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Biomedical subjects

S Simon

Publications and source records attributed to S Simon.

At least 55 records · Page 3Linked to original sources
PubMed1999

The binding sites of inhibitory monoclonal antibodies on acetylcholinesterase. Identification of a novel regulatory site at the putative "back door".

We investigated the target sites of three inhibitory monoclonal antibodies on Electrophorus acetylcholinesterase (AChE). Previous studies showed that Elec-403 and Elec-410 are directed to overlapping but distinct epitopes in the peripheral site, at the entrance of the catalytic gorge, whereas Elec-408 binds to a different region. Using Electrophorus/rat AChE chimeras, we identified surface residues that differed between sensitive and insensitive AChEs: the replacement of a single Electrophorus residue by its rat homolog was able to abolish binding and inhibition, for each antibody. Reciprocally, binding and inhibition by Elec-403 and by Elec-410 could be conferred to rat AChE by the reverse mutation. Elec-410 appears to bind to one side of the active gorge, whereas Elec-403 covers its opening, explaining why the AChE-Elec-410 complex reacts faster than the AChE-Elec-403 or AChE-fasciculin complexes with two active site inhibitors, m-(N,N, N-trimethyltammonio)trifluoro-acetophenone and echothiophate. Elec-408 binds to the region of the putative "back door," distant from the peripheral site, and does not interfere with the access of inhibitors to the active site. The binding of an antibody to this novel regulatory site may inhibit the enzyme by blocking the back door or by inducing a conformational distortion within the active site.

Acetylcholinesterase↗
PubMed1999

Studies with a growth hormone antagonist and dual-fluorescent confocal microscopy demonstrate that the full-length human growth hormone receptor, but not the truncated isoform, is very rapidly internalized independent of Jak2-Stat5 signaling.

UNLABELLED: We have investigated trafficking of two negative regulators of growth hormone receptor (GHR) signaling: a human, truncated receptor, GHR1-279, and a GH antagonist, B2036. Fluorescent-labeled growth hormone (GH) was rapidly internalized by the full-length GHR, with >80% of the hormone internalized within 5 min of exposure to GH. In contrast, <5% of labeled GH was internalized by cells expressing truncated GHR1-279. Using another truncated receptor, GHR1-317 fused to enhanced green fluorescent protein (EGFP), we have exploited fluorescence energy transfer to monitor the trafficking of ligand-receptor complexes. The data confirmed that internalization of this truncated receptor is very inefficient. It was possible to visualize the truncated GHR1-317-EGFP packaged in the endoplasmic reticulum, its rapid movement in membrane bound vesicles to the Golgi apparatus, and subsequent transport to the cell membrane. The GH antagonist, B2036, blocked Jak2-Stat5-mediated GHR signaling but was internalized with a similar time course to native GH. THE RESULTS: 1) demonstrate the rapid internalization of GH when studied under physiological conditions; 2) confirm the hypothesis that internalization of cytoplasmic domain truncated human GHRs is very inefficient, which explains their dominant negative action; and 3) show that the antagonist action of B2036 is independent of receptor internalization.

Golgi Apparatus↗
PubMed1999

The polymorphism of acetylcholinesterase: post-translational processing, quaternary associations and localization.

The molecular forms of acetylcholinesterase (AChE) correspond to various quaternary structures and modes of anchoring of the enzyme. In vertebrates, these molecules are generated from a single gene: the catalytic domain may be associated with several types of C-terminal peptides, that define distinct types of catalytic subunits (AChE(S), AChE(H), AChE(T)) and determine their post-translational maturation. AChE(S) generates soluble monomers, in the venom of Elapid snakes. AChE(H) generates GPI-anchored dimers, in Torpedo muscles and on mammalian blood cells. AChE(T) is the only type of catalytic subunit that exists in all vertebrate cholinesterases; it produces the major forms in adult brain and muscle. AChE(T) generates multiple structures, ranging from monomers and dimers to collagen-tailed and hydrophobic-tailed forms, in which catalytic tetramers are associated with anchoring proteins that attach them to the basal lamina or to cell membranes. In the collagen-tailed forms, AChE(T) subunits are associated with a specific collagen, ColQ, which is encoded by a single gene in mammals. ColQ contains a short peptidic motif, the proline-rich attachment domain (PRAD), that triggers the formation of AChE(T) tetramers, from monomers and dimers. The critical feature of this motif is the presence of a string of prolines, and in fact synthetic polyproline shows a similar capacity to organize AChE(T) tetramers. Although the COLQ gene produces multiple transcripts, it does not generate the hydrophobic tail. P, which anchors AChE in mammalian brain membranes. The coordinated expression of AChE(T) subunits and anchoring proteins determines the pattern of molecular forms and therefore the localization and functionality of the enzyme.

Acetylcholinesterase↗
PubMed1999

Molecular diagnosis of group B coltiviruses infections.

The group-B of genus Coltivirus encompasses isolates from humans, ticks or mosquitoes collected in Indonesia and China. Subgroup-B1 includes the strain JKT/dsR-7075 and subgroup-B2 strains JKT/dsR-6423, JKT/dsR-6969, JKT/dsR-7043 and the Banna virus. Data are described for the PCR-based diagnosis of infection by group B coltiviruses. Sets of primers were designed from the sequences of the 7th, 9th and 12th viral segments and RT PCR assays were developed. Consensus primers permitted the detection of all known isolates of subgroup 1 or 2. Viral strains could be characterised further using primers specific for type B2a or B2b, or based on the length of the amplification products. All primers gave negative results when using RNAs from Orbiviruses or Group-A coltiviruses. These primers permitted the detection of Group-B coltiviruses-RNA in infected mouse blood at the acute stage of the disease. Accordingly, they could be used for the diagnosis of infection in humans.

Animals↗
PubMed1999

Nutritional care of the patient: nurses' knowledge and attitudes in an acute care setting.

Concern is growing about the occurrence of malnutrition in hospitals throughout the developed world. Reduced involvement of nurses in patients' nutritional care may be one of the contributing factors. This study explored nurses' attitudes and knowledge about nutrition and food service in hospital. Semi-structured interviews were conducted with seven nurses from the internal medical service of a large Australian acute care hospital. Analysis of the interview transcripts revealed that many nurses lacked the in-depth knowledge needed to give proper nutritional care to their patients. Although nurses considered nutritional care to be important many had difficulty in raising its priority above other nursing activities, as a result of time constraints and multitasking issues. Several problems relating to food service arrangements were also highlighted. The findings suggest a need to raise nurses' awareness of the importance of nutrition in patient outcome. This study provides information which will guide in-service nurse education programs about nutrition, and suggests strategies for practice and organizational change.

Acute Disease↗
PubMed1999

Towards safer drug prescribing, dispensing and administration in hospitals.

A multidisciplinary workshop was held in order to identify strategies likely to produce a reduction in adverse drug events, by targeting hospital systems involved in drug prescribing, dispensing and administration. Strategies identified at the workshop included: (i) improving the education and practice development of medical and nursing staff, concerning drug therapy and safe prescribing principles; (ii) introducing and using information technology and electronic prescribing processes; (iii) implementing the Australian Pharmaceutical Advisory Council (APAC) national guidelines to achieve the continuum of quality use of medicines between hospitals and the community; (iv) enhancing the importance of medication history taking as a routine part of the admission process; (v) instituting individual patient supply as the standard method of drug distribution in hospitals; and (vi) stimulating the hospital-based clinical pharmacy workforce.

Australia↗
PubMed1999

TT virus infection in French hemodialysis patients: study of prevalence and risk factors.

The TT virus (TTV) is a recently discovered DNA virus which was first identified in patients with non-A to -G hepatitis following blood transfusion. In this study, we tested 150 attendees of two hemodialysis (HD) units of the public hospitals of Marseilles, France, for the presence of TTV genome by using a PCR-based methodology. The overall prevalence of TTV viremia was 28% (compared to 5.3% in blood donors from the same region). We demonstrated the existence of chronic infections and superinfections by strains belonging to different genotypes. The prevalence of infection was higher in patients originating from Africa, in patients with previous blood transfusion or organ transplantation, in patients with antibody to hepatitis B core antigen, and in those with diabetes mellitus. A high prevalence of TTV infection (50%) was also observed in a population of patients with diabetes mellitus but without renal disease. No significant relationship was found between TTV viremia and hepatitis C virus or GB virus C, transaminases, age, sex, and duration of HD treatment. The PCR amplification products (located in open reading frame 1 of the TTV genome) were sequenced. These genomic sequences were submitted to phylogenetic analysis by using the Jukes-Cantor algorithm for distance determination and the neighbor-joining method for tree building. In several instances, sequences from viruses isolated in a HD unit were grouped in the same phylogenetic cluster. These results together with the different distribution of cases in the two HD units suggest there is viral transmission within each.

Adult↗
PubMed1999

Acute hypoxic pulmonary vasoconstriction in conscious dogs decreases renin and is unaffected by losartan.

Acute hypoxic pulmonary vasoconstriction (HPV) may be mediated by vasoactive peptides. We studied eight conscious, chronically tracheostomized dogs kept on a standardized dietary sodium intake. Normoxia (40 min) was followed by hypoxia (40 min, breathing 10% oxygen, arterial oxygen pressures 36 +/- 1 Torr) during both control (Con) and losartan experiments (Los; iv infusion of 100 microg. min-1. kg-1 losartan). During hypoxia, minute ventilation (by 0.9 l/min in Con, by 1.3 l/min in Los), cardiac output (by 0.36 l/min in Con, by 0.30 l/min in Los), heart rate (by 11 beats/min in Con, by 30 beats/min in Los), pulmonary artery pressure (by 9 mmHg in both protocols), and pulmonary vascular resistance (by 280 and 254 dyn. s. cm-5 in Con and Los, respectively) increased. Mean arterial pressure and systemic vascular resistance did not change. In Con, PRA decreased from 4.2 +/- 0.7 to 2.5 +/- 0.5 ng ANG I. ml-1. h-1, and plasma ANG II decreased from 11.9 +/- 3.0 to 8.2 +/- 2.1 pg/ml. The renin-angiotensin system is inhibited during acute hypoxia despite sympathetic activation. Under these conditions, ANG II AT1-receptor antagonism does not attenuate HPV.

Angiotensin II↗
PubMed1999

Phototoxic effects of Hypericum extract in cultures of human keratinocytes compared with those of psoralen.

Extracts of Hypericum perforatum (St. John's wort) are used in the treatment of depression. They contain the plant pigment hypericin and hypericin derivates. These compounds have light-dependent activities. In order to estimate the potential risk of phototoxic skin damage during antidepressive therapy, we investigated the phototoxic activity of hypericin extract using cultures of human keratinocytes and compared it with the effect of the well-known phototoxic agent psoralen. The absorbance spectrum of our Hypericum extract revealed maxima in the whole UV range and in parts of the visible range. We cultivated human keratinocytes in the presence of different Hypericum concentrations and irradiated the cells with 150 mJ/cm2 UVB, 1 J/cm2 UVA or 3 h with a white light of photon flux density 2.6 mumol m-2 s-1. The determination of the bromodeoxyuridine incorporation rate showed a concentration- and light-dependent decrease in DNA synthesis with high hypericin concentrations (> or = 50 micrograms/mL) combined with UVA or visible light radiation. In the case of UVB irradiation a clear phototoxic cell reaction was not detected. We found phototoxic effects even with 10 ng/mL psoralen using UVA with the same study design as in the case of the Hypericum extract. These results confirm the phototoxic activity of Hypericum extract on human keratinocytes. However, the blood levels that are to be expected during antidepressive therapy are presumably too low to induce phototoxic skin reactions.

Antidepressive Agents↗
PubMed1998

A four-to-one association between peptide motifs: four C-terminal domains from cholinesterase assemble with one proline-rich attachment domain (PRAD) in the secretory pathway.

The major type of acetylcholinesterase in vertebrates (AChET) is characterized by the presence of a short C-terminal domain of 40 residues, the 'tryptophan amphiphilic tetramerization' (WAT) domain. The presence of this domain is not necessary for catalytic activity but is responsible for hydrophobic interactions and for the capacity of AChET subunits to form quaternary associations with anchoring proteins, thereby conditioning their functional localization. In the collagen tail of asymmetric forms, we characterized a small conserved region that is sufficient for binding an AChET tetramer, the proline-rich attachment domain (PRAD). We show that the WAT domain alone is sufficient for association with the PRAD, and that it can attach foreign proteins (alkaline phosphatase, GFP) to a PRAD-containing construct with a glycophosphatidylinositol anchor (GPI), and thus anchor them to the cell surface. Furthermore, we show that isolated WAT domains, or proteins containing a WAT domain, can replace individual AChET subunits in PRAD-linked tetramers. This suggests that the four WAT domains interact with the PRAD in a similar manner. These quaternary interactions can form without intercatenary disulfide bonds. The common catalytic domains of AChE are not necessary for tetrameric assembly, although they may contribute to the stability of the tetramer.

Acetylcholinesterase↗
PubMed1998

Effect of electromyogram-force relationships and method of gain estimation on the predictions of an electromyogram-driven model of spinal loading.

STUDY DESIGN: An experimental study of fatiguing isometric trunk extension was conducted to investigate the spinal loading estimated from an electromyogram-assisted biomechanical model. OBJECTIVE: To evaluate the sensitivity of the model outputs to two crucial assumptions: electromyogram-force relationship and method of gain estimation. SUMMARY OF BACKGROUND DATA: In the proposed electromyogram-assisted models of the trunk, the nature of the electromyogram-force relationship and the wide variation in reported muscle gains can result in a wide variation in estimates of spinal loading. Given the absence of any gold standard for validation of muscle forces, the delineation of confidence intervals for the estimated loads has become critical. METHODS: Ten subjects performed a fatiguing isometric trunk extension while the net muscular torque output and trunk muscular activity were measured. An electromyogram-assisted model was used to estimate the torque output and spinal loading. Linear and nonlinear erector spinae electromyogram-force relationships and three methods for gain estimation were investigated: constant gain determined from an initial maximum extension exertion, constant gain based on the fatiguing exertion, and a time-varying gain from the fatigue test. RESULTS: The predicted torque was not sensitive to the electromyogram-force relationship; the nonlinear model produced 10% lower estimates of peak spinal compression force and 14% higher estimates of peak anterior shear force. The gain determined from an initial calibration exertion underestimated the external torque and underpredicted the peak compression force by 20%, compared with gains calculated in the fatigue test. CONCLUSION: The nature of the electromyogram-force relationship and of the method for estimating the gain significantly affect the outcomes of an electromyogram-assisted model of spinal loading.

Adult↗
PubMed1998

Standardized structure and modular design of a pharmacokinetic database.

BACKGROUND: The accumulated knowledge on drugs can be used for an individual drug dosage adjustment if it is placed at our disposal in an informatically structured form. THEORY AND METHODS: We have started building up a pharmacokinetic database aimed at adjusting drug dosages, in exemplary form, to patients with renal impairment. Parameters needed for the three dosage adjustment rules (Dettli, Kunin, Holford) and the most general concept of pharmacokinetics constituted the theoretical basis. TWO PROCESSES PERTAIN TO ALL DRUGS: Distribution and elimination. Total drug clearance and at least two parameters representing distribution and elimination processes are closely interdependent in mathematical terms (clearance = volume of distribution*rate of elimination). This relation yields the unifying concept that serves as a prerequisite for a structured recording of 30 assigned pharmacokinetic and pharmacodynamic parameters within an informatic database. SOLUTIONS AND RESULTS: The information is retrieved and referenced from 2383 original publications by means of a standardized input module. The complete database at present contains 15,397 records for 1573 drugs. A programmed meta-analytic algorithm is used to calculate the statistical measures for the central value and variance--as available--from the pooled values of primary records. The statistically standardized parameters are extracted for 6601 pharmacokinetic parameters, and placed at the users disposal with the output module. PRACTICAL UTILITY: Following meta-analysis, published pharmacokinetics can be used as statistical estimates of population parameters. The statistical estimates with variances permit an individual drug dosage adjustment by applying the Bayesian approach or neural networks.

Algorithms↗
PubMed1998

Resource allocation during the rereading of scientific texts.

Two experiments examined how cognitive resources are allocated to comprehension processes across two readings of the same scientific texts. In Experiment 1, readers read and later reread texts describing scientific topics. The results indicated that across readings, readers decreased resources allocated to proposition assembly, increased resources allocated to text-level integration, and expended a similar amount of resources to lexical access. Subjects who reread the texts after a week delay showed a similar pattern, except that they did not show the increase for text-level integration. Experiment 2 revealed a similar pattern of results with a moving window procedure, except that there was a significant decrease in resources allocated to lexical access across exposures. This experiment also indicated that the rereading speedup was greatest at sentence boundaries, suggesting that the prior exposure enabled readers to immediately process each word. Overall, the results are consistent with the claim that readers allocate proportionally more available resources to text-level integration during rereading because proposition assembly, which enables text-level integration, can be completed with fewer resources.

Adult↗
PubMed1998

The effect of lifting belt use on multijoint motion and load bearing during repetitive and asymmetric lifting.

The evaluation of the effect of lifting belts on multijoint coordinated lifting performance has been limited. Thirteen subjects participated in two experiments: (a) fatiguing repetitive sagittal lifting and (b) asymmetric lifting. Both experiments were performed with and without the use of a common flexible lifting belt to determine the effect of belt use on the trunk and lower extremity motion and load sharing. During both tests, the use of the belt was observed to restrict the sagittal trunk range of motion and velocity, while the hip motion and velocity increased. Although one of the risk factors for acquisition of low back pain may be reduced while wearing the belt, the results also demonstrate a need for greater study of the consequences on the risk of injury to the other joints. More laboratory experiments and prospective epidemiological studies are needed before a conclusive recommendation could be made in favor of using the belt as a valid preventive measure.

Adult↗
PubMed1998

[Arterial hypertension and socioeconomic status in a representative population of French railway drivers].

UNLABELLED: High blood pressure (HDP) is known as a cardiovascular risk factor depending both on environmental and socio-economic factors. METHODS: From October 1993 to october 1994 a cross sectional study was carried out among 1,855 French railway drivers (FRD) representative of the 17,432 males FRD, aged 25 to 54 years. Age, weight, height, hip and waist, smoking, living area, type of train they drove (goods, suburban, TGV, inter-city trains), their grade (3 grades) were recorded. HBP corresponds to systolic blood pressure (BP) 160 mmHg or diastolic BP > or = 95 mmHg or to normal BP under antihypertensive medication. The analysis was carried out according to 2 age classes: 20-36/37-54 years. RESULTS: In our sample 8.5% of FRD suffered from HBP, 3.5% in the younger class, and 13.5% in the other one. Using univariate analysis, among the oldest, subjects with lower grades suffered more often from HBP (19%). Paris area was more often related to HBP for the 20-36 years (6.7%). This was the case for the oldest living in Paris area (19.7%), and the North East (15.2%). Subjects with central obesity (19.9 vs 6%), and hyperlipidemic FRD (20.9 vs 10.9%) were more often related to HBP in the 35-54 years group Whatever the type of train they drove no difference was found. In multivariate analysis, (stepwise logistic regression BMDP LR) independent HBP factors are: age OR 3.4 IC 1.9-5.9 (20-36 vs 37-54), central obesity OR 1.7 IC 1.1-2.6, tobacco consumption OR 2.1 IC 1.2-3.5 (smokers vs non smokers), ex-smokers: OR 2.3 IC 1.3-3.9 (Ex-smokers vs non smokers), living area (all regions vs South East in the Mediterranean border). Nevertheless, grades and type of train they drove were not independent factors. CONCLUSION: These results show the determining part played by environmental factors: age, central obesity, living area and tobacco consumption in the determinism of HBP in professional background: these factors can account for the difference observed in professional factor (grade).

Adult↗
PubMed1997

Cloning and expression of acetylcholinesterase from Electrophorus. Splicing pattern of the 3' exons in vivo and in transfected mammalian cells.

We cloned and expressed a cDNA encoding acetylcholinesterase (AChE) of type T from Electrophorus electricus organs. When expressed in COS, HEK, and Chinese hamster ovary cells, the AChET subunits generated dimers and tetramers. The cells produced more activity at 27 than at 37 degrees C. The kinetic parameters of a recombinant enzyme, produced in the yeast Pichia pastoris, were close to those of the natural AChE. Analysis of genomic clones showed that the coding sequence is interrupted by an intron that does not exist in Torpedo and differs in its location from that observed in the mouse. This intron is preceded by a sequence encoding a non-conserved 29-amino acid peptide, which does not exist in Torpedo or mammalian AChEs. According to a three-dimensional model, this non-conserved peptide is located at the surface of the protein, opposite from the entry of the catalytic gorge; its deletion did not modify the catalytic parameters. Sequence analyses and expression of various constructs showed that the gene does not contain any H exon. We also found that splicing of transcripts in mammalian cells reveals cryptic donor sites in exons and acceptor sites in introns, which do not appear to be used in vivo.

Acetylcholinesterase↗
PubMed1997

The effect of fatigue on multijoint kinematics and load sharing during a repetitive lifting test.

STUDY DESIGN: A repetitive lifting test in the sagittal plane was performed with a submaximal load at a maximal lifting rate to understand the effects of fatigue on kinematic and kinetic measures of performance. OBJECTIVES: To quantify the effect of fatigue during a highly repetitive lifting task, in terms of lifting force transmitted to the load, joint motion patterns, and internal joint load sharing. SUMMARY OF BACKGROUND DATA: Industrial surveillance and epidemiologic data suggest that repetitive lifting is a risk factor for low back pain. Previous studies examining the effect of fatigue have either been constrained to isolated trunk movement, or have not explored the internal load distribution and potential alteration in the loading patterns. METHODS: Sixteen healthy male subjects performed repetitive lifting in the sagittal plane with a load equal to 25% of their maximal lifting capacity, at a maximal lifting rate. Changes in lifting performance were determined from the power transferred to the box, joint kinematics, and joint kinetics. Data from three cycles at the start and end of the exercise were tested for the effect of fatigue using repeated-measures analysis of variance. RESULTS: Fatigue was documented by a reduction in average lifting force and hip and spine torque generation, whereas internal joint load sharing was relatively unchanged. The fatigue was associated with decreased knee and hip motion, and increased lumbar flexion. Decreased postural stability also was evident. CONCLUSIONS: The significant decrease in postural stability and force generation capability because of the repetitive lifting task indicated a higher risk of injury in the presence of unexpected perturbation. Multijoint coordinated lifting tasks provide a more realistic protocol to study neuromuscular fatigue.

Adult↗