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S Marinoni

Publications and source records attributed to S Marinoni.

At least 19 recordsLinked to original sources
PubMed2001

Mutations in the general transcription factor TFIIH result in beta-thalassaemia in individuals with trichothiodystrophy.

The transcription factor TFIIH is involved in both basal transcription and DNA repair. Mutations in the XPD helicase component of TFIIH can result in the diverse clinical features associated with xeroderma pigmentosum (XP) and trichothiodystrophy (TTD). It is generally believed that the multi-system abnormalities associated with TTD are the result of a subtle deficiency in basal transcription. However, to date, there has been no clear demonstration of a defect in expression of any specific gene in individuals with these syndromes. Here we show that the specific mutations in XPD that cause TTD result in reduced expression of the beta-globin genes in these individuals. Eleven TTD patients with characterized mutations in the XPD gene have the haematological features of beta-thalassaemia trait, and reduced levels of beta-globin synthesis and beta-globin mRNA. All these parameters were normal in three patients with XP. These findings provide the first evidence for reduced expression of a specific gene in TTD. They support the hypothesis that many of the clinical features of TTD result from inadequate expression of a diverse set of highly expressed genes.

Cells, Cultured↗
PubMed1998

Analysis of mutations in the XPD gene in Italian patients with trichothiodystrophy: site of mutation correlates with repair deficiency, but gene dosage appears to determine clinical severity.

Xeroderma pigmentosum (XP) complementation group D is a heterogeneous group, containing patients with XP alone, rare cases with both XP and Cockayne syndrome, and patients with trichothiodystrophy (TTD). TTD is a rare autosomal recessive multisystem disorder associated, in many patients, with a defect in nucleotide-excision repair; but in contrast to XP patients, TTD patients are not cancer prone. In most of the repair-deficient TTD patients, the defect has been assigned to the XPD gene. The XPD gene product is a subunit of transcription factor TFIIH, which is involved in both DNA repair and transcription. We have determined the mutations and the pattern of inheritance of the XPD alleles in the 11 cases identified in Italy so far, in which the hair abnormalities diagnostic for TTD are associated with different disease severity but similar cellular photosensitivity. We have identified eight causative mutations, of which four have not been described before, either in TTD or XP cases, supporting the hypothesis that the mutations responsible for TTD are different from those found in other pathological phenotypes. Arg112his was the most common alteration in the Italian patients, of whom five were homozygotes and two were heterozygotes, for this mutation. The presence of a specifically mutated XPD allele, irrespective of its homozygous, hemizygous, or heterozygous condition, was always associated with the same degree of cellular UV hypersensitivity. Surprisingly, however, the severity of the clinical symptoms did not correlate with the magnitude of the DNA-repair defect. The most severe clinical features were found in patients who appear to be functionally hemizygous for the mutated allele.

Abnormalities, Multiple↗
PubMed1998

Melatonin regulates the respiratory burst of human neutrophils and their depolarization.

The effect of different doses of melatonin on the respiratory burst as well as on the membrane potential changes of human neutrophils stimulated with phorbol 12-myristate 13-acetate (PMA) was investigated. The intracellular production of reactive oxygen species (ROS) in stimulated neutrophils was quantified in individual cells by flow cytometry, measuring the oxidation of nonfluorescent dihydrorhodamine 123 to the green fluorescent rhodamine 123. The transmembrane potential change was measured using the fluorescent probe oxonol. Preincubating the cells with micromolar concentrations of the indole resulted in an increase of the response to PMA. In two of six subjects investigated, the respiratory burst was also increased by a 10 nM concentration of the indole, but when the melatonin concentration was increased to 2 mM the respiratory burst was inhibited. The change in the transmembrane potential of neutrophils paralleled the respiratory burst. Indeed, the treatment of the cells with doses of melatonin up to 0.5 mM increased the depolarization occurring subsequent to PMA stimulation, whereas 2 mM melatonin concentration decreased the extent of depolarization. To investigate whether melatonin could directly affect the transmembrane potential changes of neutrophils, the extent of depolarization, induced by increasing the extracellular potassium concentration, was measured in cells preincubated with 2 mM melatonin. This treatment resulted in a decrease of the extent of depolarization, which suggests that melatonin can directly alter membrane ion conductance in human neutrophils.

Antioxidants↗
PubMed1994

Trichothiodystrophic hair reveals an abnormal pattern of viscoelastic parameters.

Separate analysis and quantitative determination of the viscous and elastic parameters of hair performed in 5 patients with trichothiodystrophy and in 20 sex- and age-matched control subjects revealed an abnormal pattern of the mechanical behavior of trichothiodystrophic hair. The change of the viscous parameter is probably associated with the profound alterations in the high-sulfur proteins of the interfilamentary matrix; the changes in the elastic parameters may be related to the reduced stability of the irregularly arranged microfibrils of trichothiodystrophic hair caused by the marked reduction of the disulfide cross-links.

Adolescent↗
PubMed1992

DNA repair investigations in nine Italian patients affected by trichothiodystrophy.

Trichothiodystrophy (TTD) is a rare autosomal recessive disorder characterized by brittle hair, mental and growth retardation, peculiar face, ichthyosis, and in 20% of the reported cases photosensitivity. Cellular photosensitivity due to the same genetic defect present in xeroderma pigmentosum group D (XP-D) has been described in several patients. Nine patients with clinical symptoms diagnostic for TTD have been identified in Italy to date. We report the results of DNA repair investigations performed in cultured fibroblasts from these patients and 8 TTD parents. Survival, DNA repair synthesis and RNA synthesis following UV irradiation were all normal in the 8 TTD heterozygous cell strains. Among the 9 TTD-affected individuals, normal cellular UV sensitivity was observed in the 2 patients without signs of clinical photosensitivity. In contrast, the other 7 TTD cell strains showed a notable reduction in UV-induced DNA repair synthesis (UDS) levels, ranging between 40% and 5-15% of normal values. Complementation analysis indicated that in the repair-deficient TTD cell strains the genetic defect is the same as that present in XP-D cells. The biochemical heterogeneity of the XP-D defect in TTD patients characterized by different degrees of defective UDS results in different patterns of response to the killing effect of UV light in non-proliferating cells.

Cells, Cultured↗
PubMed1992

Immune defects in families and patients with xeroderma pigmentosum and trichothiodystrophy.

Xeroderma pigmentosum (XP) is a rare autosomal recessive disease characterized by photosensitivity, a high incidence of cancer in sun-exposed portions of the skin and a reduced capacity to repair the u.v.-induced DNA damage. One of the XP mutations (XP-D) has also been identified in patients affected by trichothiodystrophy (TTD), a rare autosomal recessive disease characterized by brittle hair, mental and physical retardation, peculiar face and ichthyosis. However, in these patients there is no evidence of increased skin tumour incidence. Since an impairment of cell-mediated immunity has been proposed as a co-factor in the cancer proneness of XP patients, we investigated the involvement of immune defect(s) in five XP patients, five TTD patients, their parents, and 24 TTD relatives. We evaluated the phenotype of circulating lymphocytes, natural killer (NK) cell lytic activity, target cell binding of NK cells at single cell level and the effect of interferons (IFN) alpha and beta on NK cell activity. The relative proportion of CD3+ and CD4+ circulating lymphocytes was reduced in XP but not in TTD patients. NK cell lytic activity was decreased in XP patients and their mothers, but their fathers showed normal lytic activity. NK activity varied among TTD families: four out of five patients and their relatives presented low NK cell activity, and one family was normal. In TTD family members, NK activity increased after incubation with IFN-alpha or IFN-beta, but never reached normal values. In contrast, in XP patients and their mothers, the defect was almost completely corrected after in vitro incubation with IFN-alpha or IFN-beta. Our study indicates impaired NK lytic activity in the majority of TTD and XP patients and that this defect is present also in members of their families. In addition, XP patients present a low number of circulating T cells. These multiple abnormalities, together with DNA repair defects, could be related to the increased cancer risk in XP patients.

Abnormalities, Multiple↗
PubMed1990

Neonatal-onset panhypopituitarism in a girl with Brachmann-De Lange syndrome.

We report on a girl with recurrent hypoglycemia since age 2 days and severe impairment of physical and neurological development. Panhypopituitarism was recognized at age 5 months. The diagnosis of Brachmann-De Lange syndrome (BDLS) was also made. Replacement therapy has avoided further episodes of hypoglycemia, improved growth, and allowed partial psychomotor catch-up. Though we are not aware of any other report of panhypopituitarism in patients with BDLS, we suggest that hormonal derangement may play a role in the manifestations of this syndrome.

De Lange Syndrome↗
PubMed1990

Calcium and phosphorus balance in very low birth weight babies on total parenteral nutrition.

A balance study of Ca and P has been performed in 12 Very Low Birth Wt babies receiving prolonged Total Parenteral Nutrition. The mean intake of both minerals was 54.4 mg/kg/day (range 40-70). In order to avoid the formation and precipitation of CaP crystals in the solution, fructose-1,6-diphosphate was used as a source of P. 30 balance studies were performed between the seven and 63 day of life: they were always positive with a mean retention of 47.4 mg/kg/day of Ca and 48.1 mg/kg/day of P. For both minerals, 88% of the amount infused was retained: the correlation between intake and retention was linear and statistically significative (Ca:r = 0.9, p < 0.0001; P:r = 0.68, p < 0.0001). The post-natal and post-conceptional ages of the babies had no influence on Ca and P balance. The blood levels of Ca and P were poorly correlated to both intake and excretion, and were not as indicative of the mineral balance as the retention rates calculated on the basis of the 24 h urinary excretion of the minerals. A very useful test for clinical monitoring of Ca and P balance proved to be the Ca/creatinine and P/creatinine ratios measured on simple urine samples, which were strongly correlated to 24 h excretion. All infants developed radiological signs of mild osteopenia, but there was no case of acute metabolic derangement or rickets. Our data demonstrated that even in sick VLBW infants on TPN it is possible to achieve good retention rates of Ca and P, which are not different from those observed in well VLBW babies fed a 'standard' premature formula.

Journal Article↗
PubMed1990

Search for consanguinity within and among families of patients with trichothiodystrophy associated with xeroderma pigmentosum.

The association of two rare hereditary disorders, trichothiodystrophy (TTD) and xeroderma pigmentosum (XP), was found in four patients from three families, apparently unrelated but living in the same geographical area. In order to test the hypothesis of a common ancestor, consanguinity within and among the families was checked using three different approaches: reconstruction of genealogical trees, typing of blood markers, and surname analysis. The results of the three types of analyses strengthen the hypothesis that, in at least two out of the three families, the genetic defect determining the TTD/XP phenotype is identical by descent, as a consequence of remote inbreeding. This implies that if two mutations are responsible for the two diseases they are at linked loci or affect the same gene.

Blood Group Antigens↗
PubMed1989

High frequency of empty sella syndrome in children with growth hormone deficiency.

Computer-assisted tomography (CT) with 2 mm axial sections and reconstructions was carried out in 31 children affected by GH deficiency (GHD): 18 with idiopathic complete isolated GHD, 3 with idiopathic partial isolated GHD, 2 with idiopathic panhypopituitarism, 4 with isolated acquired GHD and 4 with acquired panhypopituitarism. Density in the intrasellar area on CT corresponded to that of cerebrospinal fluid in 13/20 cases with idiopathic hypopituitarism and in 2/8 cases with acquired hypopituitarism. The overall incidence of primary empty sella syndrome (PESS) in the GH deficient patients studied was thus over 48%, while in children without endocrine dysfunction, it was only 5/213 (2.4%). It is concluded that PESS is more frequent in childhood than assumed until now and that it is frequently associated with GHD.

Adolescent↗
PubMed1988

Chromosome and blood marker studies in families of patients affected by xeroderma pigmentosum and trichothiodystrophy.

Chromosome and blood marker studies were performed in the families of 4 patients in which the association of 2 rare recessive Mendelian disorders, xeroderma pigmentosum (XP-D) and trichothiodystrophy (TTD), was present. Blood genotypes did not indicate any linkage with the pathologic condition, nor any segregation anomaly. Cytogenetic analysis using high-resolution banding techniques showed a normal karyotype both in the heterozygous and in the homozygous individuals. These findings lead us to exclude a cytologically detectable chromosome rearrangement, such as a microdeletion, as a possible cause of the association of XP-D and TTD in our patients.

Blood Group Antigens↗
PubMed1986

Xeroderma pigmentosum (complementation group D) mutation is present in patients affected by trichothiodystrophy with photosensitivity.

We studied the response to UV irradiation in cells from four patients, from three apparently unrelated families, affected by trichothiodystrophy (TTD). They showed all the symptoms of this rare autosomal recessive disorder (brittle hair with reduced sulfur content, mental and physical retardation, ichthyosis, peculiar face) together with photosensitivity. We found a decreased rate of duplicative DNA synthesis in stimulated lymphocytes, reduced survival in fibroblasts, and very low levels of unscheduled DNA synthesis (UDS) in Go lymphocytes and fibroblasts after UV irradiation. Complementation studies showed that normal values of UDS are restored in heterokaryons obtained by fusion of TTD cells with normal and xeroderma pigmentosum (XP)-complementation group A-cells. In contrast the defect is not complemented by fusion with XP-complementation group D-fibroblasts.

Cells, Cultured↗
PubMed1984

Inhibitory effect of cimetidine on L-dopa-stimulated growth hormone release in normal man.

Some evidence suggests the existence of a histaminergic influence on GH secretion in animals and man. We used cimetidine, a specific H2-receptor antagonist, to study the possible interference of H2-receptor blockade on plasma GH release by L-dopa and on PRL inhibition by L-dopa in normal man. Seven healthy normal male volunteers aged 23-36 years received a single oral dose of L-dopa (500 mg) or an i.v. bolus of cimetidine (300 mg) or both (L-dopa 30 min before cimetidine). Blood samples were taken at various times over 2 h and plasma GH and PRL levels measured. Cimetidine alone did not alter basal plasma GH values; L-dopa elicited the well-known GH releasing effect with peak values at 75 min (15.65 +/- 2.8 ng/ml); cimetidine injected 30 min after L-dopa ingestion significantly blunted the GH response to L-dopa and peak values (4.7 +/- 1.6 ng/ml) were delayed to 105 min. Cimetidine provoked a rapid rise in plasma PRL with the peak value of 15 +/- 3 ng/ml at 15 min, followed by a return to near basal values in 90-120 min. L-Dopa completely inhibited the PRL response to cimetidine. We conclude that there is an inhibitory influence of the H2-receptor antagonist cimetidine on GH release by L-dopa. This, together with the action of cimetidine on PRL secretion (with or without L-dopa), suggests a possible antidopaminergic effect of H2-receptor blockade at the level of the central nervous system.

Adult↗
PubMed1982

Home treatment of seizures as a strategy for the long-term management of febrile convulsions in children.

A cooperative study evaluating compliance and efficacy of Diazepam clisma in home treatment of febrile seizures in children was conducted from January 1979 to June 1981. Parents of 601 children admitted to hospital for a febrile convulsion were taught to use Diazepam clisma in the eventuality of a new seizure and asked to record the length of the episode. Complete follow-up was possible in 564 cases for an average time of 16.7 months. During the research period 109 convulsive episodes were registered in 76 children. Four of these children presented a seizure without fever. Diazepam clisma was administered correctly in 70 episodes (64.2%). In 26 of the remaining 39 cases, therapy was not administered because the seizure ended before the treatment was started. Prolonged seizures (greater than 15 min) have been reported in 8 cases. Six were in the non-treated group and 2 in the treated group. In both these last cases Diazepam was expelled immediately after being administered. The results of the study suggest that home treatment of febrile convulsions by Diazepam clisma represents a well accepted and useful strategy for prevention of prolonged seizures, provided that continuous contact and complete understanding between family and physician can be ensured.

Child↗
PubMedDate not supplied

[Comparison of high-dose immunoglobulin and cyclosporine in newly diagnosed diabetic children].

A controlled trial was carried out on type I diabetic children to evaluate and to compare the clinical effects of two different kinds of immunotherapy: high doses intravenous gammaglobulin (IVIgG) and cyclosporine A (CyA). 30 newly diagnosed patients were admitted to the trial, 10 of whom served as controls (group A), 10 received 400 mg/kg b.w. of IVIgG on 5 consecutive alternate days and subsequently after 15 days and monthly thereafter for up to six months (group B), 10 patients received CyA 5-10/kg b.w. by mouth in two daily doses for a period comprised between 6 and 18 months (group C). Serum post-prandial C-peptide level was significantly higher after 6 months in group B and C than in group A; after 12 months, only group C showed significantly higher values. This difference was no longer significative at 18 and 24 months. Insulin requirement in the treated groups was significantly lower than in control group at 6 months, this difference was no longer significative at 12 months. We didn't find any difference concerning insulin requirement during the study comparing the two groups treated with the two different immunosuppressive therapies. In 3 patients in group B and in 3 patients in group C we didn't observe any appreciable response to immunosuppressive therapy (defined as insulin requirement greater than 0.5 UI/kg b.w. at 6 months and/or greater than 0.8 UI/kg b.w. at 12 months). We couldn't find any significant difference between responders and not responders to the immunosuppressive therapies regarding age, symptoms lasting before the diagnosis, weight loss, ketoacidosis intensity and serum post-prandial C-peptide level at the onset.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗