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PubMed1993

New activation model for the histamine H2 receptor, explaining the activity of the different classes of histamine H2 receptor agonists.

Recently we developed amthamine [2-amino-5-(2-aminoethyl)-4-methylthiazole]. This cyclic analogue of dimaprit proved to be the most potent and selective histamine H2 receptor agonist of a series of substituted 4- or 5-(2-aminoethyl)thiazoles. Quantum chemical studies on histamine (N pi-H tautomer), dimaprit, and amthamine revealed that, based upon geometries of molecular electrostatic potentials, it is likely that these agonists accept a proton from the proton-donating receptor site on their double-bonded (heteroaromatic) nitrogen atoms. In contrast to reported models, this new model is able to accommodate and explain the agonistic activities of all known (including nontautomeric) histamine H2 receptor agonists. Quantitative structure-activity relationship studies with a series of substituted histamine derivatives and heterocyclic analogues support the presented model, in which the monocations in extended conformation interact with the receptor surface; their affinities correlate with the proton association constants of the heteroaromatic nuclei. The negatively charged anchoring site for the ethylammonium side chain of these agonists in this model is a functional group with a pKa value of 4.17.

Histamine↗

PubMed1994

Immunodominant mink cell focus-inducing murine leukemia virus (MuLV)-encoded CTL epitope, identified by its MHC class I-binding motif, explains MuLV-type specificity of MCF-directed cytotoxic T lymphocytes.

H-2b mice are immunologic responders to the tumorigenic MCF1233 murine leukemia virus (MuLV), an AKV-related virus derived from endogenous C57BL MuLV. We have identified an immunodominant CTL epitope that is expressed on MCF1233 MuLV-induced lymphomas of H-2b mice. C57BL/10 (B10) mice were immunized with an MCF1233-induced B10 B cell lymphoma, and tumor-specific CTL cultures were generated in vitro. These were tested for recognition of synthetic class I-binding MuLV peptides, selected for class I allele-specific motifs. One of 28 candidate peptides sensitized target cells for CTL recognition. This peptide seems to be an immuno-dominant epitope, because it was recognized by all independent CTL clones, isolated from the tumor-specific bulk culture. The epitope (KSPWFTTL) is derived from the MCF1233 MuLV envelope (env)-p15E region and is shared by all endogenous AKV types of MuLV. It has an optimal length of eight amino acids and is presented by the Kb H-2 class I molecule. Interestingly, Friend, Moloney, and Rauscher (FMR) types of MuLV are not recognized by MCF MuLV-directed CTL. The FMR env-p15E proteins have a single amino acid difference at the first position of the MCF1233 MuLV epitope (RSPWFTTL instead of KSPWFTTL). The corresponding FMR-encoded peptide bound class I H-2 Kb equally well as the MCF peptide, but it was poorly recognized by MCF1233 MuLV-specific CTL. Moreover, in the Rauscher MuLV-induced cell line RMA the FMr peptide seems not to be processed for recognition by CTL, which was illustrated by experiments with CTL elicited against this peptide. Altered TCR interaction as well as lack of processing thus may explain the type specificity of MCF1233 MuLV-directed CTL.

Amino Acid Sequence↗

PubMed1993

Two competing influences that may explain concomitant tumor resistance.

A second tumor inoculum is often inhibited in its growth by the presence in the recipient animal of an earlier implanted, growing tumor. The tumor resulting from the first inoculum may, paradoxically, continue to grow despite the simultaneous inhibition of the growth of the second inoculum, a phenomenon usually called "concomitant immunity." Evidence now suggests that the phenomenon can be observed in the absence of any recognizable type of immune reaction and might often be named more appropriately "concomitant tumor resistance." Consideration of a variety of probably related observations suggests that concomitant tumor resistance can best be explained by the competitive interaction of two opposing influences: a local diffusible, tumor-facilitating environment, produced by both tumor and normal tissues, that is counteracted by circulating inhibitors that are also produced by both tumor and by normal tissues. In an implanted small tumor, because of geometric considerations and diffusion, the action of the local facilitating environment is weak; in a larger tumor the local facilitating environment has a relatively greater influence and thus the larger tumor can continue to grow despite levels of circulating tumor inhibitors capable of inhibiting the smaller growth.

Animals↗

PubMed1993

Linkage analysis versus association analysis: distinguishing between two models that explain disease-marker associations.

Human genetics researchers have been intrigued for many years by weak-to-moderate associations between markers and diseases. However, in most cases of association, the cause of this phenomenon is still not known. Recently, interest has grown in pursuing association studies for complex diseases, either instead of or in addition to linkage studies. Hence, it is timely to reconsider what a disease-marker association, particularly in the weak-to-moderate range (relative risk < 10), can tell us about disease etiology. To this end, this study accomplishes three aims: (1) It formulates two different models explaining weak-to-moderate associations and derives the relationship between them. One is a linkage disequilibrium model, and the other is a "susceptibility," or pure association, model. The importance of drawing the distinction between these two models and the implications for our understanding of the genetics of human disease will also be discussed. It will be argued that the linkage disequilibrium model represents true linkage but that the susceptibility model does not. (2) It examines two family-based association tests proposed recently by Parsian et al. and Spielman et al. and derives formulas for their behavior under the two models described above. It demonstrates that these tests yield almost identical results under these two models. It shows that, whereas these tests can confirm an association, they cannot determine whether the association is caused by the linkage disequilibrium model or the susceptibility model. The study also characterizes the probabilities yielded by the family association tests in the presence of weak-to-moderate associations, which will aid researchers using these tests. (3) It proposes two approaches, both based on linkage analysis, which can distinguish between the two models described above. One approach involves a straightforward linkage analysis of the data; the other involves a partitioned association-linkage (PAL) test, as suggested by Greenberg. Formulas are derived for testing identity by descent in affected sib pairs by using both approaches. (4) Finally, the formulas and arguments are illustrated with two examples from the literature and one computer-simulated data set.

Alleles↗

PubMed1993

Amino acid exchange and covalent modification by cysteine and glutathione explain isoforms of fatty acid-binding protein occurring in bovine liver.

A unique property of the liver-type member of the family of fatty acid-binding proteins is the heterogeneic pattern observed upon isolation, which can only partly be ascribed to the state of lipidation. Here we unraveled the structural basis of the heterogeneity of delipidated liver-type fatty acid-binding protein (L-FABP). Charge fractions of L-FABP focusing at pH 6.0 and at pH 7.0/7.1 were first isolated from bovine liver. Upon reduction, however, two distinct isoforms, namely pI 6.0 L-FABP and pI 7.0 L-FABP, were observed. From these isoforms peptides were generated enzymically and chemically by four independent methods. Peptides were separated by reverse phase high performance liquid chromatography and analyzed by Edman degradation and plasma desorption mass spectrometry. The complete amino acid sequences of the isoforms were established; they consist of 127 amino acids and each is N-terminally blocked with an acetyl group. The difference between pI 6.0 L-FABP and pI 7.0 L-FABP was attributed to an asparagine-aspartate exchange at position 105. When tryptic peptides of the pH 7.0/7.1 fraction were analyzed, discrepancies between sequence and mass data of the peptides containing at position 69 the sole cysteine of L-FABP led to the disclosure of a cysteinylation occurring at this position and giving rise to the slightly more basic pH 7.1 species. Moreover, chemical modification studies revealed that a part of the pH 6.0 fraction was pI 7.0 L-FABP that was glutathionylated at Cys69. Neither modification, however, prevented the binding of fatty acids. Together amino acid exchange and covalent modification of cysteine entirely explain the heterogeneity of L-FABP from bovine liver.

Amino Acid Sequence↗

PubMed1993

Ligand-induced accelerated dissociation of (+)-cis-diltiazem from L-type Ca2+ channels is simply explained by competition for individual attachment points.

We have studied the kinetics of (+)-[3H]cis-diltiazem binding to L-type Ca2+ channels. The association reaction was of the second order with a rate constant of k1 = 5.3 x 10(-5) nM-1 min-1. A dissociation rate of the first order (k-1 = 0.0022 min-1) and the monophasic equilibrium binding curve (KD = 42 nM) seemed to reflect the simple case of one ligand binding to one site. However, when dissociation was monitored after isotopic rather than volume dilution, the dissociation rate constant increased with the concentration of added non-radioactive (+)-cis-diltiazem. Half-logarithmic plots were linear with rate constants of 0.0058, 0.011, 0.015, and 0.020 min-1 when 3, 10, 30, and 50 microM (+)-cis-diltiazem was added, respectively. We quantitatively analyzed our experimental data in terms of three different binding models, which can account for ligand-induced accelerated dissociation: 1) the classical allosteric model of pre-existing conformational states, 2) a general reaction scheme for two sites with negative cooperativity, and 3) competition of ligands for single attachment points within one binding site. Computer fitting of the experimental data to simplified reaction schemes derived from these models revealed that all three can be used to fit our data. However, only the multipoint attachment model does not require additional structural assumptions, not even an additional binding site, and is supported by structure-activity relationship analysis of diltiazem analogues. We conclude that ligand-induced accelerated dissociation should be a widely observed phenomenon that does not prove a non-competitive binding mechanism. Instead, it can be explained with the thermodynamics of non-covalent binding, where high affinity results from the cooperative interaction of a ligand molecule with multiple attachment points.

Allosteric Regulation↗

PubMed1993

Cellular drug resistance profiles that might explain the prognostic value of immunophenotype and age in childhood acute lymphoblastic leukemia.

Immunophenotype and age have prognostic value in childhood acute lymphoblastic leukemia (ALL) but how this operates is not understood. In 84 children with ALL at initial diagnosis we studied the correlation between these factors and the in vitro resistance to eight drugs, determined with the 3-(4,5-dimethylthiazol-2-yl-2, 5-diphenyl tetrazolium bromide (MTT) assay. B-lineage ALL samples were classified into four differentiation stages: the CD10- proB ALL; cALL; preB ALL with cytoplasmic mu positive ALL cells; and B-ALL with surface immunoglobulin-positive (Ig+) cells. cALL and preB ALL cases have the best prognosis; proB and T-ALL cases show a worse prognosis and B-ALL the poorest prognosis. Patients aged < 18 months and > 10 years have a poor prognosis compared to patients in the intermediate age group. Our results show that cALL and preB ALL cells were the most drug-sensitive cells compared to the other phenotypes. No differences were found between cALL and preB ALL cases with the exception that preB cells were more sensitive to mustine and mafosfamide (Maf). Compared to cALL and preB ALL cases, T-ALL cases were significantly more resistant to prednisolone (Pred), daunorubicin (DNR), L-asparaginase (L-Asp), cytosine arabinoside (AraC), and Maf; proB ALL cases were more resistant to Pred, DNR, L-Asp, and 6-thioguanine. The three B-ALL cases were resistant to vincristine and DNR. Two out of three B-ALL were resistant to Pred. Compared to cells from patients aged 18 months to 10 years, cells from children < 18 months were more resistant to Pred and DNR; cells from children > 10 years were more resistant to Pred. We conclude that cellular drug-resistance patterns might at least partly explain the prognostic value of immunophenotype and age in childhood ALL.

Aging↗

PubMed1993

Can changes in microcirculation explain capillary growth in skeletal muscle?

Capillary growth (increase in capillary/fibre (C/F) ratio by 20%) was elicited in skeletal muscles either by long-term increase in blood flow (5 weeks administration of prazosin in drinking water, 50 mg/l) or 7 days electrical stimulation (8 h/day at 10 Hz). Mechanisms that could explain it ((a) increased interaction of blood components with endothelial cells (due to increased haematocrit or decreased intermittency of flow); (b) increased velocity of flow and thus shear stress; (c) increased capillary diameters and thus wall tension) were studied in vivo. Red blood cell velocity (Vrbc), vessel diameters and intermittency of capillary flow were measured in superficially located capillaries in rat tibialis anterior muscles about 18 hours after the last treatment, in prazosin treated and chronically stimulated animals, and also in animals where red blood cell interaction with capillary endothelium was increased by elevating haematocrit from 43.2 +/- 1.7% to 60.9 +/- 0.72% by 11 weeks administration of CoCl2. Animals of comparable size and sex were used as controls. Capillaries in chronically stimulated muscles had increased Vrbc at rest (0.42 +/- 0.06 mm/s vs 0.27 +/- 0.04 in control muscles) and somewhat wider diameters, although the intermittency of flow was not different from control muscles. Capillaries in prazosin treated rats had a lower intermittency of flow, similar diameters and considerably higher Vrbc (0.53 +/- 0.06 mm/s) than control animals. CoCl2 treatment resulted in a similar intermittency of flow, did not alter capillary diameters or Vrbc and did not result in an increase in C/F ratio.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1996

The interaction of pH, bile, and Helicobacter pylori may explain duodenal ulcer.

BACKGROUND: Inhibition of Helicobacter pylori growth by bile suggests that it should be difficult for H. pylori to colonize the duodenum and cause duodenal ulcer. To search for a common mechanism, we investigated the relationship between H. pylori strain (duodenal ulcer vs gastritis), type of bile acid conjugate, and inhibition of H. pylori growth. METHODS: H. pylori isolates from patients with duodenal ulcer and from volunteers with asymptomatic gastritis (six each) were grown in brain heart infusion broth medium containing mixtures of glycocholate, taurocholate, glycodeoxycholate, taurodeoxycholate, glycochenodeoxycholate, and taurochenodeoxycholate with and without lecithin. RESULTS: Synthetic human bile with or without lecithin inhibited H. pylori growth in a dose-dependent manner. There was no difference in inhibition between H. pylori gastritis and duodenal ulcer isolates. Glycine and mixed glycine and taurine-conjugated bile acids inhibited H. pylori more than taurine-conjugated bile acids (e.g., 51%, 67%, and 80% compared to 21%, 39%, and 46% for 1, 2, and 4 mM mixed conjugates compared with taurine conjugates, p < 0.05, respectively. CONCLUSIONS: The ability of H. pylori to grow in the presence of taurine-conjugated bile acids and the precipitation of glycine but not taurine bile acid conjugates by acid may provide one missing link among inhibition of H. pylori by bile, acid secretion, ability of antisecretory therapy to accelerate ulcer healing, and the ability of H. pylori to colonize the duodenal bulb of ulcer patients, leading to duodenal ulcer. These data also explain the disparate results of previous investigations of the effect of bile reflux in the stomach on the presence of H. pylori.

Bile↗

PubMed1996

The cation distribution set by surface charges explains a paradoxical membrane excitability behavior.

It is widely accepted that divalent cations can affect membrane excitability by interacting with negative charges on the membrane surface. This effect is generally supposed to arise from a modulation of the surface charge electrostatic field within the membrane. As an alternative mechanism, we propose that this effect may also be due to a generalized coupling between ion currents mediated by ionic composition changes at the membrane surface. To test this hypothesis we have computed the transmembrane potential using ionic current relations in which bulk external Ca2+ and K+ activities are substituted with superficial activities deduced from a Grahame-Langmuir isotherm. The model behavior agrees well with published results on Paramecium electrophysiology and furthermore explains 2 paradoxical observations on the cell membrane excitability upon changes of external Ca2+ and K+.

Animals↗

PubMed1995

An amino acid polymorphism in histidine-rich glycoprotein (HRG) explains 59% of the variance in plasma HRG levels.

A pedigree-based maximum likelihood method developed by Lange et al. (12) was used to study the contribution of a newly defined di-allelic polymorphism in histidine-rich glycoprotein (HRG) to the plasma levels of HRG. In four families (n = 99) and 20 volunteers we found a heritability of 70%, an age effect of 3% and an effect of individual environmental factors of 27%. These results are remarkably similar to the results found in a previous parent-twin study in which a heritability of 69% and an effect of random environment of 31% was found. The overall genetic influence in the present study can be subdivided into an effect of 59% by the HRG phenotype and 11% by residual genetic factors. The influence of the HRG phenotype of 59% can entirely be explained by adding up the effect of the two alleles that make up the phenotype. These results indicate a codominant inheritance pattern of HRG levels in which the genetic influences can almost completely be ascribed to the additive effect of the di-allelic HRG locus whereas only a small part is due to other loci.

Alleles↗

PubMed1996

Alendronate stimulation of nocturnal parathyroid hormone secretion: a mechanism to explain the continued improvement in bone mineral density accompanying alendronate therapy.

The major effect of currently available antiresorptive therapy for osteoporosis is to slow or arrest bone loss. Although antiresorptive therapies demonstrate increases in bone mineral density, the effect is usually transient, and a plateau in bone mineral density usually emerges at 1 year. A unique and unexplained feature of treatment with the antiresorptive agent alendronate is continued, and steady improvement in bone mineral density occurs in years 2 and 3. We postulated that a potential mechanism for this unanticipated effect might be an exaggerated nocturnal increase in parathyroid hormone (PTH), which can act as an anabolic agent. We examined day-night levels and diurnal variation of PTH, serum calcium, ionized calcium, and markers of bone formation (osteocalcin) and resorption (N-telopeptide cross-links) over 24 hours in a randomly selected subset of 38 women (placebo: N = 13; mean age +/- SD, 69 +/- 3 years; alendronate: N = 25; mean age +/- SD, 69 +/- 3 years) who had completed 12 to 15 months of a larger (N = 120), randomized, double-blind, placebo-controlled trial with alendronate, 5 mg/day. By month 12, increases in the bone density of the spine (4.6%) and femoral neck (2.7%) were observed in the group treated with alendronate compared with placebo, (spine, 2.2%, p = .05; femoral neck, -0.2%, p < or = .05). Mean nocturnal PTH (10 PM-8 AM) was 21% higher (39 versus 32 pg/ml), and nocturnal serum calcium averaged 3% lower (8.7 versus 9.0 mg/dL) in the alendronate-versus-placebo group (both p < or = .05). Daytime levels (8 AM-10 PM) of PTH did not differ significantly between groups. We observed accompanying decreases in coupled markers of bone formation (osteocalcin, 38% lower, p < or = .01) and resorption (N-telopeptide cross-links, 50% lower, p < or = .01) in the alendronate group. Significant diurnal variations of PTH, serum calcium, and osteocalcin were present in both groups. We conclude that following 1 year of alendronate therapy, women have significant increases in bone mineral density and in nocturnal PTH levels, associated with decreases in nocturnal serum calcium and markers of bone turnover with maintenance of the diurnal variation. The nocturnal increase in PTH may mimic the anabolic effect of low-dose intermittent PTH administration to stimulate bone formation. Therefore, the increase might be a potential mechanism to explain the continued improvement in bone density following more than 1 year of alendronate therapy.

Aged↗

PubMed1995

Explaining changes in married mothers' employment over time.

Employment of married mothers with preschool children rose dramatically between 1971 and 1990. Using CPS data, we find that about one-fifth of the increase in labor supply can be attributed to changes in mothers' demographic characteristics (age, education, and number of children). Changes in the earnings opportunities of new mothers and their husbands explain another one-fifth of the growth in employment. Over the two decades, infants up to three months old became less of a barrier to employment, while women's labor supply became more sensitive to their own earnings opportunities and less sensitive to those of their husbands.

Adult↗

PubMedDate not supplied

Explaining breast self-examination practice.

Research efforts to discover why women do or do not perform breast self-examination (BSE) have produced contradictory findings with poor explanatory power. In this study, ethnoscience was used to elicit the perceptions of women who perform BSE and of those who do not. The components of the emerging taxonomies are broader than those currently thought to be associated with this practice. A new model (BSE frequency model) explaining compliance with BSE was developed.

Adult↗

PubMed1997

[Development of a model for explaining health inequality].

The article proposes a model for systematizing the discussion about the mechanisms of production and reproduction of health inequalities. It starts from existing explanation approaches for combining social and health inequalities in West German literature, from contributions of stress and health lifestyle research and from internationally discussed approaches. The proposed model tries to integrate possibilities of explaining different existing approaches.

Germany↗

PubMed1977

The health belief model as a conceptual framework for explaining contraceptive compliance.

The problem of compliance in family planning is discussed in relation to the lack of theoretical and conceptual clarity in research, which has produced contradictory, and often inconsistent findings. Current research has contributed little to explaining the phenomenon of compliance and to directing further research. The Health Belief Model, which has been demonstrated to have application in the areas of preventive health behavior and compliance with medical regimens, is offered as a potentially useful conceptual framework for family planning research. The generalization of the Health Belief Model to family planning behavior is seen as an out-growth of the theoretical strength of the Model and the similarities between family planning and other health behavior.

Attitude to Health↗

PubMed1997

[PNH--paroxysmal nocturnal hemoglobinuria. An old disease explained by new technology].

The review outlines developments in research on paroxysmal nocturnal haemoglobinuria (PNH). The disease is due to a somatic mutation of the PIG-A gene. This results in deficiency of the protein, GPI (glucosyl phosphatidyl inositol), which serves as an anchor for several membrane-bound proteins including MIRL (CD59; membrane inhibitor of reactive lysis) and DAF (CD55; decay accelerating factor). The absence of these proteins results in increased cellular sensitivity to complement-mediated lysis, affecting not only red cells, leukocytes and platelets, but also haemopoietic stem cells. This explains the often complex clinical picture in PNH (haemolysis, pancytopenia and increased thrombotic predisposition), and the well known relationship between PNH and aplastic anaemia.

Hemoglobinuria, Paroxysmal↗

PubMed1997

Explaining fertility transitions.

In this essay, I suggest that the crisis in our understanding of fertility transitions is more apparent than real. Although most existing theories of fertility transition have been partially or wholly discredited, this reflects a tendency to assume that all fertility transitions share one or two causes, to ignore mortality decline as a precondition for fertility decline, to assume that pretransitional fertility is wholly governed by social constraints rather than by individual decision-making, and to test ideas on a decadal time scale. I end the essay by suggesting a perceptual, interactive approach to explaining fertility transitions that is closely allied to existing theories but focuses on conditions that lead couples to switch from postnatal to prenatal controls on family size.

Birth Rate↗