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Biomedical subjects

M Fiorini

Publications and source records attributed to M Fiorini.

At least 37 records · Page 2Linked to original sources
PubMed1998

Mutation analysis by a non-radioactive single-strand conformation polymorphism assay in nine families with X-linked severe combined immunodeficiency (SCIDX1).

X-linked severe combined immunodeficiency (SCIDX1) is an inherited disease characterized by profound abnormalities of cell-mediated and humoral immunity. Patients with SCIDX1 have defects in the common cytokine receptor gamma chain gene (IL2RG) that encodes a shared, essential component of the receptors for interleukin-2 (IL-2), IL-4, IL-7, IL-9 and IL-15. We have characterized nine SCIDX1 families by using a DNA-based, non-radioactive screening method and DNA sequencing. Nine different mutations were found, scattered from exon 1 to exon 5 of the IL2RG gene. Two of these mutations have been previously identified in other unrelated patients; the other seven are novel mutations that differ from all of the 95 already reported in the IL2RG mutation data base. In addition to describing novel mutations in the IL2RG gene, this study shows that the knowledge of the genetic defect and the use of an efficient, non-radioactive, and rapid screening approach have important implications for prenatal and postnatal diagnosis, carrier female identification, and possibly prenatal therapy.

DNA Mutational Analysis↗
PubMed1997

Structural and functional basis for JAK3-deficient severe combined immunodeficiency.

Mutations of the Janus family kinase JAK3 have been found to be responsible for autosomal recessive severe combined immunodeficiency (SCID) in humans. We report here the analysis of four new unrelated patients affected by JAK3-deficient SCID. The genetic defects were heterogeneous and included a large intragenic deletion as well as different point mutations, leading to missense substitutions, early stop codons, or splicing defects. We performed a series of studies of the biochemical events induced by cytokines on lymphoblastoid B-cell lines obtained from these patients. Abnormalities in tyrosine phosphorylation of JAK3 in response to interleukin-2 (IL-2) and IL-4 were present in all patients. Accordingly, IL-2-mediated phosphorylation of STAT5 was also absent or barely detectable. On the contrary, in all cases, we could show reduced but clear phosphorylation of STAT6 upon IL-4 stimulation. In one patient carrying a single amino acid change (Glu481Gly) in the JH3 domain of JAK3, we observed partially conserved IL-2 responses resulting in reduced but detectable levels of JAK3 and STAT5 phosphorylation. Interestingly, the patient bearing this mutation developed a substantial number of circulating CD4(+)/CD45RO+ activated T lymphocytes that were functionally impaired. In two cases, patients' cells expressed JAK3 proteins with mutations in the JH2 pseudo-kinase domain. A single cysteine to arginine substitution (Cys759Arg) in this region resulted in high basal levels of constitutive JAK3 tyrosine phosphorylation unresponsive to either downregulation by serum starvation or cytokine-mediated upregulation. The characterization of the genetic defects and biochemical abnormalities in these JAK3-deficient patients will help define the role of JAK3 in the ontogeny of a competent immune system and may lead to a better understanding of the JAK3 functional domains.

B-Lymphocytes↗
PubMed1997

Selegiline in the treatment of hypersomnolence in myotonic dystrophy: a pilot study.

Patients with myotonic dystrophy frequently complain of hypersomnolence, a symptom which seriously restricts their social life. The pathogenesis of this symptom is a matter of debate: it has been attributed to both alveolar hypoventilation and pathological changes in the brainstem. As selegiline has been shown to reduce the number of sleep attacks in nacrolepsy, we tested whether hypersomnolence in myotonic dystrophy would respond to the same treatment. Ten patients with myotonic dystrophy received selegiline/placebo (20 mg daily) in a double-blind crossover trial. We monitored daytime sleepiness by means of a multiple sleep latency test. Treatment appeared to be well tolerated but did not alter hypersomnolence in myotonic dystrophy. Further studies to assess the effect of higher doses of selegiline are warranted.

Adult↗
PubMed1997

Mutation pattern in the Bruton's tyrosine kinase gene in 26 unrelated patients with X-linked agammaglobulinemia.

Mutation pattern was characterized in the Bruton's tyrosine kinase gene (BTK) in 26 patients with X-linked agammaglobulinemia, the first described immunoglobulin deficiency, and was related to BTK expression. A total of 24 different mutations were identified. Most BTK mutations were found to result in premature termination of the translation product. Mutations were detected in most BTK exons with a predominance of frameshift and nonsense mutations in the 5' end of the gene and missense mutations in its 3' part, corresponding to the catalytic domain of the enzyme. Nonsense and frameshift mutations were associated with diminished levels of BTK mRNA expression, except for a frameshift mutation in exon 17 and two nonsense mutations in exon 2, indicating that these cases are not confined to penultimate exons. One amino acid substitution (R28H) was found in the pleckstrin homology domain's residue, which is mutated in mice bearing the X-linked immunodeficiency phenotype; another substitution (R307G) was identified in the src homology domain 2. All remaining amino acid substitutions were found in the catalytic domain of Btk.

Agammaglobulinaemia Tyrosine Kinase↗
PubMed1997

A PCR-based non-radioactive X-chromosome inactivation assay for genetic counseling in X-linked primary immunodeficiencies.

The Wiskott-Aldrich syndrome (WAS), X-linked severe combined immunodeficiency (SCIDX1), and X-linked agammaglobulinemia (XLA) are severe congenital immunodeficiencies with X-linked inheritance. Although rare, they are all associated with severe infections from early in life, and high morbidity and mortality. Female carriers of these diseases can be identified by a non-random pattern of X-chromosomal inactivation in cell lineages targeted by each gene defect. For patients with WAS, SCIDX1 or XLA, the demonstration of non random X-Chromosome inactivation in their mothers can be used to confirm clinical diagnosis. Furthermore, analysis of X-Chromosome inactivation in at risk females allows preconceptional carrier detection, thus representing an important aid in genetic counseling. For each disease we established a PCR-based, non radioactive assay at the human androgen receptor (HUMARA) locus, that allows analysis of X-Chromosome inactivation in the affected cell types and in tissue specific controls to exclude the issue of skewed X-chromosomal inactivation. In our study, 50 females with a known family history of XLA [19], WAS [18], and SCIDX1 [13],were examined. A carrier status was established in 19 females (7 XLA, 6 WAS, 6 SCIDX1) and excluded in 29 ( 11 XLA, 11 WAS, 7 SCIDX1). Only in 2 cases (4%) the assay was not informative.

Cell Lineage↗
PubMed1996

In-utero transplantation of parental CD34 haematopoietic progenitor cells in a patient with X-linked severe combined immunodeficiency (SCIDXI).

BACKGROUND: X-linked severe combined immunodeficiency (SCIDXI) is an inherited immune defect which leads to death in infancy from severe infections. The defect is caused by mutations of the IL-2RG gene that encodes for the common gamma chain shared by several cytokine receptors. The disease is characterised by lack of T and NK cells with normal numbers of B cells. SCIDXI can be cured by bone marrow transplantation (BMT) or prevented by abortion after prenatal diagnosis. METHODS: A male fetus was diagnosed as having SCIDXI by molecular, immunophenotypic, and functional analyses. The fetus was injected intraperitoneally under ultrasound guidance with CD34 haematopoietic progenitor cells purified from paternal bone marrow and T-cell depleted by E rosetting. Chimerism analysis was by HLA-DQ alpha typing and gamma-chain staining on cord blood. FINDINGS: A healthy 3.6 kg boy was delivered by caesarean section at 38 weeks of gestation with no clinical or laboratory signs of graft-versus-host disease. Engraftment of donor-derived CD2 cells was found at birth. At 3.5 months of age the infant is well and his T-cell counts and function are normal. INTERPRETATION: In-utero transplantation of haematopoietic progenitor cells allowed immune reconstitution of a fetus with SCIDXI and may be an alternative to elective abortion. Our report should encourage applications of this method to other inherited disorders curable by BMT.

Antigens, CD34↗
PubMed1996

Power spectrum analysis contribution to the detection of cardiovascular dysautonomia in multiple sclerosis.

In multiple sclerosis (MS) autonomic cardiovascular dysfunction is an uncommon, but potentially dangerous event, to which studies of spectral analysis of heart rate variability have not been applied, yet. MATERIAL AND METHODS--We studied 16 patients with definite MS (11 women and 5 men, mean age 30.3 +/- 7.4 yrs., mean EDSS 2.06 +/- 1.42) and 16 sex- and age-matched healthy controls. Besides cardiovascular reflex tests (valsalva manoeuvre, deep breathing, lying to standing, Blood Pressure response to standing and sustained handgrip), each underwent spectral analysis of the R-R interval short-term variability at rest and after tilting, to detect three components: very low frequency (VLF), low frequency (LF) and high frequency (HF). A recent brain MRI was obtained from patients, to compare plaque characteristics with spectral parameters. RESULTS--At cardiovascular reflexes, only four patients (25%) showed an impairment, mostly of a mild degree. VLF and LF at rest were lower in MS subjects than in controls (p < 0.01). No significant correlation was found between spectral parameters and lesion area or localization as detected on MRI. CONCLUSIONS--Spectral analysis could usefully flank reflex tests to detect autonomic subclinical cardiovascular abnormalities.

Adult↗
PubMed1996

Cardiac autonomic dysfunction in relapsing-remitting multiple sclerosis during a stable phase.

The autonomic cardiovascular system was studied by means of autonomic tests and heart rate variability related to body movements during sleep, in 20 patients with relapsing-remitting multiple sclerosis in a stable phase and in 9 normal subjects. Responses to autonomic tests in multiple sclerosis and control subjects were similar. Heart rate variability, instead, showed a lower degree of adaptability in patients with multiple sclerosis than in controls during sleep, because of sympathetic system dysfunction. No significant correlation between magnetic resonance lesions and cardiovascular sleep indexes was found.

Adult↗
PubMed1995

Sleep abnormalities in traumatic apallic syndrome.

Sleep patterns in 10 patients with traumatic apallic syndrome were studied, together with 10 healthy controls matched for sex and age. All patients underwent neurological examination, brain CT, and polysomnographic recording within six months (mean 99 (SD 45) range 47-180 days) from the onset of symptoms. Clinical follow up was performed six months after enrollment in the study. Sleep patterns were recorded in nine out of 10 patients. In the tenth patient there was no rhythm resembling physiological sleep. This patient was the only one who remained in a persistent vegetative state and died before the six month follow up. The severity of neurological deficit at follow up was significantly related to the duration of coma. There was no significant difference between patients and controls with respect to sleep architecture. The time spent awake after sleep onset was longer in patients than controls. Our data highlight the presence of sleep fragmentation in traumatic apallic syndrome, which might be due to changes in brain structures responsible for sleep maintenance. The absence of sleep-wake cycles might indicate a poor outcome.

Adolescent↗
PubMed1992

[Malignant schwannoma metastasizing to the heart].

We introduce the case of a 34-year-old male with a malignant metastasizing tumor in the heart associated with skin manifestations. The patient was submitted to heart surgery to resect the tumor. The correct diagnosis was done by pathological findings and immunohistochemical methods and showed, malignant schwannoma.

Adult↗
PubMed1991

Effect of stress on cardiovascular regulation in neurological diseases with dysautonomia.

Ten patients with Multiple Sclerosis (MS) and ten with Myotonic Dystrophy (MD) underwent an evaluation of cardiovascular reflexes by classic tests, tilt table test and mental stressors. Sympathetic and parasympathetic changes were detected by classical tests in MS patients. Mental stressors appeared able to reveal blood pressure control impairment in MD patients. Lower differential blood pressure was observed during mental stressors administration in MS with brainstem lesions at MRI.

Adult↗
PubMedDate not supplied

[Tissue engineering applications: cartilage lesions repair by the use of autologous chondrocytes].

Promising new therapies based on tissue engineering have been recently developed for cartilage repair. The association of biomaterials with autologous chondrocytes expanded in vitro can represent a useful tool to regenerate this tissue. The scaffolds utilised in such therapeutical applications should provide a pre-formed three-dimensional shape, prevent cells from floating out of the defect, have sufficient mechanical strength, facilitate uniform spread of cells and stimulate the phenotype of transplanted cells. Hyaff-11 is a hyaluronic-acid based biodegradable polymer, that has been shown to provide successful cell carrier for tissue-engineered repair. From our findings we can state that human chondrocytes seeded on Hyaff-11 are able to maintain in vitro the characteristic of differentiated cells, expressing and producing collagen type II and aggrecan which are the main markers of cartilage phenotype, down-regulating collagen type I. Moreover, it seems to be a useful scaffold for cartilage repair both in animal models and clinical trials in humans, favouring the formation of a hyaline-like tissue. In the light of these data, we can hypothesise, for the future, the use of autologous chondrocyte transplantation together with gene therapy as a treatment for rheumatic diseases such as osteoarthritis.

Animals↗