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Biomedical subjects

G Cavaletti

Publications and source records attributed to G Cavaletti.

At least 55 records · Page 3Linked to original sources
PubMed1995

Experimental peripheral neuropathy induced in adult rats by repeated intraperitoneal administration of taxol.

Taxol, a natural extract with antineoplastic properties, is known to be neurotoxic in humans. Its neurotoxicity after systemic administration, however, has never been studied in detail at the morphological level in humans and in animals. In this study we administered taxol intraperitoneally to female Wistar rats and we performed an extended neurophysiological and morphological examination of the peripheral nerves, dorsal root ganglia, spinal rootlets, and spinal cord. The results obtained in this experimental model indicate that taxol induces pathological changes mainly in the peripheral nerves, but they are present also in the ventral and dorsal spinal rootlets and spinal dorsal column fibers. The dorsal root ganglia and spinal cord neurons were, on the contrary, unaffected. The most impressive change induced by systemic taxol administration was intraaxonal neurotubule accumulation. Schwann cells showed signs of "activation" but clear demyelination was not observed. We conclude that with the use of this model it is possible to induce a peripheral neuropathy in the Wistar rat which resembles that reported in humans and which can, therefore, be used to better understand the basic mechanism(s) of taxol toxicity and to evaluate protective strategies in an attempt to reduce it.

Animals↗
PubMed1995

Cryoglobulinaemic neuropathy: lack of progression in patients with good haematological control.

Nine consecutive patients with essential mixed cryoglobulinaemia type II (EMCII) were investigated by a follow-up study of 3-6 years (mean 5.3), to verify the long-term outcome of the peripheral nerve involvement in the disease. At the beginning of the study, a peripheral neuropathy, mild or moderate, mainly sensory, was present approximately in 50% of cases. All patients maintained good general conditions, low-staging of EMCII, were well controlled by therapy or did not need any medical treatment. During the neurological follow-up all patients had regular controls, usually at 1-year intervals, and only slight changes were seen with respect to the first evaluation. Therefore, we conclude that peripheral neuropathy during EMCII is less progressive that it can be thought at least in patients with benign course of the disease.

Aged↗
PubMed1995

Ultrastructural aspects of DRG satellite cell involvement in experimental cisplatin neuronopathy.

Different substances may induce neurological impairment, clinically expressed as peripheral neuropathies, due to damage of the neuronal bodies (neuronopathy) of sensory or motor neurons. Neuronopathies have generally been studied referring to neurons, although other cellular components may also be damaged. Cisplatin (CDDP) is known to be neurotoxic to the neurons of the dorsal root ganglia (DRG). The scarcity of information as to the possible involvement and role played by dorsal root ganglion (DRG) satellite cells in neuronopathies prompted this study using the chronic DRG neuronopathy induced by the repeated administration of CDDP in rats as a model. Eighteen female Wistar rats were treated according to 3 different schedules of CDDP administration (6 rats for each group). Six further animals were used as controls. At the end of the experiment the L4-L5-L6 dorsal root ganglia were examined at the light and electron microscope. Ag-NOR reaction was also examined in 4 further CDDP-treated rats and 4 controls. Pathological changes in satellite cells of animals treated with CDDP were remarkable in the nucleus where heterochromatin clumps were reduced or even completely absent. Morphometric analysis of the area occupied by heterochromatin indicated that this nuclear component decreased in an exposure-time dependent manner. Frequently, nucleolar-like structures became apparent in the nucleus of the rats treated with the higher doses of CDDP. Ag-NOR positive regions in the nuclei of treated rats were increased with respect to the controls. Cytoplasmic changes in DRG satellite cells of CDDP treated rats were limited, being characterized by an increased electron-density of the matrix. In treated rats deep invaginations between satellite cells and the neuronal surface were evident, leading to the formation of vacuoli. The interstitial connective space often showed edematous areas. Our observations demonstrate that in chronic cisplatin neuronopathy, DRG satellite cells are also involved in the pathological changes induced by drug exposure, and that these changes may be interpreted as being mainly reactive.

Animals↗
PubMed1995

An ultrastructural study of neuronal changes in dorsal root ganglia (DRG) of rats after chronic cisplatin administrations.

In humans, the main dose-limiting side-effect of cisplatin (CDDP) treatment is a peripheral sensory neuropathy secondary to dorsal root ganglion (DRG) neuron involvement. To investigate further for neuronal alterations responsible for CDDP neurotoxicity we undertook the present experimental ultrastructural study, based on observations of 3 different groups of rats (6 animals in each group). Group A rats were treated with 1 mg/kg weekly for 9 weeks; Group B with 2 mg/kg weekly for 9 weeks; and group C rats served as untreated controls. At the end of the experiment, rats were perfused with 3% glutaraldehyde and lumbar DRGs were prepared for electron microscopic observations. In CDDP-treated rats somatic, nuclear and, above all, nucleolar size was reduced. Ultrastructurally, the nucleolus was the most affected structure. Nucleolar alterations were quantified morphometrically. Less marked changes were seen in the nucleus and in the RER and Golgi apparatus of the cytoplasm. The number of lysosomes and lipofuscins was greatly increased in CDDP-treated rats. The ultrastructural alterations observed in CDDP rats suggest that CDDP may be neurotoxic due to a reduction in protein synthesis. This assumption would explain why cells such as neurons, which are non replicating, but which have a high rate of protein synthesis, may be the target of the neurotoxic action of CDDP. The lack of an efficient blood/nerve barrier in the DRG explains the involvement of this particular type of neuron.

Animals↗
PubMed1994

Protective effects of glutathione on cisplatin neurotoxicity in rats.

PURPOSE: Different attempts have been made to minimize the neurotoxicity of cisplatin (DDP) and the use of "neuroprotective" drugs seems to be a promising strategy. In rats we compared the effects on the dorsal root ganglia neurons and peripheral nerves of the administration of DDP alone or in combination with glutathione (GSH), a putative "neuroprotective" drug. METHODS AND MATERIALS: Twenty-four Wistar rats were treated with DDP alone (2 mg/kg/week) or with the same dose of DDP plus GSH (300 mg/week) for nine cycles and they were compared to 12 untreated age-matched rats. All the animals underwent either neurophysiological examination of the tail nerve or pathologic examination of the dorsal root ganglia. Analytical determination of the platinum concentration in dorsal root ganglia was also performed. RESULTS: Morphologic and morphometric evaluations demonstrated a reduced incidence of pathologic changes in DDP plus GSH-treated rats with respect to DDP-treated ones. In agreement with the morphological findings, the platinum concentration in the dorsal root ganglia was lower and sensory nerve conduction velocity in the tail nerve less markedly decreased in the animals treated with DDP plus GSH with respect to those treated with DDP alone. CONCLUSION: We conclude that the administration of GSH is effective in reducing the neurotoxic effects of DDP, thus supporting the preliminary results obtained in clinical trials in humans.

Animals↗
PubMed1994

Frequency and clinical correlates of anti-neural IgM antibodies in neuropathy associated with IgM monoclonal gammopathy.

We studied the frequency and clinical correlates of different IgM specificities in 75 patients with neuropathy associated with IgM monoclonal gammopathy. Patients were tested for IgM reactivity with the myelin-associated glycoprotein, P0, neurofilaments, and tubulin by immunoblot; with GM1, asialo-GM1, GM2, GD1a, GD1b, sulfatide, and chondroitin sulfate C by enzyme-linked immunosorbent assay; and with brain and nerve glycolipids by overlay high-performance thin-layer chromatography. Forty-two patients (56%) had high titers of IgM antibodies to MAG; 4 (5%), to sulfatide (1 also to myelin-associated glycoprotein); 4 (5%), to the 200-kd neurofilament (2 also to myelin-associated protein); and 1 each, to GD1b and chondroitin sulfate C. No reactivity was found in 26 patients (35%). More patients with anti-myelin-associated glycoprotein IgM (62%) than with unknown IgM reactivity (31%) had a predominantly sensory neuropathy (p < 0.025). Nerve conduction findings were consistent with a demyelinating neuropathy in 77% of patients reactive to myelin-associated glycoprotein and 24% with unknown reactivity (p < 0.0001) and the mean conduction velocity of peroneal nerve was lower in the former group (22.9 m/sec) than in the latter group (39.6 m/sec) (p < 0.000001). Patients with anti-sulfatide IgM had a sensorimotor neuropathy with morphological evidence of demyelination while anti-neurofilament IgM was not associated with homogeneous findings. Patients with anti-GD1b or anti-chondroitin sulfate C IgM had a predominantly motor impairment. The frequent occurrence of anti-neural IgM antibodies in neuropathy associated with IgM gammopathy, and their frequent, though not constant association with similar neuropathy features, support their possible pathogenetic role in the neuropathy.

Adult↗
PubMed1994

Homozygous hypertrophic hereditary motor and sensory neuropathies.

We compared 25 autosomal dominant hereditary motor and sensory neuropathy (HMSN) type I patients with 7 subjects affected by hypertrophic HMSN with non-dominant inheritance. All the autosomal dominant HMSN I cases carried the chromosome 17p11.2 duplication, providing evidence that it is widely represented in HMSN I families. The second group included: two siblings born to unrelated, unaffected parents and suffering from hypertrophic HMSN of strikingly different severity; two sisters with HMSN I phenotype, born to first-cousin unaffected parents; two brothers with HMSN III phenotype born to unrelated parents both showing HMSN II phenotype; a child with classic HMSN III phenotype, born to unrelated, unaffected parents. The 17p11.2 duplication was not found in any of the patients of the second series or in their parents. Our data provide further evidence that: HMSN III is heterogeneous and encompasses the homozygous expressions of different neuropathic genes; it is advisable to separate autosomal recessive hypertrophic HMSN from dominant HMSN Ia, because they appear to be due to different DNA mutations.

Adolescent↗
PubMed1994

Low-dose glutathione administration in the prevention of cisplatin-induced peripheral neuropathy in rats.

So far various drugs have been used in an attempt to prevent or reduce cisplatin (CDDP)-induced peripheral neuropathy. Of those tried reduced glutathione (GSH) is one of the most promising. Its effectiveness has already been demonstrated by means of morphological methods in CDDP-treated rats in which high doses of GSH (up to 1200 mg/kg) were given. In the current study neurophysiological and morphological methods were used to evaluate the effect of low doses (150-300 mg/kg) of GSH i.p. on the peripheral nervous system of the rat. Four groups of 8 female Wistar rats were treated as follows: (A) CDDP 2 mg/kg i.p. weekly for 9 courses; (B) same as (A) plus GSH 150 mg/kg i.p. weekly; (C) same as (A) plus GSH 300 mg/kg i.p. weekly; (D) same as (A) plus GSH 150 mg/kg i.p. on the day of DDP injection followed by 150 mg/kg/day over the next 2 days. Eleven age-matched untreated rats were used as controls. Sensory conduction velocity was recorded in the tail nerve and morphologic and morphometric examinations were performed on the dorsal root ganglia neurons (L4-L6) in each animal. The results demonstrated that the neurophysiological and pathological changes induced by CDDP administration were less severe in rats co-treated with GSH. No significant differences could be related to the 3 different regimens of GSH co-treatments. This experiment confirms that GSH is able to reduce the neurotoxicity of CDDP and that it is effective even at doses as low as those used in the present study.

Animals↗
PubMed1993

Long-lasting neuropsychological changes after a single high altitude climb.

Acute neuropsychological changes due to high altitude climbing without supplementary oxygen are well known. However, many climbers report vague symptoms of brain dysfunction after return to sea level suggesting that long-lasting neuropsychological impairment may ensue even after a single ascent. In this study we evaluated a series of neuropsychological functions in a group of 11 climbers who ascended over 5000 m. Besides memory, also reaction time and concentration were less efficient when the climbers were evaluated 75 days after their return to sea level, confirming that even a single high altitude climb may be harmful for central nervous system functions.

Adult↗
PubMed1993

Topology of two DBI receptors in human lymphocytes.

High-affinity binding sites for the isoquinoline carboxamide PK 11195 and 4'-chlorodiazepam (4'CD) in human lymphocytes are recognized by two putative endogenous ligands: diazepam binding inhibitor (DBI) and protoporphyrin IX. We have now demonstrated that several synthetic DBI peptides--analogues to naturally processed human DBI (H-DBI) fragments--differ from protoporphyrin IX in the manner in which they displace [3H]PK 11195 and [3H]4'CD from binding sites associated with intact and cell-free lymphocyte preparations. In particular, the peptide fragments DBI37-80 and DBI37-70 displaced [3H]PK 11195 and [3H]4'CD with higher affinity from their binding sites on intact lymphocytes (Ki approximately 3-5 microM) than from the sites in the cell-free preparation (Ki approximately 20 microM). In contrast, protoporphyrin IX displaced [3H]PK 11195 and [3H]4'CD with higher affinity in the cell-free preparation (Ki - 0.4 microM) than in intact lymphocytes (Ki > 50 microM). Because DBI peptide fragments and protoporphyrin IX do not readily penetrate the plasma membrane of lymphocytes, our results suggest the existence of binding sites located both on the external face of the plasma membrane and intracellularly. The plasma membrane binding sites, recognized essentially only by DBI fragments, are termed here plasma membrane DBI receptors (PDRs). In contrast, the intracellular binding sites, recognized by both DBI fragments and protoporphyrin IX, are presumably located on mitochondria and are termed mitochondrial DBI receptors (MDRs). Immunohistochemical electronmicroscopic studies with antibodies to the synthetic peptide fragments 62-76 of the rat MDR support the hypothesis that PDRs are expressed on lymphocyte plasma membranes.

Amino Acid Sequence↗
PubMed1992

Cisplatin-induced peripheral neurotoxicity is dependent on total-dose intensity and single-dose intensity.

The authors prospectively evaluated the effects of three different schedules of cisplatin (DDP) administration in 60 patients with advanced epithelial ovarian cancer. The individual total dose of DDP was 450 mg/m2 in all three groups, and the anti-cancer response at the end of treatment was similar for the different regimens. The clinical and neurophysiologic results confirmed that axonal sensory neuropathy occurred after the standard administration of DDP (75 mg/m2 in 3-week cycles) and probably not only the peripheral, but also the central sensory pathway, was involved. Although the total dose of the drug was identical, the two less conventional schedules were less neurotoxic. These results suggest that not only the total-dose intensity, but also the single-dose intensity are relevant in the onset of DDP-induced sensory neuropathy; therefore, the use of less neurotoxic schedules may prevent or reduce sensory nerve damage.

Aged↗
PubMed1992

Morphometric study of the sensory neuron and peripheral nerve changes induced by chronic cisplatin (DDP) administration in rats.

We performed a morphological, morphometric and toxicological study on the spinal ganglia and peripheral nerves of the rat after chronic administration of cisplatin (cis-dichlorodiammineplatinum II; DDP) with two different schedules. Severe damage of the spinal ganglia neurons was demonstrated with predominant involvement of the nucleus and nucleolus associated with a decrease in the cell size. Morphological and morphometric changes also occurred in the sciatic and peroneal nerves with the features of axonopathy. All these changes were more marked in the group of rats which underwent the most intense DDP treatment and the tissue platinum concentrations were also higher in this group. This experimental model is the first available for chronic DDP administration in which concomitant spinal ganglia and peripheral nerve damage has been confirmed pathologically. Our study supports the hypothesis that DDP-induced peripheral nerve fiber degeneration may result from nuclear and nucleolar changes in the sensory ganglion cell perikaryon.

Animals↗
PubMed1992

Evaluation by somatosensory evoked potentials of the neurotoxicity of cisplatin alone or in combination with glutathione.

The use of high doses of cisplatin (DDP) in the treatment of different solid tumors is often prevented by the onset of a disabling sensory neuropathy. In an attempt to minimize DDP-induced neurotoxicity different schedules of DDP administration have been tested. Moreover, during the past few years some putative neuroprotective drugs have been reported as reducing DDP neurotoxicity. In this prospective, randomized study we evaluated in a series of 33 patients affected by relapsing ovarian cancer the effect on the sensory pathway of a non-conventional schedule of DDP administration as monochemiotherapy or in combination with one of the neuroprotective drugs (i.e. glutathione). The results of the neurophysiologic examinations performed before and immediately after chemotherapy suggest that these schedules besides being safe and effective in the treatment of the ovarian cancer, have an extremely low peripheral neurotoxicity.

Cisplatin↗
PubMed1991

The incidence and course of paraneoplastic neuropathy in women with epithelial ovarian cancer.

Sensorimotor polyneuropathy is the most common of the paraneoplastic syndromes involving the nervous system. Its incidence is high (more than 50%) in the patients undergoing neurophysiological investigation, and it is considered to be more frequent in subjects with lung and breast cancers. In this study we evaluated a series of 58 women with epithelial ovarian cancer at FIGO stages I and III. The aim of the study was to assess the incidence and characteristics of peripheral nerve involvement during the course of the disease both clinically and neurophysiologically. Our results suggest that in women with epithelial ovarian cancer (1) the incidence of subclinical polyneuropathy is high; (2) sensory involvement is predominant in stage I, but motor involvement is frequent in stage III; and (3) the incidence of peripheral nerve involvement increases with progression of the cancer.

Adolescent↗
PubMed1991

Infantile hereditary neuropathy with hypomyelination: report of two siblings with different expressivity.

We report the cases of two siblings both affected by inherited sensory-motor neuropathy of a demyelinative nature but with markedly different severity and pathological findings. The clinical, neurophysiological and morphological features in these two cases were consistent with the diagnosis of Hereditary Motor Sensory Neuropathy type 3 (HMSN 3), according to the classification of Dyck, with different expressivity. These results raise the still unsettled question of the phenotypic variants in inherited neuropathies. In fact the most severely affected of our cases had clinical and neurophysiological findings identical to those reported in cases of Congenital Hypomyelination Neuropathy (CHN), but the morphological picture in the sural nerve was inconsistent with this diagnosis. The criteria for the diagnosis and the reported cases of CHN have been reviewed.

Biopsy, Needle↗