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Biomedical subjects

G Tedeschi

Publications and source records attributed to G Tedeschi.

At least 73 records · Page 4Linked to original sources
PubMed1997

Proton magnetic resonance spectroscopic imaging in progressive supranuclear palsy, Parkinson's disease and corticobasal degeneration.

We used proton magnetic resonance spectroscopic imaging (1H-MRSI) to assess the in vivo cortical and subcortical neuronal involvement in progressive supranuclear palsy, Parkinson's disease and corticobasal degeneration. This technique permitted the simultaneous measurement of compounds containing N-acetylaspartate (NA), choline (Cho), creatine-phosphocreatine (Cre) and lactate, from four 15-mm slices divided into 0.84-ml single-volume elements. The study included 12 patients with progressive supranuclear palsy, 10 with Parkinson's disease, nine with corticobasal degeneration and 11 age-matched normal control subjects. Regions of interest were selected from the brainstem, caudate, thalamus, lentiform nucleus, centrum semiovale, and from frontal, parietal, precentral, temporal and occipital cortices. Progressive supranuclear palsy patients, compared with control subjects, had significantly reduced NA/Cre in the brainstem, centrum semiovale, frontal and precentral cortex, and significantly reduced NA/Cho in the lentiform nucleus. Corticobasal degeneration patients, compared with control subjects, had significantly reduced NA/Cre in the centrum semiovale, and significantly reduced NA/Cho in the lentiform nucleus and parietal cortex. There were no significant differences between Parkinson's disease patients and control subjects, or between patients groups in any individual region of interest. In the parietal cortex of corticobasal degeneration patients, NA/Cho was significantly reduced contralateral to the most affected side. There were statistically significant group differences in the regional pattern of NA/Cre and NA/Cho reduction, comparing normal control subjects with all patient groups, Parkinson's disease with corticobasal degeneration, and Parkinson's disease with progressive supranuclear palsy. Although the occurrence of significant groups differences does not imply that it is possible to differentiate between individual patients using 1H-MRSI in progressive supranuclear palsy and corticobasal degeneration, detection of specific cortical and subcortical patterns of neuronal involvement is possible with this technique. We suggest that this regional pattern of neuronal involvement found in progressive supranuclear palsy and corticobasal degeneration may help in the diagnostic evaluation of affected individuals.

Aged↗
PubMed1997

Relative sparing of extraocular muscles in myotonic dystrophy: an electrooculographic study.

We studied 40 patients with myotonic dystrophy (MD) to investigate whether saccadic eye movement (SEM) abnormalities have a central or peripheral origin. SEMs were recorded by electrooculography and analyzed by a computer system. Six patients were followed up to 2-7 years. Slow SEMs were present in 70% of patients, while saccadic latency and accuracy were within normal ranges. Peak saccadic velocity (PSV) did not correlate with disease duration and muscular disability, and showed a significant reduction only in 1 patient during the follow-up. Muscular disability correlated significantly with age and disease duration and worsened in 4 patients over time. The doll's head maneuver elicited vestibular compensatory eye movements with high velocities. These findings suggest that the extraocular muscles are at least partially spared in MD and that supranuclear structures, most likely the burst cells in brainstem reticular formation, may contribute to the slowing of SEMs.

Adolescent↗
PubMed1997

Increased choline signal coinciding with malignant degeneration of cerebral gliomas: a serial proton magnetic resonance spectroscopy imaging study.

The authors tested the hypothesis that proton magnetic resonance spectroscopy (1H-MRS) imaging can be used as a supportive diagnostic tool to differentiate clinically stable brain tumors from those progressing as a result of low- to high-grade malignant transformation or posttherapeutic recurrence. Twenty-seven patients with cerebral gliomas verified on histological examination were studied repeatedly with 1H-MRS imaging over a period of 3.5 years. At the time of each 1H-MRS imaging study, clinical examination, MR imaging, positron emission tomography with 18F-fluorodeoxyglucose, and biopsy findings (when available) were used to categorize each patient as having either stable or progressive disease. Measures of the percentage changes in the choline (Cho) 1H-MRS imaging signal intensity between studies, which were obtained without knowledge of the clinical categorization, allowed the investigators to segregate the groups with a high degree of statistical significance. All progressive cases showed a Cho signal increase between studies of more than 45%, whereas all stable cases showed an elevation of less than 35%, no change, or even a decreased signal. The authors conclude that increased Cho levels coincide with malignant degeneration of cerebral gliomas and therefore may possibly be used as a supportive indicator of progression of these neoplasms.

Adult↗
PubMed1996

L-aspartate oxidase from Escherichia coli. I. Characterization of coenzyme binding and product inhibition.

This paper reports the biochemical characterization of the flavoprotein L-aspartate oxidase from Escherichia coli. Modification of a previously published procedure allowed overexpression of the holoenzyme in an unproteolysed form. L-Aspartate oxidase is a monomer of 60 kDa containing 1 mol of noncovalently bound FAD/mol protein. A polarographic and two spectrophotometric coupled assays have been set up to monitor the enzymatic activity continuously. L-Aspartate oxidase was subjected to product inhibition since iminoaspartate, which results from the oxidation of L-aspartate, binds to the enzyme with a dissociation constant (Kd) equal to 1.4 microM. The enzyme binds FAD by a simple second-order process with Kd 0.67 microM. Site-directed mutagenesis of the residues E43, G44, S45, F47 and Y48 located in the putative binding site of the isoallossazinic portion of FAD reduces the affinity for the coenzyme.

Amino Acid Oxidoreductases↗
PubMed1996

L-aspartate oxidase from Escherichia coli. II. Interaction with C4 dicarboxylic acids and identification of a novel L-aspartate: fumarate oxidoreductase activity.

L-Aspartate oxidase is a monomeric flavoprotein that catalyzes the first step in the de novo biosynthetic pathway for pyridine nucleotide formation under both aerobic and anaerobic conditions. In spite of the physiological importance of this biosynthesis in particular in facultative aerobic organisms, such as Escherichia coli, little is known about the electron acceptor of reduced L-aspartate oxidase in the absence of oxygen. In this report, evidence is presented which suggests that in vitro fumarate can play such a role. L-Aspartate oxidase binds succinate and fumarate with Kd values of 0.24 mM and 0.22 mM, respectively. A competitive behaviour was observed for these two dicarboxylic acids towards iminoaspartate and sulfite ions. Photoreduction experiments suggest that fumarate and succinate bind at or close to the active site of the molecule. A new fumarate reductase activity of L-aspartate oxidase is reported using benzylviologen or L-aspartate as reductants and fumarate as oxidant. Steady-state kinetics for the oxidase and the fumarate reductase activity of L-aspartate oxidase were obtained using either fumarate or oxygen as electron acceptor and L-aspartate as electron donor. Finally, succinate was identified as the product of the L-aspartate:fumarate oxidoreductase activity using radiolabeled fumarate under anaerobic conditions. The results suggest that fumarate can be a valuable alternative to oxygen as a substrate for L-aspartate oxidase.

Amino Acid Oxidoreductases↗
PubMed1996

Proton magnetic resonance spectroscopic imaging in patients with cerebellar degeneration.

Using proton magnetic resonance spectroscopic imaging, we studied the cerebellum of 9 patients with cerebellar degeneration and of 9 age-matched normal control subjects. This technique permits the simultaneous measurement of N-acetylaspartate, choline-containing compounds, creatine/phosphocreatine, and lactate signal intensities from four 15-mm slices divided into 0.84-ml single-volume elements. Because patients with cerebellar degeneration often show substantial atrophy on magnetic resonance imaging (MRI), we specifically chose to analyze the spectroscopic signals only from tissue that did not have an atrophic appearance on the MRI. The spectroscopic findings showed a significant reduction of N-acetylaspartate in all parts of the cerebellum, a significant correlation with MRI scores of cerebellar atrophy, and a significant correlation with clinical rating scores of cerebellar disturbance. Our method of analysis suggests the presence of a neurodegenerative process in cerebellar areas that do not appear to be atrophic on the MRI. Some limitations of proton magnetic resonance spectroscopic imaging in the present study were related to the partial field inhomogeneity characteristics of the posterior fossa, the anatomical location of the cerebellum, and the particularly severe cerebellar atrophy in some of the patients.

Adult↗
PubMed1996

Quantified-EEG in normal aging and dementias.

The value of quantitative electroencephalography (q-EEG) in the differential diagnosis of multi-infarct dementia (MID) and dementia of Alzheimer's type (DAT) is controversial. To evaluate the possible diagnostic role of q-EEG in these two conditions we studied 18 healthy adults, 16 healthy elderly (HE), 29 DAT patients and 45 MID patients. MID patients showed a significant increase of delta activity on the occipital regions, a significant widespread increase of theta activity, a significant widespread decrease of alpha activity. DAT patients showed a significant widespread increase of delta and theta activity, a significant widespread decrease of alpha activity. Spectral profile analysis showed an asymptotic exponential peak frequency at 4.33 HZ, and the disappearance of dominant activity in DAT patients; a 1 Hz decrease of peak frequency with a preserved normal profile in MID patients. We conclude that q-EEG is a useful ancillary test to differentiate MID from DAT.

Aged↗
PubMed1996

Regionally specific pattern of neurochemical pathology in schizophrenia as assessed by multislice proton magnetic resonance spectroscopic imaging.

OBJECTIVE: Several single-voxel proton magnetic resonance spectroscopy (1H-MRS) studies of patients with schizophrenia have found evidence of reductions of N-acetyl-aspartate (NAA) concentrations in the temporal lobes. Multislice proton magnetic resonance spectroscopy imaging (1H-MRSI) permits simultaneous acquisition and mapping of NAA, choline-containing compounds (CHO), and creatine/phosphocreatine (CRE) signal intensities from multiple whole brain slices consisting of 1.4-ml single-volume elements. We have used 1H-MRSI to assess the regional specificity of previously reported changes of metabolite signal intensities in schizophrenia. Hippocampal volume was also measured to test the relationship between 1H-MRSI findings and tissue volume in this region. METHOD: Ratios of areas under the metabolite peaks of the proton spectra were determined (i.e., NAA/CRE, NAA/CHO, CHO/CRE) for multiple cortical and subcortical regions in 10 inpatients with schizophrenia. RESULTS: Patients showed significant reductions of NAA/CRE and NAA/CHO bilaterally in the hippocampal region and in the dorsolateral prefrontal cortex. There were no significant changes in CHO/CRE or in NAA ratios in any other area sampled. No significant correlation was found between metabolite ratios in the hippocampal region and its volume. CONCLUSIONS: NAA-relative signal intensity reductions in schizophrenia appear to be remarkably localized, involving primarily the hippocampal region and the dorsolateral prefrontal cortex, two regions implicated prominently in the pathophysiology of this disorder.

Adult↗
PubMed1996

Cortical and subcortical chemical pathology in Alzheimer's disease as assessed by multislice proton magnetic resonance spectroscopic imaging.

BACKGROUND: Multislide proton magnetic resonance spectroscopic imaging (1H-MRSI) permits the simultaneous acquisition of N-acetylaspartate (NA), choline (Cho), creatine/phosphocreatine (Cre), and lactate (Lac) signal intensities from four 15-mm slices divided into 0.84-ml single-volume elements. NA is inferred to be a neuron-specific molecule, whereas Cho mainly reflects glycerophosphocholine and phosphocholine, compounds involved in phospholipid metabolism. OBJECTIVE: To assess whether 1H-MRSI could detect a regional pattern of cortical and subcortical involvement in the brain of Alzheimer's disease (AD) patients. METHODS: 1H-MRSI was performed in 15 patients with probable AD and 15 age-matched healthy controls. Regions of interest (ROIs) were selected from frontal (FC), temporal (TC), parietal (PC), occipital, and insular cortices, subcortical white matter (WM), and thalamus. RESULTS: In AD patients, we found a significant reduction of NA/Cre in the FC, TC, and PC and a significant reduction of Cho/Cre in the WM. CONCLUSIONS: This 1H-MRSI study of AD patients shows a regional pattern of neuronal damage in the associative cortices, as revealed by significant reduction of NA/Cre in the FC, TC, and PC, and regional derangement of phospholipid metabolism, as revealed by significant reduction of Cho/Cre in the WM.

Aged↗
PubMed1995

A site-directed mutagenesis study at Lys-113 of NAD(P)H:quinone-acceptor oxidoreductase: an involvement of Lys-113 in the binding of the flavin adenine dinucleotide prosthetic group.

NAD(P)H: quinone-acceptor oxidoreductase (EC 1.6.99.2), also referred to as DT-diaphorase, is a flavoprotein that catalyzes the two-electron reduction of quinones and quinonoid compounds to hydroquinones, using either NADH or NADPH as the electron donor. Using an Escherichia coli expression system developed previously, we prepared three mutants of the rat liver quinone reductase. These mutants are Lys-113-His (K113H), Lys-113-Asp (K113D), and Lys-113-Ala (K113A). While the mutant K113H was readily purified using the same procedure as for the purification of the wild-type quinone reductase and found to have an activity similar to that of the wild-type enzyme, K113D and K113A were purified only in very small quantities, mainly in the form of apoprotein, and had very low activities. The results suggest that a positively charged amino acid at this position is important for the binding of the flavin adenine dinucleotide (FAD) prosthetic group. Flavin spectral studies of 6-mercapto-FAD-reconstituted mutants revealed that mutation at Lys-113 affects the protein environment around position-6 of the isoalloxazine ring.

Amino Acid Sequence↗
PubMed1995

An 8.5-kDa ribonuclease from the extreme thermophilic archaebacterium Sulfolobus solfataricus.

Protein p3, a ribonuclease we previously isolated from the archaebacterium Sulfolobus solfataricus [P. Fusi et al. (1993) Eur. J. Biochem. 211, 305-310], was subjected to complete amino acid sequencing. It consisted of 75 residues, with a calculated M(r) of 8582, a pI of 10.1, and had some degree of monomethylation at Lys-4 and Lys-6. p2, a previously sequenced, 62-residue ribonuclease from the same organism, had an identical sequence for 57 consecutive residues starting from the N-terminus. p2 and p3 also showed a striking similarity to five other proteins previously isolated from Sulfolobus strains and identified as DNA-binding proteins. However, the C-terminus, 10 residue region of p3 did not show any similarity to these proteins; in contrast, it was significantly similar to stretches in three eubacterial ribonucleases from Bacillus strains. No difference between p2 and p3 has so far been detected as regards their catalytic properties. Available data suggest that these molecules have a narrow substrate specificity and probably play specific roles in RNA processing.

Amino Acid Sequence↗
PubMed1995

Active site studies of DT-diaphorase employing artificial flavins.

NAD(P)H:quinone oxidoreductase (EC 1.6.99.2) (DT-diaphorase) is an FAD-containing enzyme that catalyzes the 2-electron reduction of quinones to hydroquinones using either NADH or NADPH as the electron donor. In this study, FAD was removed by dialyzing the holoprotein against 2 M KBr, and synthetic analogs of FAD were substituted in the flavin binding site as structural probes. Spectral analysis indicates that the benzoquinoid forms of 8-mercapto-FAD and 6-mercapto-FAD are stabilized on binding to the enzyme. This is consistent with the fact that the native flavoprotein forms the anion flavin radical upon photoreduction and suggests the presence of a positive charge near the N(1)C(2)O position of the isoalloxazine ring. Reactivity studies using 8-chloro- and 8-mercapto-flavins suggest that the 8 position of the FAD is accessible to the solvent. However, the rates of the reactions were dramatically decreased in the presence of the competitive inhibitor, dicumarol. 6-Mercapto-, 6-thiocyanato-, 6-azido-, and 6-amino-flavins were also used as structural probes. The results indicate that the 6 position is accessible to solvent. Dicumarol binding increases the pK alpha of the enzyme-bound 6-mercapto-flavin from below pH 5.0 to higher than pH 9.0. The results suggest that DT-diaphorase shows the same properties as the C-C transhydrogenases, and the binding of dicumarol elicits a conformational change or an adjustment in the polarity of the FAD pocket. The enzyme reconstituted with oxidized 5-deaza-FAD has significant catalytic activity, confirming that DT-diaphorase is an obligatory 2-electron transfer enzyme and plays a role in the detoxification of quinones and quinoid compounds by reducing them to the relatively stable hydroquinones.

Binding Sites↗
PubMed1995

DT-diaphorase. Redox potential, steady-state, and rapid reaction studies.

NAD(P)H:quinone oxidoreductase (DT-diaphorse) appears to be a 2-electron transfer flavoprotein, which catalyzes the conversion of quinones into hydroquinones. Upon photoreduction in the presence of dimethylformamide, the enzyme forms a red semiquinone. In the absence of dimethylformamide, only 10% of the radical form is thermodynamically stabilized. This indicates a redox potential of the enzyme-bound semiquinone/reduced flavin couple that is higher than the midpoint potential for the oxidized flavin/semiquinone couple. The 2-electron redox potential was determined to be -159 +/- 3 mV at 25 degrees C, pH 7.0. In the presence of benzoquinone or 3-aminopyridine adenine dinucleotide phosphate, as NADPH analogue, there is no change in the redox properties of the enzyme flavin. A significant decrease is observed in the presence of the competitive inhibitor dicumarol (Em = -234 +/- 2 mV at pH 7.0). The reaction mechanism of the flavoprotein has been investigated by steady-state and stopped-flow kinetic methods using NADPH, NADH, deamino-NADPH, and 3-acetylpyridine adenine dinucleotide reduced form (APADH) as electron donors and K3Fe(CN)6, 4,5-dihydro-4,5-dioxo-1H-pyrrolo-[2,3-f]quinoline-2,7,9-tricarboxylic acid (PQQ), and 2,5-diaziridinyl-3,6-bis(carboethoxy-amino)-1,4-benzoquinone (AZQ) as electron acceptors in 50 mM phosphate buffer, pH 7.0, 25 degrees C. No evidence could be obtained to indicate that semiquinoid intermediates play a part in the catalytic mechanism of DT-diaphorase with quinones as acceptors. The rates of the reduction by NADPH, NADH, deamino-NADPH, and APADH (1.3 x 10(9), 8.8 x 10(8), 8.3 x 10(8) and 9.8 x 10(8) m-1 min-1, respectively) as well as the rates of the reoxidation by PQQ and AZQ (9 x 10(4) and 2.8 x 10(6) M-1 min-1, respectively) are directly proportional to substrate concentration, and there is no evidence of the formation of enzyme-substrate complexes. If such complexes do indeed exist, the affinity of the enzyme for substrate must be extremely low. Using K3Fe(CN)6 as electron acceptor, the rate of oxidation of fully reduced enzyme is 4.6 x 10(7) M-1 min-1 and it is accurately proportional to ferricyanide concentration. This rate represents that of flavin semiquinone formation, with the subsequent oxidation of the semiquinone being much faster, since no spectral evidence for semiquinone formation could be obtained. Studies were also conducted attempting to use apo-DT-diaphorase reconstituted with PQQ as coenzyme. The lack of activity toward AZQ, K3Fe(CN)6, and menadione suggests that DT-diaphorase can use PQQ only as electron acceptor and not as redox cofactor.

Flavin-Adenine Dinucleotide↗
PubMed1995

High speed 1H spectroscopic imaging in human brain by echo planar spatial-spectral encoding.

We introduce a fast and robust spatial-spectral encoding method, which enables acquisition of high resolution short echo time (13 ms) proton spectroscopic images from human brain with acquisition times as short as 64 s when using surface coils. The encoding scheme, which was implemented on a clinical 1.5 Tesla whole body scanner, is a modification of an echo-planar spectroscopic imaging method originally proposed by Mansfield Magn. Reson. Med. 1, 370-386 (1984), and utilizes a series of read-out gradients to simultaneously encode spatial and spectral information. Superficial lipid signals are suppressed by a novel double outer volume suppression along the contours of the brain. The spectral resolution and the signal-to-noise per unit time and unit volume from resonances such as N-acetyl aspartate, choline, creatine, and inositol are comparable with those obtained with conventional methods. The short encoding time of this technique enhances the flexibility of in vivo spectroscopic imaging by reducing motion artifacts and allowing acquisition of multiple data sets with different parameter settings.

Artifacts↗
PubMed1995

Cerebral white matter in the centrum semiovale exhibits a larger N-acetyl signal than does gray matter in long echo time 1H-magnetic resonance spectroscopic imaging.

Long echo time (272 ms) 1H magnetic resonance spectroscopic imaging was used to measure the relative magnitudes of the N-acetylaspartate (NAA) signal in a variety of anatomically defined brain structures (centrum semiovale, thalamus, medial frontal cortex, and genu of the corpus callosum) composed primarily of gray matter or white matter. Six normal young adult humans aged 30-40 were studied. With a 95% level of statistical confidence, the white matter in the centrum semiovale (CSO) produced a more intense NAA signal than did the gray matter in the thalamus and the frontal cortex. Differences between the white matter regions were also noted. The CSO white matter's NAA signal yielded a larger NAA signal than did the white matter of the genu of the corpus callosum. Possible reasons for the anatomical variation in the cerebral NAA signal intensity are discussed.

Adult↗
PubMed1995

Response of non-Hodgkin lymphoma to radiation therapy: early and long-term assessment with H-1 MR spectroscopic imaging.

PURPOSE: To determine whether proton magnetic resonance (MR) spectroscopic imaging is a sensitive technique for defining tumor extent and assessing response of cerebral lymphoma to therapy. MATERIALS AND METHODS: Four hydrogen-1 MR spectroscopic imaging studies were performed in a patient with non-Hodgkin lymphoma (NHL) before, during, and after radiation therapy and at follow-up at 33 months after diagnosis of the recurrence of disease. The patient had a single, large lesion in the brain and underwent hyperfractionated radiation therapy for 4 weeks. A series of MR images was also obtained. RESULTS: The pretreatment study showed a lesion with a distinct spectral pattern: marked elevation of choline and lipids and great reduction of creatine and N-acetylaspartate. During and after treatment, H-1 MR spectroscopic images depicted a progressive reduction of the abnormal choline and lipid signals. Thirty-three months after treatment, multiple-section H-1 MR spectroscopic images showed normal spectral patterns in all sections examined. CONCLUSION: H-1 MR spectroscopy may contribute to the neuroradiologic evaluation of NHL and, in particular, may be useful in monitoring therapeutic response.

Aspartic Acid↗
PubMed1995

Brain regional distribution pattern of metabolite signal intensities in young adults by proton magnetic resonance spectroscopic imaging.

Proton magnetic resonance spectroscopy (1H-MRS) is evolving from single-volume localized acquisitions to multiple-volume acquisitions using magnetic resonance spectroscopic imaging (1H-MRSI). The normal regional patterns of 1H-MRSI-detectable metabolite signal intensities have yet to be established. We studied 13 healthy young adults with a multiple-section 1H-MRSI technique. The metabolite signals measured were N-acetylaspartate (NA), choline-containing compounds (CHO), creatine-phosphocreatine (CRE), and lactate. Ten neuroanatomic regions (nine bilateral) were identified in gray matter, white matter, and basal nuclei. Analysis of the data led to the following conclusions: (1) NA and CHO signals from centrum semiovale (CSO) can be used as a normalizing factor to reduce intersubject variability due to external causes; (2) in normal human brain, there is no left versus right asymmetry in the regions studied; (3) statistically significant patterns of signal distribution of NA, CHO, and CRE can be identified in normal human brain; and (4) CSO-normalized metabolite signal intensities and metabolite ratios complement each other for the detection of significant regional differences.

Adult↗