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Biomedical subjects

M Baron

Publications and source records attributed to M Baron.

At least 127 records · Page 7Linked to original sources
PubMed1992

Positive and negative symptoms. Relation to familial transmission of schizophrenia.

The authors assessed the relevance of clinical symptoms to genetic research in schizophrenia in the nuclear families of 65 chronic schizophrenic probands. The morbidity risk for schizophrenia and schizotypal personality (a 'spectrum' disorder) was markedly reduced in first-degree relatives of probands with predominant negative symptoms, as compared with relatives of probands with other symptom patterns. The data support the notion that negative-symptom schizophrenia has an attenuated genetic component.

Adult↗
PubMed1992

Mortality in systemic sclerosis (scleroderma).

Two hundred and thirty-seven patients with systemic sclerosis were followed prospectively in a scleroderma clinic. The overall 3, 6, and 9-year survival rates were 86, 76 and 61 per cent respectively. Renal, cardiac and pulmonary disease, and older age at enrollment were adverse prognostic factors associated with reduced survival. There were no significant differences in survival between males and females or in patients with restricted compared to those with diffuse skin thickening. Death from systemic sclerosis was most frequently due to pulmonary hypertension, with fewer than expected deaths from renal or cardiac causes. Twenty-eight per cent of deaths were due to causes unrelated to systemic sclerosis, most commonly cancer and ischaemic heart disease, and in older patients.

Coronary Disease↗
PubMed1991

Three-dimensional structure of a complement control protein module in solution.

The complement control protein (CCP) modules (also known as short consensus repeats) are defined by a consensus sequence within a stretch of about 60 amino acid residues. These modules have been identified more than 140 times in over 20 proteins, including 12 proteins of the complement system. The solution structure of the 16th CCP module from human complement factor H has been determined by a combination of 2-dimensional nuclear magnetic resonance spectroscopy and restrained simulated annealing. In all, 548 structurally important nuclear Overhauser enhancement cross-peaks were quantified as distance restraints and, together with 41 experimentally measured angle restraints, were incorporated into a simulated annealing protocol to determine a family of closely related structures that satisfied the experimental observations. The CCP structure is shown to be based on a beta-sandwich arrangement; one face made up of three beta-strands hydrogen-bonded to form a triple-stranded region at its centre and the other face formed from two separate beta-strands. Both faces of the molecule contribute highly conserved hydrophobic side-chains to a compact core. The regions between the beta-strands are composed of both well-defined turns and less well-defined loops. Analysis of CCP sequence alignments, in light of the determined structure, reveals a high degree of conservation amongst residues of obvious structural importance, while almost all insertions, deletions or replacements observed in the known sequences are found in the less well-defined loop regions. On the basis of these observations it is postulated that models of other CCP modules that are based on the structure presented here will be accurate. Certain families of CCP modules differ from the consensus in that they contain extra cysteine residues. As a test of structural consensus, the extra disulphide bridges are shown to be easily accommodated within the determined CCP model.

Amino Acid Sequence↗
PubMed1991

The structure and function of protein modules.

Analysis of protein sequences shows that many proteins in multicellular organisms have evolved by a process of exon shuffling, deletion and duplication. These exons often correspond to autonomously folding protein modules. Many extracellular enzymes have this modular structure; for example, serine proteases involved in blood-clotting, fibrinolysis and complement. The main role of these modules is to confer specificity by protein-protein interactions. Lack of structural information about such proteins has required a new strategy for studying the structure and function of protein modules. The strategy involves the production of individual modules by protein expression techniques, determination of their structure by high resolution nuclear magnetic resonance and definition of functional patches on the modules by site-directed mutagenesis and biological assays. The structures of the growth factor module, the fibronectin type 1 module and the complement module are briefly described. The possible functional roles of modules in various proteins, including the enzymes factor IX and tissue plasminogen activator, are discussed.

Amino Acid Sequence↗
PubMed1991

Key residues involved in calcium-binding motifs in EGF-like domains.

Many extracellular proteins with diverse functions contain domains similar to epidermal growth factor (EGF), a number of which have a consensus Asp/Asn, Asp/Asn, Asp*/Asn*, Tyr/Phe (where the asterisk denotes a beta-hydroxylated residue). These include the coagulation factors IX and X, proteins with two EGF-like domains, the first of which contains the consensus residues. The first EGF-like domain of human factor IX contains a calcium-binding site, which is believed to be responsible for one of the high-affinity sites detected in this protein. Similar results have been obtained for bovine factor X. We have now used protein engineering and 1H-NMR techniques to investigate the importance of individual consensus residues for ligand binding. Measurement of a calcium-dependent Tyr 69 shift in the isolated first EGF-like domain from human factor IX demonstrates that Asp 47, Asp 49, and Asp 64 are directly involved in this binding. Gln 50, whose importance has previously been overlooked, is also involved in this binding. Two mutations in this domain, Asp 47----Glu, and Asp 64----Asn, present in patients with haemophilia B, reduce calcium binding to the domain greater than 4-fold and greater than 1,000-fold, respectively. Furthermore, the defective calcium binding of Asn 64 can be partially rescued by the compensatory mutation Gln 50----Glu. This latter mutation, when introduced singly more than doubles the affinity of the domain for calcium. This study thus defines residues involved in a new type of calcium-binding site and provides strong circumstantial evidence for calcium-binding motifs in many extracellular proteins, including the developmentally important proteins of Drosophila, notch, delta and crumbs.

Amino Acid Sequence↗
PubMed1991

Secondary structure of a complement control protein module by two-dimensional 1H NMR.

The complement control protein (CCP) module (also known as the short consensus repeat) is a consensus sequence of about 60 amino acid residues which is thought to fold independently. It occurs over 140 times in more than 20 extracellular mosaic proteins including 12 proteins of the complement cascade. An isolated CCP module, the 16th repeat from human complement factor H, has been expressed in a yeast vector and shown to fold with the same pattern of disulfide bond formation as is seen in the native protein. Two-dimensional 600-MHz 1H NMR spectra of this module have been recorded at pH 3.3 and 6.0 and analyzed to permit determination of secondary structure in solution. The CCP module comprises two predominantly extended segments (Glu1-His13 and Ala17-Glu27), two segments of double-stranded antiparallel beta-sheet (Gly14-Val16 paired with Tyr31-Cys33 and Gly38-Asp40 paired with Ser57-Ile59), and a short piece of triple-stranded beta-sheet (Glu27-Thr30, Ile44-Leu48, and Lys51-Ser53). Turns occur at Asp22, Gly36, and Glu50, while Gly41-Ala43 appear to form a looped-out segment or bulge. This structure is compared with a secondary structure prediction made on the basis of an alignment scheme of 101 sequences for CCP modules [Perkins, S. J., Haris, P. I., Sim, R. B., & Chapman, D. (1988) Biochemistry 27, 4004-4012]--the experimentally determined secondary structure bears an overall resemblance to the predicted one but differs in the number and position of turns. Some of those amino acid residues which are highly conserved throughout the range of CCP modules appear to play a role in stabilizing the global fold.

Amino Acid Sequence↗
PubMed1991

Protein modules.

As the database of protein sequences grows it is becoming apparent that many proteins are constructed from relatively few modular units that appear many times. Determination of the three-dimensional structure of such modules by NMR has been possible due to their production in relatively large quantities by recombinant DNA techniques. The knowledge gained about the structure of individual modules can then be used to predict their properties in a variety of intact proteins.

Amino Acid Sequence↗
PubMed1991

Heterocyclic quinones. 17. A new in vivo active antineoplastic drug: 6,7-bis(1-aziridinyl)-4-[[3-(N,N-dimethylamino)propyl]amino]-5,8- quinazolinedione.

A series of heterocyclic quinones, 6-substituted and 6,7-disubstituted 4-(alkylamino)-5,8-quinazolinediones, have been synthesized in order to evaluate their in vitro cytotoxicity on L1210 leukemia cells. Among 14 derivatives that have been prepared and studied for the structure-activity relationship, the most potent cytotoxic compound on L1210 leukemia cells was the 6,7-bis(1-aziridinyl)-4-[[3-(N,N-dimethylamino)propyl]amino]-5,8- quinazolinedione (24). This compound has been tested with the use of a cell-image processor on MCF-7 human mammary and HBL human melanoma cell lines. The results show that compound 24 influences cell proliferation and blocks both cells lines in the S phase. In vivo antineoplastic activity of compound 24 has been demonstrated on a broad spectrum of murine experimental models, but it was found highly toxic and produced long-delayed deaths.

Animals↗
PubMed1991

Schizophrenia and affective disorder: are they genetically linked?

The relationship between schizophrenic 'spectrum' disorders and affective illness was studied in the nuclear families of 90 chronic schizophrenic probands. An increased risk of schizophrenia and related disorders was demonstrated among the first-degree relatives of probands with a family history of major affective disorders. Conversely, relatives of probands with a family history of schizophrenic 'spectrum' disorders were at a greater risk of affective illness (major depression) than relatives of probands with no family history. These results lend support to the notion that a subset of affective disorders is associated with the liability to schizophrenia.

Adult↗
PubMed1991

Factor analysis of responses to the WISC-R for gifted children.

Several researchers have focused on the question of whether the traditional two-factor interpretation of WISC--R scores proposed by Wechsler (1974) is appropriate in selecting students to be admitted to gifted programs. Some researchers have suggested that the two-factor solution (Verbal and Performance) of Karnes and K. E. Brown provides the appropriate model, while others have proposed an alternative model based on exploratory research with gifted and average students. The current study expands exploratory findings of S. W. Brown with Rood in 1982 and Yakimowski in 1987, using confirmatory factor analytical procedures. The confirmatory factor analyses for selected groups of gifted (n = 158) and average (n = 195) students (M = 9.6 yr.) indicate that the alternative three-factor solution model may be a better system for interpreting the pattern of WISC--R subtest scores of gifted students than the conventional Verbal and Performance solution.

Child↗
PubMed1991

Radionuclide esophageal transit studies in progressive systemic sclerosis: an analysis of longitudinal data.

Nineteen patients with progressive systemic sclerosis (PSS) were studied by radionuclide esophageal transit (ET) and followed longitudinally for 3 to 5 years. Results were expressed as percent retention at 20 s and 10 min. There was gradual deterioration of ET at both 20 s and 10 min. When results were grouped into quartiles, deterioration occurred in 58.5% of followup studies in patients who initially had potential to deteriorate regarding 20 s retention and in 48% of similar patients regarding 10 min retention.

Adult↗
PubMed1991

[Intestinal obstruction after Nissen's fundo-plication].

Nissen's fundal plication is acknowledged as the most effective procedure to suppress gastroesophageal reflux. It entails some morbidity (dysphagia, gas bloat syndrome), in which obstruction is the least frequently evoked but most severe risk. We report about 6 cases (4 children and 2 adults). The 4 children had been operated 3 times during the first few months of life, and their reflux was secondary to the cure of atresia of the esophagus in 2 cases, and caused severe apneas in 1 case, a former premature infant. In three cases, the obstruction was complicated within a few hours by intestinal ischemia causing death. In one case, the emergent insertion of a gastric tube allowed the decompression of the digestive tract and second surgery; the obstruction recurred 2 months later, with no postoperative complications. Two adults (aged 64 and 66) presented with gastric perforation 7 days and 9 months after fundal pliction; one of them died. These cases show how serious these obstructions are (4 deaths/6 cases). The emergent measure in such cases consists of inserting a gastric tube, although which may be impossible (1 case). The patients and their parents must be informed of this risk of complication and of its expressions. Prevention is based on a strictly submesocolic surgical approach, without any exposure of the small bowel.

Aged↗
PubMed1991

Genetics of manic depressive illness: current status and evolving concepts.

The bipolar affective spectrum is clinically heterogeneous and genetically complex. Current methods for assessment and analysis of familial traits with variable phenotypic expression and unclear mode of inheritance are reviewed. Recent evidence for a major gene localized on the X-chromosome is presented and other linkage findings are discussed. The limitations and prospects of psychiatric genetics are discussed in the light of recent advances in diagnostic nomenclature, statistical genetic techniques, and molecular biology. Methodological uncertainties notwithstanding, the powerful new techniques in genetic research portend well for unraveling the genetics of bipolar affective illness.

Bipolar Disorder↗
PubMed1990

Structure-function relationships in epidermal growth factor (EGF) and transforming growth factor-alpha (TGF-alpha).

The solution structures of the homologous growth factors human epidermal growth factor (hEGF) and human transforming growth factor-alpha (hTGF-alpha), as determined by high resolution NMR and various computational methods, are described. Knowledge of these structures and the sequences of other homologous proteins leads to predictions about growth factor residues which may be involved in the receptor/ligand interface. Recent experiments designed to check these predictions are described briefly. These involve site-specific mutagenesis, receptor binding assays and high resolution NMR studies.

Amino Acid Sequence↗