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PubMed1994

Proton NMR studies of the structural and dynamical effect of chemical modification of a single aromatic side-chain in a snake cardiotoxin. Relation to the structure of the putative binding site and the cytolytic activity of the toxin.

This paper presents the comparative comprehensive analysis of NMR structural parameters (NOEs, scalar coupling, chemical shifts) of toxin gamma, a cardiotoxin isolated from the venom of Naja nigricollis, and three chemical derivatives, i.e. the 2-nitrophenylsulphonyl (NPS)-Trp11, 3-nitro-Tyr22 and 3-nitro-Tyr51 derivatives. In previous work, the chemical modifications of single side chains have suggested that these aromatic residues, in association with several lysine residues, contributed to the cytotoxicity of toxin gamma. Analysis of these results based on the refined solution structure of the toxin has resulted in the proposal of a conserved phospholipid binding site through which cardiotoxins are likely to interact with the membrane of target cells. The present work shows that modifications of either the tryptophan residue or the tyrosine residues, which are within or near the proposed binding site, have no influence on the three-dimensional structure of the protein. On the other hand, the proton exchange study of the backbone amides indicates that the structural core of the protein is destabilized in the three derivatives. This corresponds to a decrease of the overall stability of the protein as indicated by the comparative solvent denaturation study of the unmodified toxin gamma and the Trp11 derivative. More specifically, the dynamics of the three-stranded beta sheet, a part of the structural core, are highly perturbed by the chemical modifications. This sheet was previously proposed as a part of the phospholipid binding site of cardiotoxins. The dynamical perturbation of this site appears to be correlated with the decrease in toxicity of the chemical derivatives.

Animals↗
PubMed1994

International Commission for Protection Against Environmental Mutagens and Carcinogens. The subtlety of alkylating agents in reactions with biological macromolecules.

Genotoxic agents known to modify DNA by alkylation reactions (alkylating agents, AAs), either directly or after metabolic conversion to ultimately reactive intermediates, by no means represent a homogeneous class. For instance, their effectiveness for genotoxic damage, when expressed as the number of events (e.g., mutations) per unit exposure dose, varies over a more than 1-million-fold range in dose. Despite the multiplicity of chemical and biological processes involved between DNA adduct formation and expression of genotoxic damage, the principal aims of studies on structure-activity relationships (SARs) are to (a) dissect the multi-step process of genetic damage formation into its most essential components, (b) use SARs for making predictions and, at a later step (c) as a basis for regulatory measures. The analytical tools available for such a comprehensive analysis in eukaryotic systems include determination of multiple genetic endpoints: molecular mutation spectra, relative clastogenicity (clastogenic events in relation to forward mutation induction) and the quantitative measure of enhanced mutagenicity in repair-deficient conditions. The genetic activity profiles obtained in this way can then be compared with fundamental physico-chemical properties of the AAs under consideration (such as Swain-Scott's s value, a useful indicator of the selectivity of an AA in its reactions with nucleophiles of distinct nucleophilic strength n in DNA, RNA and proteins), their functionality (monofunctional versus cross-linking) and their tumorigenic potency (TD50s compared with measures of initial DNA interaction, i.e., O6-/N7-alkylguanine ratios, s values or the covalent binding index determined in the liver in vivo). The combination of these different methods revealed that carcinogenic potencies of AAs in rodents vary over a 10,000-fold range in dose, with the extremes having the following characteristics: (i) Chemicals of a relatively "high carcinogenic potency", as indicated by a low TD50 in rodents, either have low nucleophilic selectivity (and therefore mainly act through O-alkylation in DNA) or are capable of cross-linking DNA. The monofunctional members of this group, typified by N-ethyl-N-nitrosourea, are active in both spermatogonia and post-spermatogonial stages in the mouse and in Drosophila. Cross-linking agents also have a low TD50 value in rodents but are expected generally not to display genetic action in premeiotic stages (exceptions mitomycin C and chlorambucil). (ii) A relatively low carcinogenic potential is associated with AAs of high Swain-Scott s values, typified by trimethyl phosphate, epichlorohydrin or methyl methanesulphonate.(ABSTRACT TRUNCATED AT 400 WORDS)

Alkylating Agents↗
PubMedDate not supplied

Minimal-deviation adenocarcinoma (adenoma malignum) of the uterine cervix; four case reports.

Four cases of minimal-deviation adenocarcinoma (adenoma malignum) of the uterine cervix are analysed in this clinicopathological study. Four patients, one Ib, two IIb and one IIIb stage, showed poor prognosis, which included three patients who died within 36 months, because of diagnostic delays of 5 years, 6 months and 1 year due to cytohistologically benign appearances. Cytologically, the nuclei were somewhat more irregular in size and shape than those of normal columnar epitherial cells. Slightly multilayered cell clusters were arranged as honeycombs, palisades or sheets with glandular openings. The characteristic histological features were the presence of sharp points projecting from the glands and marked variation in the size and shape of the glands. Ultrastructurally, intestinal metaplastic cells containing both microvilli with core filaments and rootlets, and secretary granules in the same cell were present in the specimens of two evaluable patients. These features indicate a disorder of differentiation. In order to diagnose this tumor accurately, comprehensive analysis should be required concerning the clinical features, cytohistological findings and ultrastructural findings.

Adenocarcinoma↗
PubMed1988

Clinical indicators of radiographically detectable dental diseases in the adult patient.

A comprehensive analysis of the relationship between clinical observations in dental patients without symptoms and oral disease as detected by full-mouth and panoramic dental radiographs in a large population of patients has never been reported. Knowledge of these relationships is necessary in the design of a diagnostic decision process (clinical algorithm) that can predict which patients require dental radiographs for the diagnosis of dental caries or periodontal disease to be confirmed or refined. An accurate clinical algorithm could reduce the number of radiographs that are taken of certain routinely seen dental patients without symptoms, thus reducing unnecessary exposure x-radiation as well as potentially reducing health care costs for these patients. A sample of 602 adult men on whom a complete series of panoramic, posterior bitewing, and periapical dental radiographs and an independent oral examination were performed provided the opportunity to evaluate the relationship between clinically observed oral disease indicators and independent radiographic evidence of dental caries and periodontal disease. The analysis suggests that combinations of several clinical indicators can predict with some success which patients without symptoms will benefit most from oral radiographs. The presence of several carious lesions on oral examination was the best predictor of radiographic detection of dental caries. Clinical indicators tht appear to predict radiographic evidence of periodontal disease are clinical measures of pocket depth, mobility, and the patient's denture status. An important finding is that because of the high prevalence of gingivitis and plaque, these indicators were not related to radiographic evidence of periodontal disease.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1990

Energetics of resting anaerobic frog gastrocnemius at different temperatures by 31P-NMR.

The net rate of phosphocreatine hydrolysis [PCr] [symbol; see text], and tissue pH were determined in anaerobic resting frog (Rana Ridibunda Ridibunda) gastrocnemii by 31-P-NMR in the temperature (T) range from 5 to 30 degrees C. Absolute [PCr] [symbol; see text] values from 0.36 to 10.07 mM/h were estimated assuming a resting [PCr] of 26 mM at 20 degrees C. The corresponding Q10 values ranged from 2.1 (30 degrees C) to 17.5 (5 degrees C). Muscle pH was found to be T-dependent with a 10 degrees C drop in T resulting in an increase of 0.1 pH units. At any given T, pH was found to be constant over a period of at least one hour (30 degrees C) from the onset of anaerobiosis. Based on simultaneous [PCr] [symbol; see text] and pH estimates, the contribution of anaerobic glycolysis ([ATPLA]) to the overall rate of ATP resynthesis ([ATPTot]) was estimated assuming a approximately P/La ratio of 1.2. [ATPTot] was then calculated for each investigated T value as the sum of [PCr] and [ATPLa]. [ATPTot] was found to vary between 5 and 30 degrees C from 0.79 mM/h to 22.15 mM/h. The present study, besides proposing a methodology for the assessment of high energy phosphates hydrolysis by 31P-NMR spectroscopy at changing T, provides a comprehensive analysis of the T-dependence of anaerobic metabolism of the resting anaerobic frog gastrocnemius which may be extrapolated to other tissues.

Adenosine Triphosphate↗
PubMed1989

Enzyme activities in perikaryal and synaptic mitochondrial fractions from rat hippocampus during development.

When pharmacological or basic neurochemical systematic characterization of mitochondrial enzymatic systems correlated to energy transduction processes is attempted, studies must be based on subcellular fractions with a high degree of purity from specific brain areas and from individual animals. Distinct populations of mitochondria heterogenous with respect to biochemical enzyme characteristics from rat brain hippocampus are described. Two mitochondrial populations were derived from synaptosomes by lysis and a third consists of free non-synaptic mitochondria. The maximum rate of some cerebral enzyme activities which are part of energy transduction (citrate synthase, malate dehydrogenase; total NADH-cytochrome c reductase, cytochrome oxidase) and amino acid metabolism (glutamate dehydrogenase) were tested on these mitochondrial populations of 8- and 16-week-old rats. A comprehensive analysis of the data suggests that extensive but highly diversified catalytic expressions of the enzymes studied occur in the hippocampus. This is true even when a short period of the rat life span is studied. Hence the varying pattern of evolution of the differing cerebral mitochondria, probably a consequence of different metabolic functions, should be taken into account in any pharmacological study on these systems.

Age Factors↗
PubMed1986

Molecular genetics and potential gene therapy.

Contemporary molecular techniques including gene cloning, DNA sequencing, and gene transfer permit precise and comprehensive analysis of genetic disorders. For example, the molecular basis of hemoglobin synthesis disorders (the thalassemias) can now be ascribed to more than 30 different specific mutations. These affect virtually all aspects of gene expression. The more recent capacity to reintroduce cloned genes into mammalian cells in a functional form has raised the prospect of gene therapy, that is, the replacement of an abnormal gene with its normal counterpart or merely the introduction of a normal gene into a cell containing a defective copy. Genetic correction of enzyme-deficiency disorders whose effects are manifest in bone-marrow-derived cells seems most likely to be amenable to "somatic" (as opposed to germ line) gene therapy. Treatment of severe combined immunodeficiency due to adenosine deaminase (ADA) deficiency may be a suitable model for this approach. This report will review the molecular genetics of ADA, the methods by which ADA gene sequences may be transferred into various cells, and goals for current and future research.

Adenosine Deaminase↗
PubMed1992

Long-term results of transplantations to repair median, ulnar, and radial nerve lesions by a microsurgical interfascicular autogenous cable graft technique.

A comprehensive analysis of 187 patients (78 median, 86 ulnar, and 23 radial nerve lesions) treated by an interfascicular autogenous nerve grafting technique is presented. After a follow-up of at least 18 months good motor recovery was achieved in 72% of median nerve lesions, 77% of ulnar nerve lesions, and 57% of radial nerve lesions. Good functional sensory recovery was found in 36% of median, 45% of ulnar, and 48% of radial nerve lesions. It appears by multivariate analysis that the results obtained generally were better in younger patients, in patients with a shorter preoperative delay, and in cases with a shorter transplant.

Adolescent↗
PubMed1983

Forces under the foot.

A transducer has been developed to record the shear or horizontal components of force beneath the sole of the foot. When used with a vertical force transducer it has enabled a comprehensive analysis of the mechanical forces acting beneath the foot when walking in various types of footwear. Considerable differences have been recorded between the footwear. Particularly low forces are present in a plaster cast and to a lesser extent with Plastazote insoles. The possible application of these findings to the management of ulceration of the sole of the foot in diabetes mellitus and leprosy is discussed.

Biomechanical Phenomena↗
PubMed1990

Moving child abuse and neglect prevention programs forward: improving program evaluations.

This paper focuses on evaluations of programs to prevent child abuse and neglect. It discusses the quality of the evaluations and offers suggestions for improvement to evaluators, program planners, and funders. Thirteen evaluations recommended by experts and published from 1978 through 1988 were reviewed. Using the true experiment as the standard of quality, we found evaluations frequently characterized by careful attention to methodologic detail. Evaluators describe eligibility criteria; half of the studies had control groups or followed progress. However, to learn more about prevention of abuse and neglect the caliber of evaluation research must improve. Evaluators do not define abuse or neglect; they accept reports of abuse. This has the effect of shifting the responsibility to others whose concerns and reporting standards differ. Lack of definition is reflected in a paucity of valid measurements; we could not assess the characteristics of families who benefit most from programs. Evaluators also omit important topics. Although seven evaluations studied health-related variables, no comprehensive analysis of the consequences and costs of medical neglect could be found; very little information on costs and benefits of any kind was available.

Child↗
PubMed1992

Fluoxetine: no association with suicidality in obsessive-compulsive disorder.

Since (a) obsessive-compulsive disorder (OCD) may involve serotonergic neural transmission abnormalities also though to be related to regulation of suicide and aggression, (b) comorbidity between OCD and depression is substantial, and (c) depression is a major risk factor for suicide, a comprehensive analysis of clinical trial data was undertaken to assess the potential association of fluoxetine, a serotonin uptake inhibitor, and suicidality (suicidal acts and ideation). Pooled data from clinical trials comparing fluoxetine (n = 266) and placebo (n = 89) in patients with DSM-IIIR OCD were analyzed retrospectively. No suicidal acts occurred during placebo lead-in or double-blind therapy. Mean Hamilton Depression Scale item 3 (suicide item) scores improved statistically significantly with fluoxetine compared with placebo. Worsening in suicidal ideation was statistically significantly more frequent with placebo than with fluoxetine. Emergence of substantial suicidal ideation (change in baseline item 3 score of 0 or 1 to 3 or 4) was numerically greater with placebo than with fluoxetine (3.6% vs. 1.7%; not statistically significant). The incidence of suicidality in fluoxetine-treated patients with OCD was low, compared favorably with rates in corresponding placebo-treated patients, and was well within the range of estimates in previous studies of patients with OCD. These controlled clinical trial results suggest no undue risk of suicidality in patients with OCD treated with fluoxetine.

Adult↗
PubMed1990

Consideration of both genotoxic and nongenotoxic mechanisms in predicting carcinogenic potential.

Bacterial and cell culture genotoxicity assays have proven to be valuable in the identification of DNA reactive carcinogens because mutational events that alter the activity or expression of growth control genes are a key step in carcinogenesis. The addition of metabolizing enzymes to these assays have expanded the ability to identify agents that require metabolic activation. However, chemical carcinogenesis is a complex process dependent on toxicokinetics and involving at least steps of initiation, promotion and progression. Identification of those carcinogens that are activated in a manner unique to the whole animal, such as 2,6-dinitrotoluene, require in vivo genotoxicity assays. There are many different classes of non-DNA reactive carcinogens ranging from the potent promoter 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) that acts through a specific receptor, to compounds that alter growth control, such as phenobarbital. Many compounds, such as saccharin, appear to exhibit initiating, promotional and/or carcinogenic activity as events secondary to induced cytotoxicity and cell proliferation seen only at the chronic lifetime maximum tolerated doses mandated in rodent bioassays. Simple plus/minus vs. carcinogen/noncarcinogen comparisons used to validate the predictivity of bacterial and cell culture genotoxicity assays have revealed that a more comprehensive analysis will be required to account for the carcinogenicity of so many diverse chemical agents. Predictive assays and risk assessments for the numerous types of nongenotoxic carcinogens will require understanding of their mechanism of action, reasons for target organ and species specificity, and the quantitative dose-response relationships between endpoints such as induced cell proliferation and carcinogenic potential.

Animals↗
PubMed1990

A strategy for founding a global lymphocyte proteinpaedia and gene catalogue.

In this article, Ivan Lefkovits, John Kettman and Christopher Coleclough describe a strategy for a comprehensive analysis of the genes active in lymphocytes. It allows direct access to the coding sequence of any gene, provided that the two-dimensional gel spot coordinate position is known. The authors have constructed representative lymphocyte cDNA libraries and partitioned them into many sectors, each containing a unique set of cDNA clones. Data from the analysis of natural lymphocyte proteins is compiled into a 'proteinpaedia', which is matched to a gene catalogue comprising the partitioned recombinant phage collection.

Animals↗
PubMed1994

Recognition of regulatory regions in genomic sequences.

For the functional interpretation of genomic sequences, effective algorithms have to be developed that will recognize regions of specific function and thus will suggest experiments for their verification. As a first step, relevant data have to be collected in an appropriate database from which suitable training sets can be extracted. In this paper, I discuss the requirements for a database that collects information about regulatory DNA sequences and describe the structure and contents of such a database (TRANSFAC). This compiled information will serve as a basis for comprehensive analysis of sites that regulate transcription, e.g., by statistical methods. It will thus facilitate the recognition of regulatory genomic sequence information and the assignment of the corresponding regulators. Moreover, it will provide all relevant data about the regulating proteins which will allow to trace back transcriptional control cascades to their origin.

Algorithms↗
PubMed1993

The hepatitis C virus genome: a guide to its conserved sequences and candidate epitopes.

A comprehensive analysis of reported hepatitis C virus genomic sequences comprising 151 partial or complete nucleotide sequences and 159 partial or complete amino acid sequences revealed an irregular composition of conserved and variable regions. There were but eight conserved nucleotide sequences, none outside the 5' noncoding and structural regions. A search among conserved amino acid sequences revealed 14 candidate B-cell epitopes, which were chosen mainly on the basis of their hydrophilicity profiles. Twenty five candidate T-cell epitopes were selected according to the criteria of absolute conservation of amino acid sequence, together with characteristic sequence motifs, amphipathic helical structure, or both. Conserved peptide sequences, with the characteristics of both B- and T-cell epitopes, were identified in the nonstructural 5 (NS5) region of the genome.

Amino Acid Sequence↗
PubMedDate not supplied

GRF analogs and fragments: correlation between receptor binding, activity and structure.

GH-releasing activity in vitro was directly correlated with GRF receptor binding affinity for all hGRF analogs examined. hGRF(1-29)-NH2 analogs with Ala15-substitution (for Gly15) displayed 4-5 times higher affinity for the GRF receptor relative to hGRF(1-44)-NH2. Replacement of Gly15 with Sar15 resulted in a dramatic loss of activity and receptor binding. The present data supports the proposal that Ala15-substitution increases receptor affinity, and hence potency, due to increased amphiphilic alpha-helical interactions. Fragments of hGRF, representative of DPP-IV and trypsin-like cleavage, are inactive as a consequence of greatly diminished GRF receptor binding. These results provide a comprehensive analysis of the structural features required for both GRF receptor binding and activation.

Animals↗
PubMed1995

Structural and biosynthetic properties of peptides in cone snail venoms.

Venoms of the predatory cone snails Conus textile, Conus striatus, and Conus magus were subjected to comprehensive analysis of peptide content. With the fish-eating cone snails C. magus and C. striatus, the most abundant venom peptides were of > 30-50 residues, whereas the predominant peptides in the venom of the mollusc-eating snail, C. textile, were of 20-35 residues. Amino acid sequencing revealed an identical but unusual amino acid in a conserved position in four novel omega-type peptides from the C. textile venom. Two conserved amino acid sequences were obtained from the venoms of both C. magus and C. striatus. The amino acid compositions of the isolated C. textile peptides and the expected processing products of the propeptides (42) were compared. Despite the recovery in abundance of the carboxyl-terminal omega-type peptides, none of the isolated peptides had compositions expected from the propeptide amino-terminal fragments. We conclude that there are likely mechanisms for excluding the amino-terminal propeptide fragments from this venom, resulting in a venom with greater potency. Amounts of the different omega-type peptides in the venom vary widely, suggesting a distinct mechanism that results in the selective synthesis of different bioactive carboxyl-terminal propeptide fragments at elevated levels.

Amino Acid Sequence↗
PubMedDate not supplied

Relationship between age and GSH metabolism in synaptosomes of rat cerebral cortex.

A comprehensive analysis on glutathione metabolism in rat cerebral cortex synaptosomes as a function of age was performed. All different glutathione system components (GSH, GSSG, total GSH, and GSH redox index) changed significantly only during aging. GSH, total GSH, and GSH redox index decreased by about 40%, 24%, and 52%, respectively, while GSSG showed a remarkable increase of about 60%. On the contrary, some GSH-related enzyme activities showed characteristic changes both during growth and aging. GSH peroxidase and GSH-S-transferase activities significantly increased both during growth and aging, GSH reductase and gamma-glutamylcysteine synthetase activities showed lower levels only during aging, while glucose-6-phosphate dehydrogenase activity did not change throughout the life of the rat. The results obtained suggest an increase of the oxidative status due to a reduced antioxidant capacity of the GSH system in the synaptosomal compartment during aging. The main cause of these metabolic modifications is a lowering of the rates of both GSSG reduction to GSH and GSH synthesis. Moreover, an irreversible loss of GSH as GSH-S-conjugates due to a high detoxification mechanism during aging is also possible. These alterations in glutathione metabolism, found mainly during aging in rat cerebral cortex synaptosomes may contribute to clarify some aspects of cerebral diseases.

Aging↗