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Biomedical subjects

A Bizzi

Publications and source records attributed to A Bizzi.

At least 37 records · Page 2Linked to original sources
PubMed1991

Axonal transport of two major components of the ubiquitin system: free ubiquitin and ubiquitin carboxyl-terminal hydrolase PGP 9.5.

Ubiquitin (Ub), a stress protein thought to target abnormal proteins for degradation, is present in abnormal structures that occur in neuronal perikarya and axons of degenerative diseases including Alzheimer disease. To begin to assess the role of the Ub system in the axon, we studied expression and axonal transport of Ub and other stress proteins, as well as of Ub carboxyl-terminal hydrolase PGP 9.5, in the rat visual system in normal conditions and following heat-shock (HS). In the retina, both the constitutive and inducible forms of HSPs 70 were expressed under normal conditions, while in the superior colliculus the inducible form was detected only following HS. Ub, PGP 9.5 and HSPs 70 were transported in the axon exclusively with the slow component b (SCb), known to carry cytoskeletal and cytoplasmic proteins. The exceedingly long time needed for stress proteins to reach distant axonal locales at the rate of SCb (approximately 3 mm/day) makes it unlikely that they could contribute significantly to the stress response at those sites.

Animals↗
PubMed1991

Role of 5-HT receptors in the effect of d-fenfluramine on gastric emptying and feeding behaviour as examined in the runway test.

In one experiment, the effect of d-fenfluramine (DF) on gastric emptying was studied in rats treated i.p. with metergoline, a non-selective serotonin (5-HT) receptor antagonist, ritanserin, a selective 5-HT2 and 5-HT1C receptor antagonist, and xylamidine, a 5-HT antagonist which has poor access to the brain. Metergoline (1 mg/kg) but not ritanserin (0.5 mg/kg) or xylamidine (3 mg/kg) blocked the effect of 2.5 mg/kg DF studied 2 and 4 h after injection. In a second experiment, we studied the ability of metergoline to antagonise the effect of DF, administered after a meal, on runway performance, food intake and gastric emptying assessed 4 h later. Metergoline at a dose of 1 mg/kg did not antagonise the effect of DF (2.5 mg/kg) on runway performance but completely blocked the effect on gastric emptying. The data clearly show that DF delays gastric emptying by indirectly activating 5-HT1 receptors; this effect is not important for the ability of DF to reduce runway performance and food intake when the drug is injected after a pre-feeding period. While there is evidence that DF hastens the termination of the meal by a 5-HT mechanism, the data suggest that DF may prolong the satiating effect of food during the post-absorptive phase by mechanisms other than 5-HT.

Animals↗
PubMed1991

Comparative studies on the anorectic activity of d-fenfluramine in mice, rats, and guinea pigs.

The present study compares the anorectic activity of d-fenfluramine and its metabolite d-norfenfluramine in three animal species. d-Fenfluramine and d-norfenfluramine show anorectic activity at increasing doses (ED50) in rats, guinea pigs, and mice, d-norfenfluramine being more active than d-fenfluramine in all three species. Equiactive anorectic activities are reached with different brain levels of d-fenfluramine and d-norfenfluramine, guinea pigs being the most sensitive species, followed by rats then mice. The metabolite most probably plays a major role in the anorectic effect of d-fenfluramine in guinea pigs, contributes to the anorectic activity in rats, but adds little to the action of the parent drug in mice. The different sensitivity to d-fenfluramine and d-norfenfluramine in these three species does not appear to be explained by a number of biochemical parameters, including serotonin uptake or release, receptor subtypes, or 3H-d-fenfluramine binding and uptake.

Animals↗
PubMed1991

Diazepam binding inhibitor (DBI) increases after acute stress in rat.

Diazepam binding inhibitor (DBI) acts in brain by binding to GABAA/benzodiazepine receptors (GBR) and to mitochondrial benzodiazepine receptors (MBR). Because DBI acting at MBR, has been shown to be an effector of ACTH-induced steroidogenesis and stress is known to change the level of GBR and MBR, the model of acute noise stress in rats was used to study modifications of DBI and GRB or the content of MBR in various areas of the brain and adrenal gland. It was found that, in the brain of stressed rats, DBI and its processing products (ODN-like immunoreactivity), increased selectively in the hippocampus. This increase in the content of DBI was preceded and followed by a net decrease of GBR and an increase of MBR. Similarly, in adrenal cortex, the content of DBI and MBR increased during the first hour, following acute stress and this increase paralleled the increase in plasma corticosterone. These data suggest that DBI, acting on MBR may regulate steroidogenic function in stress.

Adrenal Glands↗
PubMed1990

Role of cell cholesterol in modulating antineoplastic ether lipid uptake, membrane effects and cytotoxicity.

Membrane-interactive ether lipids (EL) exert toxic and antiproliferative effects on cancer cells in vitro. They appear to be selectively more toxic to cancer cells than to normal cells and thus they are ideal candidates for bone-marrow purging procedures. However, no conclusive explanation has yet been provided for this property. We now present some data indicating that the cholesterol concentration in the incubation medium modulates EL toxicity against the HL60 leukemic cell line in vitro. Furthermore, model membranes richer in cholesterol take up EL more slowly, and cell cholesterol enrichment of HL60 cells counteracts EL biophysical membrane interaction, but not toxicity, in our experimental model. However, the K562 cell line, a leukemia line less sensitive to EL toxic action, has higher levels of cell cholesterol. Our data provide evidence to explain differences in sensitivity to EL among different cell types and contribute to the understanding of the mechanism of action of EL.

Antineoplastic Agents↗
PubMed1990

Role of iron and ferritin in MR imaging of the brain: a study in primates at different field strengths.

The authors measured in vivo signal intensity on magnetic resonance (MR) images and postmortem iron concentrations in the brains of three young and two old rhesus monkeys. T2-weighted MR imaging was done at 0.5, 1.5, 2.0, and 4.7 T. Relative assessment of iron concentration was made from the optical density of brain sections stained with the Perls' method intensified with diaminobenzidine. MR imaging and optical density measurements were made in the centrum semiovale (white matter) and in four gray matter areas: the insular cortex, caudate nucleus, putamen, and globus pallidus, the latter three of which accumulate significant iron deposits with age. High optical density and decreased signal intensity were found in these areas, and the inverse correlation between gray matter/white matter signal ratio and optical density was in good agreement with the theory of T2 shortening caused by diffusion of water through magnetic inhomogeneities. However, the dependence of T2 shortening on field strength was not quadratic, as expected for paramagnetic iron, but instead showed a marked leveling off at higher field strengths. This magnetic "saturation" is explainable by antiferromagnetism and superparamagnetism of the ferritin core and has been observed in ferritin solutions at low temperatures. Similar observations at body temperature are needed before the iron-ferritin explanation for T2 shortening can be considered proved.

Aging↗
PubMed1990

Metabolism of human gliomas: assessment with H-1 MR spectroscopy and F-18 fluorodeoxyglucose PET.

Localized hydrogen-1 magnetic resonance (MR) spectroscopy and fluorine-18 fluorodeoxyglucose (FDG) positron emission tomography (PET) were employed to obtain metabolic information from intracranial gliomas. Advantages and difficulties associated with comparison of results from the two modalities were realized. Forty patients were studied with H-1 MR spectroscopy. MR signal intensities from lactate, N-acetylaspartate (NAA), choline, and creatine from a volume of interest containing the tumor and a contralateral volume were obtained and evaluated. NAA signal intensities were generally decreased in the tumor spectra, and choline signal intensities were elevated. H-1 MR spectroscopy was unsuccessful in eight patients, and FDG PET scans were not obtained in four of the patients with successful MR spectroscopic examinations. Lactate signal intensity was detected in 10 of the 28 patients who had successful H-1 MR spectroscopic and FDG PET studies. Lactate signal intensities were observed in lesions shown at FDG PET to be hypermetabolic, as well as in lesions found to be hypometabolic.

Adult↗
PubMed1990

Cerebral blood flow in experimental ischemia assessed by 19F magnetic resonance spectroscopy in cats.

We evaluated a 19F magnetic resonance spectroscopic technique that detects Freon-23 washout as a means of measuring cerebral blood flow in halothane-anesthetized adult cats during and after transient cerebral ischemia produced by vascular occlusion. The experiments were performed to test the ability of this recently developed method to detect postischemic flow deficits. Results were consistent with postischemic hypoperfusion. The method also proved valuable for measuring small residual flow during vascular occlusion. Our experiments indicate that this method provides simple, rapid, and repeatable flow measurements that can augment magnetic resonance examinations of cerebral metabolic parameters in the study of ischemia.

Animals↗
PubMed1988

Steroid receptors in epithelial ovarian carcinoma: relation to clinical parameters and survival.

Estrogen receptor (ER) and progestin receptor were measured in samples of tumors obtained at first laparotomy from 97 previously untreated patients suffering with a primary ovarian epithelial tumor, for whom a 3-year follow-up was available. The presence or absence of steroid receptors (threshold arbitrarily fixed at 10 fmol/mg of cytoplasmic protein) was determined by the dextran coated charcoal method and related to a number of patient characteristics such as the residual disease (cutoff, 2 cm), histological type, International Federation of Gynecologists and Obstetricians grade and stage, and age. Results were analyzed by univariate and multivariate methods. (a) The tumor ER positivity was associated with better survival; progestin receptor showed a similar trend but did not reach statistical significance. (b) After stratification for residual tumor the association ER positivity/better survival was still statistically significant in the subset of patients with residual tumor greater than 2 cm. (c) When the median survival times were considered it became apparent that progestin receptor absence nullified the effect associated with positive ER. (d) Multivariate analysis confirmed that among the variables considered the main determinants of prognosis were the size of the residual tumor, serous histological type, and positive ER.

Adult↗
PubMed1988

Progress in assessing the role of serotonin in the control of food intake.

There is evidence that serotonin inhibits food intake, particularly intake of carbohydrate and that induced by activation of catecholamine-containing neurons in different brain circuits. An agent that has contributed considerably to the hypothesis of a role of serotonin in feeding is fenfluramine, used as an anorexigenic drug in obese people. Experiments using synaptosomal preparations for studying monoamine uptake and release have shown that d-norfenfluramine preferentially releases serotonin from a reserpine-insensitive compartment. Studies on brain monoamine release and metabolism in intact animals have shown that d and l isomers of fenfluramine at relatively low doses have a specific action on brain serotonin and catecholamines, respectively. Several findings suggest that d-fenfluramine and d-norfenfluramine cause anorexia by increasing the availability of serotonin at postsynaptic receptors. Evidence has recently been provided that d-fenfluramine uses preferentially serotonin1 sites, particularly of the serotonin1B type, in the rat brain to cause anorexia in this animal species. Activation of serotonin1A sites by agents such as 8-OH-DPAT and buspirone instead has been shown to cause overeating. It is suggested that serotonin1B sites in the hypothalamus and serotonin1A sites in the serotonin neurons of the midbrain raphe nuclei mediate these effects. Evidence is provided that [3H]d-fenfluramine binding to rat brain membranes is different from serotonin uptake sites ([3H]imipramine binding) and serotonin receptors. It is, however, displaced by some drugs using serotonin to cause anorexia, raising the possibility that it is somewhat related to serotonin mechanisms involved in feeding control. These studies provide evidence that the serotoninergic system in the brain is a likely target for drugs affecting food intake and suggest new ways to develop novel and potent strategies for the treatment of clinical hyperphagia and anorexia.

Eating↗
PubMed1988

Factors affecting plasma free fatty acids rise during hemodialysis.

We studied the mechanisms responsible for causing acute changes in plasma lipids during hemodialysis. Dialysis decreased plasma triglycerides to the same extent as when heparin was given without dialysis. Cholesterol increased in proportion to hemoconcentration. Plasma free fatty acids (FFA) levels were also increased, but more so than with heparin alone. Glucose and acetate did not play a role, nor did carnitine loss, and hemofiltration elicited similar effects. The rise in plasma FFA is therefore likely to be caused by other as yet unknown mechanism.

Carnitine↗
PubMed1987

Amiodarone induced phospholipidosis. Biochemical, morphological and functional changes in the lungs of rats chronically treated with amiodarone.

Amiodarone, an antiarrhythmic drug, causes pulmonary fibrosis in some patients during chronic treatment but the mechanism is unknown. We studied the effects of amiodarone on pulmonary biochemistry, morphology and function at doses of 25 and 50 mg/kg/12 hr given to rats by gavage for four weeks. Plasma and pulmonary phospholipids were significantly augmented, 13% and 88% respectively, in the group given amiodarone 50 mg/kg/12 hr compared to pair-fed controls. Typical phospholipidosis-like light and electron microscopic alterations were seen in the lung, their severity related to the extent of biochemical changes induced by amiodarone. Pulmonary function tests revealed mild but not significant changes in O2 and CO2 alveolar exchange efficiency and lung compliance (P-V curve) of treated animals in comparison to pair fed controls. Plasma average concentrations of amiodarone and its main metabolite, desethylamiodarone, after four weeks were 2.46 +/- 0.18 and 0.73 +/- 0.13 micrograms/ml, respectively, in the 50 mg/kg/12 hr group. In the same group amiodarone and desethylamiodarone concentrations in lung were 163 +/- 26 and 569 +/- 153 times higher than those in plasma. A highly significant correlation was found between amiodarone concentrations in plasma and lung and phospholipid content in the lung. A subgroup of animals received amiodarone 50 mg/kg/12 hr for 8 weeks. The pulmonary phospholipidosis-like lesions were similar to those observed after one month of treatment, no fibrosis was evident on light microscopic examination.

Amiodarone↗
PubMed1987

Amiodarone and desethylamiodarone tissue uptake in rats chronically treated with amiodarone is non-linear with the dose.

Four groups of rats were given amiodarone chronically at 25, 37.5, 50, 75 mg kg-1/12 h for 3 weeks; on day 21 the animals were killed and blood, plasma, heart, lung, liver and fat were collected and assayed for amiodarone and desethylamiodarone. Amiodarone plasma concentrations ranged from 0.74 to 4.68 micrograms mL-1 and desethylamiodarone from 0.08 to 2.05 micrograms mL-1. Plasma, blood and tissue concentrations of amiodarone and desethylamiodarone increased significantly with the dose. Blood/plasma and tissue/plasma partition ratios of amiodarone and desethylamiodarone increased significantly at the higher doses. Blood/plasma ratio was a good predictor of tissue/plasma ratios of amiodarone and its metabolite, except in fat. Total phospholipid concentrations in lung were correlated with amiodarone and desethylamiodarone concentrations in plasma, blood and lung.

Amiodarone↗
PubMed1986

Effects of oral administration of maltitol on plasma glucose, plasma sorbitol, and serum insulin levels in man.

The present study was aimed to investigate the metabolic effects of acute and chronic oral administration of maltitol (4-O-i-D-glucopyranosyl-D-glucitol), a hypocaloric sweetener obtained from maltose by catalytic hydrogenation. Fifty grams of maltitol induced a increase lower glycemic and insulinemic than the same dose of glucose or sucrose. No variations of plasma glucose and serum insulin levels were observed after 180 min. A slight increase of plasma maltitol was observed 45 min after maltitol. The chronic administration of maltitol (10 g 3 X daily for 5 days) induced no variations of glycemia or insulinemia when compared with the same dose of sucrose. Plasma sorbitol levels were slightly higher after maltitol than after sucrose. Low amounts of maltitol were detected in the urine and feces.

Administration, Oral↗
PubMed1986

Phosphorylation of neurofilaments is altered in aluminium intoxication.

A series of monoclonal antibodies that distinguish phosphorylated and nonphosphorylated neurofilament (NF) epitopes was used to immunostain brain stem neurons from control rabbits and from rabbits chronically intoxicated with Aluminium (Al). In controls, none of the monoclonal antibodies to phosphorylated NF stained the perikaryon of neurons. In contrast, in animals treated with Al, all neuronal perikarya containing Al-induced neurofilament bundles (NB) and some lacking well-formed NB immunoreacted with two of the five antibodies to phosphorylated NF. Axons were stained by all five antibodies to phosphorylated NF in both control and Al-treated animals. A broadly reacting monoclonal antibody to a nonphosphorylated NF epitopes immunoreacted with neuronal cell bodies, dendrites and axons in control and Al-intoxicated animals regardless of the presence of Al-induced NB. Staining of Al-induced NB with one of the antibodies to phosphorylated NF was greatly diminished after treatment of sections with trypsin and phosphatase. It is concluded that NF which compose the Al-induced NB have different immunocytochemical characteristics from those of the NF present in the perikaryon of normal neurons. It is likely that, contrary to normal perikaryal NF, NF of Al-induced NB are phosphorylated. Moreover, phosphorylation of NF of Al-induced NB is probably abnormal, since NF of Al-induced NB have immunostaining characteristics different from NF of normal axons. Al-induced NB may result from abnormal phosphorylation of NF in the perikaryon, preventing normal axonal transport of these structures.

Aluminum↗
PubMed1984

Effect of hydrocortisone on the macrophage content, growth and metastasis of transplanted murine tumors.

Hydrocortisone (HC) reduced the macrophage content of four murine tumors to less than half of control values. Since HC causes monocytopenia and inhibits the recruitment of mononuclear phagocytes at sites of inflammation but does not affect the viability and proliferative capacity of macrophages, this finding suggests that the maintenance of macrophage levels in growing tumors is in part dependent upon the entry into the neoplasm of circulating monocytes. HC inhibited the growth of these tumors. The effect of HC was most marked on the mFS6 and MN/MCA1 sarcomas and 3LL carcinoma, with only marginal inhibition in the M109 carcinoma. HC augmented spontaneous and/or artificial (i.v.) metastasis in these tumor models. Cells from metastatic foci of the mFS6 sarcoma and M109 carcinoma inoculated i.m. were as susceptible to HC as cells from primary tumors. The effects of HC on macrophage content, growth and metastasis of the M109 carcinoma and mFS6 sarcoma were similar in mice with defective T-cell function (nude or thymectomized) or defective NK activity (beige or antiasialo GM1-treated) and in controls. The in vitro growth of the mFS6 and MN/MCA1 sarcomas was not modified by HC. Some inhibition of tumor-cell proliferative capacity was observed with the 3LL and M109 tumors. Tumor cell had high-affinity binding sites for glucocorticoid hormones, but these were not correlated to susceptibility in vivo. Thus it is unlikely that a direct interaction of HC with tumor cells accounts for the inhibition of tumor growth observed in vivo. To evaluate whether HC affected tumor growth by reducing the macrophage content of tumors, mFS6 sarcoma cells were transplanted, mixed with peritoneal macrophages into normal or HC-treated mice. Macrophages did not affect the growth of tumor cells in normal mice, whereas in HC-treated animals lesions from mixtures of macrophages and sarcoma cells appeared earlier and weighed more than those from tumor cells alone or tumor cells and thymocytes. However, macrophages did not reconstitute growth of the other sarcoma (MN/MCA1) in HC-treated mice. These results are consistent with the hypothesis that HC inhibited growth of some poorly immunogenic transplanted murine tumors, at least in part, by interfering with the macrophage levels in neoplastic tissues, tumor-associated macrophages providing the conditions for optimal tumor-cell proliferation at least in some neoplasms.

Animals↗