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Biomedical subjects

P M Doyle

Publications and source records attributed to P M Doyle.

At least 19 recordsLinked to original sources
PubMed2002

Quality of life studies in unselected gynaecological outpatients and inpatients before and after hysterectomy.

Quality of life was measured in 348 women attending gynaecological outpatients using EuroQol 5D. Their responses were compared to the results taken from a UK national questionnaire (Kind et al., 1998). Quality of life was then measured in 131 women before and after hysterectomy. Of the outpatient group 50% of the women reported problems with pain and 40% with depression which were significantly more than a representative sample of normal UK women. Women undergoing hysterectomy reported similar preoperative levels of pain and depression. However, 6 months postoperatively there were significantly fewer women complaining of both pain and depression. Mean calculated scores of self-rated quality of life improved significantly from 0.72 preoperatively to 0.89 postoperatively (P < 0.0001). In conclusion, quality of life can be simply quantified using the EuroQol instrument and is suitable for gynaecological patients. Hysterectomy for the treatment of benign conditions improves the overall quality of life for the majority of women.

Adolescent↗
PubMed2000

Bioactive beta-bend structures for the antagonist halpha CGRP(8 - 37) at the CGRP(1) receptor of the rat pulmonary artery.

The aim of this study was to determine beta-bend structures and the role of the N- and C-terminus in the antagonist halpha CGRP(8 - 37) at the rat pulmonary artery CGRP receptor mediating halpha CGRP relaxation. Halpha CGRP(8 - 37) Pro(16) (10(-6) M), with a bend-biasing residue (proline) at position 16, did not antagonize halpha CGRP responses, while a structure-conserving amino acid (alanine(16)) at the same position retained antagonist activity (apparent pK(B) 6.6+/-0.1; 10(-6) M). Halpha CGRP(8 - 37) Pro(19) (10(-6) M), with proline at position 19 was an antagonist (apparent pK(B) 6.9+/-0.1). Incorporation of a beta-bend forcing residue, BTD (beta-turn dipeptide), at positions 19 and 20 in halpha CGRP(8 - 37) (10(-6) M) antagonized halpha CGRP responses (apparent pK(B) 7.2+/-0.2); and BTD at positions 19,20 and 33,34 within halpha CGRP(8 - 37) was a competitive antagonist (pA(2) 7.2; Schild plot slope 1.0+/-0.1). Halpha CGRP(8 - 37) analogues, substituted at the N-terminus by either glycine(8) or des-NH(2) valine(8) or proline(8) were all antagonists (apparent pK(B) 6.9+/-0.1; (10(-6) M), 7.0+/-0.1 (10(-6) M), and pA(2) 7.0 (slope 1.0+/-0.2), respectively); while replacements by proline(8) together with glutamic acid(10,14) in halpha CGRP(8 - 37) (10(-6) M) or alanine amide(37) at the C-terminus of halpha CGRP(8 - 37) (10(-5) M) were both inactive compounds. In conclusion, possible bioactive structures of halpha CGRP(8 - 37) include two beta-bends (at 18 - 21 and 32 - 35), which were mimicked by BTD incorporation. Within halpha CGRP(8 - 37), the N-terminus is not essential for antagonism while the C-terminus may interact directly with CGRP(1) receptors in the rat pulmonary artery.

Alanine↗
PubMed1999

Conformational restraints revealing bioactive beta-bend structures for halpha CGRP8-37 at the CGRP2 receptor of the rat prostatic vas deferens.

1. The main aim of this study was to identify putative beta-bends and the role of the N- and C-terminus in the CGRP receptor antagonist halpha CGRP8-37, which was measured against halpha CGRP inhibition of twitch responses in the rat prostatic vas deferens. 2. With a bend-biasing residue (proline) at position 16 in halpha CGRP8-37 (10(-5) M) an inactive compound was produced, while alanine at the same position retained antagonist activity (apparent pKB 5.6+/-0.1 at 10(-5) M). Proline at position 19 within halpha CGRP8-37 (10(-5) M) was an antagonist (apparent pKB 5.8+/-0.1). 3. Incorporation of a bend-forcing structure (beta-turn dipeptide or BTD) at either positions 19,20 or 33,34 in halpha CGRP8-37 (10(-5) M) antagonized halpha CGRP responses (apparent pKB 6.0+/-0.1 and 6.1+/-0.1, respectively). Replacement by BTD at both positions 19,20 and 33,34 within halpha CGRP8-37 competitively antagonized responses to halpha CGRP (pA2 6.2; Schild plot slope 1.0+/-0.1). 4. Halpha CGRP8-37 analogues (10(-5) M), substituted at the N-terminus by either glycine8, or des-NH2 valine8 or proline8 were all antagonists against halpha CGRP (apparent pKB 6.1+/-0.1, 6.5+/-0.1 and 6.1+/-0.1, respectively), while halpha CGRP8-37 (10(-5) M) substituted in three places by proline8 and glutamic acid10,14 was inactive. 5. Replacement of the C-terminus by alanine amide37 in halpha CGRP8-37 (10(-5) M) failed to antagonize halpha CGRP responses. 6. Peptidase inhibitors did not alter either the agonist potency of halpha CGRP or the antagonist affinities of halpha CGRP8-37 BTD19,20 and 33,34 and halpha CGRP8-37 Gly8 (against halpha CGRP responses). 7. In conclusion, two beta-bends at positions 18-21 and 32-35 are compatible with high affinity by BTD and is the first approach of modelling the bioactive structure of halpha CGRP8-37. Further, the N-terminus of halpha CGRP8-37 is not essential for antagonism, while the C-terminus interacts directly with CGRP receptor binding sites of the rat vas deferens.

Alanine↗
PubMed1998

Design, synthesis and structure of a zinc finger with an artificial beta-turn.

We have incorporated a bicyclic beta-turn mimetic (BTD; beta-turn dipeptide) into a zinc finger, creating a zinc finger with an artificial beta-turn. The designed peptide chelates zinc and has the same fold as the unmodified native zinc finger (finger 3 of the human YY1 protein). A combination of 1H NMR and structure calculations reveals that, in solution, this zinc finger has a fold similar to the known wild-type crystal structure and to other zinc fingers containing the consensus sequence X3-Cys-X4-Cys-X12-His-X3-His-X. The peptide was designed with BTD between the chelating cysteine residues, with BTD forming a type II' beta-turn linking the two strands of a distorted anti-parallel beta-sheet. The C-terminal portion of the peptide forms a helix with zinc co-ordinating histidine residues on successive turns of the helix. This work represents a step towards developing methods by which parts of a target protein may be replaced by peptide mimetics.

Amino Acid Sequence↗
PubMed1996

Multiple solution conformations of the integrin-binding cyclic pentapeptide cyclo(-Ser-D-Leu-Asp-Val-Pro-). Analysis of the (phi, psi) space available to cyclic pentapeptides.

The aqueous solution structure of the cyclic pentapeptide cyclo(-Ser-D-Leu-Asp-Val-Pro-) has been determined by two-dimensional 1H-NMR spectroscopy, combined with a conformational search and distance-geometry calculations. As many as five conformers in slow exchange were observed, and the rate of interconversion between components was measured from the build-up rates of exchange peaks. NMR data allowed the structures of the two predominant conformers to be determined. The major component (66%) contained a cis-proline as part of a type-VIa2 beta-turn encompassing residues Asp-Val-cis-Pro-Ser. The second component (16%) contained only trans-amide bonds, and a type-VIII beta-turn formed by residues Val-Pro-Ser-D-Leu. These structures are discussed in relation to the (phi, psi), space available to the cyclic pentapeptide, determined by a conformational search, and in relation to previously published cyclic-pentapeptide structures. The molecule exhibits activity in a scintillation-proximity assay for the inhibition of the interaction between the integrin very-late antigen-4 (VLA-4; alpha 4 beta 1) and vascular-cell-adhesion molecule-1 (VCAM-1). The structure/activity relationship of the LDV sequence is discussed and related to the recently published X-ray structure of VCAM-1. The relevance of the work to the design of anti-inflammatory drugs is discussed.

Amino Acid Sequence↗
PubMed1996

Towards meeting the Paracelsus Challenge: The design, synthesis, and characterization of paracelsin-43, an alpha-helical protein with over 50% sequence identity to an all-beta protein.

In response to the Paracelsus Challenge (Rose and Creamer, Proteins, 19:1-3, 1994), we present here the design, synthesis, and characterization of a helical protein, whose sequence is 50% identical to that of an all-beta protein. The new sequence was derived by applying an inverse protein folding approach, in which the sequence was optimized to "fit" the new helical structure, but constrained to retain 50% of the original amino acid residues. The program utilizes a genetic algorithm to optimize the sequence, together with empirical potentials of mean force to evaluate the sequence-structure compatibility. Although the designed sequence has little ordered (secondary) structure in water, circular dichroism and nuclear magnetic resonance data show clear evidence for significant helical content in water/ethylene glycol and in water/methanol mixtures at low temperatures, as well as melting behavior indicative of cooperative folding. We believe that this represents a significant step toward meeting the Paracelsus Challenge.

Algorithms↗
PubMed1996

Solution structure of a biologically active cyclic LDV peptide analogue containing a type II' beta-turn mimetic.

The solution structure of cyclo-[Gly-Leu-Asp-Val-BTD] (BTD = beta-turn dipeptide) has been determined by two-dimensional 1H-NMR (nuclear magnetic resonance) spectroscopy and systematic conformational searching combined with molecular dynamics studies. The structure contains two hydrogen bonds between the Gly and Val residues, and a type I beta-turn with Leu and Asp at the (i + 1) and (i + 2) positions of the turn. The cyclic compound shows activity in a scintillation proximity assay (SPA) for the inhibition of the interaction between the integrin alpha 4 beta 1 and vascular cell adhesion molecule-1 (VCAM-I). The structure-activity relationship of the LDV sequence is discussed.

Cloning, Molecular↗
PubMed1995

The clinical effect of dentifrices containing stabilized stannous fluoride on plaque formation and gingivitis--a six-month study with ad libitum brushing.

The effects of stabilized 0.454% stannous fluoride dentifrices on supragingival plaque, gingival inflammation and gingival bleeding were studied in 549 adult male and female subjects who completed a six-month, double blind clinical study. Following an oral prophylaxis, subjects were randomly assigned to brush with one of the following dentifrices: 1) 0.454% SnF2 stabilized with 2.08% sodium gluconate, 2) 0.454% SnF2 stabilized with 4.16% sodium gluconate, 3) an experimental dentifrice, or 4) 0.243% NaF control dentifrice. Follow-up examinations were conducted at 3 and 6 months. Compared to the control dentifrice at 6 months, stannous fluoride dentifrices stabilized with 2.08% or 4.16% sodium gluconate significantly reduced gingivitis by 18.8% and 18.0%, respectively. There were no statistically significant differences between the two stabilized SnF2 groups with respect to their beneficial effects on gingival health. Gingival bleeding was also reduced, relative to the control dentifrice, for both stabilized SnF2 dentifrices. However, these differences were not statistically significant at p=0.05. The stabilized SnF2 dentifrices were not significantly different from the control dentifrice in their effects on supragingival plaque. No significant differences in adverse oral soft tissue effects were observed between the test and control groups. As expected, accumulation of extrinsic tooth stain increased in the stabilized SnF2 groups. However, the difficulty in removing accumulated dental stain was similar between the control and stabilized SnF2 dentifrices. Since use of SnF2 dentifrices has been reported to produce tooth stain, gingivitis examinations were done with and without custom-made tooth covers to evaluate the potential for examiner bias. Comparable gingivitis and gingival bleeding benefits were observed when the evaluations were conducted with or without the tooth covers. Results from this study support that 0.454% stabilized stannous fluoride dentifrices can provide an important adjunct to the prevention and control of gingivitis when used in combination with regular personal oral hygiene procedures and professional care.

Adult↗
PubMed1994

Characterisation of the solution conformation of a cyclic RGD peptide analogue by NMR spectroscopy allied with a genetic algorithm approach and constrained molecular dynamics.

The solution conformation of a cyclic RGD peptide analogue, cyclo-(S,S)-2-mercaptobenzoate-arginine-glycine-aspartate-2-mer captoanilide, has been determined via two independent approaches for the searching of conformational space and identification of conformations consistent with NMR and CD spectroscopic data: (i) the use of a binary genetic algorithm and (ii) a molecular dynamics simulation. Inter-proton distances were obtained via analysis of cross-peak volumes from a two-dimensional ROESY NMR spectroscopy experiment at 600 MHz and were used as constraints for the computational calculations. The mercaptoanilide amide proton resonance chemical shift had a very small temperature coefficient, indicating that this proton was hydrogen-bonded. Circular dichroism data showed that, in solution, the torsion angle about the disulfide bond was negative, consistent with one of the distinct conformations around this bond in the 200 ps molecular dynamics simulation. The backbone conformations of the structures resulting from the two different approaches were very similar.

Amides↗
PubMed1994

Near infrared spectroscopy used to observe changes in fetal cerebral haemodynamics during labour.

Near Infrared Spectroscopy (NIRS) has been used in the neonate to observe changes in the cerebral haemodynamics and concentration of oxygenated haemoglobin. Specific changes have been demonstrated in response to spontaneous bradycardias and alterations in the inspired oxygen concentration. We report here changes in fetal cerebral haemodynamics using NIRS in response to rapid spontaneous delivery and the "topping up" of a maternal epidural with bupivacaine. NIRS offers a new way of observing changes in cerebral haemodynamics in the fetus during labour.

Brain Chemistry↗
PubMed1992

Constant time delay with discrete responses: a review of effectiveness and demographic, procedural, and methodological parameters.

Constant time delay, a variation of progressive time delay, is a response prompting strategy designed to provide and remove prompts in a systematic manner on a time dimension. Constant time delay has two defining characteristics: (a) initial trials involve presentation of the target stimulus followed immediately by delivery of a controlling prompt; and (b) on all subsequent trials, the target stimulus is presented, a response interval of a fixed duration is delivered, the controlling prompt is provided, and a second response interval is delivered as needed. Reports of 36 studies using the constant time delay procedure with discrete behaviors were identified and analyzed. The results are described in terms of demographic variables (i.e., the types of subjects, settings, behaviors, instructors, and instructional arrangements), and the procedural parameters of the strategy. The effectiveness of the strategy and the outcome measures are summarized. Finally, the methodological adequacy of the constant time delay research is examined. Implications for practice and for further research are presented.

Adolescent↗
PubMed1991

Assessing the acquisition of incidental information by secondary-age students with mental retardation: comparison of response prompting strategies.

The effectiveness and efficiency of four response prompting conditions (progressive time delay, progressive time delay with a descriptive consequent event, system of least prompts, and system of least prompts with a descriptive consequent event) were compared. Students with moderate to severe mental retardation were taught to read functional recipe words. Maintenance and students' acquisition of incidental information were assessed when it was (a) embedded in the prompts of the system of least prompts procedure, (b) included in the descriptive praise statements following correct performance with the progressive time delay and system of least prompts procedures, and (c) not presented. A multiple probe design across behaviors, replicated across subjects, was used. Results indicated that (a) each of the procedures produced criterion level responding: (b) efficiency data on traditional measures were roughly equal; (c) maintenance checks showed no differential effects related to the instructional condition; and (d) incidental information was acquired, although it was not directly targeted for instruction.

Activities of Daily Living↗
PubMed1990

Comparison of constant time delay and the system of least prompts in teaching preschoolers with developmental delays.

This investigation compared the effectiveness and efficiency (sessions, errors, percent of errors, and minutes of instructional time through criterion) of constant time delay and the system of least prompts in teaching sight words to developmentally delayed preschoolers. Maintenance of sight words and generalization across instructors and materials were assessed. Also, students' acquisition of relationships between the target behavior and previously learned information were assessed. Two sessions were conducted each day in their classroom, one with each procedure. Two of the children were taught 16 words and one child learned 12 words. The parallel treatments design was used to assess the effectiveness of the two instructional strategies. The results indicated that (a) both strategies produced criterion level responding in the instructional setting, (b) constant time delay resulted in fewer total trials, errors, percent of errors, and minutes of direct instructional time through criterion than the system of least prompts, (c) both strategies produced criterion-level responding that maintained in 1-, 3- and 5-week follow-up probes, (d) both strategies resulted in generalization across instructors and materials, and (e) both strategies resulted in cross-modal generalization from expressive to receptive, receptive and expressive identification of the words' function or action, and matching the written word to a photograph of its referent.

Attention↗