Antitumor activity of interferon-ß1a in hormone refractory prostate cancer with neuroendocrine differentiation.

PURPOSE: Type I interferons (IFN-α and IFN-ß) are a class of cytokines that exert several biological activities, such as modulation of cell proliferation and differentiation and of the immune system. Although these cytokines interact with a common receptor complex, IFN-ß showed a more potent antitumor activity than IFN-α in several tumor models. New recombinant human IFN-ß products, such as IFN-ß1a and IFN-ß1b, have been produced in order to improve the stability and bioavailability of natural IFN-ß. In this report, we analyzed the effects of recombinant IFN-ß1a on the cell proliferation of two human androgen-resistant prostate cancer cell lines with neuroendocrine differentiation (DU-145, PC-3) and related mechanisms of action. METHODS: The effects of IFN-ß1a on the cell growth proliferation, cell cycle, and apoptosis have been evaluated in DU-145 and PC-3 cells through MTT assay, DNA flow cytometry with propidium iodide, and Annexin V-FITC/propidium iodide staining, respectively. Moreover, the expression of neuron-specific enolase (NSE), cleaved caspase-3, caspase-8, and PARP was evaluated through Western blotting. RESULTS: IFN-ß1a showed a significant anti-proliferative activity in both androgen-resistant cell lines. This effect was related to cell cycle perturbation and induction in apoptosis, as shown by flow cytometric analysis, the activation of caspase-3 and caspase-8 and PARP cleavage during incubation with IFN-ß1a. Moreover, this cytokine reduced the expression of NSE in both cell lines. CONCLUSIONS: Recombinant IFN-ß1a (Rebif) showed a potent in vitro anti-proliferative activity in androgen-resistant prostate cancer cells, and it could represent a promising tool for the treatment of this tumor.

Left ventricular diastolic function and responses to adrenergic stimuli in borderline arterial hypertension.

OBJECTIVE: To detect the existence of a possible relationship between arterial hypertension and adrenergic reactivity to pressure stimuli, and changes in left ventricular diastolic function (LVDF). PATIENTS: Fifty-nine young subjects with borderline arterial hypertension and ten sex- and age-matched controls were investigated. After three medical examinations, the subjects were divided into hypertensive and borderline groups on the basis of the blood pressure reading at visit 3. A complete echocardiographic study was performed in 25 of the 59 subjects. DESIGN: Blood pressure was measured in baseline conditions and during pressure stimuli (mental stress, handgrip and cold pressor tests). LVDF was evaluated primarily by means of filling velocities during diastolic phases taken from the left ventricular volume curve (obtained from a complete echocardiographic study). RESULTS: No significant changes in blood pressure responses were observed for the borderline or hypertensive groups during the adrenergic test. The echocardiographic indices of diastolic function were statistically different for the two groups when compared with the control group. The LVDF parameters correlated significantly with systolic blood pressure and diastolic blood pressure measured at the time of the echocardiogram, but not with blood pressure measured occasionally. CONCLUSIONS: Blood pressure increases similarly during adrenergic stimuli in both the hypertensive and borderline groups. The correlation between systolic blood pressure, diastolic blood pressure and LVDF parameters may indicate a very early onset of reduced compliance of the left ventricle, even in a preclinical phase of hypertension.

Unstable superheavy relic particles as a source of neutrinos responsible for ultrahigh-energy cosmic rays

Decays of superheavy relic particles may produce extremely energetic neutrinos. Their annihilations on the relic neutrinos can be the origin of the cosmic rays with energies beyond the Greisen-Zatsepin-Kuzmin cutoff. The redshift acts as a cosmological filter selecting the sources at some particular value z(e)+/-deltaz, for which the present neutrino energy is close to the Z pole of the annihilation cross section. We predict no directional correlation of the ultrahigh-energy cosmic rays with the galactic halo. At the same time, there can be some directional correlations in the data, reflecting the distribution of matter at redshift z = z(e)+/-deltaz. Both of these features are manifest in the existing data. Our scenario is consistent with the neutrino mass reported by super-Kamiokande and requires no lepton asymmetry or clustering of the background neutrinos.

Evaluation of erythrocyte deformability in pre-menopausal and post-menopausal women.

Whole blood filterability expressed as volume of red blood cells filtered per minute (VRBC) was evaluated in 10 pre-menopausal and 10 post-menopausal women. In addition, blood concentrations of total and high-density lipoprotein (HDL), cholesterol, triglycerides, uric acid, fasting glucose and fibrinogen were measured and correlated with VRBC values. Whole blood filterability was significantly lower in the post-menopausal than in the pre-menopausal women. All the other parameters examined were higher after the menopause, except for HDL-cholesterol levels, which were found to be lower. The VRBC values correlated strongly with fibrinogen, triglyceride and HDL concentrations. These findings indicate that the higher plasma fibrinogen and triglyceride concentrations and the lower HDL-cholesterol levels observed in women after the menopause might be associated with haemorrheological changes. These might be partly responsible for the increased incidence of cardiovascular diseases in post-menopausal women.

Effects of ovariectomy on blood and plasma viscosity, fibrinogen and whole blood filterability.

Blood and plasma viscosity, fibrinogen concentrations and whole blood filterability (VB) were evaluated before surgery and 7 and 30 days postoperatively in 2 groups of subjects, one of which comprised 10 hysterectomized women and the other 14 women who had undergone both hysterectomy and ovariectomy. Oestrogens and various metabolic haematological parameters were measured and correlated with the haemorrheological data. By day 7 after surgery fibrinogen concentrations and plasma viscosity had increased, while VB had decreased. Plasma viscosity and fibrinogen levels correlated negatively with VB in the non-ovariectomized women. Three weeks later almost complete normalization of all parameters was observed in all of the subjects, except for the persistence of low oestrogen concentrations and a further decrease in VB values in the ovariectomized patients, these parameters showing a positive correlation. This study demonstrates that haemorrheological alterations occur after hysterectomy (with or without ovariectomy) in the early post-operative period. The striking decrease in VB values and its correlation with the oestrogen concentrations observed 1 mth after ovariectomy suggest that the fall in oestrogen levels might be responsible for the decrease in whole blood filterability.

Hepatic alterations in indomethacin-treated rabbits.

Indomethacin was parenterally administered (6 mg/Kg/day) for 30 days to rabbits, to evaluate changes in serum biochemical parameters and any ultrastructural alterations induced by the drug at the hepatic level. An analysis of the results demonstrated that when the group of rabbits, a statistically significant increase in the serum ALT was found in the treated rabbits. Ultrastructural observations showed the following hepatocyte alterations: 1) minimum mitochondrial alterations 2) mild signs of cholestasis (pericanalicular osmophilic bodies) 3) Smooth endoplasmic reticulum hyperplasia. These findings suggest that indomethacin has the capacity to induce hepatic lesions in the rabbit and this is probably due to the surfactant mechanism.

Relationship between serum cholesterol and thromboxane B2 levels and atherosclerotic lesions in rabbits fed a high cholesterol diet.

The aim of our study was to evaluate the effects of diet induced hypercholesterolemia and associated atherosclerosis in rabbits on serum thromboxane B2 levels. We have determined thromboxane B2 in serum of hypercholesterolemic rabbits with atherosclerosis and in normocholesterolemic rabbits without atherosclerosis. Our data show only a mildly higher serum thromboxane levels in hypercholesterolemic rabbits and extensive atherosclerosis than in controls without atherosclerosis. In conclusion, these results show that diet induced hypercholesterolemia was not associated with thromboxane B2 generation, in spite of a diffuse experimental atheromatosis.

Syndromes of resistance to TSH.

The resistance to TSH action is a genetic disease characterized by molecular defects hampering the adequate transmission of TSH stimulatory signal into thyroid cells. In principle the defect may affect every step along the cascade of events following the binding of TSH to its receptor (TSHR) on thyroid cell membranes. The phenotypic expressivity of TSH resistance is highly variable going from severe congenital hypothyroidism (CH) with thyroid hypoplasia to mild hyperthyrotropinemia (hyperTSH) associated with an apparent euthyroid state. More severe forms follow a recessive pattern of inheritance and occur in patients with biallelic mutations both causing a severe loss of TSHR function. Differential diagnosis in these cases includes the exclusions of other causes of isolated thyroid dysgenesis. Mildest forms may instead occur in patients with monoallelic TSHR defects following a dominant mode of inheritance. In these cases we described the dominant negative effect exerted by some mutants on the activity of the receptor encoded by the wild type allele. In these cases, differential diagnosis involves the exclusion of autoimmune thyroid disease or pseudohypoparathyroidism associated with defects at the GNAS locus. This review will focus on the variable clinical expression of this disease.

Educational and formative training reduce stress in the caregivers of demented patients.

The present study has been organized for appraising if the formation of the caregivers of insane patients can bring benefits to the conditions of stress that bear every day. The evaluation has considered 74 caregivers participants to 5 courses of formation organized in 12 evenings of around 2 each. The subjects have been valued before and 6 months after the course through the administration of two staircases of evaluation: the relative stress scales (RSS) and the caregiver burden inventory (CBI). Besides, they have been considered questionnaire for the harvest of social and registry data and questionnaire for the harvest of information around the emotional state of the caregiver and the relationship among. The data show that 6 months after the course the values obtained by the RSS and by the CBI, they are statistically improved in meaningful way in comparison to the initial evaluation. The emotional aspects that are meaningfully improved after the course in comparison to before were the following: anxious, nervous, dissatisfied, pessimist, depressed, I feel me in guilt. The relationships of the caregiver with the sick that are meaningfully improved to the time 1 in comparison to the time 0 are the following: affectionate, deep, serene, gratifying. To confirmation of preceding theories, it is the woman, the sick daughter, of inclusive age of 40-60 years, the principal caregiver. Our data show that to participate to a suitable course of formation induces a diminution of the level of stress of the caregiver and it improves its emotional state as well as the insane patient relationship.

[Evaluation of age-related changes of erythrocyte filtration]. / Valutazione delle variazioni della filtrazione eritrocitaria in rapporto all'età.

In two groups of subjects (young and elderly), the red blood cell (RBC) deformability was examined determining the filtration time by means of two different methods (filtration of whole blood and filtration of RBC suspension with hematocrit adjusted at 20%, respectively). In addition, the DFE (Debit de filtration erythrocytaire), an indirect index of capillary blood flow, was mathematically derived. Since the filtration times appear to be positively correlated with age, it is conceivable that in the elderly, erythrocytes are less deformable than in the young, and that this change may impair both capillary blood flow and tissue oxygen delivery; this alteration is further emphasized when the relationship between whole blood filtration time and hematocrit is taken into account.

[Effect of blood levels of carboxyhemoglobin (COHb) on erythrocyte filtration time in young smokers]. / Influenza del tasso ematico di carbossiemoglobina (COHb) sul tempo di filtrazione eritrocitaria in giovani fumatori.

The effects of chronic exposure to carbon monoxide on some rheologic parameters (erythrocyte filtration time in particular) and on FEV1, and on FEF25-50 were studied in young smokers. A positive correlation among number of cigarettes day, COHb blood levels and erythrocyte filtration time was found. Packed red cell volume, fibrinogen concentration and platelet count were unaffected; no evidence of small-airway obstruction was observed. The alteration of erythrocyte deformability may be an early sign of hemorheological impairment which can progressively worse if high COHb blood levels are chronically maintained, with damaging effects on vessel function.

Effect of diet and weight loss on whole blood filterability and plasma fibrinogen values in hypertensive obese postmenopausal women.

The authors evaluated whole blood filterability (VB) in 29 post-menopausal obese women with (n = 14) or without (n = 15) hypertension, and in 22 age matched women with normal body weight. After 3 months of a low-calorie (18 kcal/kg IBW) and moderately low-salt (max 6 g NaCl/day) diet, the obese subjects were restudied. In all women plasma fibrinogen values and various indices of metabolic status were evaluated before and after the diet and correlated to VB values. VB values and plasma fibrinogen concentrations were similar in normal controls and in women with simple obesity, whereas they were, respectively, significantly lower and higher in obese subjects with hypertension. Three months of diet significantly improved whole blood filterability and decreased fibrinogen levels in these patients. Before the diet a significant negative correlation was found between VB and plasma fibrinogen values in hypertensive obese patients. Metabolic parameters did not change in the different groups before and after the diet and did not correlate with VB values. The present study indicates that low-calorie, low-salt diet decreases plasma fibrinogen levels and improves whole blood filterability in elderly obese women with hypertension.

Evaluation of whole blood filterability with increasing age in healthy men and women.

Whole blood filterability, expressed as volume of red blood cells filtered per minute (VRBC), was evaluated in 53 healthy men and 56 healthy women; in each sex, subjects were divided into 4 groups according to their age: adult age (20-50 yr.), advanced adult age (51-60 yr); presenile age (61-70 yr.) and senile age (greater than 70 yr.). In addition, plasma fibrinogen, PCV, white cell and platelet total counts were measured and correlated with VRBC. Whole blood filterability and plasma fibrinogen levels were also correlated with age. VRBC and PCV decreased, whereas fibrinogen levels increased with increasing age. VRBC values showed a significant negative correlation with age and plasma fibrinogen values; a significant positive correlation was found between fibrinogen levels and age. No other examined parameter changed with increasing age nor correlated with VRBC values. These findings indicate that with aging there are modifications of some rheological parameters, such as an increase in plasma fibrinogen levels and a decrease in whole blood filterability.

Whole blood filterability in elderly obese women.

In order to establish whether obesity alters whole blood filterability, the corrected whole blood filtration (VRBC) was measured in 54 elderly obese women (mean age +/- SE = 67 +/- 2 years) without (n = 15) or with associated cardiovascular risk factors such as impaired glucose tolerance (IGT) (n = 11), non-insulin dependent diabetes mellitus (NIDDM) (n = 14) or hypertension (n = 14). Twenty-two age matched women with normal body weight participated as controls. VRBC values were similar in normal controls and obese women with normal glucose tolerance (NGT), whereas they were significantly lower in obese subjects with hypertension, NIDDM or IGT. When subjects with normal and impaired glucose tolerance were combined, a significant negative correlation was found between glucose incretory areas during OGTT and VRBC values. These data demonstrate that obesity per se does not alter whole blood filterability; furthermore, our results indicate that this modification is a precocious and sensitive index of altered glucose metabolism.

Left ventricular diastolic function during adrenergic stress in essential hypertension: acute and chronic effects of ACE inhibition.

We studied the changes in left ventricular (LV) diastolic function induced by angiotensin-converting enzyme (ACE) inhibition at rest and during adrenergic stimulation and their relation to blood pressure (BP) variations to determine whether reductions in the renin-angiotensin system may improve diastolic function irrespective of BP reduction. Echocardiographic indices of systolic and diastolic function, plasma catecholamines as estimated by high-pressure liquid chromatography, and BP variations (Dynamap) were determined at rest and during the cold pressor test (CPT) before and 6 hours and 20 days after ACE inhibition (lisinopril), 20 mg/day by mouth in 10 subjects with uncomplicated essential hypertension. Blood Pressure was significantly reduced after both 6 hours and 20 days of therapy. The cold pressor test induced similar increases in BP in both basal conditions and after acute and chronic treatment. Catecholamine levels were unchanged by the therapy. Systolic function, evaluated by fractional shortening, ejection fraction, and systolic dV/dt, was normal and unchanged during CPT and after treatment. Diastolic function, assessed by volume curve analysis, showed a reduced percentage contribution of rapid filling to total diastolic filling, an increase in the contribution of the atrial systole, and an increase in the isovolumetric relaxation time. During CPT these parameters deteriorated further in response to increased afterload. Lisinopril therapy induced significant increases in end-diastolic volume (p < 0.005) with a progressive increase in the rapid filling dV/dt (p < 0.005 at rest; p < 0.001 during CPT) and a reduction in isovolumetric relaxation (p < 0.0001 at rest and p < 0.01 during CPT). The correlation between systolic BP (afterload) and the rapid filling dV/dt, both at rest and during CPT, was modified by treatment with the ACE inhibitor, with significantly higher rapid filling dV/dt values, and with the pressure loads equal (reduction of the slope and rightward shift of the correlation line). The improvement in diastolic function achieved by ACE inhibition at rest and during CPT appears unrelated to plasma catecholamines and only partly ascribable to the reduced pressure load. The tissue angiotensin II reduction might by itself improve the myocardial response to the pressure load and adrenergic stimulation.

Nicotinic and M1-, M2-muscarinic cholinergic control of ACTH response to insulin-induced hypoglycaemia in man.

The possible mediation of muscarinic and/or nicotinic-cholinergic receptors in the response of ACTH to insulin-induced hypoglycaemia was evaluated in 18 normal men. Subjects were tested with the insulin (0.15 U/kg) tolerance test (ITT) in basal conditions and in the presence of the M1- and M2-muscarinic antagonist atropine (600 micrograms iv just before insulin injection (time 0) plus 600 micrograms 20 min later in 6 subjects) or the M1-muscarinic receptor blocker pirenzepine (40 mg iv 10 min before ITT or 20 mg at time 0 plus 30 mg at time 20 in 6 subjects). The remaining 6 men were treated with the nicotinic receptor antagonist trimethaphan (0.3 mg/min x 30 min before ITT). ACTH rose 4.7 times in response to hypoglycaemia. The ACTH response to hypoglycaemia did not change after pirenzepine administration, whereas it was significantly increased by atropine and decreased by trimethaphan treatment. These data indicate that nicotinic and muscarinic (M2 but not M1) receptors participate in a different manner in the regulation of the hypoglycaemia-induced ACTH release.

[Etiopathogenetic role of metabolic, circulatory, sex factors and type and duration of diabetes in diabetic retinopathy. Investigation with vitreofluorophotometry]. / Ruolo eziopatogenetico di fattori metabolici, emovascolari, sesso, tipo e durata del diabete nella retinopatia diabetica. Indagine compiuta con la vitreofluorofotometria.

We have studied metabolic, circulatory and vascular parameters in a group of 57 diabetics (37 affected by IDDM, 20 affected by NIDDM; 35 were males, 22 were females). Goals of present study were: 1) quantitative evaluation of the blood retinal barrier; 2) influence of the metabolic state, blood pressure, sex, type and duration of the diabetes on the ocular conditions; 3) relationship between ophthalmoscopic appearance of the retina and vitreous fluorophotometric recordings. We concluded that: a) ocular alterations depend by lipidic metabolism, blood pressure, sex, type and duration of the diabetes; b) vitreous fluorophotometry has proved a good device for early detection of retinal damages in the diabetic retinopathy.

Oxytocin response to insulin-induced hypoglycemia in obese subjects before and after weight loss.

The response of plasma oxytocin to an iv bolus injection of crystalline insulin (0.15 U/kg) was evaluated in 14 normal weight [mean body mass index (BMI) = 23] and in 9 obese (mean BMI = 42) men. Similar blood glucose decrements after insulin injection were observed in the two groups. Obese and normal weight subjects presented similar basal oxytocin levels. In both groups, oxytocin rose significantly during the insulin tolerance test (ITT); however, the peak oxytocin response in the obese men was significantly lower than in the normal weight subjects. Obese men were restudied after substantial weight loss. Basal oxytocin levels and glucose response to insulin did not change after weight reduction. The oxytocin response to the ITT was significantly higher than before slimming and did not differ from that observed in the normal weight subjects. A significant negative correlation between BMI values and oxytocin peak levels during ITT was observed in the lean controls and obese subjects (r = 0.516, p less than 0.02). These results demonstrate that in obese subjects the oxytocin secretory response during an insulin tolerance test is reduced, suggesting the existence of a hypothalamic-pituitary disorder in obesity.