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M Valli

Publications and source records attributed to M Valli.

At least 55 records · Page 3Linked to original sources
PubMed1996

Growth hormone treatment in osteogenesis imperfecta with quantitative defect of type I collagen synthesis.

OBJECTIVES: We studied growth rate, bone density, and bone metabolism in patients affected by type I osteogenesis imperfecta (OI) with quantitative defect in type I collagen synthesis during treatment with human growth hormone (hGH), being aware of its collagen-stimulating synthesis activity in vitro. STUDY DESIGN: Fourteen patients (6 boys; ages 4.8 to 10.8 years) were studied. Any structural alteration in the collagen chains was excluded, and reduced production of structurally normal type I collagen (increase in type III/type I collagen; reduction in the messenger ribonucleic acid alpha 1 (I)/ alpha 2 (I) ratio) was demonstrated. The patients were divided into two groups comparable in sex, age, height, and clinical severity of OI; seven patients (three boys) were treated for 12 months with hGH at a dosage of 0.2 mg/kg per week (0.6 IU/kg per week), in six injections subcutaneously, and seven were followed as control subjects. Auxologic data were measured every 3 months, and bone age was determined at the start, after 1 year of treatment, and 1 year after its completion. Every 3 months, serum insulin-like growth factor type I, osteocalcin, carboxyterminal propeptide of type I procollagen, alkaline phosphatase, calcium, and phosphorus levels and urinary hydroxyproline and calcium levels were determined. Bone mass measurements were carried out at the start of the study in all patients and repeated after 12 months in treated patients at the lumbar spine by dual-energy x-ray absorptiometry and by anteroposterior (second, third, and fourth lumbar vertebrae) and lateral (third lumbar vertebra) scan. Results were expressed as areal (anteroposterior and lateral) bone density (in milligrams per square centimeter) and as calculated true density (in milligrams per cubic centimeter). RESULTS: After 12 months, linear growth velocity in treated patients increased significantly in comparison with the pretreatment period (from 3.57 +/- 0.55 to 6.04 +/- 0.69 cm/yr; p < 0.05) and with the untreated group (p < 0.05). Bone age did not advance faster than chronologic age. The fracture index per year was low before treatment, and during therapy no patient had any fractures. Serum osteocalcin levels were statistically lower than in control subjects before treatment and increased significantly after 12 months (3.3 +/- 1.0 vs 2.1 +/- 0.9 nmol/L; p < 0.05). Serum levels of carboxyterminal propeptide of type I procollagen were significantly lower than normal values before treatment (164.6 +/- 46.7 vs 310.3 +/- 97.6 ng/ml; p < 0.05) and rose, but not significantly, during and after treatment. Before therapy, patients with OI had significantly lower lumbar anteroposterior, lateral, and calculated true bone density than the normal population of the same sex compared for both age and height. After hGH treatment, bone density increased significantly in the lumbar spine, in anteroposterior and lateral scans (+2.6 +/- 2.5% and +9.8% +/- 14.0%, respectively; p < 0.05). CONCLUSIONS: From our results, we conclude that hGH treatment in moderate OI does not increase the fracture risk in treated patients in the short term, significantly increases the rate of linear growth velocity, and increases bone turnover and mineral content in trabecular bone at the lumber spine.

Alkaline Phosphatase↗
PubMed1996

Quantitative study of ductal breast cancer progression. A progression index (P.I.) for premalignant lesions and in situ carcinoma.

The diagnostic subjective assessment of ductal premalignant proliferative lesions and in situ carcinoma of the breast produces unsatisfactory results. Since the phenotypical cell changes in tumour progression toward infiltrating cancer constitute a continuum, a grading on a continuous scale of values produces a more reliable and reproducible characterization. The diagnostic assessment for any individual patient may be expressed by a progression index (P.I.): its numerical values are based on the cellular changes measured in the individual cases. In this study, the progression index is based on two morphometric features, nuclear size and nucleolar area. In addition, the method presented may produce a ratio, stating the relative likelihood that each case represents one of the conventional diagnostic categories. Such a likelihood ratio may be obtained from the bivariate distribution of nuclear size and nucleolar area for the conventional diagnostic categories.

Breast Neoplasms↗
PubMed1996

Treatment of benign prostatic hyperplasia with 5-alpha-reductase inhibitor: morphological changes in patients who fail to respond.

AIMS: To describe the prostatic adenectomy specimens of six patients with symptomatic benign prostatic hyperplasia (BPH) who failed to respond to long term treatment with a 5-alpha-reductase inhibitor, finasteride. METHODS: Histological sections from six cases of BPH who had been treated with finasteride were investigated. Five patients were prescribed 5 mg finasteride daily for six months and one patient 5 mg daily for 12 months. The patients underwent adenectomy as their urethral obstruction failed to resolve. Twenty cases of untreated BPH served as controls. RESULTS: In patients taking finasteride for six months the prostatic adenectomy specimens showed a reduction in the size of the prostate and an increase in the stroma:epithelial and stroma:lumen ratios compared with controls. The size of the ducts and acini was not as uniform as in the controls. In particular, some ducts and acini were still lined by a bistratified epithelium similar to that found in controls but lacked undulations at the epithelial border; other ducts/acini were atrophic. Some scattered clusters of small acini with a focally fragmented basal cell layer were observed in two of the five treated cases. One prostatic adenectomy specimen, from the patient treated for one year, showed extensive lobular atrophy and diffuse squamous and transitional cell metaplasia. At the periphery of the transition zone, there was a complex intra-acinar papillary-cribriform proliferation of clear cells without nuclear atypia, similar to clear cell papillary hyperplasia. The periurethral region showed stromal nodules in both patients and controls. CONCLUSIONS: Morphological evaluation of finasteride treated BPH showed changes in the lobules of the transition zone, but not in the periurethral stroma.

5-alpha Reductase Inhibitors↗
PubMed1996

Achilles and patellar tendinopathies in athletes: pathogenesis and surgical treatment.

In the period from 1985 to 1992, 136 athletes underwent 148 surgical exploration of Achilles (98 operations in 90 patients) and patellar (50 operations in 46 patients) tendons for persistent pain. The morphology and the biochemistry of tendon samples taken at operation were investigated. A marked increase of glycosaminoglycans, especially chondroitin sulphate, was present. The complete alleviation of pain and the return to full activity were obtained in 79% of the athletes, while the remaining 21% were not able to return to their sports activities. Generally, successful outcome after surgery was experience by younger patients who had tendon pain of short duration--which was correlated to a lesser degree of tendon degeneration.

Achilles Tendon↗
PubMed1994

A base substitution at IVS-19 3'-end splice junction causes exon 20 skipping in pro alpha 2(I) collagen mRNA and produces mild osteogenesis imperfecta.

Molecular investigations on a young patient and her family were undertaken to identify the molecular defect responsible for a mild form of osteogenesis imperfecta (OI) with blue sclerae, dentinogenesis imperfecta and joint laxity. Analysis of collagenous proteins from the proband's fibroblasts showed the presence of two populations of alpha 2(I) chains, one normal and one migrating faster on SDS gels, thereby suggesting deletion of amino acid sequences. The faster migrating chains were retained mainly in the cell layer and not found in the extracellular matrix deposited by cultured fibroblasts. Chemical cleavage of mismatch (CCM) analysis on the patient's pro alpha 2(I) mRNA: normal cDNA heteroduplexes localized the molecular defect. cDNA sequencing revealed a deletion of exon 20 (54 bp) in about half of the molecules. Genomic DNA sequencing revealed heterozygosity for a G-to-C transversion of the last nucleotide of intron 19, which changed the 3' consensus splicing site. As a consequence pro alpha 2(I)mRNA was abnormally spliced from the last codon of exon 19 to the first codon of exon 21. To our knowledge, this is the first acceptor site mutation so far described in an OI patient. Restriction analysis indicated that the mutation was present also in three other affected family members. The full sequence of COL1A2 introns 19 and 20 are reported.

Base Sequence↗
PubMed1994

Quantitative study of ductal breast cancer progression. Morphometric evaluation of phenotypical changes occurring in benign and preinvasive epithelial lesions.

Fifty-nine cases of Breast Epithelial Proliferative Lesions (BEPL) and Ductal Carcinoma in Situ (DCIS), were studied by image analysis, to evaluate the nuclear changes occurring in the conventional diagnostic categories of ductal hyperplasia, atypical ductal hyperplasia and DCIS with quantitative methods. Diagnosis reproducibility is the main practical problem of these breast lesions. In fact, with subjective methods, the reproducibility appears to be very low and precarious especially for clinical demands. The objective, quantitative evaluation of cell phenotypical changes should be the method for both practical diagnostic problems and study of ductal cancer progression. The distribution pattern of the data in the feature, obtained with quantitative analysis, strongly suggests a continuum of changes, indicating an evolutionary process of Breast Ductal Carcinoma (BDC) progression in its preinvasive stage. Each observed case may be characterised by its own cellular, objective alterations and a progressive trend toward BDC can be stated. Since the actual changes of the proliferative phenotypes can be measured, and the values are reproducible, karyometric measurement may allow an objective grading of individual cases.

Adult↗
PubMed1994

Severe (type III) osteogenesis imperfecta due to glycine substitutions in the central domain of the collagen triple helix.

The molecular defects responsible for three cases of severe (type III) osteogenesis imperfecta (OI) were investigated. The mutation sites were localized in pro alpha 1(I) and pro alpha 2(I) mRNA molecules, respectively, by chemical cleavage of mismatch in heteroduplex nucleic acids. Mutation identification was achieved by reverse transcription-polymerase chain reaction-DNA amplification, followed by cloning and sequencing. Two unrelated patients were demonstrated to bear the same G-A transition at nucleotide 2418 of the pro alpha 1(I) coding region, leading to G589S substitution and resulting in very similar clinical manifestations. In the latter patient, a G-T transversion at nucleotide 2166 was found in one pro alpha 2(I) allele, which caused a G586V substitution and again severe OI. Presumably all three mutations occurred de novo in the probands, since they were not found in their parents' DNA. The biochemical findings on type I collagen were very similar in all the probands: the mutations here described had little destabilizing effects on triple helix formation, secretion and stability. The half-life of the collagen incorporated into the insoluble matrix was comparable with that of controls. These mutations are localized in the gap zone of the fibrils where mineral nucleation occurs. This fact suggests that they probably do not exert destabilizing effects on the individual collagen molecules, but rather on the mineralization process, once the defective molecules are incorporated into the fibrils, hence causing severe phenotypes.

Base Sequence↗
PubMed1994

Benign, borderline, and well-differentiated malignant intestinal mucinous tumors of the ovary: a clinicopathologic, histochemical, immunohistochemical, and nuclear quantitative study of 57 cases.

Mucinous ovarian tumors are still a subject of controversy because they can show either intestinal or endocervical differentiation. Morphologic distinction between borderline and malignant tumors is sometimes difficult, and their clinical behavior has not been definitively ascertained. We selected 10 mucinous cystadenomas (MCAs), 32 intestinal mucinous borderline tumors (IMBTs), and 15 well-differentiated mucinous carcinomas (MCCs), all with goblet cells, at least focally. In all cases, we studied the clinicopathologic features, mucin content, intermediate filament expression, and some nuclear quantitative features, namely, the volume-corrected mitotic index (M/Vi), percentage of nucleolated nuclei, mean number of nucleoli per nucleus, percentage of nucleoli touching the nuclear membrane, and mean nuclear area. The quantitative nuclear study included cytometric DNA analysis and the results were expressed as relative mean ploidy value (RMPV) and as diploid-tetraploid or aneuploid histograms. The results of the quantitative study were evaluated statistically. All patients had stage IA tumors, had received surgical therapy only, and were alive and well after a follow-up of more than 5 years. Light microscopic examination revealed that destructive stromal invasion was not present in any MCCs and that IMBTs and MCCs were easily recognizable using the Hart and Norris criteria, later expanded by Hart. Mucin histochemistry and intermediate filament immunohistochemistry failed to detect substantial differences between the diagnostic categories. DNA analysis demonstrated an increase in aneuploid tumors going from IMBTs to MCCs, but these differences were not statistically significant. On the other hand, nuclear quantitative morphology showed significant differences among the three groups of tumors for all features considered. Forward stepwise discriminant analysis highlighted that MCAs, IMBTs, and MCCs were contiguous but different categories. These data support the separation of IMBTs and MCCs into morphologically different categories as underlined by the results of quantitative nuclear morphologic analysis. The favorable outcome of all patients confirms the excellent prognosis of stage I IMBTs and suggests that well-differentiated MCCs without destructive stromal invasion at stage IA could be assimilated, in terms of prognosis and therapy, into stage I IMBTs.

Adenocarcinoma, Mucinous↗
PubMed1994

Atypical carcinoid tumour of the lung: a study of 33 cases with prognostic features.

Atypical carcinoids of the lung (well-differentiated neuroendocrine carcinomas) are rare tumours of uncertain prognosis. We have studied 33 cases--male to female ratio 2:1, age range 22-75 years, mean 55 years, 80% smokers, 15 peripheral and 18 central, tumour size 1.2-9.5 cm. Microscopically they had a nesting/insular, trabecular or lobular pattern. Nuclear morphology was variable, round cells, large cells and spindle cells being identified with small cell areas in five tumours. Mitotic activity varied from 4 to 80 per 1.52 mm2. Areas of necrosis were seen in all tumours. All 33 tumours were cytokeratin positive (AE1/AE3 and CAM5.2), 32 were positive for neuron-specific enolase, synaptophysin and chromogranin A. Electronmicroscopy showed dense core granules in 29 available cases. Nineteen cases were stage I, nine stage II, four stage III and one stage IV. Follow-up information was available for 22 cases. Size, location, stage and large cell/small cell morphology were important prognostic indicators. Large tumour size, large cell or mixed large cell/small cell morphology, peripheral localization and advanced stage were adverse prognostic indicators. Mitotic activity and the presence of necrosis did not appear to influence stage or behaviour.

Adult↗
PubMed1994

Atypical carcinoid tumour of the thymus: a study of eight cases.

Atypical carcinoids of the thymus are rare neoplasms of uncertain prognosis. We have studied eight cases (six male, two female; age range 48-60 years, mean 55 years), none with evidence of a paraneoplastic neuroendocrine syndrome. Tumour size was large and ranged from 7.5 to 10 cm. Microscopically, all had a nesting/insular or trabecular pattern, eosinophilic cytoplasm, round nuclei with fine chromatin and small nucleoli. No small cell features were evident. Mitotic activity ranged from 2 to 21 per 1.52 mm2. Focal necrosis was seen in all cases. All were positive for cytokeratin (AE1/AE3, CAM 5.2) and the neuroendocrine markers NSE, synaptophysin and chromogranin; five cases were positive for calcitonin. On electronmicroscopy all contained dense core granules, often numerous. Three cases were stage I and five stage III (infiltrating lung or chest wall). Follow-up information was available in four cases (one stage I and three stage III): the stage I tumour had local recurrence and metastasis to the lung within a year whilst the three patients with stage III tumours died of liver, bone and brain metastases within 3 years.

Carcinoid Tumor↗
PubMed1993

Gly85 to Val substitution in pro alpha 1(I) chain causes mild osteogenesis imperfecta and introduces a susceptibility to protease digestion.

In this paper we describe a mild moderate form of osteogenesis imperfecta caused by a point mutation in COL1A1 which converted glycine 85 to valine. The valine substitution introduced into the triple-helical domain of type-I collagen a conformational perturbation causing susceptibility to digestive proteases. In fact, SDS/PAGE of pepsin-treated collagen showed the presence of a faint band, migrating between alpha 1(I) and alpha 2(I), both in the medium and in the cell layer. On trypsin digestion the band, a shortened form of alpha 1(I), had a melting temperature of 39.5 degrees C. If the triple-helical collagen was obtained after trypsin or chymotrypsin digestion of procollagen, two shortened bands were identified; the enzymes cleaved about 40% of the trimers. The mutant procollagen was normally secreted and processed in the extracellular matrix at a normal rate. When native type-I collagen was formed after dextran-sulfate incubation, only chains of normal length were found, suggesting that the fibroblast proteases did not recognize the alteration introduced by the mutation. The effects of glycine 85 to valine substitution are compared with those produced by a previously described arginine substitution of the same residue (Deak et al., 1991).

Adult↗
PubMed1993

Osteogenesis imperfecta and type-I collagen mutations. A lethal variant caused by a Gly910-->Ala substitution in the alpha 1 (I) chain.

In this study we describe a new dominant point mutation in COL1A1 causing a lethal form of Osteogenesis imperfecta (type II B). Dermal cultured fibroblasts from the proband were shown to produce both normal and heavily overmodified type-I collagen. The mutation introduced a local conformational perturbation, which causes abnormal exposure of arginine residues; the triple helical domain was susceptible to trypsin digestion even at 30 degrees C. The chains bearing the point mutation were poorly secreted and short-term pulse experiments showed that the extensive intracellular retention of mutant trimers also impaired the secretion of normal chains. The molecular defect was localized in a COL1A1 allele by cloning and sequencing a cDNA region corresponding to the CB6 peptide. A G to C transversion which causes the substitution in the triple helical region of Gly910 with alanine was found. The mutation also causes the disappearance of a MspI-recognition site at nucleotide 3263 of the pro alpha 1 (I) coding sequence. Restriction analysis, along with the biochemical screening of collagens, allowed us to perform prenatal diagnosis on cells from chorionic-villus sampling and to exclude the recurrence of the mutation in the sibling.

Alanine↗
PubMed1993

Possible role of overglycosylation in the type I collagen triple helical domain in the molecular pathogenesis of osteogenesis imperfecta.

The underlying defect in patients affected by a form of osteogenesis imperfecta (OI) clarified at the molecular level regards the amount or the structure of type I collagen synthesized. This leads to a decreased and/or abnormal mineral deposition in bone and affects bone mass and/or strength. Abnormal interactions between collagen molecules in the presence of mutant trimers could give rise to abnormal fibrils, which, in turn, can determine incorrect interactions with noncollagenous matrix macromolecules. The interactions can be disturbed or modulated by an abnormal distribution on the collagen fibril surface of electrically charged or hydrophobic groups, or by an increased presence of sugar moieties linked to hydroxylysyl residues due to chain post-translational overmodifications (lysyl overhydroxylation and hydroxylysyl overglycosylation) of the portion of the triple helical domain of abnormal type I collagen molecules N-terminal with respect to the defect localization.

Amino Acid Sequence↗
PubMed1993

Paternal mosaicism for a COL1A1 dominant mutation (alpha 1 Ser-415) causes recurrent osteogenesis imperfecta.

We describe a dominant point mutation in the COL1A1 gene causing extremely severe osteogenesis imperfecta (OI type II/III) which was detected in the dermal fibroblasts of a proband, diagnosed by ultrasonography at 24 weeks of gestation. Type I collagen secretion was reduced and pro alpha 1(I) chains were overmodified. The mutation was localised in one COL1A1 allele by chemical cleavage of mismatched bases in normal cDNA/proband's mRNA heteroduplexes, and identified by cloning and sequencing. A G-to-A transition which causes the substitution of Gly-415 with serine in the alpha 1(I) triple helical domain was found. The same mutation was detected in the father's spermatozoa and lymphocytes. Mosaicism in the father's germline explains the occurrence in the family of two additional OI pregnancies, which were documented by X-ray and ultrasound investigations.

Adult↗
PubMed1993

Extracellular matrix deposition in cultured dermal fibroblasts from four probands affected by osteogenesis imperfecta.

Type I procollagen biosynthesis and matrix deposition were studied in cultured fibroblasts of four probands affected by Osteogenesis Imperfecta and in whom the mutations have been characterized. The mutations along the triple helix altered all biochemical parameters considered, i.e. thermal stability, kinetics of procollagen secretion and rate of maturation from procollagen to collagen. The biochemical findings were peculiar for each case considered, but there was no correlation between biochemical parameters and clinical phenotype. In all our probands, regardless of the clinical severity, mutant chains appeared in the insoluble matrix formed by fibroblasts cultured in the presence of dextran sulfate. The densitometric scanning revealed a relative increased amount of fibronectin, suggesting that the matrix contained a lower quantity of type I collagen. Furthermore, the amount of mutant chains found in the insoluble fraction was clearly less than expected, considering that 75% of new synthesized trimers are abnormal. Therefore, in the presence of a mutation, the protein available for extracellular matrix formation is reduced and the mutant trimers incorporated in the matrix probably interfere with normal fibril performance. The abnormal fibril morphology has a dramatic effect in bone, interfering presumably with a correct mineral deposition and interactions with non/collagenous bone proteins.

Cells, Cultured↗
PubMed1993

Deposition of mutant type I collagen in the extracellular matrix of cultured dermal fibroblasts in osteogenesis imperfecta.

To study how mutant type I collagen interferes with matrix deposition we investigated the extracellular matrix produced by cultured skin fibroblasts in thirteen patients affected by different forms of Osteogenesis Imperfecta. Two different approaches were used: a) the pericellular matrix produced during 24 h label was analyzed by SDS-PAGE; b) type I collagen present in the insoluble cell-layer fraction in long-term cultures was studied. Results showed that a very small amount of abnormal type I trimers were present regardless of the clinical phenotype. In only two cases mutant chains were clearly incorporated. These data indicate a selective deposition of normal collagen trimers over abnormal ones. Moreover, in long-term cultures a decreased amount of type I collagen was deposited as indicated by the relative increase in type V collagen. These data are discussed in light of results found in bone by other authors and suggest that decreased deposition of type I collagen could be a general feature in OI and not limited to null-allele OI probands.

Cells, Cultured↗