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At least 685 records · Page 38Linked to original sources
PubMed2005

Ah receptor- and TCDD-mediated liver tumor promotion: clonal selection and expansion of cells evading growth arrest and apoptosis.

The Ah receptor (AhR) has been characterized as a ligand-activated transcription factor which belongs to the bHLH/PAS (basic helix-loop-helix/Per-Arnt-Sim) family of chemosensors. Transgenic mouse models revealed adaptive and developmental functions of the AhR in the absence of exogenous ligands. Use of persistent agonists such as dioxins including 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and related compounds demonstrated that the AhR mediates a plethora of species- and tissue-dependent toxicities, including chloracne, wasting, teratogenicity, immunotoxicity, liver tumor promotion and carcinogenicity. However, molecular mechanisms underlying most aspects of these toxic responses as well as biological functions of the AhR are currently unknown. Previous studies of liver tumor promotion in the two-stage hepatocarcinogenesis model indicated that TCDD mediates clonal expansion of 'initiated' preneoplastic hepatocytes, identified as enzyme-altered foci (EAF) by inhibiting apoptosis and bypassing AhR-mediated growth arrest. In contrast, the Ah receptor has been shown in cell models to stimulate growth arrest and apoptosis. Possible underlying mechanisms of these AhR responses are discussed, including enhanced metabolism of retinoic acid which attenuates TGFbeta-mediated apoptosis and interaction of the Ah receptor with the hypophosphorylated retinoblastoma tumor suppressor protein. The discrepancy between in vivo findings in EAF and AhR functions may be solved by hypothesizing that sustained activation of the Ah receptor generates a strong selective pressure in liver treated with genotoxic carcinogens leading to selection and expansion of clones evading growth arrest and apoptosis. Models are discussed which may facilitate verification of this hypothesis.

Animals↗
PubMed1995

An essential role for gp39, the ligand for CD40, in thymic selection.

The interactions between CD40 on B cells and its ligand gp39 on activated T helper cells are known to be essential for the development of thymus-dependent humoral immunity. However, CD40 is also functionally expressed on thymic epithelial cells and dendritic cells, suggesting that gp39-CD40 interactions may also play a role in thymic education, the process by which self-reactive cells are deleted from the T cell repertoire. Six systems of negative selection were studied for their reliance on gp39-CD40 interactions to mediate negative selection. In all cases, when the antigen/superantigen was endogenously expressed (in contrast to exogenously administered), negative selection was blocked by loss of gp39 function. Specifically, blockade of gp39-CD40 interactions prevented the deletion of thymocytes expressing V beta 3, V beta 11, and V beta 12, specificities normally deleted in BALB/c mice because of the endogenous expression of minor lymphocyte-stimulating determinants. Independent verification of a role of gp39 in negative selection was provided by studies in gp39-deficient mice where alterations in T cell receptor (TCR) V beta expression were also observed. Studies were also performed in the AND TCR transgenic (Tg) mice, which bear the V alpha 11, V beta 3 TCR and recognize both pigeon cytochrome c (PCC)/IEk and H-2As. Neonatal administration of anti-gp39 to AND TCR Tg mice that endogenously express H-2As or endogenously produce PCC prevented the deletion of TCR Tg T cells. In contrast, deletion mediated by high-dose PCC peptide antigen (administered exogenously) in AND TCR mice was unaltered by administration of anti-gp39. In addition, deletion by Staphylococcus enterotoxin B in conventional mice was also unaffected by anti-gp39 administration. gp39 expression was induced on thymocytes by mitogens or by antigen on TCR Tg thymocytes. Immunohistochemical analysis of B7-2 expression in the thymus indicated that, in the absence of gp39, B7-2 expression was substantially reduced. Taken together, these data suggest that gp39 may influence negative selection through the regulation of costimulatory molecule expression. Moreover, the data support the hypothesis that, for negative selection to some endogenously produced antigens, negative selection may be dependent on TCR engagement and costimulation.

Amino Acid Sequence↗
PubMed2004

ParSeq: searching motifs with structural and biochemical properties.

SUMMARY: Searches for variable motifs such as protein-binding sites or promoter regions are more complex than the search for casual motifs. For example, in amino acid sequences comparing motifs alone mostly proves to be insufficient to detect regions that represent proteins with a special function, because the function depends on biochemical properties of individual amino acids (such as polarity or hydrophobicity). Pure string matching programs are not able to find these motifs; hence, we developed ParSeq, a program that combines the search for motifs with certain structural properties, the verification of biochemical properties, an approximate search mechanism and a stepwise creation of the motif description by allowing to search on previously obtained results. AVAILABILITY: http://www-pr.informatik.uni-tuebingen.de/parseq

Algorithms↗
PubMed1998

Correcting for verification bias in studies of a diagnostic test's accuracy.

Standard methods for assessing the accuracy of diagnostic tests require determination of true disease status for each study patient. In practice, some study patients might not have verified disease status. If the decision to verify a patient is influenced by the test result, analysis using only verified cases might lead to biased results, commonly known as verification bias. This paper reviews recent developments in bias-correction methods for studies on the accuracy of diagnostic tests.

Diagnostic Techniques and Procedures↗
PubMed1993

Loci of achromatic points throughout the life span.

Mixtures of monochromatic lights that appear achromatic were measured for 50 normal, trichromatic observers ranging in age from 11 to 78 years. Stimuli were presented to one eye as a 1 degree-diameter, 1-s flash (10-s interstimulus interval) in Maxwellian view. We found the achromatic locus by varying the intensity ratio of each observer's spectral unique blue and unique yellow while maintaining constant overall retinal illuminance. Measurements were made for three levels of retinal illuminance (10, 100, 1000 trolands). Additional verification of the position of the achromatic locus in color space was obtained for 23 subjects with the use of a mixture composed of 600-nm light and its spectral complement. There were no significant changes in the achromatic loci as a function of age. The mean achromatic locus in CIE chromaticity space was x, y = 0.31, 0.31 or u',v' = 0.21, 0.46. These results suggest that partial compensation for age-related changes in visual mechanisms occurs in a way that preserves constancy of the achromatic locus across the life span.

Adolescent↗
PubMedDate not supplied

[Symptoms and musculo-skeletal changes among personnel of the State Police exposed to mechanical risk].

The aim of this present study was to inquire about spine morfo-functional alterations among policemen with jobs regarded as potentially hazardous, in order to identify preclinical alterations of column and to plan adequate preventive measures. A physiopathologic and working anamnesis was carried out by means of questionnaire about personal data, jobs, reported rachidian symptomatology and presence of orthopedic diseases, given to policemen on duty in Bari. Every chosen worker was subject to orthopedic and neurological examination, radiography of column, Formetric tridimensional examination, telethermography of spine. We stratified the sample on the basis of age and job. Under the jobs we individuated 4 biomechanical hazardous activities, performed separately or together: driving motorcycle, driving car, flying helicopter, video terminal use. The whole sample, formed by 211 subjects, all male, had the average age of 39 years (Standard Deviation: +/- 4). About the reported rachidian symptomatology, only 41 (17, 98%) subjects were asymptomatical, contrary to clinical results, that were normal in almost the entire sample, with the exception of 3 workers (1, 31%), who had neurological clinical alterations. Structural alterations were checked by radiography among 64, 9% of subjects. The Formetric examination found alterations in different tract of rachis, also coexiting between each other. The telethermographic changes affected 63,99% of the sample and involved especially the lumbar tract (38,86%), dorsal region (18%) and cervical zone (7,1%). The relative frequency of dorsal tract increased with growing of age. The morfo-functional changes of the sample seem to depend rather on the performed job, than on degenerative process of age, partly because the average age of the sample is not much elevated and because the enlistment in Italian Police Force is subordinated to verification of optimum conditions, also characterized by absence of anomaly of column. The absence of clinical alteration, in contrast to reported rachidian symptomatology by 82,02% of subjects and with discovered objectivity, demands more clinical attention in presence of symptomatology and proposes supplementary non-invasive techiniques of investigation, as the telethermography and the formetric tridimensional examination.

Adult↗
PubMed1995

Chemical shifts and three-dimensional protein structures.

During the past three years it has become possible to compute ab initio the 13C, 15N and 19F NMR chemical shifts of many sites in native proteins. Chemical shifts are beginning to become a useful supplement to more established methods of solution structure determination, and may find utility in solid-state analysis as well. From 13C NMR, information on phi, psi and chi torsions can be obtained, permitting both assignment verification, and structure refinement and prediction. For 15N, both torsional and hydrogen-bonding effects are important, while for 19F, chemical shifts are primarily indicators of the local charge field. Chemical shift calculations are still slow, but shielding hypersurfaces - the shift as a function of the dihedral angles that define the molecular conformation - are becoming accessible. Over the next few years, theoretical and computer hardware improvements will enable more routine use of chemical shifts in structural studies, including the study of metal-ligand interactions, the analysis of drug and substrate binding and catalysis, the study of folding/unfolding pathways, as well as the characterization of conformational substates. Rather than simply being a necessary prerequisite for multidimensional NMR, chemical shifts and chemical shift non-equivalence due to folding are now beginning to be useful for structural characterization.

Computer Simulation↗
PubMed1994

Anal endosonography in healthy subjects and patients with idiopathic fecal incontinence.

PURPOSE: This study investigates the normal ultrasonographic morphology of pelvic floor striated muscle and evaluates whether there are differences between males and females and between healthy subjects and patients with idiopathic fecal incontinence. METHODS: Manometric and ultrasonographic studies of the anal canal were performed in 30 healthy volunteers and in 26 patients with idiopathic fecal incontinence. Verification of ultrasonographic findings was obtained by studying anatomic preparations. RESULTS: Ultrasonography reliably identified the internal and external anal sphincter and frequently visualized neighboring structures. In addition, it detected muscular structures that have not clearly been described previously. However, differences in external sphincter function between males and females and between healthy subjects and incontinent patients were not reflected by alterations in muscle thickness. CONCLUSIONS: Endosonography of the anal canal clearly delineates muscular structures and may even visualize structures that have been previously incompletely defined. However, it remains to be shown that differences in certain muscular functions have a morphologic correlate that can be detected by endosonography.

Adult↗
PubMed1990

Role of site-specific, metal-catalyzed oxidation in lens aging and cataract: a hypothesis.

The evidence reviewed here supports the hypothesis that metal catalyzed oxidation reactions occur in the lens and may make a significant contribution to the changes seen in the lens with age and in cataract formation. The major support for this hypothesis is as follows. (1) All of the components of the non-enzymic metal catalyzed oxidation systems are present in the lens normally. Ascorbate, glutathione and oxygen are present in much lower concentrations. Although, even at low concentrations, the reactions could occur over many years with significant consequences. Components of some of the enzymic systems are also present, although primarily in the epithelial layer and outer cortical region. Copper and iron levels may be increased in some cataracts. (2) Protein carbonyl derivatives are increased in both aging and cataractous lenses. Amino acid-derived protein carbonyl derivatives have only been demonstrated in oxidative reactions derived from oxygen radical generation, particularly those catalyzed by metal-catalyzed oxidation systems. (3) Treatment of isolated bovine crystallins with metal catalyzed oxidation systems generates modifications similar to those found in vivo. The proposed mechanism of site-specific metal catalyzed oxidation appears to be a feasible mechanism of oxidation in the lens, and verification of the mechanism requires further study. Although the focus of this manuscript has been on the oxidative modification induced in proteins,m oxidative damage to DNA or membrane resulting from similar mechanisms may also play an important role in alteration of lens function during aging and cataractogenesis.

Aging↗
PubMed2005

Studies of intestinal drug transport using an in silico epithelio-mimetic device.

We report the development and use of a synthetic, discrete event, discrete space model that functions as an epithelio-mimetic device (EMD). It is intended to facilitate the study of intestinal transport of drug-like compounds. We represent passive paracellular and transcellular transport, carrier-mediated transport and active efflux using stand-alone components. Systematic verification of the EMD over a wide physiologically realistic range is essential before we can use it to address questions regarding the details of the interacting mechanisms that are believed to influence absorption. We report details of key verification experiments. We demonstrate that this device can generate behaviors similar to those observed in the in vitro Caco-2 transwell system. To do that we used a series of hypothetical drugs and we simulated behaviors for two clinically used drugs, alfentanil and digoxin. The results support the feasibility and practicability of the EMD as a tool to expand the experimental options for better understanding the biological processes involved in intestinal transport and absorption of compounds of interest.

Alfentanil↗
PubMed2000

Simulation modeling of nuclear steam generator water level process--a case study

Simulation modeling of the nuclear steam generator (SG) water level process in Qinshan Nuclear Power Plant (QNPP) is described in this paper. A practical methodology was adopted so that the model is both simple and accurate for control engineering implementation. The structure of the model is in the form of a transfer function, which was determined based on first-principles analysis and expert experience. The parameters of the model were obtained by taking advantage of the recorded historical response curves under the existing closed-loop control system. The results of process dimensional data verification and experimental tests demonstrate that the simulation model depicts the main dynamic characteristics of the SG water level process and is in accordance with the field recorded response curves. The model has been successfully applied to the design and test of an advanced digital feedwater control system in QNPP.

Journal Article↗
PubMed1990

A randomized multicentre trial of pefloxacin plus metronidazole and gentamicin plus metronidazole in the treatment of severe intra-abdominal infections. Report from a Swedish Study Group.

In order to compare the efficacy and safety of pefloxacin plus metronidazole with those of gentamicin plus metronidazole, 271 patients with severe intraabdominal infection were enrolled in an open, randomized comparative trial. Seventy males and 66 females (mean age 54 years; range 18-90) were enrolled in the pefloxacin/metronidazole group and 74 males and 61 females (mean age 52 years; range 18-90) in the gentamicin/metronidazole group. After verification of the intra-abdominal infection by laparotomy, drainage or puncture and microbiological cultures, patients received iv either pefloxacin 400 mg, bd, after an 800-mg loading dose, or gentamicin 1.4 mg/kg body weight every 8-24 h depending on the renal function. Metronidazole was given to both groups as a 500 mg intravenous infusion tid. Eighty-seven patients were excluded from the efficacy analysis, principally because of unproven infection, previous antimicrobial therapy or treatment duration less than three days. Ninety-four of 104 patients receiving pefloxacin/metronidazole (90.4%) were cured or improved and there were two failures and eight relapses. In the gentamicin/metronidazole group, 64 of 80 patients (80.0%) were cured or improved while there were three failures, nine relapses, and two deaths. The bacteria originally isolated were eradicated in similar proportions of the patients in the two groups. Eleven of 136 patients receiving pefloxacin/metronidazole (8.1%) and seven of 135 patients given gentamicin/metronidazole (5.2%) had adverse reactions. This study shows that pefloxacin can be considered as effective and safe as gentamicin for the treatment of severe intraabdominal infections.

Abdomen↗
PubMed1982

Evaluation of factors affecting the membrane filter technique for testing drinking water.

The following studies were done in response to questions regarding the adoption and use of the membrane filter (MF) technique for testing drinking water for the total coliform indicator group. A comparison with the most-probable-number technique showed that MF procedures with m-Endo agar LES were somewhat superior to the most-probable-number methods in terms of numbers of coliform organims recovered. Medium preparation and storage studies indicated that rehydration of m-Endo agar LES should be done with boiling water for less than 15 min, that m-Endo agar LES should not be exposed to light for more than 4 to 6 h, and that m-Endo agar LES plates may be used for up to 4 weeks and broth verification media for up to 3 weeks under given storage conditions. MF culture colonies were commonly found which did not produce sheen as expected for coliforms and yet were verified as coliforms. The occurrence and morphology of these atypical colonies were studied. Parallel inoculation of both lauryl tryptose (LT) and brilliant green bile (BGB) broth was found to be a better colony verification approach than recommended LT preenrichment before transfer to BGB. Comparison of parallel verification results indicated very little justification for the use of LT medium in MF verification procedures. In the case of overgrown or confluent cultures, the best coliform recoveries resulted from swabbing the MF plate and directly inoculating BGB medium with the swab. The occurrence of overgrowth was defined and evidence was collected suggesting that overgrowth is a function of sample holding time. Evaluation of routine test data and bacterial population reductions as a function of time indicated that nonquantitative recovery of coliforms may not be significantly affected for at least a 72-h sample holding time.

Bacteria↗
PubMed1992

Nonsteroidal signals originating in the gonads.

The discovery of the various peptide factors in the gonads followed different paths. A number of factors were specifically searched for because of physiological experiments that predicted that an activity from the gonads was necessary to explain phenomena. Such was the case for gonadal steroids and for such peptide factors as inhibin, MIS, OMI, FRP, seminal plasma inhibin, relaxin, PA factor and other proteases, and ABP. In the process other factors such as activin and follistatin were serendipitously discovered. A second group of factors was discovered because in vitro experiments of various combinations of gonadal cell types failed to replicate in vivo findings, suggesting missing signals. Such substances are the panoply of growth factors aiding in differentiation and growth promotion and inhibition: LS and LI, P-Mod-S, clusterin, and various components of the ECM. Finally, and most recently, another set of peptides has been identified because immunological or molecular probes have been used to search gonadal tissue for factors originally discovered elsewhere; these include POMC, GnRH-like peptide, oxytocin, AVP, angiotensin, ANF, CRF, neural peptides, and c-mos. Our understanding of the relationship of most of these peptides to the local signals necessary for gonadal function is still very elementary. Clearly some like relaxin and inhibin function as important hormones, and ABP, for example, probably functions importantly in transporting testosterone down the tubule. Most local paracrine or autocrine peptide signals appear to act in relationship to gonadotropin levels probably in local differentiation in the process of gamete maturation, but this is only conjecture at this point. No experimental verification that any of these factors is involved in follicle selection for recruitment or for atresia is yet available. For many of the factors local receptors have not yet been identified. The richness of the variety of peptides in the gonads suggests that microanalysis of cell-cell signaling would be rewarding, but at the time of this writing such investigations are not yet possible.

Animals↗
PubMed1985

Dual coding: a cognitive model for psychoanalytic research.

Four theories of mental representation derived from current experimental work in cognitive psychology have been discussed in relation to psychoanalytic theory. These are: verbal mediation theory, in which language determines or mediates thought; perceptual dominance theory, in which imagistic structures are dominant; common code or propositional models, in which all information, perceptual or linguistic, is represented in an abstract, amodal code; and dual coding, in which nonverbal and verbal information are each encoded, in symbolic form, in separate systems specialized for such representation, and connected by a complex system of referential relations. The weight of current empirical evidence supports the dual code theory. However, psychoanalysis has implicitly accepted a mixed model-perceptual dominance theory applying to unconscious representation, and verbal mediation characterizing mature conscious waking thought. The characterization of psychoanalysis, by Schafer, Spence, and others, as a domain in which reality is constructed rather than discovered, reflects the application of this incomplete mixed model. The representations of experience in the patient's mind are seen as without structure of their own, needing to be organized by words, thus vulnerable to distortion or dissolution by the language of the analyst or the patient himself. In these terms, hypothesis testing becomes a meaningless pursuit; the propositions of the theory are no longer falsifiable; the analyst is always more or less "right." This paper suggests that the integrated dual code formulation provides a more coherent theoretical framework for psychoanalysis than the mixed model, with important implications for theory and technique. In terms of dual coding, the problem is not that the nonverbal representations are vulnerable to distortion by words, but that the words that pass back and forth between analyst and patient will not affect the nonverbal schemata at all. Using the dual code formulation, and applying an investigative methodology derived from experimental cognitive psychology, a new approach to the verification of interpretations is possible. Some constructions of a patient's story may be seen as more accurate than others, by virtue of their linkage to stored perceptual representations in long-term memory. We can demonstrate that such linking has occurred in functional or operational terms--through evaluating the representation of imagistic content in the patient's speech.

Cognition↗
PubMed1975

[Intracranial pressure. III. Trial generalized theory].

The authors reported previously an elementary mathematical model of intracranial pressure (ICP) as well as result from an experimental verification of the model. The experimental tests revealed that certain factors had been neglected in the theoretical formation, and the present article offers an expanded version of model which takes into account those factors: changes in the formation of the CSF as a function of ICP; cerebral vasomotricity; cortical and sinusal venous pressures, and variations of the filtration coefficient of the subarachnoidal spaces. A generalized mathematical model of ICP, in the form of four equations, is proposed. The major aspects of both normal and pathological ICP are studied in the light of this model, and are integrated into a generalized theory.

Brain Death↗
PubMed1980

Sterols of human gallstones: the recent identification of eight different digitonin precipitable sterols.

In this study, we report for the first time the presence of many noncholesterol sterols in human gallstones. Gallstones were obtained from 17 patients at cholesystectomy. They were rich in sterol composition, some 52.8% by weight. A number of different sterols were found: 22-dehydrocholesterol 0.29% of total sterols; cholestanol, 1.54%; lathosterol, 1.92%; 24-methylene cholesterol and campesterol, 0.64%; stigmasterol, 0.02%; beta-sitosterol, 0.21%; and cholesterol, 95.33%. These individual sterols were identified by a variety of methods which included final verification by combined gas chromatography-mass spectroscopy. These unusual sterols were derived either from the diet or from the metabolism of cholesterol in the body. Their presence might well affect the lithogenicity of the bile and raises questions about their metabolism and function generally in the body.

Cholelithiasis↗