Biomedical subjects

A Florence

Publications and source records attributed to A Florence.

11 recordsLinked to original sources

PubMed1999

Effects of desferrithiocin and its derivatives on peripheral iron and striatal dopamine and 5-hydroxytryptamine metabolism in the ferrocene-loaded rat.

Iron overload disorders, such as beta-thalassaemia, are currently treated with the iron chelator desferrioxamine (DFO) or 1,2-dimethyl-3-hydroxypyridin-4-one (L1), which is currently under clinical evaluation. However, DFO is inactive orally and needs to be administered by intramuscular infusion, whilst there are concerns over the long-term effectiveness and toxicity of L1. In addition, both DFO and L1 affect brain dopamine (DA) and 5-hydroxytryptamine (5-HT) metabolism. In this study, the 3,5,5-trimethylhexanoyl ferrocene rat model of iron overload was used to compare the iron-chelating capabilities of a novel orally active siderophore, desferrithiocin (DFT) and its desmethyl derivatives DFT-D and DFT-L, to that of DFO, along with their ability to affect brain DA and 5-HT metabolism. Chronic administration of ferrocene produced a 12-fold increase in liver iron levels, as assessed by electrothermal atomic absorption. Subsequent treatment with DFT over a two-week period produced a 37% reduction in liver iron levels, whereas similar treatment with DFT-D and DFT-L produced a more marked reduction in these levels (65% and 59%, respectively) in the ferrocene-treated animals. In contrast, using the same dosing regimen, DFO and L1 only produced a 16% and 18% reduction, respectively, in liver iron levels. Both DFT and its derivatives failed to affect either striatal DA or 5-HT metabolism when assessed by HPLC. In view of the previously described oral bioavailability of DFT, the marked ability of DFT and its derivatives to chelate hepatic iron, and their inability to affect brain DA or 5-HT metabolism, such siderophores appear potentially useful clinical iron chelators.

Administration, Oral↗

PubMed1995

Brain iron in the ferrocene-loaded rat: its chelation and influence on dopamine metabolism.

After administration of the ferrocene derivative 3,5,5-trimethyl hexanoyl ferrocene to rats for 4 weeks various brain regions including substantia nigra, cerebellum and cerebral cortex showed up to 50% increase in iron content. Subsequent administration of one of the hydroxypyridones CP20, CP24 and CP94, or the siderophore desferrioxamine caused a significant decrease in the iron content of these various brain regions. Each of the hydroxypyridones and the siderophore influenced dopamine metabolism by causing significant variations in both homovanillic acid and dopamine turnover.

Animals↗

PubMed1994

Control of cellular iron homeostasis by iron-responsive elements in vivo.

It has recently been proposed that cellular iron homeostasis in mammalian cells is regulated at the post-transcriptional level by the reciprocal control of transferrin receptor and ferritin mRNA expression via an iron-regulatory factor. This iron-regulatory factor has been shown to be a cytoplasmic aconitase which can bind to iron-responsive elements in the corresponding mRNAs with greater or lesser affinity as a function of the iron status of the cell. In the present study, we show that in vivo the affinity of iron-regulatory factor for iron-responsive elements in liver reflects the long-term iron status of the tissue in animal models for iron overloading and iron deficiency, when combined with altered transferrin saturation and serum iron levels. In contrast hepatic iron overload achieved without altering such haematopoeitic indices, had a less pronounced effect. In both spleen and heart, the affinities of iron-regulatory factor changed in parallel with both altered iron status and haematological markers. In brain and duodenum, there were no consistent changes in iron-regulatory-factor activity with iron loading or depletion. Iron-regulatory-factor activity in kidney responded in an as yet unexplained manner.

Animals↗

PubMed1994

Ultrastructural changes in brain parenchyma during normal aging and in animal models of aging.

During aging, the brain parenchyma of animals and humans share many similarities, both in the gray and the white matter. Unfortunately, until now, neither aged animals nor animal models reproduce the two hallmarks of aging of the human brain: senile plaques and tangles. Therefore, observations performed on animals are limited to some aspects of the involutive process which affects brain parenchyma during aging and their appropriateness to the human situation. One striking aspect concerns the occurrence of vacuolated necrotic cells whose number increases with advancing age. These cells can constitute markers of the brain involutive process and they characterize, both in animal and human, the more vulnerable areas of the brain affected by the neuronal rarefaction. Experimental animal models can be used to study the various conditions which sustain the cell survival and to determine, at the cellular level, the factors leading the brain parenchyma to an irreversible state of degradation.

Adult↗

PubMed1993

MRI exploration of the intrapetrous facial nerve.

We report our experience of intrapetrous facial nerve evaluation in 33 patients examined by three-dimensional MRI (3D-FT) with intravenous gadolinium injection. The examinations were performed by a 1 Tesla magnet, using Flash and Turbo-Flash sequences which enabled us to obtain contiguous millimetric sections and to make reconstructions in all planes. Among these 33 patients, 31 had facial palsy and 2 a facial nerve lesion without clinical signs and discovered by chance. Facial palsy had started rather abruptly in 26 cases. It was either idiopathic (n = 20) or caused by herpes zoster (n = 1), injuries (n = 2), metastasis (n = 1) and tumour (n = 1); it was concomitant with a granuloma in 1 case. Five patients seen or explored late had congenital cholesteatoma (n = 2), facial nerve neurinoma (n = 2) or persistent idiopathic facial palsy (n = 1). There was no contrast enhancement in "chronic" non tumoral facial palsy. All tumours (neurinoma, neurofibroma, metastasis) were contrast-enhanced, as were the 2 cases of traumatic palsy and the case with granuloma of the labyrinth. In acute idiopathic facial palsy (n = 20), contrast enhancement was demonstrated in 11 patients; among these, recovery was complete at 2 months in 1 case and incomplete in 9 cases; 1 patient was lost sight of. In the 9 patients without contrast enhancement, recovery was complete in 7; 2 patients were lost sight of. This study shows that minute lesions of the facial nerve can be detected with millimetric MRI T1-weighted sequences and contrast enhancement. It also suggests that contrast enhancement has some prognostic value in patients with acute idiopathic facial palsy.

Acute Disease↗

PubMed1992

Chemical and structural characterisation of iron cores of haemosiderins isolated from different sources.

The elemental content of the iron cores of haemosiderins isolated from animal and human tissues has been determined to ascertain whether changes in composition are correlated with structural differences previously identified in these mineralisation products. Significant differences were observed in the elemental composition of haemosiderins isolated from patients subjected to desferrioxamine-chelation therapy compared to patients who had been venesected. The P/Fe molar ratio was considerably higher in haemosiderin isolated from treated primary haemochromatosis (0.83), compared to untreated primary haemochromatosis (0.10) and treated secondary haemochromatosis (0.25), and this could account for the amorphous nature of these iron cores. The levels of M/Fe (M = Ca, Cu, Zn) were reduced in the haemosiderins derived from treated secondary haemochromatosis patients, possibly due to the chelation of these ions by desferrioxamine therapy. In an experimentally iron-loaded rat, receiving either desferrioxamine or 1,2-diethyl-3-hydroxypyrid-4-one, selective decreases in these three elements were also observed after two weeks of desferrioxamine therapy. Such changes may be important determinants in the modification of biomineralisation of the iron cores.

Animals↗

PubMed1992

Studies of in vivo iron mobilization by chelators in the ferrocene-loaded rat.

The oral efficacy of the oral iron chelators 1,2-dimethyl-3-hydroxypyrid-4-one (CP20), 1,2-diethyl-3-hydroxypyrid-4-one (CP94) and desferrioxamine B (DFO) has been compared with intraperitoneal DFO in an experimental model of iron overload with similar biochemical and biophysical characteristics to those observed for human genetic haemochromatosis. The hepatic iron stores in the ferrocene-loaded rat were relatively stable and did not decrease at the end of the loading period. In contrast, the iron dextran rat model showed a rapid depletion of its iron stores 2 weeks after cessation of intraperitoneal injection. When CP20 and CP94 were administered to the ferrocene-loaded rat model in combination with an iron-free diet there were significant decreases in (i) total homogenate iron and (ii) hepatic ferritin iron when compared to the iron-loaded rat receiving the iron-free diet alone. Desferrioxamine, when administered by gavage, only showed chelation of ferritin iron, while intraperitoneal injection of desferrioxamine showed significant depletion of iron both in the total homogenate and ferritin. Subcellular fractionation of the hepatic organelle clearly showed that where there was depletion of homogenate iron there was a net decrease in the lysosomal fraction, while changes in ferritin iron were reflected by decreases in the cytosolic iron content. Although no assessment of net iron excretion was made, we suggest that the use of this animal model should ascertain the site of chelation by iron chelators.

Animals↗

PubMed1991

Vestibular neurotomy by retrosigmoid approach: technique, indications, and results.

During the past 15 years, 96 retrosigmoid vestibular neurotomies have been used in the surgical management of incapacitating Meniere's disease for the control of vertigo and preservation of hearing. This posterior approach of the pontocerebellar angle gives the best view on the acousticofacial nerve bundle, through a 2 x 2 cm suboccipital craniotomy immediately behind the mastoid and sigmoid sinus. Then the vestibular nerve is easily identified, separated from the cochlear nerve and sectioned, the facial nerve not being at risk, as it lies much deeper. Actually, the majority of authors agree that vestibular neurotomy is the most effective surgical treatment in relieving disabling vertigo (96% of cases) with serviceable hearing, but few surgeons know that the retrosigmoid approach is simpler and more reliable than the middle fossa or retrolabyrinthine approaches, with a low incidence of complications. The purpose of this paper is to emphasize the routine use of the retrosigmoid approach.

Aged↗

PubMed1990

[Otospongiosis: different surgical technics, identical results. Why?].

Both platinectomy and platinotomy are currently used to treat otosclerosis surgically. Though the techniques are different from one another, especially by the new area ratio between tympanic membrane and stapes foot-plate, the results are similar. It should be clear that the simple "piston model" of the tympanic ossicular system cannot explain this results. If, for the seesaw mechanical view, a vibratory molecular system conducting acoustic energy is substituted, a pertinent explanation can be given for this result. Thus, understanding of the pattern motion of the tympanic ossicular system has to change drastically.

Ear, Middle↗

PubMed1990

[Retraction pockets, pathological entity?].

Retraction pockets are not a pathological entity per se but take after various ear diseases, with which they share the same morphological eardrum alterations. The authors believe that any holistic evaluation of retraction pockets, as though these were forming a single group of like pathogenic origin, i.e., tubal dysfunction, would be artificial and raise therapeutic problems. The statistical analysis of the causes for retraction pocket formation provides little information. Otologists are still looking into chronic otitis media and cholesteatoma as a possible, long-suspected, unproved etiology. Electron microscopy and, more particularly, istological-enzymological analyses of mounts prepared by the authors have shown, in some cases, the anomalous presence, in the pocket, of Langerhans' cells, which the authors consider as strongly indicative of cholesteatoma. While confirming the clinical diagnosis, anatomopathological examination allows to differentiate poor-prognosis retraction pockets from benign ones. The pathogenesis of these pockets is still poorly understood. It is the authors' contention that tympanic invagination is more likely traceable to some biopathological/biochemical phenomenon than to occupational mechanical disorders involving the tube. The clinical characteristics of retraction pockets are the basis for their classification into three groups, according to their evolutional tendency. Thus, developing cholesteatomas bear a poor prognosis; sequelae of benign otitis are associated with small risk; lastly, there is a small group of pockets the evolution of which is hard to specify. The authors believe that such differentiation between retraction pockets is mandatory to have a clear picture of therapeutic indications, and to assess the various outcomes.

Cholesteatoma↗

PubMed1989

Desferrithiocin and desferrioxamine B. Cellular pharmacology and storage iron mobilization.

3H-Desferrithiocin (DFT) has been synthesized from desmethyl desferrithiocin. The uptake and release of this 3H siderophore and of its iron complex have been studied in cultured rat hepatocytes and systematically compared to 14C desferrioxamine B (DFO). At 37 degrees, the uptake of both chelators is strictly proportional to the extracellular concentration and no toxicity is observed up to, at least, 1 mM. Uptake of 3H DFT is rapid and reaches a plateau after ca. 1 hr. The accumulation of 3H DFT attains a maximum three times that of 14C DFO and the plateau is reached much more rapidly. Upon reincubation in a drug-free medium of cells that had accumulated 3H DFT, most of the 3H label is rapidly released in the culture medium. These kinetic parameters suggest that the accumulation of these two chelators results from their diffusion across cellular membranes, as a function of the gradient of concentration between the cellular compartment and the extracellular medium. Differential centrifugation of homogenates from hepatocytes incubated with 3H DFT shows that the bulk of cell associated 3H-label (82%) is found in the cytosol, whereas a small proportion (14.5%) is present in the particulate fraction. Isopycnic centrifugation on sucrose gradients suggests that 3H-label associated with the particulate fraction is localized within mitochondria. In contrast, 14C DFO distributes in almost equal proportions between cytosol and the particulate fraction (MLP). At least part of the 14C-label in MLP is associated with lysosomes. Rat hepatocytes cultivated for long term in synthetic culture medium have been used to study iron mobilization by chelators from 59Fe loaded cells. DFT mobilizes iron more rapidly than DFO. This effect is also observed in vitro with ferritin, where, in addition, DFT is much more efficient than DFO to mobilize iron at acidic pH. These results strongly suggest that different iron mobilization from cultured hepatocytes results from differences in the cellular pharmacology of these two chelators and, in particular, in their rate of uptake, cellular accumulation levels and subcellular localizations. DFT could mobilize iron from cytosol and, possibly, to a small extent from mitochondria, whereas DFO would do so from cytosol and lysosomes.

Animals↗