Multi-objective optimization of nitinol stent design.

Nitinol stents continuously experience loadings due to pulsatile pressure, thus a given stent design should possess an adequate fatigue strength and, at the same time, it should guarantee a sufficient vessel scaffolding. The present study proposes an optimization framework aiming at increasing the fatigue life reducing the maximum strut strain along the structure through a local modification of the strut profile.The adopted computational framework relies on nonlinear structural finite element analysis combined with a Multi Objective Genetic Algorithm, based on Kriging response surfaces. In particular, such an approach is used to investigate the design optimization of planar stent cell.The results of the strut profile optimization confirm the key role of a tapered strut design to enhance the stent fatigue strength, suggesting that it is possible to achieve a marked improvement of both the fatigue safety factor and the scaffolding capability simultaneously. The present study underlines the value of advanced engineering tools to optimize the design of medical devices.

Topographic correspondence between white matter hyperintensities and brain atrophy.

White matter hyperintensities (WMHs) are a common finding in normal elderly persons. We studied the biological damage associated with WMHs by assessing the correspondence between WMH location and regional gray matter loss.Voxel-based morphometry of the gray matter was carried out with statistical parametric mapping on high resolution MR images.Neurologically intact persons with mainly anterior (frontal>parieto-occipital; N = 39) and mainly posterior WMHs (parieto- occipital>frontal; N = 14) were compared with a group devoid of WMHs (N = 80). Subjects with mainly frontal WMHs had bilateral frontal (medial, superior, and inferior gyri) atrophy in gray matter, while subjects with mainly posterior WMHs had more diffuse atrophy, involving mainly the frontal but also the right insular region. Our findings suggest that frontal WMHs are associated with frontal gray matter damage while parietooccipital WMHs seem to have a weaker and more diffuse impact on gray matter.

Identification and phenotypic characterization of a subpopulation of T84 human colon cancer cells, after selection on activated endothelial cells.

The extravasation of metastatic cells is regulated by molecular events involving the initial adhesion of tumor cells to the endothelium and subsequently the migration of the cells in the host connective tissue. The differences in metastatic ability could be attributed to properties intrinsic of the various primary tumor types. Thus, the clonal selection of neoplastic cells during cancer progression results in cells better equipped for survival and formation of colonies in secondary sites. A cell line (T84SF) exhibiting an altered phenotypic appearance was selected from a colon cancer cell line (T84) by repetitive plating on TNFalpha-activated human endothelial cells and subsequent selection for adherent cells. Cell growth, motility, chemoinvasive abilities, tyrosine phosphorylation signaling, and the metastasis formation in nude mice of the two cell lines was compared. T84SF cells displayed in vitro an higher proliferation rate and a more invasive behavior compared to the parental cells while formed in vivo a greater number of metastatic colonies in nude mice. As concerns the signaling underlying the phenotypes of the selected cells, we examined the general tyrosine phosphorylation levels in both cell lines. Our results indicate that T84SF have an increased basal tyrosine phosphorylation of several proteins among which src kinase was identified. Treatment of cells with a specific inhibitor of src activity caused a greater in vitro inhibition of proliferation and invasive properties of T84 parental cells with respect to T84SF cells and diminished metastasis formation in vivo. Altogether, these data provide evidences that this new cell line may be valuable for identifying molecular mechanisms involved in the metastatic progression of colon cancer.

Sea urchin neural alpha2 tubulin gene: isolation and promoter analysis.

Expression of Talpha2 gene, during sea urchin Paracentrotus lividus development, is spatially and temporally regulated. In order to characterize this gene, we isolated the relevant genomic sequences and scanned the isolated 5'-flanking region in searching for cis-regulatory elements required for proper expression. Gel mobility shift and footprinting assays, as well as reporter gene (CAT and beta-gal) expression assays, were used to address cis-regulatory elements involved in regulation. Here we report that an upstream 5'-flanking fragment of PlTalpha2 gene drives temporal expression of reporter genes congruent with that of endogenous Talpha2 gene. The fragment contains cis-elements able to bind nuclear proteins from the gastrula stage (at which the Talpha2 gene is expressed) whose sequences could be consistent with the consensus sequences for transcription factors present in data bank.

Role of calcium in E-selectin induced phenotype of T84 colon carcinoma cells.

The adhesion of cancer cells to the endothelium during the metastatic process involves the interaction of specific cell-cell adhesion receptors on the cell surface. E-selectin on endothelial cells and sialyl Lewis X carbohydrate component on tumor cells are mainly implicated in the adhesion of colon carcinoma cells to the endothelium of target organ. In this paper we show that binding of E-selectin to T84 colon tumor cells causes approximately a twofold increase in intracellular calcium concentration. In particular, using two inhibitors of receptor operated calcium channels, CAI and SK&F 96365, we present evidences that the augmentation in cytoplasmic calcium originates from ionic influx from extracellular sources. Furthermore, we demonstrated that modulation of [Ca2+]i by engagement of E-selectin receptor starts signal transduction pathways that affect cell spreading, tyrosine phosphorylation signaling, and cancer cell motility.

E-selectin modulates the malignant properties of T84 colon carcinoma cells.

The extravasation of metastatic cells is regulated by molecular events involving the initial adhesion of tumor cells to the endothelium and subsequently the migration of cells in the host connective tissue. E-selectin on endothelial cells and sialyl Lewis X carbohydrate component on tumor cells are mainly involved in the adhesion of colon carcinoma cells to the endothelium of target organ. Interaction of T84 colon cancer cells to purified E-selectin in vitro caused an increase in the tyrosine phosphorylation of a number of proteins as well as the modulation of cellular properties correlated to the metastatic phenotype. Specifically, E-selectin-stimulated actin reorganization, increased collagenase secretion, and induced cell migration. Treatment of T84 cells with herbimycin A inhibited cell adhesion as well as selectin-induced increase of cell migration, and cytoskeleton assembly. Our data demonstrate that binding of cancer cells to E-selectin starts signal transduction pathways which may affect the tumor metastatic abilities.

Zymographic analysis of circulating and tissue forms of colon carcinoma gelatinase A (MMP-2) and B (MMP-9) separated by mono- and two-dimensional electrophoresis.

Gelatinase A (MMP-2) and gelatinase B (MMP-9) play a key role in the proteolytic cascade leading to ECM degradation during invasion and metastasis. The enzyme activity is regulated both at the intra- and extra-cellular level. Extracellular regulation is achieved mainly through the balance between proenzyme activation and inhibition, which appears to be altered in cancer patients. One of the mechanisms of MMP inhibition is the binding of the enzymes to appropriate tissue inhibitors (TIMP). In the recent literature, it has been suggested that MMP-2 and/or MMP-9 are indeed over-produced in many carcinomas, while the identity of the various enzymatic forms (latent, activated and enzyme/inhibitor complexes) remains to be elucidated. In this study we have analyzed the circulating forms of MMP-9 and MMP-2 in serum samples of patients with colon carcinoma, as well as the enzymatic activities present in tissue extracts from surgical fragments (primary tumor and its paired healthy tissue). Proteins were separated by means of mono-dimensional or bidimensional electrophoresis, and the enzymes detected by gelatin zymography and immunological assays. The results of densitometric analyses demonstrate that proMMP-9, but not proMMP-2, is significantly higher in the oncologic sera vs. the normal sera. In addition, several oligomeric circulating and tissue forms of MMP-9 are preferentially found in the oncologic samples, both in mono- and second-dimension zymograms. The activated forms of MMP-2 and MMP-9 are uniquely present in the primary tumor extracts, thus confirming the involvement of the tissue microenvironment in gelatinase activation and function.

High-dose prolonged combination therapy in non-responders to interferon monotherapy for chronic hepatitis C.

BACKGROUND: Therapy of chronic hepatitis C non- responders to interferon monotherapy with standard doses of interferon plus ribavirin is usually ineffective. AIM: To evaluate the efficacy and tolerability of high-dose prolonged combination retreatment in non- responder patients. METHODS: Patients were retreated for 6 months with 6 MU alphaIFN on alternate days and 1000 or 1200 mg/day ribavirin. HCV-RNA negative patients continued therapy for an additional 6 months. RESULTS: Forty patients (29 males, mean age 49.7 years, 34 genotype 1b, 11 with F3 fibrosis) were treated. At 6 months, 20 (50%) patients were HCV-RNA negative but six of them discontinued therapy because of adverse events. A sustained response was achieved in 28% of patients (11/40). A sustained response was more frequent among patients with genotype non-1b than in those with genotype 1b (67 vs. 21%, P=0.005) and clearance of HCV-RNA in the first 3 months had a high predictive value for sustained response (100% of sustained responders vs. 24% of non-responders, P=0.0001). CONCLUSIONS: High-dose prolonged combination therapy in non-responders to IFN monotherapy leads to a higher rate of sustained response than the standard combination regimen. Tolerability may be a rate-limiting factor. Maximal effectiveness can be predicted in patients with non-1b genotype and in those who clear HCV-RNA soon after starting retreatment.

Left ventricular function response to exercise in normotensive obese subjects: influence of degree and duration of obesity.

This study has been designed to evaluate whether duration and severity of obesity can influence left ventricular function response to exercise in obese subjects without other known cardiovascular risk factors such as hypertension, diabetes or hyperlipoproteinemia. A total of 29 obese subjects were included and they were divided, according to their body mass index and to Garrow's criteria as follows: Overweight or mildly obese subjects: body mass index from 25 to 30 kg/m2; moderately obese subjects: body mass index > 30 and < 40 kg/m2. Both obese groups were further subdivided according to their duration of obesity evaluated by accurate anamnesis in subgroup A (duration of obesity less than 120 months) and subgroup B (duration of obesity more than 120 months). Left ventricular ejection fraction was detected by blood pool gated radionuclide angiocardiography both at rest and after symptom-limited bicycle ergometer procedure. At peak exercise left ventricular ejection fraction increased significantly (p < 0.05) only in overweight subjects. Exercise produced an increase of left ventricular ejection fraction in 14 overweight and in 5 moderately obese subjects and a decrease in 2 moderately obese subjects. At peak exercise mean heart rate and mean blood pressure increased significantly (p < 0.001) in both groups. When obese subjects were subgrouped according to duration of obesity, left ventricular ejection fraction increased significantly (p < 0.05) only in overweight subjects with duration of obesity less than 120 months. Duration of obesity correlated inversely with percent change in left ventricular ejection fraction (EF) at peak exercise (delta EF) (r = -0.59; p < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

[Cardiac arrhythmias in hypertensive subjects with and without left ventricular hypertrophy compared to the circadian profile of the blood pressure]. / Aritmie cardiache in soggetti ipertesi con e senza ipertrofia ventricolare sinistra in rapporto al profilo circadiano della pressione arteriosa.

To evaluate possible correlations between cardiac arrhythmias and circadian pattern of blood pressure (BP) and of heart rate (HR), we studied 2 groups of 20 males with stable arterial hypertension of mild to moderate entity, with (Group I) or without (Group II) left ventricular hypertrophy (LVH). In patients with LVH the mean age (56 vs 46 years), the duration of the hypertensive state (48.1 vs 15.7 months), the thickening of interventricular septum (IVS; 13.7 vs 9.6 mm) and of the posterior wall of the left ventricle (13.2 vs 9.2 mm) and the mass of LV (149.8 vs 99.7 g/m2) were significantly greater (p less than 0.01). On the contrary, the 2 groups did not show significant differences concerning casual BP determined in the morning (178.3/108.4 vs 171.5/106.2 mmHg). After a pharmacological washout of 2 weeks, patients underwent a noninvasive, intermittent, monitoring of BP (every 15 min during daytime and every 30 min from 11 pm to 7 am), using a pressure meter II Del Mar Avionics, and a continuous monitoring of ECG for 24 hours, employing an instrument 445/B Del Mar Avionics. Mean 24-hour BP was not different in the 2 groups of patients (161.7/99.0 vs 158.2/98.3 mmHg); however, patients with LVH showed a significantly greater variability of BP in the morning (7 am-3 pm), while mean 24-hour HR was significantly less (71.6 vs 78.2 b/min).(ABSTRACT TRUNCATED AT 250 WORDS)

Cardiac arrhythmias as correlated with the circadian rhythm of arterial pressure in hypertensive subjects with and without left ventricular hypertrophy.

To evaluate the relationship among supraventricular and ventricular arrhythmias with blood pressure and heart rate (HR) values, we studied 2 groups of 20 hypertensive men with (group I) and without (group II) left ventricular hypertrophy. Ambulatory electrocardiographic tracings were recorded continuously, together with ambulatory arterial pressure. Systolic (SBP) and diastolic (DBP) blood pressure values measured over 24 h showed no difference between the two groups, but we found greater variability in SBP in group I. The incidence of ventricular and supraventricular arrhythmias was significantly higher in patients of group I; moreover, we found a strong correlation between the incidence of ventricular extrasystoles (VPCs) and SBP, DBP, and HR values in group I, whereas in group II the incidence of supraventricular extrasystoles (APCs) was higher during peaks of SBP and HR values. The relationship between APCs and SBP observed in group II may be attributable to the pressure stimulus on a normal atrium, and the significant correlation between VPCs and SBP, DBP, and HR values may be due to episodes of subendocardial ischemia or to the influence of adrenergic stimulation on previously compromised myocardial tissue.

[Effect of a long-term treatment with simvastatin, an inhibitor of HMG-CoA reductase, in dyslipidemic patients at high risk]. / Effetti di un trattamento cronico con simvastatina, un inibitore dell'HMG-CoA reduttasi, in pazienti dislipidemici ad alto rischio.

The reduction of total and LDL cholesterol (TC and LDLc), apoprotein B (ApoB) and in some instances triglycerides (TG) and the increase of HDL cholesterol (HDLc) and apoprotein A (ApoA) seem to be associated to a reduced coronary risk. Aim of our work was to evaluate the effects of a chronic treatment with the HMG-CoA reductase inhibitor simvastatin (MK-733), in a group of 8 dyslipidemic patients, 5 women and 3 men, aged between 48 and 69 years (mean age 59 +/- 8 years) at high risk being already affected by clinical compliances of atherosclerosis and not previously controlled by diet and/or other antidyslipidemic drugs. At the beginning and at the end (6 months) of this open study it was performed a clinical, ECG and ophthalmological examination, as well as an evaluation of the routine laboratory parameters. The initial dosage of simvastatin was a tablet of 10 mg/day, increased after a month to 20 mg and then to 40 mg/die. The mean dosage was 26.25 mg at the 3rd month and 21.25 mg at the 6th. Long-term simvastatin treatment was well tolerated (lack of important side effects as well as of significant changes of other clinical and laboratory parameters) and effective, reducing significantly (p less than 0.01) TC (317.9 +/- 30.8 vs 238.5 +/- 37.9 mg/dl), LDLc (210.6 +/- 48 vs 147.9 +/- 52 mg/dl), ApoB (144.7 +/- 17.5 vs 104.5 +/- 18), and TG (272.9 +/- 184 vs 200.5 +/- 117.6 mg/dl) and increasing in contrast HDL and ApoA values.(ABSTRACT TRUNCATED AT 250 WORDS)

[Cardiac arrhythmia in relation to the leaflet morphology in subjects with mitral valve prolapse]. / Disturbi del ritmo cardiaco in rapporto alla morfologia dei lembi in soggetti con prolasso valvolare mitralico.

Aim of this study was to verify the prevalence of cardiac arrhythmias in subjects with mitral valve prolapse (MVP) and redundant leaflets in comparison with subjects with MVP without leaflets redundance. So, 60 subjects (aged 13 to 39 years), were subdivided in 3 groups on the basis of mitral leaflets shape at 2D-echocardiography; a continuous ECG monitoring (24 hours) was also performed. Arrhythmias were more frequent and more severe in the Group III (subjects with MVP and redundant leaflets), in comparison with both Group II (subjects with MVP without leaflets redundance) and Group I (control subjects). In particular, analysing the mean values of the single arrhythmias in the 24 hours, ventricular ectopic beats (VEB), were more frequent in Group II (p less than 0.01) and Group III (p less than 0.05) in comparison with Group I; the couplets and the runs of ventricular tachycardia were more frequent in Group III than in the other groups (p less than 0.001). The number of the subjects with a Lown class greater than 3 was higher in Group III than in the other groups (p less than 0.01). In conclusion, this study confirms that MVP is a disease presenting a large variability arrhythmic risk, that seems to be real only for a subgroup of these subjects.

Noninvasive blood pressure monitoring evaluation of verapamil slow-release 240-mg antihypertensive effectiveness.

The aim of our study was to evaluate the antihypertensive effectiveness of verapamil slow-release (SR), administered once a day. We studied 11 patients, 7 male and 4 female, with an average age of 53.6 +/- 12.86 years, who had essential hypertension. After a drug washout period of at least 15 days, placebo was administered (one tablet per day), and then patients received verapamil SR 240 mg/day at 8:00 a.m. for at least 2 weeks. At the end of the washout, placebo, and active drug treatment periods we performed ambulatory intermittent blood pressure monitoring for 24 h using a Squibb Spacelabs pressurometer. After verapamil treatment, in comparison to placebo, a significant reduction of systolic (SBP) and diastolic blood pressure (DBP) (154.91 +/- 13.34/94.29 +/- 9.48 vs. 143.73 +/- 11.39/84.6 +/- 7.99 mm Hg; p less than 0.005), was observed without significant changes of the circadian blood pressure pattern. Moreover, we observed a significant reduction of SBP and DBP variability mainly during daytime, whereas this behavior was not evident for heart rate. In conclusion, verapamil SR seems useful to obtain a constant and significant reduction of 24-h blood pressure values with a significant reduction of SBP and DBP variability.

Asymptomatic episodes of ischaemia and their relation to heart rate changes in patients with chronic ischaemic heart disease.

The aim of our study was to evaluate the prevalence of asymptomatic episodes of ischaemia and their relation to heart rate in patients with effort angina pectoris undergoing continuous electrocardiographic monitoring for 24 h. We studied 91 patients with typical history of effort angina and positive stress testing (angina and rectilinear or downsloping ST segment depression more than 1 mm). During electrocardiographic monitoring 81 patients showed symptomatic or asymptomatic ischaemic episodes with ST segment depression, four patients a T wave inversion, while six patients did not show ischaemic episodes. The total number of ischaemic episodes registered was 284, of which 106 (37.32%) were symptomatic with significant heart rate increase, 130 (45.78%) asymptomatic with heart rate increase and 48 (16.9%) asymptomatic without heart rate changes. Twelve patients (13.18%) showed only symptomatic episodes of ischaemia with increase of heart rate, 26 patients (28.57%) symptomatic and asymptomatic episodes with heart rate enhancement, 12 patients (13.18%) only asymptomatic episodes with heart rate increase, eight patients (8.79%) symptomatic episodes of ischaemia with heart rate increase and asymptomatic ones with and without heart rate changes, and finally 23 patients (25.57%) showed symptomatic episodes with heart rate increase and asymptomatic ones without heart rate changes. In total, 31 (34.06%) of these patients showed during continuous electrocardiographic monitoring asymptomatic episodes of ischaemia without heart rate changes. These findings suggest a possible intervention of coronary tone modifications in determining asymptomatic ischaemic episodes without heart rate change in patients with effort angina.

Effects of low doses of amiodarone on cardiac arrhythmias in patients with chronic ischaemic heart disease.

Continuous ECG monitoring is a useful method to evaluate the efficacy of antiarrhythmic drugs. The aim of our study was to evaluate the effects of amiodarone (400 mg day-1 for seven days and then 200 mg day-1, five days a week, for 60 days) in 20 patients with chronic ischaemic heart disease ascertained by stress test, thallium-201 myocardial scintigraphy and coronary angiography and with qualitatively and quantitatively similar cardiac arrhythmias in two continuous ECG monitoring sessions performed before starting treatment. All patients were previously on treatment with isosorbide 5-mononitrate (Is-5-Mn). Patients underwent two ECG monitoring sessions for 48 h, with an ICR instrument with two leads, first during pharmacological treatment with Is-5-Mn plus placebo and then after 60 days on treatment with Is-5-Mn and amiodarone. Heart rate decreased significantly with amiodarone (from 76.9 to 69.5 beats min-1) as did premature ventricular complexes (from 4686 to 329 day-1), ventricular couplets (from 154.3 to 5.0 day-1), ventricular tachycardia runs (from 91.7 to 0). ST segment depression more than 1.5 mm was present for 93.8 min day-1 on Is-5-Mn plus placebo, and was significantly less frequently observed (for 13.8 min day-1) on Is-5-Mn plus amiodarone. Finally, transient episodes of ischaemia, both symptomatic and asymptomatic, diminished on amiodarone from 22 to 9 day-1 in a significant way. In conclusion, amiodarone is a useful drug to obtain a reduction of ventricular arrhythmias and symptomatic and asymptomatic episodes of ischaemia in patients with ischaemic heart disease.

An evaluation of the effects of isosorbide 5-mononitrate in patients with angina on effort using dynamic electrocardiography and echocardiography.

We studied 14 patients, 9 males and 5 females, with an average age of 53.6 +/- 9.2 years, having been suffering from effort angina for over 6 months, with positive ergometer test for angina and ST-segment depression greater than 1 mm. All the patients performed a washout period of 7 days at the end of which, before and after acute administration (90 min) of isosorbide 5-mononitrate or placebo some echocardiographic parameters were controlled according to a double-blind, randomized, crossover design. Moreover, after 2 months of open treatment with isosorbide 5-mononitrate (20 mg three times daily), echocardiographic parameters were investigated again. Continuous ECG monitoring (24 h) was performed after the washout period and after 2 months of treatment. After acute administration of isosorbide 5-mononitrate, we observed a reduction in pre- and afterload, whereas after 2 months of treatment the reduction in preload seems to play a more important role. Together with other mechanisms these haemodynamic changes are responsible for the substantial diminution of myocardial oxygen consumption, and consequently for the reduction of transient ischaemic episodes, both symptomatic and asymptomatic with heart rate increase. These results suggest that isosorbide 5-mononitrate exhibits a definite nitrate-typical vascular activity that is evident both after single administration and after 2 months of treatment.

Ketanserin versus propranolol in the treatment of mild and moderate essential hypertension: corroboration with ambulatory blood pressure monitoring.

In order to assess the medium-term efficacy of ketanserin in comparison with that of the beta-blocker, propranolol, a randomized double-blind crossover trial was conducted involving 13 patients suffering from mild or moderate essential hypertension. Six of these patients were also evaluated on an ambulatory basis using noninvasive intermittent blood pressure monitoring to corroborate these values. Results indicated that both ketanserin and propranolol significantly lowered systolic, diastolic, and mean blood pressure levels after 60-day treatment periods. Diastolic blood pressure levels of less than or equal to 90 mm Hg were achieved in seven patients following ketanserin therapy and in six patients after treatment with propranolol. Both ketanserin and propranolol reduced arterial blood pressure without interfering with its circadian rhythm and variability. A tendency for the blood pressure lowering effect of ketanserin to increase with age was also noted. Side effects were minimal. The results of this trial confirm the efficacy and safety of ketanserin for the treatment of mild or moderate hypertension.