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Biomedical subjects

G Magni

Publications and source records attributed to G Magni.

At least 19 recordsLinked to original sources
PubMed2006

NAD(+) and axon degeneration revisited: Nmnat1 cannot substitute for Wld(S) to delay Wallerian degeneration.

The slow Wallerian degeneration protein (Wld(S)), a fusion protein incorporating full-length nicotinamide mononucleotide adenylyltransferase 1 (Nmnat1), delays axon degeneration caused by injury, toxins and genetic mutation. Nmnat1 overexpression is reported to protect axons in vitro, but its effect in vivo and its potency remain unclear. We generated Nmnat1-overexpressing transgenic mice whose Nmnat activities closely match that of Wld(S) mice. Nmnat1 overexpression in five lines of transgenic mice failed to delay Wallerian degeneration in transected sciatic nerves in contrast to Wld(S) mice where nearly all axons were protected. Transected neurites in Nmnat1 transgenic dorsal root ganglion explant cultures also degenerated rapidly. The delay in vincristine-induced neurite degeneration following lentiviral overexpression of Nmnat1 was significantly less potent than for Wld(S), and lentiviral overexpressed enzyme-dead Wld(S) still displayed residual neurite protection. Thus, Nmnat1 is significantly weaker than Wld(S) at protecting axons against traumatic or toxic injury in vitro, and has no detectable effect in vivo. The full protective effect of Wld(S) requires more N-terminal sequences of the protein.

Animals↗
PubMed2005

Seasonal patterns of hospital treatment for inflammatory bowel disease in Italy.

AIM: It is still debated whether clinical flare-ups of chronic inflammatory bowel disease follow a seasonal pattern, and the various reports are based on general practitioners' records or hospital discharge charts. There are, however, no specific figures for treatment in hospital gastroenterology units, which serve as a reference point for these disorders. This study was therefore designed to investigate whether there is a seasonal pattern in admissions for inflammatory intestinal disease in Italy, differing from what is generally known about gastrointestinal pathologies, since there are no nation-wide figures on the subject. METHODS: The RING (Ricerca Informatizzata in Gastroenterologia) project is an observational study collecting hospital discharge forms from 22 centers in Italy. RESULTS: From winter 2000 to autumn 2003, the 22 gastroenterology units participating in the RING project discharged 32,357 patients following ordinary hospital admissions. Of these, 2,856 (8.8%) had a main diagnosis of inflammatory bowel disease: 1,541 Crohn's disease, and 1,315 ulcerative colitis. No seasonal patterns were detected for either category, or when the analysis was done by age, sex and site of disease. CONCLUSIONS: The most serious flare-ups of inflammatory bowel disease, i.e. those requiring routine hospital treatment, do not appear to follow any seasonal pattern, regardless of the site of the disease or the patient's age or sex.

Adult↗
PubMed2005

Evidence for essential catalytic determinants for human erythrocyte pyrimidine 5'-nucleotidase.

Human erythrocyte pyrimidine 5'-nucleotidase, PN-I, catalyzes the dephosphorylation of pyrimidine nucleoside monophosphates. The enzyme also possesses phosphotransferase activity, transferring phosphate groups between pyrimidine nucleoside monophosphates and various pyrimidine nucleosides. Deficiency of the enzyme activity is associated with a hemolytic anemia. PN-I cDNA has been expressed in Escherichia coli, yielding a fully active recombinant enzyme, which was purified to homogeneity and extensively characterized. Multiple sequence alignment of PN-I and homologues proteins revealed the existence of conserved regions, whose importance in catalysis was examined by performing experiments designed to intercept covalent intermediates as strongly suggested by our previous kinetic studies. Furthermore, a functional analysis of the enzyme was carried out through site-directed mutagenesis designed on the basis of the sequence of the identified conserved regions as well as mutations observed in PN-I-deficient patients.

5'-Nucleotidase↗
PubMed2005

No difference in emergence time and early cognitive function between sevoflurane-fentanyl and propofol-remifentanil in patients undergoing craniotomy for supratentorial intracranial surgery.

Balanced anesthesia with sevoflurane-fentanyl has been widely accepted as anesthetic management for neurosurgery. Propofol-remifentanil regimen has been successfully used in various surgical settings, but a comprehensive comparison of sevoflurane-fentanyl and propofol-remifentanil anesthesia in patients undergoing craniotomy for supratentorial intracranial surgery has not yet been done. The aim of this prospective, randomized, open-label clinical trial was to compare clinical properties of sevoflurane-fentanyl with propofol-remifentanil anesthesia in patients undergoing supratentorial intracranial surgery. The primary endpoint was to compare early postoperative recovery and cognitive functions within the two groups; we also evaluated hemodynamic events, vomiting, shivering, and pain. One hundred twenty patients (64 males; age 15-75 years) were randomized to either total intravenous anesthesia (group T) or sevoflurane anesthesia (group S). Emergence and extubation times and cognitive function (Short Orientation Memory Concentration Test [SOMCT]) were compared in the two groups. Brain swelling, incidence of hypotensive and hypertensive episodes, postoperative vomiting, shivering, and pain were also analyzed. The mean emergence time (12.2 +/- 4.9 minutes for group S versus 12.3 +/- 6.1 minutes for group T; P = 0.92) and extubation time (18.2 +/- 2.3 minutes for group S versus 18.3 +/- 2.1 minutes for group T; P = 0.80) were similar in the two groups. Average SOMCT scores, both 15 minutes after extubation (25.6 +/- 4.9 in group S versus 23.9 +/- 7.5 in group T; P = 0.14) and 45 minutes after extubation (27.3 +/- 2.2 in group S versus 26.0 +/- 5.1 in group T; P = 0.07) were also comparable. Brain swelling was present in seven and five patients in groups S and T, respectively (P = 0.76). Hypotension was present in 12% (group S) and 28% (group T) of patients (P = 0.02). Hypertension was present in 17% of patients in group S and 40% of patients in group T (P = 0.0046). Shivering was present in 18% and 25% of patients in groups T and S (P = 0.37). Our study demonstrates that there is no patient benefit of using total intravenous anesthesia with an ultra-short-acting opioid over the conventional balanced volatile technique in terms of recovery and cognitive functions.

Adolescent↗
PubMed2004

Inflammatory bowel disease and hospital treatment in Italy: the RING multi-centre study.

AIM: To explore the management of chronic inflammatory bowel disease, specifically Crohn's disease and ulcerative colitis, in Italian gastroenterology units. METHODS: The RING (Ricerca Informatizzata in Gastroenterologia) project is an observational study collecting hospital discharge forms from 56 centres. Factors associated with the length of hospital stay were studied using multivariate logistic regression. RESULTS: In 24 months starting from August 2000, out of 29,376 hospital discharge forms, 2131 (7.3%) were collected for inflammatory bowel disease (1163 for Crohn's disease and 968 for ulcerative colitis). The Crohn's disease and ulcerative colitis groups were compared according to demographic characteristics, diagnoses, procedures and hospital stay. In Crohn's disease, computed tomography/magnetic resonance imaging, x-rays/barium enema, number of procedures and number of diagnoses were significantly associated with a hospital stay longer than 10 days. In ulcerative colitis, this association was found for parenteral nutrition, malnutrition, computed tomography/magnetic resonance imaging and number of procedures. CONCLUSIONS: Crohn's disease was confirmed as a disabling disorder requiring more frequent hospital treatment than ulcerative colitis. For the latter, parenteral nutrition and malnutrition were related to a longer hospital stay. The number of procedures, especially abdominal computed tomography/magnetic resonance imaging, was a major item for both pathologies.

Adult↗
PubMed2004

Enzymology of NAD+ homeostasis in man.

This review describes the enzymes involved in human pyridine nucleotide metabolism starting with a detailed consideration of their major kinetic, molecular and structural properties. The presentation encompasses all the reactions starting from the de novo pyridine ring formation and leading to nicotinamide adenine dinucleotide (NAD(+)) synthesis and utilization. The regulation of NAD(+) homeostasis with respect to the physiological role played by the enzymes both utilizing NAD(+) through the nonredox NAD(+)-dependent reactions and catalyzing the recycling of the common product, nicotinamide, is discussed. The salient features of other enzymes such as NAD(+) pyrophosphatase, nicotinamide mononucleotide 5'-nucleotidase, nicotinamide riboside kinase and nicotinamide riboside phosphorylase, described under 'miscellaneous', are likewise presented.

Enzymes↗
PubMed2004

Structure and function of nicotinamide mononucleotide adenylyltransferase.

The enzyme nicotinamide mononucleotide adenylyltransferase (NMNAT), a member of the nucleotidyltransferase alpha/beta phosphodiesterase superfamily, catalyzes the reaction NMN + ATP = NAD + PPi, representing the final step in the biosynthesis of NAD, a molecule playing a fundamental role as a cofactor in cellular redox reactions. NAD also serves as the substrate for reactions involved in important regulatory roles, such as protein covalent modifications, like ADP-ribosylation reactions, as well as Sir2 histone deacetylase, a recently discovered class of enzymes involved in the regulation of gene silencing. This overview describes the most recent findings on NMNATs from bacteria, archaea, yeast, animal and human sources, with detailed consideration of their major kinetic, molecular and structural features. On this regard, the different characteristics exhibited by the enzyme from the various species are highlighted. The possibility that NMNAT may represent an interesting candidate as a target for the rational design of selective chemotherapeutic agents has been suggested.

Adenosine Triphosphate↗
PubMed2003

Thyroid abscess associated with a substernal goiter. Case report.

An abscess associated with an intrathoracic goiter is an extremely rare condition. The authors report a case of a thyroid abscess complicated by acute dyspnea and asphyxia in a patient of geriatric age with a substernal goiter. Surgical therapy was necessary to obtain a correct diagnosis and an effective treatment.

Abscess↗
PubMed2002

Serum cholesterol and psychological distress in hospitalized depressed patients.

OBJECTIVE: To assess the relationship between total serum cholesterol and various psychosocial variables in depressed in-patients. METHOD: One hundred and eighty-six patients had their total fasting serum cholesterol assessed following admission; psychiatric diagnoses were obtained with the structured clinical interview for DSM-IV (SCID) interview. Psychopathology was measured with a clinician rated scale [Montgomery and Asberg Depressive Rating Scale (MADRS)] and a self-rating scale [Symptom checklist-90 (SCL-90)]. RESULTS: Univariate analyses showed lower total serum cholesterol levels being correlated with higher scores in several psychopathological areas. Multivariate analyses indicated that male gender, lower age and higher MADRS scores were the most predictive variables for lower cholesterol levels. CONCLUSION: The data suggest, in this depressed population, an association between serum cholesterol and depressive symptoms. What is the cause and what is its effect is not possible to say from this cross-sectional study.

Cholesterol↗
PubMed2001

Genetic basis of hemolytic anemia caused by pyrimidine 5' nucleotidase deficiency.

Pyrimidine 5' nucleotidase (P5'N-1) deficiency is an autosomal recessive condition causing hemolytic anemia characterized by marked basophilic stippling and the accumulation of high concentrations of pyrimidine nucleotides within the erythrocyte. It is implicated in the anemia of lead poisoning and is possibly associated with learning difficulties. Recently, a protein with P5'N-1 activity was analyzed and a provisional complementary DNA (cDNA) sequence published. This sequence was used to study 3 families with P5'N-1 deficiency. This approach generated a genomic DNA sequence that was used to search GenBank and identify the gene for P5'N-1. It is found on chromosome 7, consists of 10 exons with alternative splicing of exon 2, and produces proteins 286 and 297 amino acids long. Three homozygous mutations were identified in this gene in 4 subjects with P5'N-1 deficiency: codon 98 GAT-->GTT, Asp-->Val (linked to a silent polymorphism codon 92, TAC-->TAT), codon 177, CAA-->TAA, Gln-->termination, and IVS9-1, G-->T. The latter mutation results in the loss of exon 9 (201 bp) from the cDNA. None of these mutations was found in 100 normal controls. The DNA analysis was complicated by P5'N-1 pseudogenes found on chromosomes 4 and 7. This study is the first description of the structure and location of the P5'N-1 gene, and 3 mutations have been identified in affected patients from separate kindreds. (Blood. 2001;97:3327-3332)

5'-Nucleotidase↗
PubMed2001

Molecular cloning, chromosomal localization, tissue mRNA levels, bacterial expression, and enzymatic properties of human NMN adenylyltransferase.

A 1329-base pair clone isolated from a human placenta cDNA library contains a full-length 837-base pair coding region for a 31.9-kDa protein whose deduced primary structure exhibits high homology to consensus sequences found in other NMN adenylyltransferases. Northern blotting detected a major 3.1-kilobase mRNA transcript as well as a minor 4.1-kilobase transcript in all human tissues examined. In several cancer cell lines, lower levels of mRNA expression were clearly evident. The gene encoding the human enzyme was mapped to chromosome band 1p32-35. High efficiency bacterial expression yielded 1.5 mg of recombinant enzyme/liter of culture medium. The molecular and kinetic properties of recombinant human NMN adenylyltransferase provide new directions for investigating metabolic pathways involving this enzyme.

Amino Acid Sequence↗
PubMed2001

Wallerian degeneration of injured axons and synapses is delayed by a Ube4b/Nmnat chimeric gene.

Axons and their synapses distal to an injury undergo rapid Wallerian degeneration, but axons in the C57BL/WldS mouse are protected. The degenerative and protective mechanisms are unknown. We identified the protective gene, which encodes an N-terminal fragment of ubiquitination factor E4B (Ube4b) fused to nicotinamide mononucleotide adenylyltransferase (Nmnat), and showed that it confers a dose-dependent block of Wallerian degeneration. Transected distal axons survived for two weeks, and neuromuscular junctions were also protected. Surprisingly, the Wld protein was located predominantly in the nucleus, indicating an indirect protective mechanism. Nmnat enzyme activity, but not NAD+ content, was increased fourfold in WldS tissues. Thus, axon protection is likely to be mediated by altered ubiquitination or pyridine nucleotide metabolism.

Action Potentials↗
PubMed2000

Structure of nicotinamide mononucleotide adenylyltransferase: a key enzyme in NAD(+) biosynthesis.

BACKGROUND: Nicotinamide adenine dinucleotide (NAD(+)) is an essential cofactor involved in fundamental processes in cell metabolism. The enzyme nicotinamide mononucleotide adenylyltransferase (NMN AT) plays a key role in NAD(+) biosynthesis, catalysing the condensation of nicotinamide mononucleotide and ATP, and yielding NAD(+) and pyrophosphate. Given its vital role in cell life, the enzyme represents a possible target for the development of new antibacterial agents. RESULTS: The structure of NMN AT from Methanococcus jannaschii in complex with ATP has been solved by X-ray crystallography at 2.0 A resolution, using a combination of single isomorphous replacement and density modification techniques. The structure reveals a hexamer with 32 point group symmetry composed of alpha/beta topology subunits. The catalytic site is located in a deep cleft on the surface of each subunit, where one ATP molecule and one Mg(2+) are observed. A strictly conserved HXGH motif (in single-letter amino acid code) is involved in ATP binding and recognition. CONCLUSIONS: The structure of NMN AT closely resembles that of phosphopantetheine adenylyltransferase. Remarkably, in spite of the fact that the two enzymes share the same fold and hexameric assembly, a striking difference in their quaternary structure is observed. Moreover, on the basis of structural similarity including the HXGH motif, we identify NMN AT as a novel member of the newly proposed superfamily of nucleotidyltransferase alpha/beta phosphodiesterases. Our structural data suggest that the catalytic mechanism does not rely on the direct involvement of any protein residues and is likely to be carried out through optimal positioning of substrates and transition-state stabilisation, as is proposed for other members of the nucleotidyltransferase alpha/beta phosphodiesterase superfamily.

Adenosine Triphosphate↗
PubMed2000

Human erythrocyte pyrimidine 5-nucleotidase, PN-I, is identical to p36, a protein associated to lupus inclusion formation in response to alpha-interferon.

Erythrocyte maturation is accompanied by RNA degradation and release of mononucleotides. We have previously purified PN-I, a pyrimidine nucleotidase whose deficiency is associated with hemolytic anemia. Computer-aided analysis of PN-I tryptic and CNBr peptide sequences revealed substantial identity with tryptic peptide sequences reported for p36, an alpha-interferon-induced protein. PN-I partial sequences were matched through the expressed sequence tag database with different human complementary DNA (cDNA) clones, whose sequences were exploited to screen a human placenta cDNA library. PN-I cDNA, coding for a 286-residue protein, was expressed in Escherichia coli, yielding a fully active recombinant enzyme. The recombinant protein sequence comprised the peptide sequences determined for PN-I and p36. Rabbit antisera raised against two peptides deriving from p36 and PN-I tryptic digestions, respectively, recognized both wild-type and recombinant PN-I. Molecular properties of the two proteins were essentially the same. We conclude that p36 and PN-I are identical proteins. (Blood. 2000;96:1596-1598)

5'-Nucleotidase↗
PubMed2000

Autonomic nervous system activity imbalance in cardiomyopathic hamster.

There is strong evidence that autonomic imbalance plays an important role in progression of heart failure. Analysis of heart rate variability (HRV) has achieved substantial acceptance as a noninvasive method for the assessment of autonomic tone. The purpose of this investigation was to study HRV in an experimental model of heart failure using cardiomyopathic (BIO TO.2) hamsters. Animals showed an autonomic imbalance of cardiac control that seems due to attenuation of parasympathetic activity and an enhanced sympathetic tone. The reduction of parasympathetic activity in BIO TO.2 hamsters is suggested by (a) the reduction of the high-frequency (HF) spectrum, and (b) the lack of atropine to generate a response. The increased sympathetic activity is indicated by (a) the decreased time-domain indexes, (b) the increased LF/HF ratio of the power spectrum, and (c) the alteration of HRV indexes induced by propranolol. These results support the notion that in heart failure, there is a similar autonomic imbalance in both human and hamster and suggest that the cardiomyopathic hamster is a suitable experimental model for studying the involvement of the autonomic nervous system in the progression of heart failure.

Animals↗