Biomedical subjects
Publications and source records attributed to G Magni.
Social adjustment scores were compared using the Social Adjustment Scale for 24 inpatients with single-episode major depression, 72 with recurrent major depression, and 28 with bipolar disorder. There were no differences between the three groups either in overall score or on single scales.
The enzyme nicotinamide mononucleotide (NMN) adenylyltransferase (EC 2.7.7.1) catalyzes the transfer of the adenylyl moiety of ATP to NMN to form NAD. A new purification procedure for NMN adenylyltransferase from Saccharomyces cerevisiae provided sufficient amounts of enzyme for tryptic fragmentation. Through data-base search a full matching was found between the sequence of tryptic fragments and the sequence of a hypothetical protein encoded by the S. cerevisiae YLR328W open reading frame (GenBank accession number U20618). The YLR328W gene was isolated, cloned into a T7-based vector and successfully expressed in Escherichia coli BL21 cells, yielding a high level of NMN adenylyltransferase activity. The purification of recombinant protein, by a two-step chromatographic procedure, resulted in a single polypeptide of 48 kDa under SDS-PAGE, in agreement with the molecular mass of the hypothetical protein encoded by YLR328W ORF. The N-terminal sequence of the purified recombinant NMN adenylyltransferase exactly corresponds to the predicted sequence. Molecular and kinetic properties of recombinant NMN adenylyltransferase are reported and compared with those already known for the enzyme obtained from different sources.
Synechocystis sp. slr0787 open reading frame encodes a 339 residue polypeptide with a predicted molecular mass of 38.5 kDa. Its deduced amino acid sequence shows extensive homology with known separate sequences of proteins from the thermophilic archaeon Methanococcus jannaschii. The N-terminal domain is highly homologous to the archaeal NMN adenylyltransferase, which catalyzes NAD synthesis from NMN and ATP. The C-terminal domain shares homology with the archaeal ADP-ribose pyrophosphatase, a member of the 'Nudix' hydrolase family. The slr0787 gene has been cloned into a T7-based vector for expression in Escherichia coli cells. The recombinant protein has been purified to homogeneity and demonstrated to possess both NMN adenylyltransferase and ADP-ribose pyrophosphatase activities. Both activities have been characterized and compared to their archaeal counterparts.
Beyond its role as an essential coenzyme in numerous oxidoreductase reactions as well as respiration, there is growing recognition that NAD+ fulfills many other vital regulatory functions both as a substrate and as an allosteric effector. This review describes the enzymes involved in pyridine nucleotide metabolism, starting with a detailed consideration of the anaerobic and aerobic pathways leading to quinolinate, a key precursor of NAD+. Conversion of quinolinate and 5'-phosphoribosyl-1'-pyrophosphate to NAD+ and diphosphate by phosphoribosyltransferase is then explored before proceeding to a discussion the molecular and kinetic properties of NMN adenylytransferase. The salient features of NAD+ synthetase as well as NAD+ kinase are likewise presented. The remainder of the review encompasses the metabolic steps devoted to (a) the salvaging of various niacin derivatives, including the roles played by NAD+ and NADH pyrophosphatases, nicotinamide deamidase, and NMN deamidase, and (b) utilization of niacins by nicotinate phosphoribosyltransferase and nicotinamide phosphoribosyltransferase.
Tolcapone is a catechol-O-methyltransferase (COMT) inhibitor that has shown efficacy in the treatment of Parkinson's disease. The authors undertook the first study on the efficacy of this COMT inhibitor in the treatment of major depressive disorder (MDD). The authors also wanted to assess the effects of tolcapone on the choline and myoinositol resonances in the left caudate and dorsolateral frontal lobe through proton magnetic resonance spectroscopy and on whole blood levels of S-adenosyl-L-methionine (SAMe). The study enrolled 21 adults (10 men and 11 women; mean age, 42.6 +/- 9.6 years) with MDD, which was diagnosed using the Structured Clinical Interview for DSM-IV, and an initial score of > or = 16 on the 17-item Hamilton Rating Scale for Depression (HAM-D-17). Patients were then treated openly for 8 weeks with tolcapone 400 mg twice daily. Treatment efficacy was assessed with the HAM-D-17, the Clinical Global Impressions Severity (CGI-S) scale, and the Beck Depression Inventory (BDI). Among all subjects (N = 21), there were significant (p < .0001) decreases at endpoint in HAM-D-17 scores (from 19.4 +/- 2.9 to 10.7 +/- 5.5), CGI-S scores (from 3.9 +/- 0.6 to 2.4 +/- 1.1), and BDI scores (from 21.6 +/- 8.1 to 12.3 +/- 8.6). Eight patients (38%) dropped out before completing the 8-week open study because of diarrhea, elevated liver function tests, increased anxiety, and noncompliance. No significant effects were noted on choline and myoinositol resonance or on SAMe levels in whole blood before and after 2 weeks of tolcapone treatment. The preliminary results suggest that tolcapone may be a promising agent in the treatment of MDD. Furthermore, double-blind, placebo-controlled studies are necessary to confirm this impression.
The first identification and characterization of a catalytic activity associated with NadR protein is reported. A computer-aided search for sequence similarity revealed the presence in NadR of a 29-residue region highly conserved among known nicotinamide mononucleotide adenylyltransferases. The Escherichia coli nadR gene was cloned into a T7-based vector and overexpressed. In addition to functionally specific DNA binding properties, the homogeneous recombinant protein catalyzes NAD synthesis from nicotinamide mononucleotide and ATP.
Increasing evidence on the importance of fluctuations in NAD+ levels in the living cell is accumulating. Therefore a deeper knowledge on the regulation of coenzyme synthesis and recycling is required. In this context the study of NMN adenylyltransferase (EC 2.7.7.1),. a key enzyme in the NAD+ biosynthetic pathway, assumes a remarkable relevance. We have previously purified to homogeneity and characterized the protein from the thermophilic archaeon Sulfolobus solfataricus. The determination of partial sequence of the S. solfataricus enzyme, together with the recent availability of the genome sequence of the archaeon Methanococcus jannaschii, allowed us, based on sequence similarity, to identify the M. jannaschii NMN adenylyltransferase gene. As far as we know from literature, this is the first report on the NMN adenylyltransferase gene.
The onset of extrapyramidal symptoms has been traditionally linked to the prescription of neuroleptic treatment: there are some reports in the international literature describing extrapyramidal effects related to antidepressant. In this paper we present a case under multiple pharmacologic treatment in whom extrapyramidal symptoms developed shortly after the adjunct of nortriptyline to a combination of venlafaxine and valproic acid administered for several months. We describe here the clinical history of this patient, affected by Bipolar Disorder, type II, and the progressive pharmacologic path in his treatment. Possible hypothesis to explain this evidence are discussed.
Study of left ventricular (LV) regional and global function represents a main point of the cardiologic evaluation. This article presents an overview of the state of the art in quantitative analysis of ventricular wall motion and describes the different techniques available in clinical settings; we also present the personal experience of the authors in comparing conventional 2-dimensional (2D) echocardiography with other recently developed, more sophisticated techniques. Conventional 2D echocardiography mainly depends on the operator's ability. Moreover, the physiologic regional pattern of myocardial wall motion in different segments of left ventricle is still not completely known as well as the heart's rotational and translational movements. Qualitative and quantitative transesophageal echocardiography allows a better and more accurate evaluation of regional wall motion, and improves the on-line border detection feasibility even in patients with poor transthoracic echocardiographic window. The automated system for on-line endocardial border detection, color kinesis, and the power Doppler are, at the moment, promising techniques. Using magnetic resonance imaging as a "gold standard" for the study of global and regional left ventricular function, the investigators describe personal experiences with tissue Doppler imaging and a new computerized system for tissue Doppler images postprocessing analysis.
Two-dimensional (2D) echocardiographic estimation of infarcted mass is limited by having only a few selected nonparallel views for data analysis. Volume-rendered three-dimensional (3D) echocardiography may be able to overcome the above limitations, because it uses multiple, parallel 2D images to derive quantitative data. Previous experimental studies demonstrated that 3D echocardiography is an accurate and reproducible method to assess dysfunctional mass. To estimate the accuracy of 3D echocardiography in humans, we evaluated 10 patients who had a single myocardial infarction. All patients underwent 2D and 3D echocardiography using the transesophageal approach, and contrast (gadolinium) magnetic resonance imaging (MRI), considered a reference standard for infarcted tissue detection. The mean extent of dysfunctional mass by MRI was 28 +/- 13 g and by 3D echocardiography was 30 +/- 12 g; the mean difference was 1.9 +/- 2.3 g (p = not significant). Linear regression analysis between the 2 measurements was y = 0.97x - 1.12, r = 0.98. Dysfunctional mass derived from 3D echocardiography reflects the real site and extension of damaged myocardium.
BACKGROUND: To evaluate the role of the endogenous opioid system (EOS) in abnormal pain perception in patients with syndrome X, we used a neuroendocrine approach, evaluating plasmatic luteinizing hormone (LH) changes after naloxone, a competitive antagonist of opioid receptors able to unblock tonic EOS inhibition on gonadotropin release. Thus LH response to naloxone test indicates the central EOS activity on hypothalamic luteinizing hormone-releasing hormone (LH-RH) inhibitory opioid receptors. METHODS: Ten patients with syndrome X, 10 age-matched male patients with coronary artery disease (CAD), and 10 normal subjects were analyzed. Naloxone tests were performed between 8 and 9 am. Basal beta-endorphin and LH levels were determined on 4 blood samples at 20-minute intervals; after naloxone (0.1 mg/kg intravenously in 4 minutes), LH was measured on 8 samples at 15-minute intervals. In all patients the test was also performed after LH-RH administration. Anginal pain on exercise testing was subjectively scored on a 1 to 10 analogic scale and wall motion abnormalities were quantified by a wall motion score index. RESULTS: Significant differences were found in LH release after naloxone (CAD 260.3 +/- 42.6 vs syndrome X 151.6 +/- 48.5 mIU/mL, P <.05), angina score (CAD 5.5 +/- 1.3 vs syndrome X 7.2 +/- 1.7, P <.05), and wall motion abnormalities (CAD 3.6 +/- 1. 2 vs syndrome X 2.8 +/- 1.9, P <.05). CONCLUSIONS: The reduced LH release after naloxone in syndrome X, with a normal LH-RH response, suggests a lower central EOS activity, which may be related to the higher anginal pain perception.
The objective of this study was to explore the relationship between suicidal ideation, suicidal attempts, depression and chronic abdominal pain in data gathered during a systematic epidemiologic survey, the Hispanic Health and Nutrition Examination Survey of the United States National Centre for Health Statistics. The material comprises data collected between 1982 and 1984 in samples of Hispanic groups in the United States. A sub-sample which initially comprised 5498 subjects had provided answers to questions concerning the thoughts about death, wishes to die, thoughts of committing suicide and suicide attempts, as well as information about complaints of chronic abdominal pain and responses to the Centre for Epidemiologic Studies Depression Scale (CES-D). Complete answers were available from 4964 subjects. The data were analyzed by tabulation, and logistic regression analyses. The lifetime prevalence of suicidality was much increased in subjects with pain compared with those without chronic abdominal pain. Rates for thoughts about death, wishing to die, suicidal ideation and suicide attempts were 2- to 3-times more frequent in those with chronic abdominal pain compared with those without. Logistic regression analyses and the calculation of odds ratios confirmed that the most powerful predictive factors for suicidality were first, the presence of significant depressive ideation, and second, the presence of chronic abdominal pain. There is a strong relationship between chronic abdominal pain and suicidality in the Hispanic population in the United States. This was particularly evident in the Puerto Rican population of the United States where both rates were much increased compared with other Hispanic citizens. The present data are new, but no conclusion can be drawn concerning causality because they are cross-sectional. They indicate the importance of the link between chronic abdominal pain and depression in this population.
OBJECTIVES: Flow variations can affect valve-area calculation in aortic stenosis and lead to inaccuracies in the evaluation of the stenosis. Knowing that transvalvular flow varies normally within one beat, we designed this study to assess the response of the valve to intrabeat variation of flow during systole. Results were compared with flow-derived measurements. BACKGROUND: Technological improvements now allow us to evaluate aortic valve area directly by short axis planimetry. This offers the possibility to perform serial planimetries during one ejection phase and analyze the intrabeat dynamic behavior of the stenotic-aortic valve and compare these measurements with flow-derived measurements. METHODS: Forty echocardiograms displaying different degrees of aortic stenosis were analyzed by frame-by-frame planimetry of the valve area from onset of opening to complete closure. Maximal-mean area, opening and closing rates and ejection times were obtained and compared with Doppler-derived data. RESULTS: Valve area varied during ejection. Stenotic valves opened and closed more slowly than normals and remained maximally open for a shorter period. Mean area by Doppler data corresponded more closely to maximal than to mean-planimetered area. Duration of flow was shorter than valve opening in severely stenotic valves. Discrepancies between Doppler-derived and two-dimensional (2D) measurements decreased in less stenotic valves. CONCLUSIONS: Our observations reveal striking differences between the dynamics of normal and stenotic valves. Surprisingly, Doppler-derived mean-valve area correlated better with maximal-anatomic area than with mean-anatomic area in patients with aortic stenosis. Discrepancies between duration of flow and valve opening could explain this phenomenon.
Two cytoplasmic forms of pyrimidine nucleotidase (PN-I and PN-II) have been purified from human erythrocytes to apparent homogeneity and partially characterized. They preferentially hydrolyse pyrimidine 5'-monophosphates and 3'-monophosphates respectively. PN-I and PN-II operate as interconverting activities, capable of transferring the phosphate from the pyrimidine nucleoside monophosphate donor(s) to various nucleoside acceptors, including important drugs like 3'-azido-3'-deoxy-thymidine (AZT), cytosine-beta-D-arabinofuranoside (AraC) and 5-fluoro-2'-deoxy-uridine (5FdUrd), pyrimidine analogues widely used in chemotherapy. Kinetic analysis showed linear behaviour for both PN-I and PN-II. PN-I phosphotransferase activity revealed higher affinity for oxynucleosides with respect to deoxy-nucleosides, whereas the contrary seems to be true for PN-II. These results show for the first time that soluble pyrimidine nucleotidases are endowed with pyrimidine-specific phosphotransferase activity.
Some studies describe an increased risk for emboli in infective endocarditis patients with large (>10 mm) and mobile vegetations. Other studies fail to demonstrate the above relation. Most studies have been performed using transthoracic echocardiography or with a monoplane transesophageal approach. The present study examines whether distinctive characteristics of vegetative lesions detected by transthoracic and multiplane transesophageal echocardiography are predictive of embolic risk. We reviewed both transthoracic and transesophageal echocardiograms of 57 patients with diagnosis of acute infective endocarditis and no documented or suspected previous embolic events. We evaluated site, length, width, mobility, and echodensity of vegetations. Twenty-five patients (44%) had embolic events. No statistical differences in age, sex distribution, location of endocarditis, or offending pathogens between embolic (n = 25) and nonembolic (n = 32) patients were found. There were no differences in any of the echo characteristics of vegetations detected by transthoracic and transesophageal approach in embolic and nonembolic groups. Thus, transthoracic and transesophageal characteristics of vegetations are not helpful in defining embolic risk in patients with infective endocarditis.
BACKGROUND: Transcatheter closure of atrial septal defects (ASDs) has been feasible and successful. Two-dimensional echocardiography (2DE) was applied to patients before selection and during device deployment. Three-dimensional echocardiography (3DE) can provide unique anatomic perspectives that might aid in improving device closure of ASDs. METHODS AND RESULTS: Twenty-two consecutive patients were enrolled in an initial protocol for ASD device closure by the new DAS-Angel Wings occluder device. On the basis of transesophageal (TEE) 2DE and 3DE, 13 patients were considered eligible for device closure (9 secundum ASDs and 4 with patent foramen ovale associated with a cerebral vascular accident). Maximal ASD diameter and surrounding rim tissues were compared by TEE 2DE and 3DE and with balloon sizing measurements at catheterization. ASD size measured by TEE 2DE and 3DE correlated well (y = 1.0x + 0.049, r = .95), with good limits of agreement. However, balloon-stretched diameter measurements were systematically larger than echocardiographic measurements. Rim tissue measurements correlated well; however, TEE 3DE could demonstrate the entire shape and perimeter of the defect. Two-dimensional imaging provided reliable information during device deployment and for closure of small ASDs. However, 3DE was superior for imaging the device, especially when abnormally placed. CONCLUSIONS: Three-dimensional imaging provides unique images and projections that were essential for understanding the spatial relationship of the device to the atrial septum. Three-dimensional echocardiography significantly enhanced our understanding of two-dimensional images and provided an imaging conceptualization that should aid in future development of device closures.
BACKGROUND: Two-dimensional echocardiography is useful for estimating the extent of infarct-related wall motion abnormalities. Such estimation, however, is based on a few selected views and extrapolated for the whole left ventricle (LV). This approach does not provide us with the actual amount of dysfunctional myocardium. Volume-rendered three-dimensional echocardiography (3DE) might overcome these limitations. In this study we explored (1) how well volume-rendered 3DE delineates regional dysfunction of the infarcted LV and (2) how well dysfunctional myocardial mass quantified by 3DE reflects the actual anatomic infarct mass. METHODS AND RESULTS: 3DE was performed before and 3 hours after coronary occlusion in 16 dogs. With the LV viewed in equidistant short-axis slices, the region of dysfunction was demarcated, and the dysfunctional myocardial mass was derived from this. With triphenyltetrazolium chloride staining, anatomic infarct regions were delineated, dissected, and weighed. The anatomic infarct mass was 16.3+/-7.7 g (mean+/-SD) (range, 6.4 to 31.4 g); the dysfunctional mass estimated by 3DE was 17.4+/-9.1 g (range, 5.2 to 39.0 g). The mean difference was 1.0 g. The correlation between dysfunctional mass (y) and infarct mass (x) was y=l.lx-0.6, r=.93 (P<.0001). The percentage of LV involved in infarction was 18.2+/-5.8% (range, 9.1% to 26.1%); the percentage of LV involved in regional dysfunction was 18.3+/-6.9% (range, 7.9% to 31.2%). The mean difference was 0.1%. The correlation between percentage of LV involved in infarction (x) and percentage of LV involved in dysfunction (y) was y=1.0x-1.1, r=.92 (P<.0001). CONCLUSIONS: Volume-rendered 3DE crisply displays regional dysfunction of infarcted LV. 3DE-measured dysfunctional mass accurately reflects the anatomic infarct mass.
We undertook this study to determine the use of transthoracic and transesophageal echocardiography in detecting valvular perforation and the clinical impact of the latter on the outcome of left-sided infective endocarditis. Transthoracic echocardiography was performed in 58 consecutive patients with infective endocarditis. According to the study protocol, a subgroup of 42 patients also underwent transesophageal echocardiogrophy. At referral, 20 (34%) of 58 patients had echocardiographic evidence of valvular perforation (group A). No valvular perforations were found in the remaining 38 patients (group B). During a follow-up period of 27 +/- 16 months, a major complication occurred in 18 of 20 patients in group A and in 11 of 38 patients in group B (p < 0.0001). Univariate analysis indicated previous infective endocarditis, aortic involvement, and New York Heart Association functional class had a predictive value for valvular perforation (p < 0.001). Stepwise regression analysis confirmed aortic valve perforation as the only independent predictive variable for surgery and death. Valvular perforation is a common complication of infective endocarditis and is associated with an adverse outcome. Transthoracic echocardiography can detect or suggest valvular perforation in infective endocarditis, but transesophageal echocardiography better defines this complication and predicts severe heart failure or the need for early surgical management.