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Biomedical subjects

C Angelini

Publications and source records attributed to C Angelini.

At least 37 records · Page 2Linked to original sources
PubMed2004

Dysferlin mutation analysis in a group of Italian patients with limb-girdle muscular dystrophy and Miyoshi myopathy.

Mutations in the dysferlin gene (DYSF) on chromosome 2p13 cause distinct phenotypes of muscular dystrophy: limb-girdle muscular dystrophy type 2B (LGMD2B), Miyoshi myopathy (MM), and distal anterior compartment myopathy, which are known by the term 'dysferlinopathy'. We performed mutation analyses of DYSF in 14 Italian patients from 10 unrelated families with a deficiency of dysferlin protein below 20% of the value in normal controls by immunoblotting analysis. We identified 11 different mutations, including eight missense and three deletion mutations. Nine of them were novel mutations. We also identified a unique 6-bp insertion polymorphism within the coding region of DYSF in 15% of Italian population, which was not observed in East Asian populations. The correlation between clinical phenotype and the gene mutations was unclear, which suggested the role of additional genetic and epigenetic factors in modifying clinical symptoms.

Adolescent↗
PubMed2004

Limb-girdle muscular dystrophies: heterogeneity of clinical phenotypes and pathogenetic mechanisms.

Limb-girdle muscular dystrophies, inherited muscle disorders characterized by progressive weakness and muscle wasting, can be classified into different types, according to their genetic inheritance, distribution of weakness, and molecular defect. The most common clinical forms are autosomal recessive and with proximal involvement, and are classified as limb-girdle muscular dystrophies 2A-2J, with clinical phenotypes ranging from severe progressive muscular dystrophy to mild late-onset forms. Advances have also been made in autosomal dominant limb-girdle dystrophies and the so-called limb-girdle muscular dystrophies 1A-1F. The recent advances in molecular pathogenetic mechanisms of limb-girdle muscular dystrophies have made an impact on the prognosis of limb-girdle muscular dystrophy patients and might be useful not only for prenatal diagnosis, in the family, but may also be of relevance for their treatment.

Genetic Heterogeneity↗
PubMed2003

Cerebellar ataxia and coenzyme Q10 deficiency.

The authors measured coenzyme Q10 (CoQ10) concentration in muscle biopsies from 135 patients with genetically undefined cerebellar ataxia. Thirteen patients with childhood-onset ataxia and cerebellar atrophy had markedly decreased levels of CoQ10. Associated symptoms included seizures, developmental delay, mental retardation, and pyramidal signs. These findings confirm the existence of an ataxic presentation of CoQ10 deficiency, which may be responsive to CoQ10 supplementation.

Adolescent↗
PubMed2003

Biological targets of neurotoxic pesticides analysed by alteration of developmental events in the Mediterranean sea urchin, Paracentrotus lividus.

Biological effects of neurotoxic insecticides widely used for agricultural purposes were studied using the early development of the Mediterranean sea urchin Paracentrotus lividus as a model. These compounds, dispersed as aerosols or powders in agricultural regions near to the coast, may affect the health of organisms in the marine environment. The biological effects of Basudin (an organophosphate compound containing 20% Diazinon), Diazinon (Dzn, a thionophosphate), Carbaryl and Pirimicarb (carbamates) on the early phases of sea urchin development were thus investigated. Morphological, biochemical, histochemical and immuno histochemical analyses were performed both during embryo and larval development. For the morphological effects on fertilisation and first cleavages, the effective concentration of insecticides was found to be 10(-4) M, while for further stages concentrations between 10(-5) and 10(-7) M were effective: 10(-3) M of any of these insecticides totally arrested development. During embryonic development, the treatment with organophosphates slowed the rate of early mitotic cycles down, affected nuclear and cytoskeletal status as well as DNA synthesis. From the gastrulation stage onwards, the main effects were exerted on the rate of primary mesenchyme cells migration, larval size, perioral arm length, and acetylcholinesterase activity distribution, thus deregulating the cholinergic system, which modulates cell-to-cell communication mediated by the signal molecule acetylcholine.

Acetylcholinesterase↗
PubMed2003

LGMD2E patients risk developing dilated cardiomyopathy.

Sarcoglycan gene mutations cause various limb-girdle muscular dystrophies. The sarcoglycans are expressed both in skeletal and cardiac muscle but, surprisingly, so far only a few sarcoglycanopathy patients have had documented cardiomyopathy. We studied six patients with beta-sarcoglycanopathy. Immunohistochemical and immunoblot analysis performed on skeletal muscle biopsies from five patients, showed the loss of all sarcoglycans in three cases and marked reduction in two patients. Non-invasive cardiac examinations revealed that three patients had cardiac involvement: one had a severe Duchenne-like dystrophy, lethal dilated cardiomyopathy, and shared the same mutation reported in another cardiomyopathic patient; the other two patients had limb-girdle dystrophy and moderate cardiac involvement (one of them has a novel gene mutation). Given the age profile of the patients studied, the 50% cardiac involvement found in our LGMD2E patients is likely to be a conservative estimate. Careful cardiac monitoring should be carried out in beta-sarcoglycanopathy patients who are at high risk of developing cardiomyopathy.

Adolescent↗
PubMed2003

Memory deficits and retrieval processes in ALS.

Subtle neuropsychological deficits have been described in patients affected by amyotrophic lateral sclerosis (ALS) without dementia. Overall, selective impairment in memory function has been reported, but the source of memory impairment in ALS has yet to be defined. We performed neuropsychological screening in 20 ALS patients. Semantic encoding and post-encoding cue effects on the retrieval of word lists were investigated in the ALS patients and normal controls. Severity of memory impairment was correlated to cerebral blood perfusion detected by single photon emission computed tomography (SPECT). ALS patients showed moderate impairments in frontal and memory tests. Short-term memory was normal, while serial position retrieval of word lists with normal recency effect but poor primacy effect showed long-term memory deficit. ALS patients performed better in cued encoding than in cued post-encoding recall condition. In the cued post-encoding condition, the primacy effect in word list recall improved significantly in controls, but not in ALS patients, as compared with both the free recall and cued encoding conditions. SPECT hypoperfusion was observed in frontal and temporal areas in ALS patients. ALS patients showed a long-term memory deficit which did not improve in cued post-encoding condition as it does for controls. We hypothesize abnormal retrieval processes related to frontal lobe dysfunction which entails difficulties in generating stable long-memory traces at encoding.

Aged↗
PubMed2003

Gastrointestinal carcinoids. Prognosis and survival.

BACKGROUND: Gastrointestinal carcinoid tumors are rare and little is known about factors related to prognosis in patients with carcinoid disease. Aim of this study is to determine the impact of clinical presentation variables on the management and survival. METHODS: We have evaluated 31 consecutive patients with gastrointestinal carcinoid tu-mours who underwent surgical intervention at the I Department of Surgery of Milano-Bicocca University over 15 years (1985-1999). Tumor distribution, hormone production, prognostic factors and survival were analysed. RESULTS: Carcinoid syndrome was the only clinical pattern diagnostic of carcinoid tumour. Most common symptoms were abdominal pain (64%), nausea and vomiting (48%). High levels of urinary 5-hydroxyindolacetic acid were significantly associated with carcinoid syndrome and metastatic disease. Tumor size, depth and gender were significant predictors of metastases. Age, gender, tumor size, metastatic spread and location were statistically significant predictors of death. CONCLUSIONS: Clinical presentation was non specific except for those patients affected by carcinoid syndrome. Ten years overall survival was 43%, with 52% metastatic spread incidence. The extent of surgical resection should be modulated on patient related risk factors. Poor prognostic factors affecting survival were: age, gender, metastatic disease, depth of invasion and tumour size.

Adult↗
PubMed2003

Alteration of hypothalamus-pituitary-adrenal gland axis in colorectal cancer patients. Preliminary report.

AIM: In advanced cancer patients a cell-mediated immunological impairment, both at baseline and during postoperative period, is often found and is associated with poor prognosis. Cortisol is strictly involved in the response to major surgical stress, is an immunosuppressor and causes a redistribution of immunological population cells in different tissues. The aim of the study was to verify serum levels and circadian rhythm of cortisol in patients with colorectal cancer at baseline before surgery and in the postoperative period, and relate it to the immune status. METHODS: In 21 patients with colorectal cancer undergoing surgery we evaluated the assessment of total lymphocytes, CD4+, cortisolemia, circadian rhythm of cortisol (11 p.m. and 8 a.m.) at baseline and in 3(rd) and 7(th) postoperative days. RESULTS: Increase of cortisolemia, as decrease of total and CD4+ lymphocytes in the postoperative period versus baseline was statistically significant. Patients with an altered circadian rhythm were 47% and 36% at 3rd and 7th postoperative days, respectively. At baseline 19% of patients had an altered cortisol circadian rhythm and it was more frequent in patients with nodal involvement (p<0.05) and with metastasis (p<0.01). No relations between lymphocytopenia and alteration of cortisolemia and cortisol circadian rhythm were found, either at baseline or postoperatively (p<0.05). CONCLUSION: Lymphocytopenia in cancer patients seems not to be associated with cortisol level and circadian rhythm alteration, either at baseline or after surgical stress. An impairment of circadian rhythm of cortisol was found at baseline in 19% of patients. It was significantly associated with the presence of metastatic disease.

Adenocarcinoma↗
PubMed2003

Morphological changes in late onset acid Maltase deficient patients with splicing gene mutation.

Clinical and morphological features have been studied in 11 late onset Acid Maltase Deficient (AMD) patients. All patients have been diagnosed on biochemical evidence of acid maltase deficiency on muscle biopsy. Molecular studies showed a heterozygous mutation (IVS1-13 T > G transversion resulting in aberrant splicing) in the GSDII gene, which is the most common mutation in late onset AMD patients. Morphological features in muscle biopsy showed a vacuolar myopathy and Golgi apparatus proliferation within fibres. The peripheral areas of autophagic vacuoles were positive for caveolin-3 and dystrophin, documenting an extensive membrane turnover. The ultrastructural study of muscle biopsy showed randomly distributed or isolated vesicles sometimes derived from the Golgi apparatus. In subsarcolemmal region, lipofucsin bodies and abnormal mitochondria with crystalline inclusions were observed. Primary and secondary lysosomes were typically filled with glycogen. These data suggest a predominant role of Golgi in vesicle proliferation and extensive intra-fibral membrane remodelling. The pathological changes observed are selective for muscle fibres (mostly in type 1) and for muscle groups (mainly proximal). An attractive hypothesis for the variability of clinical phenotype in adult and infantile onset AMD patients is that in the former, an aberrant transcript of smaller size may have originated from alternative splicing (exon 2 skipping). A residual enzyme activity is detectable in muscle, but the intracellular processing of the enzyme precursor from Golgi to the mature form in lysosomes might be blocked.

Acid Phosphatase↗
PubMed2002

Muscarinic signalling affects intracellular calcium concentration during the first cell cycle of sea urchin embryos.

The existence of a response to acetylcholine (ACh) and cholinomimetic drugs in sea urchin eggs and zygotes was investigated in two sea urchin species: Paracentrotus lividus and Lytechinus pictus. The calcium sensitive fluorescent probe, Fura-2 dextran, was employed to investigate the regulation of cytosolic free calcium concentration ([Ca(2+)](i)) by cholinomimetic drugs in unfertilised and fertilised eggs of both the sea urchin species. Exposure to cholinomimetic agonists/antagonists, either extracellularly or intracellularly, had no effect either on resting [Ca(2+)](i) levels in the unfertilised sea urchin egg, or on the transient [Ca(2+)](i) increase at fertilisation. However, following fertilisation, extracellular application of ACh receptors agonists, such as ACh and carbachol, predominantly muscarinic agonist, but not nicotine, induced a significant increase in [Ca(2+)](i), which was partially inhibited by atropine. As a consequence of exposure after fertilisation to the agonists of ACh receptors, chromatin structure was transiently affected. The hypothesis is proposed that muscarinic receptors may be involved in the (presumably Ca(2+)-dependent) modulation of the nuclear status during the first cell cycles.

Acetylcholine↗
PubMed2002

Three-dimensional mapping of cholinergic molecules by confocal laser scanning microscopy in sea urchin larvae.

Confocal laser scanning microscopy (CLSM) was used to examine molecules related to the cholinergic neurotransmission system and detected at all the larval stages of Paracentrotus lividus, by histochemical and immunohistochemical methods. CLSM, providing spatial resolution of the cells located both at the larval surface and at depth, allows a complete mapping in a three-dimensional volumetric frame. At early larval stages acetylcholinesterase- as well as choline acetyltransferase-like molecules were found mainly in the gut wall cells, and along the ciliary bands of the arms, together with muscarinic acetylcholine receptors. At perimetamorphic stages, cholinergic molecules were present in the ciliate strands along the arms, in the larval body and in the rudiment. At metamorphosis, positivity to cholinergic molecules translocated to the juvenile, where a high frequency of mAChR- and ChAT-like positive cells was found.

Animals↗
PubMed2002

Defective assembly of sarcoglycan complex in patients with beta-sarcoglycan gene mutations. Study of aneural and innervated cultured myotubes.

Mutations in the sarcoglycan (SG) genes cause autosomal recessive muscular dystrophies. The absence of each SG complex component in muscle impairs the proper assembly of the entire SG complex, resulting in sarcolemmal damage. We investigated the consequences of beta-SG gene mutations in cultured muscle from two beta-SG mutated patients, and analysed each individual SG protein expression by cross-sectional immunocytochemistry and Western blot in aneural and innervated myotubes. Patients' muscle biopsy showed total loss of SG complex; however, a limited amount of beta-SG was detected in aneural and innervated myotubes, where the protein was localized to the plasma membrane. This paradoxical beta-SG expression can be attributable to antibody cross-reaction or to the expression of an unknown SG isoform specific of immature muscle. In our cultured myotubes, the other components of the SG complex were absent, suggesting that beta-SG gene mutations result in a defective assembly of the entire SG complex in early stages of muscle development, and that the role of beta-SG is crucial for the normal structure and/or function of the SG complex in the sarcolemma.

Base Sequence↗
PubMed2002

Muscle pathology in dysferlin deficiency.

Dysferlin deficiency is being increasingly recognized in limb-girdle dystrophy and distal myopathy but its role in the development of muscle pathology is still poorly understood. For this purpose, 26 muscle biopsies from 25 dysferlinopathy patients were analysed by routine histochemistry and by immunohistochemistry with eight different antibodies, and scored for inflammatory response and type of cell infiltrate, fibre degeneration and regeneration, fibre type composition and severity of histopathological changes. In cases with an advanced-stage dystrophic pattern we observed type 1 fibre predominance exceeding 80%, suggesting a selective loss of type 2 fibres or a conversion process. The extent of muscle fibre regeneration and degeneration in dysferlinopathy was intermediate between sarcoglycanopathy and Duchenne dystrophy or myositis, suggesting a rather aggressive course of the disease. An increased inflammatory response was observed in the majority of our patients (16/26), who also showed an active dystrophic pattern. Type and localization of cellular infiltrates suggest that inflammatory reaction is secondary to necrosis. Major histocompatibility complex (MHC) class I molecules were overexpressed in dysferlinopathy, mainly in association with fibre phagocytosis and regeneration; their occasional expression in non-necrotic fibres might represent a marker of ongoing necrosis. Muscle inflammation might be triggered by the structurally altered membrane consequent to dysferlin defect.

Adolescent↗
PubMed2001

Genomic organization of the dysferlin gene and novel mutations in Miyoshi myopathy.

OBJECTIVE: Mutations in the skeletal muscle gene dysferlin cause two autosomal recessive forms of muscular dystrophy: Miyoshi myopathy (MM) and limb girdle muscular dystrophy type 2B (LGMD2B). The purpose of this study was to define the genomic organization of the dysferlin gene and conduct mutational screening and a survey of clinical features in 21 patients with defined molecular defects in the dysferlin gene. METHODS: Genomic organization of the gene was determined by comparing the dysferlin cDNA and genomic sequence in P1-derived artificial chromosomes (PACs) containing the gene. Mutational screening entailed conformational analysis and sequencing of genomic DNA and cDNA. Clinical records of patients with defined dysferlin gene defects were reviewed retrospectively. RESULTS: The dysferlin gene encompasses 55 exons spanning over 150 kb of genomic DNA. Mutational screening revealed nine novel mutations associated with MM. The range of onset in this patient group was narrow with a mean of 19.0 +/- 3.9 years. CONCLUSION: This study confirms that the dysferlin gene is mutated in MM and LGMD2B and extends understanding of the timing of onset of the disease. Knowledge of the genomic organization of the gene will facilitate mutation detection and investigations of the molecular biologic properties of the dysferlin gene.

Adolescent↗
PubMed2001

A new mutation in a family with cold-aggravated myotonia disrupts Na(+) channel inactivation.

OBJECTIVE: To identify the molecular and physiologic abnormality in familial myotonia with cold sensitivity, hypertrophy, and no weakness. BACKGROUND: Sodium channel mutations were previously identified as the cause of several allelic disorders with varying combinations of myotonia and periodic paralysis. A three-generation family with dominant myotonia aggravated by cooling, but no weakness, was screened for mutations in the skeletal muscle sodium channel alpha-subunit gene (SCN4A). METHODS: Single-strand conformation polymorphism was used to screen all 24 exons of SCN4A and abnormal conformers were sequenced to confirm the presence of mutations. The functional consequence of a SCN4A mutation was explored by recording sodium currents from human embryonic kidney cells transiently transfected with an expression construct that was mutated to reproduce the genetic defect. RESULTS: A three-generation Italian family with myotonia is presented, in which a novel SCN4A mutation (leucine 266 substituted by valine, L266V) is identified. This change removes only a single methylene group from the 1,836-amino-acid protein, and is present in a region of the protein previously not known to be critical for channel function (domain I transmembrane segment 5). Electrophysiologic studies of the L266V mutation showed defects in fast inactivation, consistent with other disease-causing SCN4A mutations studied to date. Slow inactivation was not impaired. CONCLUSIONS: This novel mutation of the sodium channel indicates that a single carbon change in a transmembrane alpha-helix of domain I can alter channel inactivation and cause cold-sensitive myotonia.

Adult↗
PubMed2001

Calpain-3 and dysferlin protein screening in patients with limb-girdle dystrophy and myopathy.

BACKGROUND: Mutations in the genes encoding for calpain-3 and dysferlin are responsible for limb-girdle muscular dystrophy (LGMD) type 2A and 2B, the most common forms of autosomal recessive LGMD. OBJECTIVE: To identify calpain-3 or dysferlin deficiency in a large cohort of patients with as yet unclassified LGMD and myopathy through candidate protein analysis. METHODS: The authors' muscle biopsy database search identified 407 candidate muscle biopsies with normal dystrophin and sarcoglycan. Calpain-3 and dysferlin were studied by Western blotting and immunohistochemistry. RESULTS: Combined calpain-3 and dysferlin Western blot analysis identified calpain-3 deficiency in 66 (16%) muscle biopsies. In 31 cases (47%), the protein was absent, and in 35 (53%), it was severely reduced in amount (3 to 50% of control). Dysferlin deficiency was found in 26 (6.5%) muscle biopsies. In 9, the protein was absent (35%), and in 17 (65%), it was severely reduced in amount (traces to 20% of control). Twenty-eight percent (53/191) of patients with LGMD phenotype had calpain-3 deficiency. Sixty percent (21/35) of patients with distal myopathy had dysferlin deficiency. Dysferlin immunohistochemistry showed, in the completely dysferlin-deficient patients, absent reaction at the sarcolemma but positive nuclear membrane labeling and, in the partially dysferlin-deficient patients, scattered granular positive cytoplasmic areas and diffuse reaction in regenerating fibers. CONCLUSION: About 25% of previously unclassified dystrophy/myopathy cases are due to calpain-3 or dysferlin protein deficiency. These results suggest that immunoblot analysis may be used to define patients for calpain-3 and dysferlin gene mutation studies.

Biopsy↗
PubMed2001

Organization of vasoactive intestinal peptide-like immunoreactive system in the brain, olfactory organ and retina of the zebrafish, Danio rerio, during development.

The localization of vasoactive intestinal peptide (VIP)-like immunoreactivity was investigated in the brain, olfactory system and retina of the zebrafish, Danio rerio, during development and in juvenile specimens, by using the indirect immunofluorescence and the peroxidase-antiperoxidase methods. In 24 h post fertilization (hpf) embryos, VIP-like immunoreactive cells were present in the olfactory pit, the retina, and several regions of the brain, including the dorsal telencephalon, the diencephalon, the tegmentum of the mesencephalon, the caudal rhombencephalon and the anterior pituitary. In 48 hpf embryos, additional VIP-like immunoreactive cell bodies were found in the ventral telencephalon, whereas in the diencephalon VIP-like immunopositive cells were more concentrated within the ventro-caudal hypothalamus. During the 7 day larval period, a dense plexus of VIP-like immunoreactive fibers first appeared in the olfactory bulbs. In 15-day-old larvae, two new groups of positive cells were observed in the periventricular preoptic nucleus and in the dorsal rhombencephalon. In 1 month/2 months old animals, VIP-like immunoreactive elements were confined to the olfactory organ, the olfactory bulbs, the periventricular preoptic nucleus and the pituitary, pars distalis. At 3 months stage, a large number of cells was observed in the periventricular preoptic nucleus. Western immunoblot analysis confirmed that VIP-like peptides, with molecular weight similar to that of synthetic VIP, are present early during the development of zebrafish. These results show that VIP-like immunoreactive structures appear early during ontogeny both in the olfactory pit, retina and brain. Transient expression of positive cells was found in the retina, telencephalon, diencephalon and brainstem. The location of VIP-like immunoreactivity indicates that, during development, VIP could be involved in several neuromodulatory functions, including the processing of visual and olfactory informations, as well as growth or survival promotion activities. The presence of VIP-like immunopositive cells in the pituitary, pars distalis, suggest that, during development, VIP may influence the secretion of pituitary hormones.

Aging↗