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Biomedical subjects

R A Preston

Publications and source records attributed to R A Preston.

At least 55 records · Page 3Linked to original sources
PubMed1995

Crouzon syndrome: mutations in two spliceoforms of FGFR2 and a common point mutation shared with Jackson-Weiss syndrome.

Dominant mutations in the fibroblast growth factor receptor 2 (FGFR2) gene have been recently identified as causes of four phenotypically distinct craniosynostosis syndromes, including Crouzon, Jackson-Weiss, Pfeiffer, and Apert syndromes. These data suggest that the genetics of the craniosynostosis syndromes is more complex than would be expected from their simple autosomal-dominant inheritance pattern. Identical mutations in the FGFR2 gene have been reported to cause both Pfeiffer and Crouzon syndrome phenotypes. We now report the finding of a mutation in exon IIIc of the FGFR2 gene in a kindred affected with Crouzon syndrome (C1043 to G; Ala344Gly) that is identical to the mutation previously associated with Jackson-Weiss syndrome. We also report finding in a Crouzon kindred a mutation in the 3' end of exon IIIu (formerly referred to as exon 5, exon 7, or exon U) (A878 to C; Gln289Pro) which encodes the amino terminal portion of the Ig-like III domain of the FGFR2 protein. This exon is common to both the FGFR2 and the KGFR spliceoforms of the FGFR2 gene, unlike all previously reported Crouzon mutations, which have been found only in the FGFR2 spliceoform. These findings reveal further unexpected complexity in the molecular genetics of these craniosynostosis syndromes. The data implies that second-site mutations in FGFR2 itself (outside of exon IIIc) or in other genes may determine specific aspects of the phenotypes of craniosynostosis syndromes.

Base Sequence↗
PubMed1995

Influenza A virus--induced acute otitis media.

To better understand the significance of viral upper respiratory tract infections in the pathogenesis of acute otitis media (OM), 27 adults underwent intranasal inoculation with influenza A virus. Monitoring consisted of antibody titer determination, tympanometry, and otoscopy. Microbiologic analysis consisted of cultures and polymerase chain reaction (PCR)-based detection for influenza A virus, Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis. All subjects became infected with the challenge virus. By day 4, 16 (59%) developed middle ear pressures of -100 mm H2O or below and 4 (25%) of them developed OM. One subject (4%) developed purulent OM requiring myringotomy for pain relief. Middle ear effusion cultures were negative. PCR analysis of that subject's middle ear effusion and nasal washes were positive for influenza A virus and S. pneumoniae. These findings support a causal role for viral upper respiratory tract infections in the pathogenesis of OM, possibly mediated by middle ear underpressures and viral and bacterial middle ear infection.

Acute Disease↗
PubMed1995

Renal parenchymal disease and hypertension.

Renal parenchymal disease is the most common cause of secondary hypertension, accounting for 2.5% to 5.0% of all cases. Hypertension associated with renal parenchymal disease occurs as a complication of a wide variety of glomerular and interstitial renal diseases and may accelerate the decline in renal function if inadequately controlled. Renal parenchymal hypertension most probably represents the combined interactions of multiple independent mechanisms: potential factors include impaired sodium handling leading to volume expansion, perturbations of the renin-angiotensin system, alterations in endogenous vasodepressor compounds, and possibly increased activity of vasoactive substances. The past several years have witnessed newer insights into both the pathophysiology and the therapeutics of this disorder. The characterization of endothelin and the nitric oxide (NO)-arginine pathway and their roles in biology and medicine has provided additional new insights with regard to the pathogenesis of hypertension in renal parenchymal disease. For example, methylated L-arginine derivatives that possess NO synthase inhibitor capabilities including NG-N-dimethylarginine and N-monomethyl-L-arginine are found in human plasma and in urine. Patients with chronic uremia have impaired elimination of these compounds, and circulating concentrations of these compounds may increase sufficiently to result in inhibition of NO production. Thus, accumulation of endogenous NO synthase inhibitors might contribute to the hypertension of advanced renal failure. Similarly, it has been proposed that increased endothelium-derived endothelin that results from hypertensive injury to vascular endothelium could lead to further vasoconstriction and worsening of hypertension. Additional insight into this fascinating problem must await further biochemical characterization of some of the mediators and a more precise delineation of their pathophysiological role.

Aldosterone↗
PubMed1994

Angiotensin-converting enzyme inhibitors in hypertension. A dozen years of experience.

Introduction of the first angiotensin-converting enzyme (ACE) inhibitor, captopril, in 1981 marked a major advance in the treatment of essential hypertension. This article reviews the 12 years of clinical experience during which it and other ACE inhibitors have become recognized as first-line agents for treating hypertension. The benefits of ACE inhibition in diabetic patients are being defined. In recent years, beneficial effects on glucose handling, left-ventricular mass, quality of life, renal function, and myocardial protection have become recognized. For these reasons, and because of their excellent safety profile, ACE inhibitors are now widely used for the treatment of hypertensive patients.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1994

A gene for Crouzon craniofacial dysostosis maps to the long arm of chromosome 10.

Crouzon craniofacial dysostosis (CFD) is an autosomal dominant craniofacial disorder characterized by premature craniosynostosis, shallow orbits and hypoplastic maxilla. To map the gene responsible, we have used a mapping strategy of testing for linkage to known developmental genes. Analysis of a large kindred established linkage between CFD and three loci (D10S190, D10S209 and D10S216) that span a 13 cM region on chromosome 10q. A maximum pairwise lod score of 4.42 (theta = 0) at D10S190 was obtained and the addition of a second kindred produced a combined pairwise lod score of 5.32 (theta = 0) at the same locus. The developmental gene, PAX2, located within this region, is an attractive candidate gene.

Chromosome Mapping↗
PubMed1994

Choice in the time-left procedure and in concurrent chains with a time-left terminal link.

In two experiments, rats chose between a standard fixed-duration food-associated stimulus and a stimulus whose duration was the time remaining to reinforcement in an elapsing comparison interval. In Experiment 1, 4 rats responded in a time-left procedure wherein a single initial-link variable-interval schedule set up two potential terminal links simultaneously. As time elapsed in the initial-link schedule, the choice was between a standard fixed-interval 30-s terminal link and a time-left terminal link whose programmed interval requirement equaled 90 s minus the elapsed time in the initial link. Rats generally responded more on the lever with the shortest programmed terminal-link duration, but the temporal parameters of the procedure were found to vary with response distributions. Contrary to previous reports, therefore, time-left data were well predicted by choice models that make no assumptions about animal timing. In Experiment 2, 8 rats responded on a concurrent-chains schedule with independent variable-interval initial links and a time-left terminal link in one of the choice schedules. On the time-left lever, the programmed terminal-link delay equaled 90 s minus the elapsed time in the time-left initial link. On the standard lever, terminal-link responses were reinforced according to a variable-interval schedule whose average value varied over four conditions. Relative time-left initial-link responses increased in the elapsing time-left initial-link schedule as the time-left terminal link became shorter relative to the standard terminal link. Scalar expectancy theory failed to predict the resultant data, but a modified version of the delay-reduction model made good predictions. An analysis of the elaboration of scalar expectancy theory for variable delays demonstrated that the model is poorly formulated for arithmetically distributed delays.

Animals↗
PubMed1993

Delay reduction: current status.

Delay-reduction theory states that the effectiveness of a stimulus as a conditioned reinforcer may be predicted most accurately by the reduction in time to primary reinforcement correlated with its onset. We review support for the theory and then discuss two new types of experiments that assess it. One compares models of choice in situations wherein the less preferred outcome is made more accessible; the other investigates whether frequency of conditioned reinforcement affects choice beyond the effect exerted by frequency of primary reinforcement.

Animals↗
PubMed1992

The VPH1 gene encodes a 95-kDa integral membrane polypeptide required for in vivo assembly and activity of the yeast vacuolar H(+)-ATPase.

Yeast vacuolar acidification-defective (vph) mutants were identified using the pH-sensitive fluorescence of 6-carboxyfluorescein diacetate (Preston, R. A., Murphy, R. F., and Jones, E. W. (1989) Proc. Natl. Acad. Sci. U.S.A. 86, 7027-7031). Vacuoles purified from yeast bearing the vph1-1 mutation had no detectable bafilomycin-sensitive ATPase activity or ATP-dependent proton pumping. The peripherally bound nucleotide-binding subunits of the vacuolar H(+)-ATPase (60 and 69 kDa) were no longer associated with vacuolar membranes yet were present in wild type levels in yeast whole cell extracts. The VPH1 gene was cloned by complementation of the vph1-1 mutation and independently cloned by screening a lambda gt11 expression library with antibodies directed against a 95-kDa vacuolar integral membrane protein. Deletion disruption of the VPH1 gene revealed that the VPH1 gene is not essential for viability but is required for vacuolar H(+)-ATPase assembly and vacuolar acidification. VPH1 encodes a predicted polypeptide of 840 amino acid residues (molecular mass 95.6 kDa) and contains six putative membrane-spanning regions. Cell fractionation and immunodetection demonstrate that Vph1p is a vacuolar integral membrane protein that co-purifies with vacuolar H(+)-ATPase activity. Multiple sequence alignments show extensive homology over the entire lengths of the following four polypeptides: Vph1p, the 116-kDa polypeptide of the rat clathrin-coated vesicles/synaptic vesicle proton pump, the predicted polypeptide encoded by the yeast gene STV1 (Similar To VPH1, identified as an open reading frame next to the BUB2 gene), and the TJ6 mouse immune suppressor factor.

Amino Acid Sequence↗
PubMed1992

Antihypertensive drug therapy does not perturb the circadian blood pressure pattern.

The literature was reviewed to determine whether failure of older antihypertensive drugs to suppress the early morning increase of blood pressure was responsible, in part, for the less than satisfactory rate of reduction in cardiovascular mortality rates in the United States. The authors found that neither the old nor the new antihypertensive drugs altered the 24-hour blood pressure curve pattern, although long-acting drugs did show continued effect at the end of the 24-hour period when compared with placebo. The efficacy of these drugs most likely lies with their blood pressure lowering and other ancillary effects and not with pattern changes. More importantly, examination of new data (1989) shows that the rate of decline in death due to diseases of the heart has exceeded that for cerebrovascular diseases. Our overall health care effort may be more successful than we thought.

Antihypertensive Agents↗
PubMed1992

Genes required for vacuolar acidity in Saccharomyces cerevisiae.

Mutations that cause loss of acidity in the vacuole (lysosome) of Saccharomyces cerevisiae were identified by screening colonies labeled with the fluorescent, pH-sensitive, vacuolar labeling agent, 6-carboxyfluorescein. Thirty nine vacuolar pH (Vph-) mutants were identified. Four of these contained mutant alleles of the previously described PEP3, PEP5, PEP6 and PEP7 genes. The remaining mutants defined eight complementation groups of vph mutations. No alleles of the VAT2 or TFP1 genes (known to encode subunits of the vacuolar H(+)-ATPase) were identified in the Vph- screen. Strains bearing mutations in any of six of the VPH genes failed to grow on medium buffered at neutral pH; otherwise, none of the vph mutations caused notable growth inhibition on standard yeast media. Expression of the vacuolar protease, carboxypeptidase Y, was defective in strains bearing vph4 mutations but was apparently normal in strains bearing any of the other vph mutations. Defects in vacuolar morphology at the light microscope level were evident in all Vph- mutants. Strains that contained representative mutant alleles of the 17 previously described PEP genes were assayed for vacuolar pH; mutations in seven of the PEP genes (including PEP3, PEP5, PEP6 and PEP7) caused loss of vacuolar acidity.

Alleles↗
PubMed1991

Astrometry of southern radio sources.

An overview is presented of a number of astrometry and astrophysics programs based on radio sources from the Parkes 2.7 GHz catalogues. The programs cover the optical identification and spectroscopy of flat-spectrum Parkes sources and the determination of their milliarc-second radio structures and positions. Work is also in progress to tie together the radio and Hipparcos positional reference frames. A parallel program of radio and optical astrometry of southern radio stars is also under way.

Astronomical Phenomena↗
PubMed1991

Isolation and characterization of PEP3, a gene required for vacuolar biogenesis in Saccharomyces cerevisiae.

The Saccharomyces cerevisiae PEP3 gene was cloned from a wild-type genomic library by complementation of the carboxypeptidase Y deficiency in a pep3-12 strain. Subclone complementation results localized the PEP3 gene to a 3.8-kb DNA fragment. The DNA sequence of the fragment was determined; a 2,754-bp open reading frame predicts that the PEP3 gene product is a hydrophilic, 107-kDa protein that has no significant similarity to any known protein. The PEP3 predicted protein has a zinc finger (CX2CX13CX2C) near its C terminus that has spacing and slight sequence similarity to the adenovirus E1a zinc finger. A radiolabeled PEP3 DNA probe hybridized to an RNA transcript of 3.1 kb in extracts of log-phase and diauxic lag-phase cells. Cells bearing pep3 deletion/disruption alleles were viable, had decreased levels of protease A, protease B, and carboxypeptidase Y antigens, had decreased repressible alkaline phosphatase activity, and contained very few normal vacuolelike organelles by fluorescence microscopy and electron microscopy but had an abundance of extremely small vesicles that stained with carboxyfluorescein diacetate, were severely inhibited for growth at 37 degrees C, and were incapable of sporulating (as homozygotes). Fractionation of cells expressing a bifunctional PEP3::SUC2 fusion protein indicated that the PEP3 gene product is present at low abundance in both log-phase and stationary cells and is a vacuolar peripheral membrane protein. Sequence identity established that PEP3 and VPS18 (J. S. Robinson, T. R. Graham, and S. D. Emr, Mol. Cell. Biol. 11:5813-5824, 1991) are the same gene.

Adaptor Proteins, Vesicular Transport↗
PubMed1991

Conditioned reinforcement value and choice.

The delay-reduction hypothesis of conditioned reinforcement states that the reinforcing value of a food-associated stimulus is determined by the delay to primary reinforcement signaled by the onset of the stimulus relative to the average delay to primary reinforcement in the conditioning situation. In contrast, most contemporary models of conditioned reinforcement strength posit that the reinforcing strength of a stimulus is some simple function only of the delay to primary reinforcement in the presence of stimulus. The delay-reduction hypothesis diverges from other conditioned reinforcement models in that it predicts that a fixed-duration food-paired stimulus will have different reinforcing values depending on the frequency of its presentation. In Experiment 1, pigeons' key pecks were reinforced according to concurrent-chains schedules with variable-interval 10-second and variable-interval 20-second terminal-link schedules. The initial-link schedule preceding the shorter terminal link was always variable-interval 60 seconds, and the initial-link schedule requirement preceding the longer terminal link was varied between 1 second and 60 seconds across conditions. In Experiment 2, the initial-link schedule preceding the longer of two terminal links was varied for each of three groups of pigeons. The terminal links of the concurrent chains for the three groups were variable-interval 10 seconds and 20 seconds, variable-interval 10 seconds and 30 seconds, and variable-interval 30 seconds and 50 seconds. In both experiments, preference for the shorter terminal link was either a bitonic function or an inverse function of the initial-link schedule preceding the longer terminal-link schedule. Consistent with the predictions of the delay-reduction hypothesis, the relative values of the terminal-link stimuli changed as a function of the overall frequency of primary reinforcement. Vaughan's (1985) melioration model, which was shown to be formally similar to Squires and Fantino's (1971) delay-reduction model, can be modified so as to predict these results without changing its underlying assumptions.

Animals↗
PubMed1991

Choice and conditioned reinforcement.

A potential weakness of one formulation of delay-reduction theory is its failure to include a term for rate of conditioned reinforcement, that is, the rate at which the terminal-link stimuli occur in concurrent-chains schedules. The present studies assessed whether or not rate of conditioned reinforcement has an independent effect upon choice. Pigeons responded on either modified concurrent-chains schedules or on comparable concurrent-tandem schedules. The initial link was shortened on only one of two concurrent-chains schedules and on only one of two corresponding concurrent-tandem schedules. This manipulation increased rate of conditioned reinforcement sharply in the chain but not in the tandem schedule. According to a formulation of delay-reduction theory, when the outcomes chosen (the terminal links) are equal, as in Experiment 1, choice should depend only on rate of primary reinforcement; thus, choice should be equivalent for the tandem and chain schedules despite a large difference in rate of conditioned reinforcement. When the outcomes chosen are unequal, however, as in Experiment 2, choice should depend upon both rate of primary reinforcement and relative signaled delay reduction; thus, larger preferences should occur in the chain than in the tandem schedules. These predictions were confirmed, suggesting that increasing the rate of conditioned reinforcement on concurrent-chains schedules may have no independent effect on choice.

Animals↗