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Biomedical subjects

S Di Giovanni

Publications and source records attributed to S Di Giovanni.

At least 19 recordsLinked to original sources
PubMed2006

Early post-operative MRI: correlation with progression-free survival and overall survival time in malignant gliomas.

Forty-seven patients with Glioblastoma (42) and Anaplastic Astrocytoma (5) were studied with MR 24 hrs after surgery. In order to evaluate the role of early MR in defining the extent of surgical resection and its relation with the prognosis of malignant glioma patients, three categories of surgical resection were considered: gross total, sub-total and partial resection. The results were correlated with progression-free survival (PFS) and overall survival (ST). As demonstrated by early-MR, gross total resection was performed in 17 patients, sub-total and partial resection in 19 and 11 patients, respectively. The PFS was 6 months in gross total resection, 6 and 3 months in sub-total and in partial resection, respectively. The median survival time was 16 months in total resection patients, 13 months and 7 months in sub-total resection and partial resection patients, respectively. The study confirms that early-MR has to be considered an accurate technique for monitoring the extension of malignant glioma surgical resection and shows a good correlation between early-MR findings, PFS and ST.

Adult↗
PubMed2004

Large-scale disruption of microtubule pathways in morphologically normal human spastin muscle.

OBJECTIVE: To investigate the molecular pathways disrupted by dominant spastin mutations in apparently unaffected skeletal muscle from patients with motor neuron disease (SPG4). METHODS: The authors studied muscle of three individuals from two unrelated families affected by spastic paraplegia caused by spastin mutations. The authors compared RNA expression profiles to 7 normal and 13 pathologic muscle U95A profiles (Duchenne dystrophy, acute quadriplegic myopathy, and spinal muscular atrophy). Data were validated with U133A arrays with seven different control specimens. mRNA and protein confirmations were done for a subset of genes. RESULTS: Both nonsense and missense mutations in the spastin gene disrupted microtubule pathways in nonpathologic tissue, including microtubule dynamics, stability, exocytosis, and endocytosis. CONCLUSIONS: Normal muscle can be used to uncover biochemical perturbation in motor neuron disease. Altered microtubule metabolism in SPG4-linked hereditary spastic paraplegia patients leads to pathology of the long descending tracks of motor neurons that likely have a stringent need for efficient microtubular transport. As many inherited neurologic conditions show a systemic biochemical defect with disease limited to neurons, our data have broader implications for biochemical pathway studies of many neurologic disorders.

Adenosine Triphosphatases↗
PubMed2001

Coenzyme Q10 reverses pathological phenotype and reduces apoptosis in familial CoQ10 deficiency.

Two brothers with myopathic coenzyme Q10 (CoQ10) deficiency responded dramatically to CoQ10 supplementation. Muscle biopsies before therapy showed ragged-red fibers, lipid storage, and complex I + III and II + III deficiency. Approximately 30% of myofibers had multiple features of apoptosis. After 8 months of treatment, excessive lipid storage resolved, CoQ10 level normalized, mitochondrial enzymes increased, and proportion of fibers with TUNEL-positive nuclei decreased to 10%. The authors conclude that muscle CoQ10 deficiency can be corrected by supplementation of CoQ10, which appears to stimulate mitochondrial proliferation and to prevent apoptosis.

Adolescent↗
PubMed2001

Apoptosis and ROS detoxification enzymes correlate with cytochrome c oxidase deficiency in mitochondrial encephalomyopathies.

The aim of this work was to investigate in muscle the role of apoptosis and of oxidative stress in mitochondrial disorders with dysfunction of respiratory chain. In patients with cytochrome c oxidase deficiency (COX) we found a variable number of myofibers with apoptotic nuclei that matched with the level of enzymatic reduction and roughly correlated with muscle weakness. In parallel, a positive immunostaining for apoptosis-related proteins and Mn and Cu/Zn superoxide dismutase (SOD) were mostly localized in COX-negative fibers. Moreover, glutathione peroxidase activity was increased in muscles with high number of SOD-positive myofibers and prominent apoptotic features. No signs of apoptosis were observed in patients with deficiencies of complexes I and II and without muscle weakness. These data suggest that apoptosis along with increased ROS production, revealed by anti-oxidant enzymes overexpression, may play an important role in the pathophysiology of mitochondrial diseases associated with COX deficiency.

Adult↗
PubMed2000

Apoptotic features accompany acute quadriplegic myopathy.

OBJECTIVE: To investigate the role of apoptosis in acute quadriplegic myopathy. BACKGROUND: Acute quadriplegic myopathy is a muscular disease characterized by diffuse flaccid weakness occurring in patients with severe systemic illness and exposure to corticosteroids or neuroblocking agents. Myofiber atrophy and thick filament loss are the distinguishing pathologic features on muscle biopsy. Increased calpains expression and lysosomal and nonlysosomal proteolytic pathways have been claimed as possible pathogenic factors. Nevertheless, the mechanisms leading to myofiber atrophy and thick filament loss need further investigation. PATIENTS AND METHODS: The expression of ubiquitin and proapoptotic proteases as well as DNA fragmentation in muscle biopsies from three patients with acute quadriplegic myopathy were studied. RESULTS: All patients exhibited an important overexpression of caspases, calpain, cathepsin B, and ubiquitin, and the presence of numerous apoptotic nuclei in over 70% of myofibers. CONCLUSIONS: These data suggest that apoptosis mediated by proteolytic proteases may play a role in the pathogenesis of acute quadriplegic myopathy.

Acute Disease↗
PubMed2000

GCG genetic expansions in Italian patients with oculopharyngeal muscular dystrophy.

OBJECTIVE: To screen Italian patients with oculopharyngeal muscular dystrophy (OPMD) for GCG repeat expansions in the Poly(A) binding-protein 2 (PABP2) gene. BACKGROUND: Oculopharyngeal muscular dystrophy is an adult-onset autosomal dominant muscle disease linked to 14q11 pathologically characterized by unique 8.5 nm intranuclear filaments in skeletal muscle fibers. Short expansions of a (GCG)6 repeat located in exon 1 of the newly isolated PABP2 gene have been demonstrated in a large number of OPMD families. METHODS: We studied 18 patients diagnosed with OPMD. A muscle biopsy was performed in 16 patients. Screening for the pathologic expansion was performed on a PCR amplified DNA fragment encompassing the GCG repeat. RESULTS: Heterozygous (GCG)-repeat expansions were detected in 13 patients in association with (GCG)6 normal allele or (GCG)7 polymorphic allele. All the patients whose muscle biopsy showed typical 8.5 nm intranuclear filaments had a mutated PABP2 allele. Five patients with no intranuclear filaments were homozygous for the normal (GCG)6 allele. The pathologic expansion appeared to be stable with no variation among family members and between different tissues as blood and skeletal muscle in the same individual. CONCLUSIONS: These data 1) further confirm PABP2 gene analysis as a valuable tool in OPMD diagnosis; 2) indicate that PABP2 gene mutations are always present among Italian patients with morphologically proven OPMD, suggesting genetic homogeneity of the disease; and 3) strengthen the putative role of mutated PABP2 protein in filamentous inclusions accumulation.

Adult↗
PubMed2000

Muscarinic receptor blockade has differential effects on the excitability of intracortical circuits in the human motor cortex.

The aim of the present study was to investigate whether muscarinic receptor blockade with scopolamine modifies the excitability of specific cortical networks of the human motor cortex as tested with transcranial magnetic stimulation. The effects of scopolamine on the excitability of human motor cortex were investigated in four healthy subjects using transcranial magnetic stimulation before and after an intravenous dose of scopolamine (0.006 mg/kg). We measured the threshold for motor responses, amplitude of motor responses, the duration of the cortical silent period, intracortical inhibition and facilitation, and short-latency inhibition produced by somatosensory input from the hand. In addition, we evaluated the amplitude of motor responses evoked by electrical anodal stimulation, since these responses originate from direct activation of corticospinal axons in the white matter and are not sensitive to changes in cortical excitability. Scopolamine decreased the threshold to magnetic stimuli and increased the amplitude of motor responses evoked by magnetic stimulation. In contrast, motor responses evoked by electrical stimulation were unaffected by administration of scopolamine. Scopolamine also led to a highly significant reduction in the amount of short-latency inhibition produced by somatosensory input from the hand. In contrast, short-latency intracortical inhibition and facilitation were not modified by scopolamine. The differential effect of scopolamine on motor responses evoked by magnetic and electrical stimulation of the motor cortex and the selective effect on somatosensory inhibition demonstrate that muscarinic blockade modifies the excitability of specific cortical networks in the human motor cortex.

Acetylcholine↗
PubMed2000

An Italian family with autosomal recessive quadriceps-sparing inclusion-body myopathy (ARQS-IBM) linked to chromosome 9p1.

We report an Italian family with autosomal recessive quadriceps-sparing inclusion-body myopathy (ARQS-IBM). The patients (two second cousins) developed a slowly progressive distal and proximal myopathy with complete sparing of the quadriceps. Muscle biopsy showed rimmed vacuoles in numerous muscle fibers, and electron microscopy documented accumulation of 15-21 nm filaments. DNA analysis established linkage to 9p1 and haplotype analysis revealed that the patients shared a recombined common haplotype. The gene locus of ARQS-IBM was initially mapped to chromosome 9p1-q1 in families of Iranian-Jewish origin and later confirmed in a few other ethnic groups. This is the first report of Italian patients with ARQS-IBM showing positive linkage to chromosome 9p1. Our data suggest that patients having distal and proximal myopathy with rimmed vacuoles and possible recessive inheritance, often classified as distal myopathies, should be thoroughly investigated according to the diagnostic criteria of h-IBM and, when positive, studied for linkage to chromosome 9p1.

Arm↗
PubMed2000

Apoptosis in mitochondrial encephalomyopathies with mitochondrial DNA mutations: a potential pathogenic mechanism.

Mitochondrial encephalomyopathies caused by mitochondrial DNA (mtDNA) defects are a genetically and phenotypically heterogeneous group of disorders. The site, percentage and distribution of mutations do not explain the overall clinical heterogeneity that is found. Apoptosis (programmed cell death) is an evolutionarily conserved mechanism that is essential for tissue development and homeostasis. Dysregulation of apoptosis has been implicated in the pathogenesis of various human diseases, such as cancer and autoimmune and neurodegenerative disorders. Recent in vitro evidence has indicated the central role of mitochondria in the apoptotic process. We investigated the occurrence of apoptosis in muscle biopsies of 36 patients carrying different mtDNA mutations and four patients with inclusion body myositis and mitochondrial abnormalities. Apoptotic features, mainly localized in cytochrome c oxidase-negative fibres, were observed in muscle fibres of patients carrying a high percentage of single mtDNA deletions (>40%) and of tRNA point mutations (>70%). By contrast, no apoptotic changes were observed in inclusion body myositis and in patients carrying mutations of mtDNA structural genes. Our study suggests that apoptosis is not simply a means whereby cells with dysfunctional mitochondria are eliminated, but that it seems to play a role in the pathogenesis of mitochondrial disorders associated with mtDNA defects affecting mitochondrial protein synthesis. The imbalance and relative abundances of nuclear-encoded and mtDNA-encoded subunits may favour cytochrome c inactivation and release. Cytochrome c, together with respiratory chain dysfunction, could activate apoptotic pathways that, in turn, inhibit the rate of mitochondrial translation and the importation of nuclear-encoded mitochondrial protein precursors. This vicious circle may amplify the biochemical defects and tissue damage and contribute to the modulation of clinical features.

Adolescent↗
PubMed1997

HLA-DM polymorphisms do not associate with multiple sclerosis: an association study with analysis of myelin basic protein T cell specificity.

The MHC region on 6p harbors at least one susceptibility gene for multiple sclerosis (MS). Within this region, HLA-DM loci are of interest being involved in class II antigen processing. We investigated the association of HLA-DM polymorphisms with MS. Sixty-three patients with MS and 46 healthy controls from continental Italy were typed for HLA-DM polymorphisms and HLA-DRB1 alleles. Besides, among the donors characterized for the DM polymorphisms, we considered 6 MS patients previously studied for the fine specificity of their MBP-specific T lymphocyte lines (TLL). The frequencies of allelic variants at the DMA and DMB loci were similar between MS patients and controls, even when HLA-DRB1*1501 positive and negative donors were analyzed separately. Patients with predominant responses to different MBP epitopes did not differ for their HLA-DM haplotype while patients with predominant responses to the same MBP epitope could present different HLA-DM haplotypes. HLA-DM polymorphisms do not associate with MS and may not affect specific patterns of T cell responses to MBP.

Adult↗
PubMed1997

Down-regulation of cell-surface CD4 co-receptor expression and modulation of experimental allergic encephalomyelitis.

Pre-immunization with autoantigens confers resistance in experimental models of autoimmune diseases. Since non-self molecules can also be protective, it is conceivable that part of the effect rests on a non-specific attenuation of the immune response. This study is aimed at identifying mechanisms by which pre-immunization with a moiety suspended in incomplete Freund's adjuvant (IFA) protects from experimental allergic encephalomyelitis (EAE). Lewis rats were immunized with each of either concanavalin A, lipopolysaccharide, bovine serum albumin, 70 or 65 kDa heat shock proteins, or myelin basic protein. All moieties were given in IFA 3 weeks prior to EAE induction. Serial cytofluorimetric monitoring of B cells and of the alpha beta TCR+, CD4+, CD8+, CD45high and CD45low cells was performed. IFN-gamma and IgG1 production was evaluated in parallel. All moieties were able to attenuate or abrogate the clinical signs of EAE. At day 4 and 10 after EAE induction, the surface expression of the CD4 molecule was down-regulated on T lymphocytes. This down-regulation was most evident in animals with the highest degree of clinical protection. By day 21 post-immunization, CD4 expression was restored. The same animals also showed an increase in the B cell percentage and Th2-related IgG1 production while IFN-gamma secretion was reduced. Pre-immunization with diverse antigens suspended in IFA confers resistance to EAE induction. The down-regulation of the CD4 co-receptor accompanied by events suggestive of an immune deviation may be a general mechanism that contributes to the protection.

Animals↗
PubMed1997

LHON mutations in Italian patients affected by multiple sclerosis.

The occurrence of a multiple sclerosis (MS)-like phenotype in subjects carrying mitochondrial DNA (mtDNA) mutations associated with Leber hereditary optic neuropathy (LHON) has suggested that mitochondrial genes may contribute to susceptibility to MS. With the present study 74 unrelated Italian patients (53 females and 21 males; mean age 37.9, SD 9.9, range 20-59) affected by MS with early and prominent optic nerve involvement and 99 normal control subjects were analysed for the presence of primary (nps 11778, 3460, 14484) and an alleged secondary one (np 15257) LHON mutations. A single MS patient carrying a virtually homoplasmic LHON mutation at np 11778 was found. Family history revealed a maternal uncle affected by MS, decreased at age of 64 in consequence of a stroke. The patient's mother harboured the same mutation in a homoplasmic way. Primary LHON mutations were not detected in any other MS patient or control. Of the MS patients 5.4% (4 out of 74), and 5.1% (5 out of 99) of the controls carried the 15257 mutation in a homoplasmic state. Present data do not support any contribution of primary LHON mutations to genetically determined susceptibility in MS. There is no evidence that the 15257 mutation has any pathogenetic significance in the Italian population.

Adult↗
PubMed1992

Natural killer cell frequency and function in patients with monoclonal gammopathies.

We evaluated the frequency and the functional activity of peripheral blood mononuclear cells (PBMCs) with natural killer (NK) cell phenotype in patients with monoclonal gammopathies. CD16+ and CD56+ PBMCs were strongly increased in monoclonal gammopathies of undetermined significance (MGUS) and multiple myeloma (MM). Furthermore, increased frequency of CD16+/CD3+ PBMCs was found in 7/15 patients with MGUS, indicating that T lymphocytes with NK-like phenotype are expanded in at least a subset of these patients. However, despite the increased frequency of PBMCs with natural killer phenotype, the functional NK activity was as comparable in both MGUS and MM patients as in normal individuals. The discrepancy between the expansion of circulating NK cells and the normal NK activity in patients with monoclonal gammopathies requires further investigation. However, at least in some MGUS patients, this discrepancy could be accounted for by the expansion of PBMCs with the rare phenotype CD16/CD3 which have been reported not to mediate significant NK activity.

Aged↗
PubMed1992

[Magnetic resonance in the staging of multiple myeloma].

The authors retrospectively reviewed the MR examinations of 46 patients with clinical and laboratory findings of monoclonal gammopathies (MG). All cases had been submitted to radiographic examination which had shown skeletal involvement in 22 cases and osteoporosis in 11, with rupture of the vertebral body in 3 patients. Scintigraphy had been performed on all patients and CT on 12; 36 patients were subsequently submitted to follow-up (at 6, 12 and 24 months). MR examinations were performed with dedicated coils and standard sequences for the subjects with skeletal localizations on X-ray images. The extant cases, with no radiographic evidence of skeletal involvement, were submitted to MRI of the spine, skull and pelvis. In agreement with clinical and laboratory findings and with follow-up results (in 36 patients), MRI diagnosed MG with no skeletal involvement in 13 cases, osteoporosis in 8 (with rupture of the vertebral body in 2), asymptomatic non-progressive myeloma in 4, solitary myeloma in 3, and multiple myeloma in 18 cases. The good identification of bone marrow and its multiplanarity make MRI the method of choice in the study of patients with suspected or known gammopathies. If compared with other modalities, MRI is more sensitive and accurate in depicting the tumor, its size and relationship to periskeletal tissues, and its possible multifocality. Moreover, the technique has proven to be a valid tool during the follow-up, showing tumor response to therapy.

Bone Diseases↗
PubMed1991

Cytokine production in patients with monoclonal gammapathies.

Increased interleukin-6 levels in culture media of mitogen-driven non adherent peripheral blood mononuclear cells were measurable in patients with monoclonal gammapathies of unknown significance but not in patients with multiple myeloma, indicating that in the former circulating mononuclear cells other than monocytes are involved in producing interleukin-6. Increased interleukin-4 levels were detected in supernatants of mitogen-driven peripheral blood mononuclear cells from patients with monoclonal gammapathies of unknown significance and from patients with multiple myeloma. The further increased interleukin-4 content in supernatants of non adherent cell cultures of multiple myeloma patients only suggests a somewhat inhibitory role of monocytes on interleukin-4 production, at least in multiple myeloma. Undetectable interleukin-2 levels in culture media were found in patients with monoclonal gammapathies of unknown significance and in patients with multiple myeloma. Serum levels of interleukin-6 and interleukin-2 were not measurable in either group, and interleukin-4 was detected only in a few patients. Our study suggests that in monoclonal gammapathies peripheral blood mononuclear cells could participate in producing cytokines involved in the regulation of B lymphocyte proliferation and differentiation. However, the pathophysiologic role in these patients of IL-6 and IL-4 in vitro, and possibly in vivo, produced by circulating lymphocytes remains to be established.

Aged↗
PubMed1989

Beta-2-microglobulin is a reliable tumor marker in chronic lymphocytic leukemia.

Serum beta 2-microglobulin (beta 2M) was measured in 22 patients with B chronic lymphocytic leukemia (CLL) and in 15 healthy age-matched control subjects. The patients were allocated in stages in accordance with the Rai and Binet systems. The beta 2M mean value in the CLL group was significantly higher than in the control group. There was a positive correlation between beta 2M and the clinical stage in both staging systems. The mean serum levels of beta 2M in stages A, B and C of Binet's system showed statistical differences while in stage A they did not differ from those found in the control group. No correlation was demonstrated between beta 2M and the peripheral lymphocyte concentration. A slight correlation was found between beta 2M and the degree of bone marrow lymphocyte infiltration, whereas a stronger relationship was observed when the type of infiltration (non-diffuse versus diffuse) was considered. Patients with bulky disease had mean beta 2M values much higher than the others.

Aged↗
PubMed1984

Acquired hemoglobin H disease in a case of refractory anemia with excess of blasts (RAEB) evolving into acute nonlymphoid leukemia.

A new case of refractory anemia with excess of blasts (RAEB) with acquired Hemoglobin H disease (HbH) evolving into acute nonlymphoid leukemia (ANLL) is reported. In this patient, both family and personal history were negative for alpha thalassemia. At time of diagnosis of RAEB, 'golf ball' erythrocytic inclusions, typical of HbH, were found. The cellulose acetate electrophoresis (pH 8.9) revealed a fast moving band, corresponding to HbH. An evolution into ANLL, M1 subtype, 25 months later, has been documented.

Aged↗