PubMed Health⌕ Search

Biomedical subjects

S Fumagalli

Publications and source records attributed to S Fumagalli.

At least 19 recordsLinked to original sources
PubMed2001

Novel mode of action of iloprost: in vitro down-regulation of endothelial cell adhesion molecules.

Iloprost is a stable prostacyclin analog commonly employed in the treatment of peripheral vascular disease and also indicated in the treatment of patients affected by systemic sclerosis (SSc) in the presence of severe Raynaud's phenomenon (RP). Several mechanisms of action of the drug other than vasodilation and antiplatelet effect have been demonstrated that may be involved in the exertion of its clinical efficacy. Aim of the present study was to investigate whether iloprost down-regulated lymphocyte adhesion to endothelium through a modulation of adhesion molecule expression on the surface of endothelial cells. In the presence of iloprost, both lymphocyte adhesion and IL-1 stimulated expression of ICAM-1 and ELAM-1 exhibited a significant reduction, while unstimulated adhesion molecule expression was not significantly affected. Our results confirm that iloprost is able to down-regulate lymphocyte adhesion to endothelial cells and indicate that endothelium itself could be target of iloprost administration. Attenuation of the inflammatory response through modulation of cellular interactions could be suggested as a potential mechanism of action of iloprost, when used in the treatment of pathological conditions characterized by endothelial activation.

Cell Adhesion↗
PubMed2000

Cardiopulmonary resuscitation of older, inhospital patients: immediate efficacy and long-term outcome.

OBJECTIVE: To determine the independent effect of advancing age on prognosis after cardiopulmonary resuscitation (CPR). DESIGN AND SETTING: Retrospective analysis of clinical records of patients who received CPR in a geriatric department equipped with an intensive care unit. PATIENTS: A total of 245 patients (146 men, 99 women; mean age, 70+/-11 yrs) received CPR. Of these, 221 had a cardiocirculatory arrest (CA) in the intensive care unit and 24 had a CA in the general ward of the department. Acute myocardial infarction was the most frequent admission diagnosis. INTERVENTIONS: CPR according to standard guidelines in all cases. MEASUREMENTS AND MAIN RESULTS: Immediate, short-term (hospital discharge), and long-term (median follow-up, 31.5 months; range, <1-124 months) survival. Older patients had a lower immediate survival (<70 yrs [72/137] 52.6% vs. > or =70 yrs [43/108] 39.4%; p < .05) and, less frequently, ventricular tachycardia/ fibrillation (VT/VF) as a cause of CA. VT/VF bore the lowest immediate mortality rate (19/104; 18.3%) as compared with asystole/complete heart block (66/102; 64.7%) or pulseless electrical activity (40/49; 81.6%; p < .001). Acute myocardial infarction, acute heart failure, hypotension, and occurrence of CA in the intensive care unit were also univariate predictors of unfavorable, immediate prognosis. However, in a multiple logistic analysis model, the mechanism of CA (asystole/complete heart block or pulseless electrical activity vs. VT/VF), acute myocardial infarction, heart failure, and hypotension were independent predictors of unfavorable immediate prognosis, whereas advancing age was not. Similarly, after initially successful CPR, short-term survival was independently associated with acute myocardial infarction, hypotension before CA, initial rhythm at CA, and need for mechanical ventilatory support after CPR, but not with age. Longterm survival (42 patients; 17.2% of the original cohort; median survival, 32 months) was also independent of age, whereas it was negatively associated with heart failure. CONCLUSION: Immediate, short- and long-term prognosis after in hospital CPR is independent of age, at least when possible confounders are simultaneously taken into account.

Aged↗
PubMed2000

Determinants of exercise tolerance after acute myocardial infarction in older persons.

OBJECTIVES: Exercise tolerance is reduced with advancing age. Identification of potentially reversible determinants of the age-related decrement in exercise tolerance, which remain largely unexplored in older subjects and in patients recovering from a recent myocardial infarction (MI), may have useful therapeutic implications. The objective of this study was to identify the independent determinants of exercise tolerance in older patients with a recent MI. DESIGN, SETTING, AND PARTICIPANTS: Data is from baseline assessment of 265 post-MI patients (age range 45-85 years) enrolled in the Cardiac Rehabilitation in Advanced Age randomized, controlled trial. Patients with major comorbidities or severe MI complications were excluded from the trial. Exercise tolerance was determined from symptom-limited exercise testing and expressed as total work capacity (TWC, kg.m) or peak oxygen consumption (VO2peak, mL/kg/min). The associations between both TWC and VO2peak and baseline demographic, social, clinical, and neuropsychological variables and an index of health-related quality of life were determined with univariate and multivariate analysis. RESULTS: With univariate analysis, TWC decreased by 1285 kg.m per decade of increasing age between 45 and 85 years of age. With multivariate analysis, TWC decreased by 922 kg.m per decade. Increasing age (P < .001), female gender (P < .001), a small body surface area (P < .001), a low level of usual physical exercise before MI (P < .002), and the presence of post-MI depressive symptoms (P < .024) were independently associated with a lower TWC. The same factors, in addition to a small arm muscle area (P < .002), were also independently associated with a lower VO2peak. CONCLUSIONS: Age per se accounts for approximately 70% of the age-related decay in TWC or VO2peak. However, the inclusion of modifiable factors such as physical exercise and depression in the prediction model reinforces the importance of a multidimensional approach to the evaluation and treatment of older patients with a recent MI.

Age Factors↗
PubMed1999

Target of rapamycin (TOR): balancing the opposing forces of protein synthesis and degradation.

Mitogenic and nutritional signals must be integrated for a cell to grow. The target of rapamycin (TOR) is emerging as an effector for signals which indicate to the cell whether the external environment is conducive for growth. Use of the immunosuppressant rapamycin, a bacterial macrolide, has been instructive in identifying potential signaling components downstream of TOR, leading to the observation that both protein synthesis and turnover are under TOR control. The central issues concerning TOR are the identification of the proliferative and anti-proliferative signals which mediate its function and the mechanisms by which these signals are transduced to downstream molecules.

Animals↗
PubMed1999

Heart failure in community-dwelling older persons: aims, design and adherence rate of the ICARe Dicomano project: an epidemiologic study. Insufficienza Cardiaca negli Anziani Residenti a Dicomano.

BACKGROUND: The prevalence of heart failure (HF) increases with age, and HF is a major cause of disability and mortality in older persons. Detection of HF in epidemiological studies has relied on criteria validated only in young and middle-age adults, and, therefore, may prove inadequate in older subjects, because they do not take into account the pathophysiologic and clinical peculiarities of HF in old age. Thus, the true prevalence of HF in the older general population remains uncertain and has probably been underestimated in previous studies. Moreover, the mechanism and the extent by which HF hinders physical functioning in older people has not been fully elucidated. OBJECTIVES: This paper describes the design of the ICARe study, carried out in an older home-dwelling population to collect data about: (1) the sensitivity and specificity of diagnostic criteria used previously in epidemiological studies of HF; (2) the prevalence of the different pathophysiologic forms of HF; and (3) the impact of HF on overall health status, and on physical functioning, in the absence or presence of chronic comorbidity. DESIGN AND SETTING: This was a cross-sectional survey. Eligible were all community-dwelling persons aged 65 years or older recorded in the Registry Office of Dicomano, a small town nearby Florence (Italy). All the domains of multidimensional geriatric assessment were explored through different phases of the study (home interview, laboratory testing, geriatric visit) that comprised an extensive cardiopulmonary instrumental assessment including: color Doppler echocardiography, echotomography of the carotid arteries used in an original method to determine arterial compliance, and bell spirometry. Presence of major chronic conditions was ascertained by predefined, standard algorithms that were based largely on clinical examination. RESULTS: There were 864 older persons eligible for the ICARe study. Even with a substantial decline from home interview (91.2%) to the cardiopulmonary study (71.1%), the adherence rate remained high throughout the study, and the population examined was fairly representative of the original eligible population. Thus, we believe that the data collected in this study offer a unique opportunity to assess the validity of the diagnostic clinical criteria for HF in the general older population, to identify the pathophysiology underlying the syndrome, and to investigate the relationship between HF, comorbidity, and disability.

Activities of Daily Living↗
PubMed1998

Disruption of the p70(s6k)/p85(s6k) gene reveals a small mouse phenotype and a new functional S6 kinase.

Recent studies have shown that the p70(s6k)/p85(s6k) signaling pathway plays a critical role in cell growth by modulating the translation of a family of mRNAs termed 5'TOPs, which encode components of the protein synthetic apparatus. Here we demonstrate that homozygous disruption of the p70(s6k)/p85(s6k) gene does not affect viability or fertility of mice, but that it has a significant effect on animal growth, especially during embryogenesis. Surprisingly, S6 phosphorylation in liver or in fibroblasts from p70(s6k)/p85(s6k)-deficient mice proceeds normally in response to mitogen stimulation. Furthermore, serum-induced S6 phosphorylation and translational up-regulation of 5'TOP mRNAs were equally sensitive to the inhibitory effects of rapamycin in mouse embryo fibroblasts derived from p70(s6k)/p85(s6k)-deficient and wild-type mice. A search of public databases identified a novel p70(s6k)/p85(s6k) homolog which contains the same regulatory motifs and phosphorylation sites known to control kinase activity. This newly identified gene product, termed S6K2, is ubiquitously expressed and displays both mitogen-dependent and rapamycin-sensitive S6 kinase activity. More striking, in p70(s6k)/p85(s6k)-deficient mice, the S6K2 gene is up-regulated in all tissues examined, especially in thymus, a main target of rapamycin action. The finding of a new S6 kinase gene, which can partly compensate for p70(s6k)/p85(s6k) function, underscores the importance of S6K function in cell growth.

Amino Acid Sequence↗
PubMed1998

Aims, design and enrollment rate of the Cardiac Rehabilitation in Advanced Age (CR-AGE) randomized, controlled trial.

Data regarding the efficacy of cardiac rehabilitation after acute myocardial infarction in advanced age are limited, and are derived from either controlled but non randomized trials, or observational studies. Several aspects of cardiac rehabilitation after myocardial infarction in advanced age, including its effectiveness on exercise tolerance and health-related quality of life, as well as the feasibility of rehabilitation programs, need clarification. The objectives of this randomized, controlled trial, Cardiac Rehabilitation in Advanced Age (CR-AGE), are to examine the effects of an 8-week comprehensive cardiac rehabilitation intervention, comparing 1) supervised outpatient, hospital-based cardiac rehabilitation, 2) home-based cardiac rehabilitation, and 3) usual care in each of three groups of post-myocardial infarction patients, 45-65, 66-75, and 76-85 years of age. The primary objective of the trial is to evaluate the change in physical fitness in each age group assessed by total work capacity at the end of the intervention, and during follow-up over both the medium- (6 months) and the long-term (1 and 2 years). Secondary objectives of the trial include an examination of the feasibility of cardiac rehabilitation in older patients, as well as the determination of the following: exercise complication rates; changes in peak oxygen consumption; changes in other outcome measures, such as health-related quality of life, prevalence of anxiety and depressive symptoms, fluid intelligence, body composition and mass index; incidence of new cardiac and non-cardiac events; and utilization rates of health care services. Enrollment in the CR-AGE trial is expected to be completed within the first half of 1998.

Aged↗
PubMed1998

Effective arterial elastance and the hemodynamic effects of intraaortic balloon counterpulsation in patients with coronary heart disease.

OBJECTIVES: The goal of the present study was to analyze the effects of different intraaortic balloon counterpulsation (IABC) inflation volumes on effective arterial elastance (Ea) in patients with complicated coronary heart disease and to determine whether Ea can predict the hemodynamic response to IABC. BACKGROUND: Ea (the central aortic end-systolic pressure to stroke volume ratio) incorporates the principal elements of input arterial impedance and has been proved useful to evaluate the effects of afterload reduction in patients with left ventricular (LV) failure. However, although the hemodynamic action of IABC can be considered as a typical example of "pure" afterload reduction, it has never been assessed in terms of changes in Ea. METHODS: After clinical stabilization, 18 patients treated with IABC for complicated acute myocardial infarction or unstable angina were enrolled in the study. Systemic hemodynamics were measured by use of right cardiac thermodilution catheters with IABC off (control) and IABC on at balloon inflation volumes of 20 and 40 ml, in randomized sequence. Aortic pressure was recorded through the central lumen of the IABC catheter to calculate Ea as the ratio of aortic dicrotic pressure to stroke volume. RESULTS: A higher control Ea was associated with a lower control LV stroke work and a larger IABC-related hemodynamic improvement (that was maximal with the 40 ml inflation volume). The increase in LV stroke work was closely related to the decrease in Ea. Accordingly, hemodynamic benefits from IABC were less evident in patients with lower control Ea. In conclusion, effects of IABC were related to both balloon inflation volume and control hemodynamics, reflecting the afterload dependence of a depressed LV function.

Aged↗
PubMed1997

Rapamycin suppresses 5'TOP mRNA translation through inhibition of p70s6k.

Treatment of mammalian cells with the immunosuppressant rapamycin, a bacterial macrolide, selectively suppresses mitogen-induced translation of an essential class of mRNAs which contain an oligopyrimidine tract at their transcriptional start (5'TOP), most notably mRNAs encoding ribosomal proteins and elongation factors. In parallel, rapamycin blocks mitogen-induced p70 ribosomal protein S6 kinase (p70s6k) phosphorylation and activation. Utilizing chimeric mRNA constructs containing either a wild-type or disrupted 5'TOP, we demonstrate that an intact polypyrimidine tract is required for rapamycin to elicit an inhibitory effect on the translation of these transcripts. In turn, a dominant-interfering p70s6k, which selectively prevents p70s6k activation by blocking phosphorylation of the rapamycin-sensitive sites, suppresses the translation of the chimeric mRNA containing the wild-type but not the disrupted 5'TOP. Conversion of the principal rapamycin-sensitive p70s6k phosphorylation site, T389, to an acidic residue confers rapamycin resistance on the kinase and negates the inhibitory effects of the macrolide on 5'TOP mRNA translation in cells expressing this mutant. The results demonstrate that the rapamycin block of mitogen-induced 5'TOP mRNA translation is mediated through inhibition of p70s6k activation.

3T3 Cells↗
PubMed1997

Increased renal formation of thromboxane A2 and prostaglandin F2 alpha in heart failure.

Renal formation of the vasoconstrictor prostaglandins thromboxane A2 (TXA2) and prostaglandin F2 alpha (PGF2 alpha) was investigated in 25 patients with cardiac failure, divided into New York Heart Association functional classes I to IV, and in eight healthy control subjects. Plasma renin activity (PRA) and hemodynamic parameters were also investigated. Renal vasoconstrictor eicosanoid formation, measured in urinary daily excretion, was not different between patients in class I and control subjects. Class II to IV patients showed progressively increasing production of PGF2 alpha (F = 49.8, p < 0.001, analysis of variance) and TXA2 (F = 37.8, p < 0.002). PGF2 alpha excretion peaked in class IV (+ 1266% vs class I, p < 0.001). Compared with class I, urinary excretion of thromboxane B2 was + 816% in class III and + 1561% in class IV (both p < 0.001). PRA was significantly increased only in class IV (+ 1558%, p < 0.001). The current results indicate a progressive increase in renal production of vasoconstrictor eicosanoids directly related to New York Heart Association class and suggest that these prostanoids may have a role in deterioration of renal function.

Adolescent↗
PubMed1997

Item re-scaling of an Italian version of the sickness impact profile: effect of age and profession of the observers.

An Italian version of the Sickness Impact Profile (SIP) obtained by professional and nonprofessional translators was checked for cross-cultural equivalence using a back-translation method followed by two scaling studies. The first scaling study involved 30 health professionals who ranked the items within each category for severity of dysfunction. By comparing Italian and US average ranks, 14 highly discordant items were identified. A revised translation was evaluated in a new study involving 120 observers stratified by age (< 65 versus > or = 65 years) and profession (health versus non health professionals) into 4 groups of the same size. The Italian and American item rank orders were almost equivalent, independently of the age and profession of the observers (93% of the ranks showing differences < 2), suggesting that this Italian version of SIP is cross-culturally unbiased. However, older age was associated with higher variability in the rank orders, and some caution is required for use in the geriatric population.

Adult↗
PubMed1996

Molecular interaction between limb deformity proteins (formins) and Src family kinases.

Ld proteins (formins) are encoded by the limb deformity (ld) gene and define a family of related gene products regulating establishment of embryonic polarity. In this study we establish that chicken and murine Ld proteins interact directly with Src family kinases (c-Src and c-Fyn). Specific binding is mediated by the proline-rich domain present in Ld proteins and the ligand binding surface of the Src SH3 domain. Co-immunoprecipitation of Ld and c-Src proteins from transfected cells shows that these proteins associate in vivo. Immunolocalization and biochemical fractionation of fibroblasts confirms the predominant nuclear localization of Ld proteins, but unexpectedly identifies a population of Ld proteins associated to cellular membranes. This population of Ld proteins co-localizes with membrane-associated c-Src proteins at both plasma and perinuclear membranes. These studies indicate that the morphoregulatory Ld proteins interact with signal transduction cascades by association to membrane-bound Src family kinases.

Amino Acid Sequence↗
PubMed1995

Requirement for Src family protein tyrosine kinases in G2 for fibroblast cell division.

The protein tyrosine kinase c-Src is transiently activated at the transition from the G2 phase to mitosis in the cell cycle of mammalian fibroblasts. Fyn and Yes, the other members of the Src family present in fibroblasts, were also found to be activated at mitosis. In cells microinjected with a neutralizing antibody specific for Src, Fyn, and Yes (anti-cst.1) during G2, cell division was inhibited by 75 percent. The block occurred before nuclear envelope breakdown. Antibodies specific for phosphatidylinositol-3 kinase alpha and phospholipase C-gamma 1 had no effect. Microinjection of the Src homology 2 (SH2) domain of Fyn was also inhibitory. Functional redundancy between members of the Src family was observed; a Src-specific antibody had no effect in NIH 3T3 cells but inhibited cell division in fibroblasts in which the only functional Src family kinase was Src itself. Thus, Src family kinases and proteins associating with their SH2 domains are required for entry into mitosis.

3T3 Cells↗
PubMed1995

Association of serum creatinine and age with headache caused by nitrates. Gruppo Italiano di Farmacovigilanza nell'Anziano.

To assess whether serum creatinine and age are associated with headache induced by nitrates, 2742 hospitalized patients taking nitrates were studied during their hospital stay. Those patients with admission serum creatinine levels from 97 to 133 mumol/L and > 133 mumol/L were compared with patients with creatinine levels < 97 mumol/L. Gender, body mass index, comorbidity, cognitive status, new intake of nitrates, number of daily administrations, and daily dosage, as well as intake of angiotensin converting enzyme inhibitors, calcium antagonists, diuretics and nonsteroidal anti-inflammatory drugs were examined as possible confounders. Fifty-six patients had headaches that had a causal link with intake of nitrates. Compared with the lowest creatinine group, after adjustment for potential confounding variables, the odds ratios and 95% confidence interval (95% CI) for headache caused by nitrates associated with increasing serum creatinine levels were 0.6 (95% CI, 0.3 to 1.1) and 0.2 (95% CI, 0.0 to 1.2), respectively (p for trend = 0.013). Increasing age was inversely associated with headache (odds ratio for 10-year increase, 0.6 [95% CI, 0.5 to 0.7]). Serum creatinine and age were independently and inversely associated with headache caused by nitrates.

Aged↗
PubMed1995

Immediate and long-term survival after intra-aortic balloon pumping: is advanced age an independent, unfavorable prognostic factor?

OBJECTIVE: To determine whether advanced age is an independent prognostic factor that may increase the risk of complications and reduce the immediate and long-term survival after treatment with intra-aortic balloon pumping (IABP) for acute ischemic heart disease. DESIGN: Retrospective analysis of a clinical series and long-term follow-up study. PATIENTS: A total of 142 patients (age range 23-86 years) in whom IABP was indicated following a standardized protocol. MEASUREMENTS: Univariate analysis of the association between age and anamnestic, clinical, and hemodynamic data significantly affecting prognosis; multivariate logistic regression analysis of variables showing significant associations. RESULTS: IABP-related complications were independent of age. At univariate analysis, pre-existing, noncardiac, associated conditions (chronic renal failure, stroke, bronchopulmonary disease) (P < .001), an indication to IABP for hemodynamic complications of acute myocardial infarction rather than for medically refractory myocardial ischemia (P < .001), a lack in hemodynamic response to IABP (P < .002), a prolonged delay to IABP initiation (P < .003), and advanced age (P < .025) were all predictors of in-hospital mortality. However, older patients were also more frequently affected by chronic comorbid conditions and by acute left ventricular failure as an indication to IABP. When these variables were entered into logistic regression models, the association between age and mortality was no longer statistically significant. Similarly, advancing age was associated (P < .012) with an increased mortality rate during an average follow-up of 94 +/- 9 months, but, again, such a significant association disappeared when simultaneously adjusting for New York Heart Association functional class, which was the single most important predictor of long-term mortality. CONCLUSIONS: Several anamnestic and clinical variables, rather than advanced age itself, are independent, prognostic factors negatively affecting the outcome of treatment with IABP. Technique-related complications are independent of age. Thus, old age should not be considered as a criterion to exclude any patient, a priori, from the potential benefits of this type of cardiocirculatory assistance.

Acute Disease↗
PubMed1994

A target for Src in mitosis.

The activity of the c-Src protein is increased during cell-cycle stage G1 in fibroblasts stimulated with certain growth factors, and at the G2/M transition, but little is known about Src substrates in these circumstances. In contrast, cells transformed with activated Src contain many tyrosine-phosphorylated proteins. We compared the phosphotyrosine content of growing and mitotically arrested Src-transformed cells. We report here that although phosphorylation of most proteins was unchanged during mitosis, phosphorylation of one of about 68K was greatly enhanced. The p68 was physically associated with activated c-Src, and it bound to the SH3 domain of c-Src in vitro. Tyrosine-phosphorylated p68 was also present in mitotic extracts of normal cells, suggesting that its phosphorylation was not just a consequence of transformation. Purification and microsequencing of p68 showed that it was related to the previously described GAP-associated protein p62 (ref. 6).

3T3 Cells↗