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Biomedical subjects

S Battaglia

Publications and source records attributed to S Battaglia.

At least 19 recordsLinked to original sources
PubMed2006

DU145 human prostate cancer cells express functional receptor activator of NFkappaB: new insights in the prostate cancer bone metastasis process.

Prostate cancer metastases to bone are observed in around 80% of prostate cancer patients and represent the most critical complication of advanced prostate cancer, frequently resulting in significant morbidity and mortality. As the underlying mechanisms are not fully characterized, understanding the biological mechanisms that govern prostate cancer metastases to bone at the molecular level should lead to the determination of new potential therapeutic targets. Receptor activator of NFkappaB ligand (RANKL)/RANK/Osteoprotegerin (OPG) are the key regulators of bone metabolism both in normal and pathological condition, including prostate cancer bone metastases. In the present study, we demonstrated that human prostate cancer cell lines, DU145 and PC3 express biologically functional RANK. Indeed, soluble human RANKL (shRANKL, 100 ng/ml) treatment induced ERK 1/2, p38 and IkappaB phosphorylations in these cells. shRANKL administration also promoted DU145 and PC3 prostate cancer cell invasion in vitro. Whereas human OPG (hOPG) administration alone (100 ng/ml) had no marked effect, combined association of both agents abolished the RANKL-induced DU145 cell invasion. As RANKL had no direct effect on DU145 cell proliferation, the observed effects were indeed related to RANKL-induced cell migration. DU145 human prostate cancer cells promoted osteoclastogenesis of osteoclast precursors generated from mouse bone marrow. Moreover, DU145 cells produced soluble factor(s) that up-regulate the proliferation of MC3T3-E1 pre-osteoblasts through the activation of the ERK 1/2 and STAT3 signal transduction pathways. This stimulation of pre-osteoblast proliferation resulted in an increased local RANKL expression that can activate both osteoclasts/osteoclast precursors and prostate cancer cells, thus facilitating prostate cancer metastasis development in bone. We confirm that RANKL is a factor that facilitates metastasis to bone by acting as an activator of both osteoclasts and RANK-positive prostate cancer cells in our model. Furthermore, the present study provides the evidence that blocking RANKL-RANK interaction offer new therapeutic approach not only at the level of bone resorbing cells, but also by interfering with RANK-positive prostate cancer cells in the prostate cancer bone metastasis development.

3T3 Cells↗
PubMed2006

Zoledronic acid activates the DNA S-phase checkpoint and induces osteosarcoma cell death characterized by apoptosis-inducing factor and endonuclease-G translocation independently of p53 and retinoblastoma status.

The molecular mechanisms responsible for the cellular effects of the nitrogen-containing bisphosphonate zoledronic acid (Zol) were assessed on several osteosarcoma cell lines differing in their p53 and retinoblastoma (Rb) status. Zol inhibited cell proliferation and increased atypical apoptosis. The Zol effects on proliferation were due to cell cycle arrest in S and G2/M phases subsequent to the activation of the intra-S DNA damage checkpoint with an increase in P-ATR, P-chk1, Wee1, and P-cdc2 levels and a decrease in cdc25c, regardless of the p53 and Rb status. In addition, the atypic apoptosis induced by Zol was independent of caspase activation, and it was characterized by nuclear alterations, increased Bax expression, and reduced Bcl-2 level. Furthermore, mitochondrial permeability was up-regulated by Zol independently of p53 in association with the translocation of apoptosis-inducing factor (AIF) and endonuclease-G (EndoG). Zol also disturbed cytoskeletal organization and cell junctions and inhibited cell migration and phosphorylation of focal adhesion kinases. The main difficulty encountered in treating cancer relates to mutations in key genes such as p53, Rb, or proteins affecting caspase signaling carried by many tumor cells. We have demonstrated for the first time that zoledronic acid activated the DNA damage S-phase checkpoint and the mitochondrial pathway via AIF and EndoG translocation, and it inhibited cell proliferation and induced cell death, bypassing these potentials mutations. Therefore, zoledronic acid may be considered as an effective therapeutic agent in clinical trials of osteosarcoma in which mutation for p53 and Rb very often occur, and where current treatment with traditional chemotherapeutic agents is ineffective.

Animals↗
PubMed2005

Small airways function and molecular markers in exhaled air in mild asthma.

BACKGROUND: Several studies suggest that the periphery of the lung is the major site of inflammation in asthma. Fractional exhaled nitric oxide (Feno) and 8-isoprostane have been proposed as biomarkers of inflammation and oxidative stress. We therefore hypothesised that small airway dysfunction in asthma is of inflammatory origin that can be detected by molecular markers in exhaled air. To test this hypothesis, we examined the relationship of Feno and 8-isoprostane in exhaled air with small airways function as assessed by the single breath nitrogen test. METHODS: Sixteen patients (14 women) with mild atopic asthma (forced expiratory volume in 1 second >80% predicted) of mean (SD) age 23.0 (5.5) years participated in a cross sectional study. Feno was recorded by chemiluminescence and 8-isoprostane was measured by ELISA in concentrated exhaled breath condensate. The slope of phase III (deltaN2) and the closing volume (CV) were assessed from the single breath washout curve. RESULTS: The median Feno level was 30.4 ppb (range 10.1-82.8), the median 8-isoprostane concentration in exhaled breath condensate was 2.2 pg/ml (range 1.6-2.7), and the mean (SD) deltaN2 value was 1.1 (0.4)% N2/l. Feno was positively associated with deltaN2 (r(s) = 0.54, p = 0.032) while 8-isoprostane was inversely correlated with FEV1% predicted (rs= -0.58; p = 0.017) and CV as a percentage of vital capacity (rs= 0.58; p = 0.019). CONCLUSIONS: Feno and 8-isoprostane in exhaled air are associated with small airways function in mild asthma. This suggests that these markers reflect small airway inflammation and favours a role for them as disease markers that is complementary to spirometry in the monitoring of patients with asthma.

Adult↗
PubMed2005

Airway hyperresponsiveness in the elderly: prevalence and clinical implications.

Airway hyperresponsiveness is associated with an increased risk of developing respiratory symptoms. The assessment of airway hyperresponsiveness can provide valuable information regarding the natural course of respiratory diseases. However, little information is available for populations of more advanced age, and data are conflicting. It was assessed whether age influences the occurrence of airway hyperresponsiveness by reviewing those studies that specifically addressed this issue, and attempting to identify the factors responsible for discrepancies between studies. Eighteen studies, published between 1983 and 2002, are included in this review. Overall, the results of the analysis are in favour of a positive association between age and airway hyperresponsiveness, the prevalence of which appears to increase in the elderly. The most important determinants were reduced lung function, probably due to geometric factors, and a history of smoking, primarily because of the length of exposure, although acute effects were also demonstrated. Atopy should also be considered as an independent determinant of airway hyperresponsiveness in the elderly population. In addition, inflammatory and neuronal mechanisms could be involved. Finally, the role of sex requires further investigation. Assessing the impact of age on the occurrence of airway hyperresponsiveness has important implications: the age-associated alterations to the lung provide a model for evaluating the contribution of structural changes to the pathogenesis of airway hyperresponsiveness. From a clinical standpoint, evaluation of the magnitude of airway hyperresponsiveness could permit the early identification of individuals who are at risk, even at more advanced age. Assessment of airway hyperresponsiveness in the aged should be considered as an additional tool in the diagnostic work-up in the subset of elderly subjects with long-term smoking exposure and/or documented atopy.

Aged↗
PubMed2001

The HCA National Disease Management Program for coronary disease detection and treatment in women.

The diagnosis and treatment of heart disease in women continues to be one of the greatest challenges facing cardiovascular medicine today. Marked reductions in mortality rates during the past 2 decades did not result in improved outcomes for women. A major rate-limiting step to improving mortality rates for women is early diagnosis and initiation of effective lifesaving therapies for women. In 1999, HCA Healthcare Systems, Inc, Nashville, TN, initiated a coordinated effort among 208 hospitals in 26 states to improve the diagnosis of coronary disease and to target women who should receive aggressive risk factor modification and referral to cardiologists. We describe the initial phases of program development, including employee risk factor screening; citywide health risk assessment; nationwide educational programs for clinicians, staff, and consumers; and a dedicated outcomes assessment program for tracking women at risk for coronary disease. We believe that these efforts provide a venue for optimal care and improved outcomes for women served by HCA facilities.

Coronary Disease↗
PubMed2001

New diagnostic criteria for diabetes and coronary artery disease: insights from an angiographic study.

OBJECTIVES: The goal of this research was to study coronary atherosclerosis in patients with type 2 diabetes compared with patients without diabetes according to the new definition of diabetes advocated by the American Diabetes Association in 1997. BACKGROUND: Patients with diabetes (fasting plasma glucose above 7.0 mM/L) have a higher risk of cardiovascular death. The correlation with the pattern and severity of their coronary atherosclerosis, especially in the new patients with "mild" diabetes (7.0 mM/L < or = fasting plasma glucose < 7.8 mM/L), remains unclear. METHODS: A cohort of 466 patients undergoing coronary angiography but free of any previous infarction, coronary intervention and insulin therapy were prospectively recruited. Ninety-three had diabetes (fasting plasma glucose > 7.0 mM/L or hypoglycemic oral treatment). Five angiographic indexes were calculated to describe severity and extent of coronary atherosclerosis. RESULTS: Overall, patients with diabetes had more diffuse coronary atherosclerosis, a greater prevalence of mild, moderate and severe stenoses and a two-fold higher occlusion rate than patients without diabetes, even after adjustment for age, gender, body mass index, hypertension, lipid parameters, smoking, family history of cardiovascular events and ischemic symptoms. Patients with "mild diabetes" had a coronary atherosclerosis pattern more similar to patients with normal fasting plasma glucose than to patients formerly defined as diabetic according to the World Health Organization criteria, except that they had a higher prevalence of <50% stenoses. CONCLUSIONS: In patients with type 2 diabetes, those with 7.0 mM/L < or = fasting plasma glucose < 7.7 mM/L have a slightly greater prevalence of mildly severe lesions that may partly explain their higher cardiovascular event rate.

Aged↗
PubMed2001

Regional lymph node dissection in the treatment of renal cell carcinoma: is it useful in patients with no suspected adenopathy before or during surgery?

OBJECTIVES: To evaluate the role of regional lymph node dissection (LND) in a series of patients with renal cell carcinoma (RCC) with no suspicion of nodal metastases before or during surgery. PATIENTS AND METHODS: A series of 167 patients with RCC, free from distant metastases at diagnosis, and who underwent radical nephrectomy at our hospital between January 1990 and October 1997, was reviewed. The mean (median, range) follow-up was 51 (45, 19-112) months. Of the 167 patients, 108 underwent radical nephrectomy alone and 59 had radical nephrectomy with regional LND limited to the anterior, posterior and lateral sides of the ipsilateral great vessel, from the level of the renal pedicle to the inferior mesenteric artery. Of these 59 patients, 49 had no evidence of nodal metastases before or during surgery. The probability of survival was estimated by the Kaplan-Meier method, using the log-rank test to estimate differences among levels of the analysed variables. RESULTS: The overall 5-year survival was 79%; the 5-year survival rate for the 108 patients who underwent radical nephrectomy alone was 79% and for the 49 who underwent LND was 78%. Of the 49 patients with no suspicion of lymph node metastases, one (2%) was found to have histologically confirmed positive nodes. CONCLUSION: These results suggest that there is no clinical benefit in terms of overall outcome in undertaking regional LND in the absence of enlarged nodes detected before or during surgery.

Adult↗
PubMed2001

Percutaneous transluminal angioplasty of the anomalous circumflex artery.

The technical experience reported in the literature concerning angioplasty in patients with anomalous origin of the left circumflex artery is limited. Balloon angioplasty seems to be a favorable approach for revascularization in these vessels, and major determinants of successful angioplasty are angiographic knowledge of their course and structure, appropriate selection of guiding catheter, and the possibility of advancing the balloon into the anomalous vessel. Five consecutive patients with severe atherosclerotic lesions on the anomalous left circumflex artery who underwent coronary angioplasty of the anomalous vessel are reported. Angiographic and clinical success were achieved in three patients with balloon alone and in one with stent implantation.

Aged↗
PubMed1998

Relation between severity of coronary artery disease, left ventricular function and myocardial infarction, and influence of the ACE I/D gene polymorphism.

Left ventricular (LV) systolic function is partly determined by severity of coronary artery disease and is improved by angiotensin-converting enzyme (ACE) inhibition, at least in post-infarct patients. Because the ACE insertion/deletion (I/D) gene polymorphism is associated with circulating and tissue ACE activity, we sought to evaluate the role of this genetic variant on LV function in patients studied with coronary angiography, taking into account coronary vessel anatomy and history of infarction. Coronary artery disease extent scores, coronary artery patency, and LV ejection fraction were assessed in 400 consecutive Caucasian patients referred for established or suspected ischemic heart disease. A previous infarction had occurred in 141 patients an average of 3.7 years before the study. The ACE DD genotype, compared with the ACE ID/II genotype, was associated with a 2.7% higher ejection fraction in noninfarct patients (p = 0.047) but a 5.0% lower ejection fraction in post-infarct patients (p = 0.047). An interaction effect between the ACE I/D gene polymorphism, the infarction status, and LV ejection fraction was observed in the whole population (p = 0.003), in patients with no disease and 1-, 2-, and 3-vessel diseases (p = 0.03 and p = 0.06, respectively), and in those with chronically occluded coronary vessels (p = 0.02). The influence of the ACE I/D gene polymorphism on LV function is modulated by infarction status and coronary anatomy.

Aged↗
PubMed1998

Percutaneous transluminal angioplasty of radial artery grafts.

The radial artery is being used with increasing frequency to replace the saphenous vein as a coronary artery bypass graft, in the belief that it will provide improved long-term patency. Several centers have confirmed that the early results of surgery using the radial artery seem to be better than those obtained with saphenous grafts. Despite these apparent gains, early failure of the radial artery graft can occur and is frequently associated with symptomatic myocardial ischemia. Percutaneous angioplasty is an alternative to reoperation to treat lesions occurring on radial artery grafts. We report on 4 patients who underwent angioplasty of radial artery grafts.

Aged↗
PubMed1997

Effect of the direct nitric oxide donors linsidomine and molsidomine on angiographic restenosis after coronary balloon angioplasty. The ACCORD Study. Angioplastic Coronaire Corvasal Diltiazem.

BACKGROUND: Nitric oxide (NO) donors, in addition to their vasodilator effect, decrease platelet aggregation and inhibit vascular smooth muscle cell proliferation. These actions could have beneficial effects on restenosis after coronary balloon angioplasty. METHODS AND RESULTS: In a prospective multicenter, randomized trial, 700 stable coronary patients scheduled for angioplasty received direct NO donors (infusion of linsidomine followed by oral molsidomine) or oral diltiazem. Treatment was started before angioplasty and continued until 12 to 24 hours before follow-up angiography at 6 months. The primary study end point was minimal lumen diameter, assessed by quantitative coronary angiography, 6 months after balloon angioplasty. Clinical variables were well matched in both groups. However, despite intracoronary administration of isosorbide dinitrate, the reference diameter in the NO donor group was significantly greater than in the diltiazem group on the preangioplasty, postangioplasty, and follow-up angiograms. Pretreatment with an NO donor was associated with a modest improvement in the immediate angiographic result compared with pretreatment with diltiazem (minimum luminal diameter, 1.94 versus 1.81 mm; P = .001); this improvement was maintained at the 6-month angiographic follow-up (minimal lumen diameter, 1.54 versus 1.38 mm; P = .007). The extent of late luminal narrowing did not differ significantly between groups (loss index in the NO donor and diltiazam groups, 0.35 +/- 0.78 and 0.46 +/- 0.74, respectively; P = .103). Restenosis, defined as a binary variable (> or = 50% stenosis), occurred less often in the NO donor group (38.0% versus 46.5%; P = .026). Combined major clinical events (death, nonfatal myocardial infarction, and coronary revascularization) were similar in the two groups (32.2% versus 32.4%). CONCLUSIONS: Treatment with linsidomine and molsidomine was associated with a modest improvement in the long-term angiographic result after angioplasty but had no effect on clinical outcome. The improved angiographic result related predominantly to a better immediate procedural result, because late luminal loss did not differ significantly between groups.

Aged↗
PubMed1997

Genetic polymorphisms of the renin-angiotensin system and angiographic extent and severity of coronary artery disease: the CORGENE study.

Genetic polymorphisms of the renin-angiotensin system (RAS) have been associated with coronary artery disease (CAD) but no relation between these polymorphisms and coronary atherosclerosis has yet been systematically evaluated. The CORGENE study is a cross-sectional study involving 463 Caucasians who underwent standardized coronary angiography for established or suspected CAD [156 patients with a previous myocardial infarction (MI), 307 without MI]. Four angiographic scores assessing the extent and severity of the coronary lesions were obtained from a double visual analysis of each angiogram, arbitration being achieved by a quantitative measurement. Three different genotypes were analyzed: the angiotensin I-converting enzyme insertion/deletion (ACE I/D) polymorphism, the Met to Thr change at position 235 of the angiotensinogen gene (AGT M235T) and the A to C transition at position 1166 of the angiotensin II type-1 receptor gene (AT1R A1166C). No significant association was observed between these polymorphisms and the clinical characteristics of MI and non-MI subjects. While most classical risk factors were positively correlated with the angiographic scores, no significant relationship could be established with the three genotypes (r ranging from -0.08 to 0.05). Only one significant correlation was observed: between the presence of the AGT 235T allele and the extent of the coronary lesions (r = -0.19, P = 0.04) in patients with low-risk status. These overall results are not in favor of a role of these RAS genetic polymorphisms in the development of coronary atherosclerosis.

Angiotensinogen↗
PubMed1997

Increased incidence of moderate stenosis among patients with diabetes: substrate for myocardial infarction?

Persons with diabetes are at higher risk for myocardial infarction and sudden death than are persons without diabetes. It has been demonstrated that the artery that occludes during acute myocardial infarction generally had less than 75% stenosis on a previous angiogram. The extent of coronary artery stenosis was analyzed for 820 consecutively examined patients who underwent coronary angiography at our institution. The patients were categorized according to the presence or absence of diabetes mellitus. The severity of stenosis was taken into consideration. Patients with diabetes had moderate (50% to 75% narrowing) stenosis much more frequently than patients without diabetes (50.6 versus 30.3%, p < 0.001). Moreover diabetes mellitus was an independent risk factor for moderate stenosis. The lesions were more frequently located on distal arteries, more frequently had a pattern of three-vessel disease, and had a trend toward more diffuse disease than described 25 years ago. This greater amount of moderate stenosis may be considered a substrate for future acute plaque rupture. It may explain the high prevalence of acute myocardial infarction and sudden death among patients with diabetes without an increase in the incidence of angina pectoris.

Aged↗
PubMed1994

Age-related distribution of endocrine cells in the human prostate: a quantitative study.

A morphometric analysis was performed to obtain quantitative data on age-related changes in prostatic endocrine cell (PrEC) density. Sixty prostates from subjects aged 14-74 years were studied with a semi-automatic image analysis system (ASM 68K, Leitz) applied to sections immunostained for chromogranin A-reactive cells. The highest density of PrECs (0.366 cells/mm of epithelial length) was found in the 25-54 year age group, which was significantly different from that found in prostates of the younger (0.311 cells/mm) and the older (0.261 cells/mm) age groups. The data probably reflect the higher incidence of incompletely developed glandular units in the younger group and the formation of new alveoli related to the usual glandular hyperplasia that occurs with increasing age in the older group.

Adolescent↗
PubMed1994

Itraconazole for experimental pulmonary aspergillosis: comparison with amphotericin B, interaction with cyclosporin A, and correlation between therapeutic response and itraconazole concentrations in plasma.

Itraconazole and amphotericin B were compared by using a newly developed model of invasive pulmonary aspergillosis in rabbits immunosuppressed with methylprednisolone and cyclosporin A (CsA). Both itraconazole at 40 mg/kg (given orally) and amphotericin B at 1 mg/kg (given intravenously) had in vivo antifungal activity in comparison with controls. At these dosages, amphotericin B was more effective than itraconazole in reducing the tissue burden (log10 CFU per gram) of Aspergillus fumigatus (P < 0.05) and the number of pulmonary lesions (P < 0.01). However, there was considerable variation in the near-peak concentrations of itraconazole in plasma (median, 4.15 micrograms/ml; range, < 0.5 to 16.8 micrograms/ml) and a strong inverse correlation between concentrations of itraconazole in plasma and the tissue burden of A. fumigatus. An inhibitory sigmoid maximum-effect model predicted a significant pharmacodynamic relationship (r = 0.87, P < 0.001) between itraconazole concentrations in plasma and antifungal activity as a function of the tissue burden of A. fumigatus. This model demonstrated that levels in plasma of greater than 6 micrograms/ml were associated with a significantly greater antifungal effect. Levels in plasma of less than 6 micrograms/ml were associated with a rapid decline in the antifungal effect. Itraconazole, in comparison with amphotericin B, caused a twofold elevation of CsA levels (P < 0.01) but was less nephrotoxic (P < 0.01). This study of experimental pulmonary aspergillosis demonstrated that amphotericin B at 1 mg/kg/day was more active but more nephrotoxic than itraconazole at 40 mg/kg/day, that itraconazole increased concentrations of CsA in plasma, and that the antifungal activity of itraconazole strongly correlated with concentrations in plasma in an inhibitory sigmoid maximum-effect model. These findings further indicate the importance of monitoring concentrations of itraconazole in plasma as a guide to increasing dosage, improving bioavailability, and optimizing antifungal efficacy in the treatment of invasive pulmonary aspergillosis.

Amphotericin B↗
PubMed1990

[Vector cardiography features of right ventricular activation delays: nosologic classification and clinical correlation].

Electrovectorcardiographic features of 150 patients showing right ventricular activation delays (RVAD) has been analyzed. This analysis of RAVD, especially for type I, which is the group with the widest morphologic variability, has permitted a more detailed classification: a type I with 5 subtypes, a type II with 1 subtype, a type III and an intermediate type between type II and III. Fifty-five per cent of the patients were included in type I and its variant and most were classified, often without cardiac disease, as belonging to the classic type I. Thirty per cent of RVAD were of type II; 12% of type III and the remaining were in the intermediate group between type II and III. The various morphologies, moreover, were correlated with the clinical picture: the classic type I was never seen in subjects with cardiac disease, while the others types and subtypes were present either in subjects with cardiac disease or in elderly subjects, also without relevant pathologies (senile heart, especially, the type IA") or in otherwise healthy subjects. In a medical-social context, checking for RVAD, in the absence of cardiac disease, might usefully avoid further investigation. It is underlined the usefulness of this correlation for clinical prognostic judgement.

Adolescent↗