Casa Sollievo della Sofferenza | Grilli M.,Scientific Institute and Regional General Hospital Casa Sollievo della Sofferenza | Dagostino M.P.,Scientific Institute and Regional General Hospital Casa Sollievo della Sofferenza | And 4 more authors.
Age | Year: 2012

Arterial and venous thrombosis have always been regarded as different pathologies and epidemiological studies have examined the association between venous thrombosis and indicators of atherosclerosis and/or arterial thromboembolic events. We measured the flow-mediated dilation (FMD), a well-known marker of arterial endothelial dysfunction, in young- middle-aged and old-aged patients with and without unprovoked deep venous thrombosis (DVT). The aim of this study was to investigate whether DVT was a significant predictor for impaired FMD, considering all the patients and young-middle-aged (age<65 years) and old-aged (age≥65 years) patients separately. FMD was measured in the brachial artery on a population of 120 subjects with the same atherosclerosis risk factors, 68 male and 52 female, 70 young-middleaged subjects (mean age±SD 49.5±10.5 years) and 50 old-aged subjects (76.2±7.7 years). Patients with DVT showed a significant decrease of FMD compared to patients without DVT (6.8±5.5% vs. 10.9±3.5%, p<0.001). Moreover, old-aged patients showed a significant decrease of FMD compared to the young-middle-aged subjects (7.4±4.1% vs. 9.8± 5.3%, p=0.005). In the whole study population, DVTwas strongly associated with FMD (risk factors adjusted β=-4.14, p<0.001). A significant interaction between age and the presence of DVT on predicting FMD was found (p=0.003) suggesting a differential behavior of DVT as predictor of FMD. In young-middle-aged group, multivariate model confirmed that DVT was the most significant predictor of continuous FMD (β=-6.06, p<0.001). On the contrary, DVT was no more a predictor of FMD in the old age group (β=-0.73, p=0.556). Furthermore, old-aged patients without DVT showed a statistically significant decrease of FMD compared to the young- middle-aged subjects without DVT (8.2±2.1% vs. 12.6±2.7%, p<0.001) and old-aged patients with DVT showed a not statistically significant decrease of the FMD compared to the young-middle-aged patients with DVT (6.7±5.3% vs. 6.8±5.7%, p= 0.932). In conclusion, young-middle-aged patients with spontaneous DVT show an impaired FMD, whereas this impairment in old-aged subjects is evident independently from the presence or absence of DVT. Aging per se may be associated with physiologic abnormalities in the systemic arteries and with endothelial dysfunction. © American Aging Association 2011.


Mazzoccoli G.,Scientific Institute and Regional General Hospital Casa Sollievo Della Sofferenza | De Cata A.,Scientific Institute and Regional General Hospital Casa Sollievo Della Sofferenza | Carughi S.,Scientific Institute and Regional General Hospital Casa Sollievo Della Sofferenza | Greco A.,Scientific Institute and Regional General Hospital Casa Sollievo Della Sofferenza | And 3 more authors.
In Vivo | Year: 2010

Background: Reciprocal influences and bidirectional connections among the nervous, endocrine and immune systems, mediated by shared neuroendocrine hormones, chemo/cytokines and binding sites contribute to the maintainment of body homeostasis. The hypothalamus-pituitary axis may play an immunomodulating role and influence cellular immune responses by releasing various hormones and neuropeptides into the blood with direct modulatory action on the immune effectors, or by regulating the hormonal secretion of peripheral endocrine glands. Aging is associated with changes in immune function. The aim of this study was to evaluate circadian variations of some endocrine and immune factors in the elderly. Materials and Methods: Serum levels of cortisol, melatonin, thyrotropin-releasing hormone (TRH), thyroid stimulating hormone (TSH), free thyroxine (FT4), growth hormone (GH), insulin-like growth factor (IGF) 1 and interleukin (IL) 2 were measured and lymphocyte subpopulation analyses were performed on blood samples collected every four hours for 24 hours from ten healthy young and middle-aged individuals (age 35-54 years) and from ten healthy elderly individuals (age 65-76 years). Results: There was a statistically significant difference between the groups in the observed values of CD20 and TSH serum levels (higher in the young and middle-aged) and CD25 and DR+ T-cells (higher in the elderly). In the group of young and middle aged subjects, a clear circadian rhythm was validated for the time-qualified changes of all the factors studied, with the exception of FT4, IGF1 and IL2. In the group of elderly individuals, a number of rhythms and correlations with neuroendocrine hormones were absent or altered. Conclusion: The results of the current study evidence aging-associated decrease of peripheral B-cell compartment, increase of activated T-cell compartment, decrease of hypophyseal thyrotropin secretion, altered circadian rhythmicity and altered hormone-immune cell correlations.


Mazzoccoli G.,Scientific Institute and Regional General Hospital Casa Sollievo Della Sofferenza | Pazienza V.,Scientific Institute and Regional General Hospital Casa Sollievo Della Sofferenza | Piepoli A.,Scientific Institute and Regional General Hospital Casa Sollievo Della Sofferenza | Muscarella L.A.,Scientific Institute and Regional General Hospital Casa Sollievo Della Sofferenza | And 4 more authors.
Journal of Biological Regulators and Homeostatic Agents | Year: 2010

There is an increased frequency of dysthyroidism in elderly people. We investigated whether there are differences among healthy young-middle-aged and elderly people in the 24-hour secretory profiles of TRH, TSH and free thyroxine. The study was carried out on fifteen healthy young-middle-aged subjects (range 36-55 years, mean age±s.e. 44.1±1.7) and fifteen healthy elderly subjects (range 67-79 years, mean age±s.e. 68.5±1.2). TRH, TSH and free thyroxine serum levels were measured in blood samples collected every four hours for 24 hours. The area under the curve (AUC), the mean of 06:00h-10:00h-14:00h and the mean of 18:00h-22:00h-02:00h hormone serum levels and the presence of circadian rhythmicity were evaluated. A normal circadian rhythmicity was recognizable for TRH and TSH in young-middle-aged subjects and for TSH in elderly subjects. Elderly subjects presented lower TSH levels, whereas there was no statistically significant difference in TRH and free thyroxine serum levels between young-middle-aged and elderly subjects. Aging is associated with an altered TSH secretion. Copyright © by BIOLIFE, s.a.s.


Mazzoccoli G.,Scientific Institute and Regional General Hospital Casa Sollievo Della Sofferenza | Sothern R.B.,University of Minnesota | De Cata A.,Scientific Institute and Regional General Hospital Casa Sollievo Della Sofferenza | Giuliani F.,Scientific Institute and Regional General Hospital Casa Sollievo Della Sofferenza | And 4 more authors.
Journal of Biological Regulators and Homeostatic Agents | Year: 2011

Specific lymphocyte cell surface molecules involved in antigen recognition and cell activation present different circadian patterns, with peaks and troughs reflecting a specific time-related compartment of immune cell function. In order to study the dynamics of variation in expression of cytotoxic lymphocyte cell surface molecules that trigger immune responses, several lymphocyte cell surface clusters of differentiation (CD) and antigen receptors, analyses were performed on blood samples collected every 4 h for 24 h from eleven clinically-healthy men. Assays for serum melatonin (peaking at night) and cortisol (peaking near awakening) confirmed 24-h synchronization of the subjects to the light-dark schedule. A significant (p≤0.05) circadian rhythm could be demonstrated for six of the 10 lymphocyte subpopulations, with midday peaks for CD8+dim (T cytotoxic cells, 11:15 h), γδTCR (gamma-delta T cell receptor-expressing cells, 11:33 h), CD8+ (T suppressor/cytotoxic cells, 12:08 h), and for CD16+ (natural killer cells, 12:59 h), and peaks during the night for CD4+ (T helper/inducer cells, 01:23 h) and CD3+ (total T cells, 02:58 h). A borderline significant rhythm (p = 0.056) was also observed for CD20+ (total B cells), with a peak late in the evening (23:06 h). Acrophases for 3 subsets, CD8+bright (T suppressor cells, 15:22 h), HLA-DR+ (B cells and activated T cells, 23:06 h) and CD25+ (activated T lymphocytes with expression of the α chain of IL2 receptor, 23:35 h), where a 24-h rhythm could not be definitively determined, nevertheless provide information on the location of their highest values and possible physiological significance. Thus, specific lymphocyte surface molecules present distinctly-timed profiles of nyctohemeral changes that indicate a temporal (i.e., circadian) organization of cellular immune function, which is most likely of physiological significance in triggering and regulating immune responses. Such a molecular cytotoxic timetable can potentially serve as a guide to sampling during experimental, diagnostic, therapeutic and/or other medical procedures. Copyright © by BIOLIFE, s.a.s.


Mazzoccoli G.,Scientific Institute and Regional General Hospital Casa Sollievo Della Sofferenza | Giuliani F.,Scientific Institute and Regional General Hospital Casa Sollievo Della Sofferenza | Sothern R.B.,University of Minnesota
Journal of Biological Regulators and Homeostatic Agents | Year: 2011

Spontaneous hormone secretory dynamics include tonic and pulsatile components and a number of periodic processes. Circadian variations are usually found for melatonin, TSH and GH, with peak secretions at night, and in cortisol secretion, which peaks in the morning. Free thyroxine (FT4) and insulin-like growth factor (IGF)1 levels do not always change with circadian rhythmicity or show only minor fluctuations. Fractional variations explore the dynamics of secretion related to time intervals, and the rate of change in serum levels represents a signal for the receptorial system and the target organ. We evaluated time-related variations and change dynamics for melatonin, cortisol, TSH, FT4, GH and IGF1 levels in blood samples obtained every 4 h for 24 h from eleven healthy males, ages 35-53 years (mean±SE 43.6±1.7). Nyctohemeral (i.e., day-night) patterns of hormone secretion levels and the fractional rate of variation between consecutive 4-hourly time-qualified hormone serum levels (calculated as % change from time 1 to time 2) were evaluated for circadian periodicity using a 24 and 12-h cosine model. A circadian rhythm was validated for serum level changes in cortisol with peaks of the 24-h cosine model at 07:48h, and melatonin, TSH and GH, with phases at 01:35h, 23:32h, and 00: 0Oh, respectively. A weak, but significant, 12-h periodicity was found for FT4 serum levels, with minor peaks in the morning (10:00h) and evening (22:00h), and for IGF1, with minor peaks in the morning (07:40h) and evening (19:40h). Circadian rhythmicity was found in the 4-hourly fractional variations with phases of increase or surge at 02:00h for cortisol, 22:29h for melatonin, 05:14h for FT4, and 21: 19h for GH. A significant 12-h periodicity was found for the 4-hourly fractional variations of TSH with two peaks in the morning (decrease or drop at 04:42h) and afternoon (surge at 16:28h), whereas IGF1 fractional variation changes did not show a significant rhythmic pattern. In conclusion, the calculation of the time-qualified fractional rate of variation allows evaluation of the dynamics of secretion and the specification of the timepoint(s) of maximal change of secretion, not only for hormones whose secretion is characterized by a circadian pattern of variation, but also for hormones that show no circadian or only weak ultradian (12 h) variations (i.e., FT4). Copyright © by BIOLIFE, s.a.s.


Mazzoccoli G.,Scientific Institute and Regional General Hospital | Dagostino M.P.,Scientific Institute and Regional General Hospital | Greco A.,Scientific Institute and Regional General Hospital Casa Sollievo della Sofferenza
Biomedicine and Preventive Nutrition | Year: 2012

Background: Epicardial adipose tissue is correlated to the amount of visceral fat and is a marker of metabolic and cardiovascular risk. Aging alters body fat mass and its function. Epicardial fat (EF) thickness, as measured by ultrasonography, reflects intra-abdominal visceral fat and is related to features of the metabolic syndrome and to cardiovascular risk. The aim of our study was to evaluate differences in the EF thickness between young-middle aged and old aged subjects. Methods: We evaluated EF thickness in 26 young-middle aged subjects (age. ±. SD 45.9. ±. 10.3 years) compared to 50 old aged subjects (age. ±. SD 76.1. ±. 7.3 years) with the common cardiovascular risk factors. Each subject underwent transthoracic M-mode echocardiogram to measure EF thickness. Results: Old aged subjects had thicker EF (11.3. ±. 1.9. mm versus 9.3. ±. 2.8. mm, p<. 0.001). A statistically significant positive trend was evidenced between age and epicardial fat thickness (R=0.437, p<. 0.001). Univariate linear regression analyses evidenced that EF correlated positively with age (p<. 0.001), obesity (p=0.003), dyslipidemia (p=0.01), arterial hypertension (p=. 0.047) and multivariate linear regression models showed that EF correlated positively with age (p<. 0.001), male gender (p=. 0.025) and obesity (p<. 0.001). Conclusion: epicardial adipose tissue is more abundant in the elderly and is correlated to visceral adipose tissue depots, indicating a higher cardiometabolic risk especially in male subjects. © 2011 Elsevier Masson SAS.

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