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Biomedical subjects

P Menzel

Publications and source records attributed to P Menzel.

At least 19 recordsLinked to original sources
PubMed2001

Ephrin-A6, a new ligand for EphA receptors in the developing visual system.

In the embryonic visual system, EphA receptors are expressed on both temporal and nasal retinal ganglion cell axons. Only the temporal axons, however, are sensitive to the low concentrations of ephrin-A ligands found in the anterior optic tectum. The poor responsiveness of nasal axons to ephrin-A ligands, which allows them to traverse the anterior tectum and reach their targets in the posterior tectum, has been attributed to constitutive activation of the EphA4 receptor expressed in these axons. EphA4 is highly expressed throughout the retina, but is preferentially phosphorylated on tyrosine (activated) in nasal retina. In a screen for EphA4 ligands expressed in chicken embryonic retina, we have identified a novel ephrin, ephrin-A6. Like ephrin-A5, ephrin-A6 has high affinity for EphA4 and activates this receptor in cultured retinal cells. In the embryonic day 8 (E8) chicken visual system, ephrin-A6 is predominantly expressed in the nasal retina and ephrin-A5 in the posterior tectum. Thus, ephrin-A6 has the properties of a ligand that activates the EphA4 receptor in nasal retinal cells. Ephrin-A6 binds with high affinity to several other EphA receptors as well and causes growth cone collapse in retinal explants, demonstrating that it can elicit biological responses in retinal neurons. Ephrin-A6 expression is high at E6 and E8, when retinal axons grow to their tectal targets, and gradually declines at later developmental stages. The asymmetric distribution of ephrin-A6 in retinal cells, and the time course of its expression, suggest that this new ephrin plays a role in the establishment of visual system topography.

Amino Acid Sequence↗
PubMed2000

Societal value, the person trade-off, and the dilemma of whose values to measure for cost-effectiveness analysis.

In a previous paper, it was argued that Societal Value measurement through person trade-off (PTO) elicitation offers a way to include the values of both general public and patients into cost-effectiveness analysis (CEA). It was said that patients' values could be used to estimate the effect that various health care dimensions have on health-related utility and that public values could be used to estimate the Societal Value of these changes in utility. However, this previous proposal still creates opportunities for the public to misvalue the benefit of health care interventions because of bias or misunderstanding about what the health-related utility really is of various illnesses or disabilities. A procedure that combines patient and public values into CEA to partially correct for this bias is suggested in this paper. In addition, it is pointed out that, although Societal Value measurement offers a role for distinctly public preferences in CEA, it still does not answer the question of whose utilities ought to be included in CEA.

Cost-Benefit Analysis↗
PubMed2000

Improving value measurement in cost-effectiveness analysis.

OBJECTIVE: Before cost-effectiveness analysis (CEA) can fulfill its promise as a tool to guide health care allocation decisions, the method of incorporating societal values into CEA may need to be improved. DESIGN: The study design was a declarative exposition of potential fallacies in the theoretical underpinnings of CEA. Two values held by many people-preferences for giving priority to severely ill patients and preferences to avoid discrimination against people who have limited treatment potential because of disability or chronic illness-that are not currently incorporated into CEA are discussed. CONCLUSIONS: Traditional CEA, through the measurement of quality-adjusted life years (QALYs), is constrained because of a "QALY trap." If, for example, saving the life of a person with paraplegia is equally valuable as saving the life of a person without paraplegia, then current QALY methods force us to conclude that curing paraplegia brings no benefit. Basing cost-effectiveness measurement on societal values rather than QALYs may allow us to better capture public rationing preferences, thereby escaping the QALY trap. CEA can accommodate a wider range of such societal values about fairness in its measurements by amending its methodology.

Attitude to Health↗
PubMed1999

Incorporating societal concerns for fairness in numerical valuations of health programmes.

The paper addresses some limitations of the QALY approach and outlines a valuation procedure that may overcome these limitations. In particular, we focus on the following issues: the distinction between assessing individual utility and assessing societal value of health care; the need to incorporate concerns for severity of illness as an independent factor in a numerical model of societal valuations of health outcomes; similarly, the need to incorporate reluctance to discriminate against patients that happen to have lesser potentials for health than others; and finally, the need to combine measurements of health-related quality of life obtained from actual patients (or former patients) with measurements of distributive preferences in the general population when estimating societal value. We show how equity weights may serve to incorporate concerns for severity and potentials for health in QALY calculations. We also suggest that for chronically ill or disabled people a life year gained should count as one and no less than one as long as the year is considered preferable to being dead by the person concerned. We call our approach 'cost-value analysis'.

Cost-Benefit Analysis↗
PubMed1999

Eph receptors and ephrins demarcate cerebellar lobules before and during their formation.

The formation of the ten cerebellar lobules is an unsolved problem in brain development. We report a screen for the four subfamilies of Eph receptors and their ligands (ephrins) in developing mouse cerebellum, using soluble receptor-immunoglobulin and ligand-immunoglobulin fusion proteins, and antibodies against EphA and ephrin-B proteins. Our results identify Eph receptors and ephrins as the first molecules known to demarcate individual lobules during development. Staining for ephrin-A ligands is in lobule VIII as it forms, across the whole width of the cerebellum. Staining for three EphA receptors approximately coincides with presumptive lobules VI and/or VII before and just after birth, whereas a fourth EphA receptor (EphA4, which binds ligands of both subfamilies) has more widespread expression. Staining for EphB receptors is in lobules VII, VIII, and IX. Staining for ephrin-B ligands is much weaker, becomes detectable only after birth, and does not appear to be lobule-specific. Staining for all subfamilies spreads to at least some adjacent lobules as maturation proceeds. The lobule-specific patterns appear before the lobules form, and initially extend across the width of the cerebellum, in spite of the lesser conservation of the lateral extensions of the lobules. These expression patterns define previously unknown developmental units and suggest that Eph family proteins may contribute to cerebellar morphogenesis.

Animals↗
PubMed1998

Expression and tyrosine phosphorylation of Eph receptors suggest multiple mechanisms in patterning of the visual system.

The EphA3 receptor tyrosine kinase has been implicated in guiding the axons of retinal ganglion cells as they extend in the optic tectum. A repulsive mechanism involving opposing gradients of the EphA3 receptor on retinal axons and its ligands, ephrin-A2 and ephrin-A5, in the tectum influences topographic mapping of the retinotectal projection. To investigate the overall role of the Eph family in patterning of the visual system, we have used in situ hybridization to localize nine Eph receptors in the chicken retina and optic tectum at Embryonic Day 8. Three of the receptors examined correspond to the novel chicken homologs of EphA2, EphA6, and EphA7. Unexpectedly, we found that many Eph receptors are expressed not only in retinal ganglion cells, but also in tectal cells, In particular, EphA3 mRNA is prominently expressed in the anterior tectum, with a pattern reciprocal to that of ephrin-A2 and ephrin-A5. Similarly, ephrin-A5 is expressed not only in tectal cells but also in the nasal retina, with a pattern reciprocal to that of its receptor EphA3 and partially overlapping with that of its other receptor EphA4. Consistent with the even distribution of EphA4 and the polarized distribution of EphA4 ligands in the retina, probing EphA4 immunoprecipitates from different sectors of the retina with anti-phosphotyrosine antibodies revealed spatial differences in receptor phosphorylation. These complex patterns of expression and tyrosine phosphorylation suggest that Eph receptors and ephrins contribute to establishing topography of retinal axons through multiple mechanisms, in addition to playing a role in intraretinal and intratectal organization.

Amino Acid Sequence↗
PubMed1998

Identification of two new hydrophobic residues on basic fibroblast growth factor important for fibroblast growth factor receptor binding.

Basic fibroblast growth factor (bFGF) is implicated in the pathogenesis of several types of vascular and connective diseases. A key step in the discovery of bFGF receptor antagonists to mitigate these actions is to define the functional epitopes required for receptor binding of the growth factor. Using structure-based site-directed mutagenesis, two critical areas on the bFGF surface for the high affinity receptor binding have already been identified [Springer, B.A., Pantoliano, M.W., Barberal, F.A., Gunyuzlu, P.L., Thompson, L.D., Herblin, W.F., Rosenfeld, S.A. and Book, G.W. (1994) J. Biol. Chem., 269, 26879-26884; Zhu, H.Y., Ramnarayan, K., Anchin, J., Miao, Y., Sereno, A., Millman, L., Zheng, J., Balaji, V.N. and Wolff, M.E. (1995) J. Biol. Chem., 270, 21869-21874; Zhu, H.Y., Anchin, J., Ramnarayan, K., Zheng, J., Kawai, T., Mong, S. and Wolff, M.E. (1997) Protein Engng, 10, 417-421]. According to these studies, one receptor binding site includes two polar residues Glu96 and Asn104 on bFGF whereas the other includes four hydrophobic residues Tyr24, Tyr103, Leu140 and Met142. Using a protein modelling technique, we report here the identification of a new hydrophobic patch on bFGF which includes residues Tyr73, Val88 and Phe93. The role of this area on receptor binding affinity was evaluated by mutating each of these residues individually and determining the mutated protein's (mutein's) receptor binding affinity. In addition, we examined the role of two other hydrophobic residues, Phe30 and Leu138, on bFGF for high-affinity receptor binding. These two residues are the neighbors of the hydrophobic residues Tyr24 and Tyr103, respectively. Replacement of Val88 and Phe93 with alanine reduced the receptor binding affinity about 10- and 80-fold, respectively, compared with wild-type bFGF. In contrast, substitution of Phe30 and Leu138 with alanine has no effect on the receptor binding affinities. We conclude that the newly identified hydrophobic residues, Val88 and Phe93, are crucial for the receptor binding. The present data, together with the previous identification of four hydrophobic residues (Tyr24, Tyr103, Leu140 and Met142), suggests that there are two hydrophobic receptor binding sites on the bFGF surface. Our findings can be employed in the discovery and design of potent bFGF antagonists using computational methods.

Amino Acid Substitution↗
PubMed1994

Risk perception, addiction, and costs to others: an assessment of cigarette taxes and other anti-smoking policies.

This paper offers a relatively comprehensive assessment of government anti-smoking policies (both taxation and other regulatory measures). I conclude that interventions to engender in smokers and prospective smokers an accurate perception of tobacco's health risks are justified, that except in the case of adolescents addiction by itself does not justify intervention beyond providing adequate information, that the proper goal of tobacco taxation policy should be to recoup only the extra costs that smokers place on others (at most a $1/pack tax on cigarettes), and that passive smoke's imposition of harm on unconsenting others strongly supports at least the development of a safe-to-others smokeless cigarette, if not direct intervention.

Attitude to Health↗
PubMed1994

Development and characterization of recombinant adenoviruses encoding human p53 for gene therapy of cancer.

We have constructed recombinant human adenoviruses that express wild-type human p53 under the control of either the Ad 2 major late promoter (MLP) or the human cytomegalovirus (CMV) immediate early gene promoter. Each construct replaces the Ad 5 E1a and E1b coding sequences necessary for viral replication with the p53 cDNA and MLP or CMV promoter. These p53/Ad recombinants are able to express p53 protein in a dose-dependent manner in infected human cancer cells. Tumor suppressor activity of the expressed p53 protein was assayed by several methods. [3H]Thymidine incorporation assays showed that the recombinant adenoviruses were capable of inhibiting DNA synthesis in a p53-specific, dose-dependent fashion. Ex vivo treatment of Saos-2 tumor cells, followed by injection of the treated cells into nude mice, led to complete tumor suppression using the MLP/p53 recombinant. Following a single injection of CMV/p53 recombinant adenovirus into the peritumoral space surrounding an in vivo established tumor derived from a human small cell lung carcinoma cell line (NIH-H69), we were able to detect p53 mRNA in the tumors at 2 and 7 days post-injection. Continued treatment of established H69 tumors with MLP/p53 recombinant led to reduced tumor growth and increased survival time compared to control treated animals. These results indicate that recombinant adenoviruses expressing wild-type p53 may be useful vectors for gene therapy of human cancer.

Adenoviruses, Human↗
PubMed1991

Characterization of motifs which are critical for activity of the cyclic AMP-responsive transcription factor CREB.

Cyclic AMP mediates the hormonal stimulation of a number of eukaryotic genes by directing the protein kinase A (PK-A)-dependent phosphorylation of transcription factor CREB. We have previously determined that although phosphorylation at Ser-133 is critical for induction, this site does not appear to participate directly in transactivation. To test the hypothesis that CREB ultimately activates transcription through domains that are distinct from the PK-A site, we constructed a series of CREB mutants and evaluated them by transient assays in F9 teratocarcinoma cells. Remarkably, a glutamine-rich region near the N terminus appeared to be important for PK-A-mediated induction of CREB since removal of this domain caused a marked reduction in CREB activity. A second region consisting of a short acidic motif (DLSSD) C terminal to the PK-A site also appeared to synergize with the phosphorylation motif to permit transcriptional activation. Biochemical experiments with purified recombinant CREB protein further demonstrate that the transactivation domain is more sensitive to trypsin digestion than are the DNA-binding and dimerization domains, suggesting that the activator region may be structured to permit interactions with other proteins in the RNA polymerase II complex.

Amino Acid Sequence↗
PubMed1990

Characterization of a bipartite activator domain in transcription factor CREB.

In this paper, we characterize a trans-activating region in CREB, termed alpha, that interacts cooperatively with the kinase A phosphorylation motif to stimulate transcription. The alpha region appears to be encoded by an alternate exon that is deleted in a CREB-related cDNA named delta CREB. Both proteins are expressed in eukaryotic cells, although the activity of CREB is 10-fold higher than that of delta CREB. Circular dichroism data on a synthetic "alpha peptide" combined with results from in vitro mutagenesis experiments support the hypothesis that the alpha region contains an amphipathic alpha helix whose structure is critical to CREB activity. We propose that phosphorylation by kinase A may stimulate CREB activity in part by modulating the structure of alpha and thus may stimulate its ability to interact with other proteins in the polymerase II complex.

Adrenal Gland Neoplasms↗
PubMed1989

A cluster of phosphorylation sites on the cyclic AMP-regulated nuclear factor CREB predicted by its sequence.

Cyclic AMP regulates the expression of a number of genes through a conserved promoter element, the CRE1. Moreover, transcriptional induction by cAMP requires the activation of cAMP-dependent protein kinase (protein kinase A). We have previously characterized the cAMP response element binding protein (CREB) in PC12 cells and brain tissue as a nuclear factor, of relative molecular mass 43,000, whose transcriptional efficacy is regulated by protein kinase A phosphorylation. CREB stimulates transcription on binding to the CRE as a dimer. Experiments suggesting that the dimerization and transcriptional efficacy of CREB are each stimulated by phosphorylation at distinct sites prompted us to suggest that CREB is regulated by multiple kinases in vivo. We now report the isolation of a cDNA clone for rat CREB using amino-acid sequence information from purified CREB protein. Sequence analysis of this CREB cDNA predicts a cluster of protein kinase A, protein kinase C and casein kinase II consensus recognition sites near the N terminus of the protein. The proximity of these potential phosphorylation sites to one another indicates that they may interact either positively or negatively to regulate CREB bioactivity.

Activating Transcription Factor 2↗
PubMed1988

Two guanosine binding sites exist in group I self-splicing IVS RNAs.

A shortened form of the self-splicing rRNA intervening sequence (IVS) of Tetrahymena thermophila can catalyze a transesterification reaction, termed G-exchange, between a monomeric guanosine derivative such as GTP and the substrate GpN (where N is A, C, G or U). The reaction is specific to the two guanosines involved, providing evidence that two guanosine binding sites exist in this group I IVS RNA. One binding site accommodates a guanosine which initiates self-splicing and the other recognizes the guanosine preceding the 3' splice site. Previously, only one guanosine binding site was thought to be involved in the mechanism of self-splicing. Based on the two functionally distinguishable guanosine binding sites, a new model is proposed to explain how the two independent transesterification reactions required for self-splicing might proceed in a concerted manner.

Animals↗