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J Coyle

Publications and source records attributed to J Coyle.

At least 19 recordsLinked to original sources
PubMed2001

RNA export mediated by tap involves NXT1-dependent interactions with the nuclear pore complex.

Nuclear export of ribonucleoprotein complexes requires cis-acting signals and recognition by receptors that mediate translocation through the nuclear pore complex. Translocation is likely to involve a series of physical interactions between the ribonucleoprotein complex and nucleoporins within the nuclear pore complex. Here, we have characterized the function of NXT1 in the context of the Tap-dependent RNA export pathway. Tap has been implicated in the nuclear export of RNA transcripts derived from Mason-Pfizer monkey virus that contain the constitutive transport element. We demonstrate that NXT1 stimulates binding of a Tap-RNA complex to nucleoporins in vitro, and we provide mutational analysis that shows these interactions are necessary for nuclear export of an intron-containing viral mRNA in vivo. Tap contains separate domains for binding to nucleoporins and NXT1, both of which are critical for its export function. RNA export is mediated by a heterodimer of Tap and NXT1, and the function of NXT1 on this pathway is to regulate the affinity of the Tap-RNA complex for nucleoporins within the nuclear pore complex. We propose that NXT1-dependent binding of the Tap-RNA complex to the nucleoporin p62, which we have reconstituted in vitro using recombinant proteins, represents a single step of the translocation reaction.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2001

Phase I and pharmacokinetic study of exatecan mesylate (DX-8951f): a novel camptothecin analog.

PURPOSE: To determine the maximum-tolerated dose (MTD), dose-limiting toxicity (DLT), pharmacokinetic (PK) profile, and recommended phase II dose of Exatecan mesylate (DX-8951f) when administered as a 24-hour continuous infusion every 3 weeks to patients with solid tumors. PATIENTS AND METHODS: Twenty-two patients with advanced solid tumors, all previously treated, and with performance status < or = 2, were entered. The starting dose of DX-8951f was 0.15 mg/m(2); the dose was escalated according to the modified continual reassessment method. The drug was administered until disease progression or until unacceptable toxic effects occurred. RESULTS: Seven dose escalations were completed, and a total of 53 courses were delivered (median, two courses; range, one to eight courses) during the study. At doses 1.2 mg/m(2) and lower, toxicities were mostly grade 1, primarily hematologic. In the initial cohort of three patients treated at 2.4 mg/m(2), grade 2 hematologic toxicity was observed. Of the six additional patients entered at 2.4 mg/m(2), three had grade 3 or 4 granulocytopenia. At doses higher than 2.4 mg/m(2), DLT granulocytopenia was observed. Nonhematologic toxicities, including nausea, vomiting, diarrhea, fatigue, and alopecia, were mild to moderate. Neither complete nor partial responses were observed, but four patients had stable disease. The PK profile of DX-8951f seemed linear at the doses administered. The plasma clearance, total volume of distribution, and terminal elimination half-life were approximately 3 L/h, 40 L, and 14 hours, respectively. CONCLUSION: The DLT of this DX-8951f schedule was granulocytopenia for minimally pretreated patients, and both granulocytopenia and thrombocytopenia for heavily pretreated patients. The MTD for both minimally and heavily pretreated patients was 2.4 mg/m(2). DX-8951f seems to have a linear PK profile on the basis of single-dose administration. The recommended phase II dose with this schedule is 2.4 mg/m(2) for minimally pretreated patients. A lower dose should be used for heavily pretreated patients.

Adult↗
PubMed2001

Galantamine, a cholinesterase inhibitor that allosterically modulates nicotinic receptors: effects on the course of Alzheimer's disease.

Despite the proven efficacy of acetylcholinesterase inhibitors in Alzheimer's disease, there is a need for new and more effective treatments. Galantamine is a novel treatment for Alzheimer's disease that inhibits acetylcholinesterase and modulates nicotinic receptors. In randomized, double-blind, placebo-controlled studies of up to 6 months duration, galantamine significantly improved cognitive function. Galantamine also had beneficial effects on instrumental and basic activities of daily living, and postponed the progression of behavioral symptoms. Patients who completed one of the 6-month, placebo-controlled studies were eligible to enter a 6-month, open-extension study of the 24-mg/day dose of galantamine. At the end of 12 months, cognitive function and activities of daily living were preserved in those patients who had been treated throughout the study with galantamine 24 mg/day. At 12 months, this group of patients had significantly better cognitive functions than patients who had been treated with a placebo for 6 months before receiving galantamine. These studies indicate that galantamine postpones the progression of symptoms in Alzheimer's disease. Since galantamine shows the greatest benefits when treatment is started early, its long-term benefits may result from an effect on the underlying disease process; such an effect might be mediated by galantamine's concomitant action on nicotinic receptors.

Aged↗
PubMed2001

Valuing people as individuals: development of an instrument through a survey of person-centredness in secondary care.

BACKGROUND: Person-centred care is regarded as the optimum way of delivering health care and is defined as valuing people as individuals (Winefield et al. 1996). So how can practitioners find out if their service 'values people as individuals'? Serious doubts have been expressed about the validity of the concept of patient satisfaction and the ability of instruments to measure patients' views of care. However, qualitative research among people who had experienced problems with their health care has identified an alternative concept better able to articulate patient's complex experiences (Coyle 1997). The study found that that patients' identity was threatened by experiences perceived as dehumanizing, objectifying, disempowering and devaluing. Thus the concept of 'personal identity threat' showed the extent to which people felt valued (or not) as individuals. AIM OF THE STUDY: The aim of the research reported in this paper is to build upon the earlier qualitative work and to identify the frequency and distribution of inpatients' experiences of 'personal identity threat'. DESIGN/METHODS: The study adopted a cross-sectional survey design. Ninety-seven patients from general medical, surgical and otolaryngology wards completed a questionnaire developed from the qualitative study containing items on dehumanization, objectification, disempowerment and devaluation. FINDINGS: Although many patients expressed positive sentiments about their care, problems were highlighted around power/control, involvement in care, and the approachability and availability of staff. The findings also revealed that women were more at risk than men of 'threats to identity' in health care settings. CONCLUSIONS: Improvements are suggested to help promote a service that truly values people as individuals. These include improving health practitioners' understanding of the impact of illness on everyday life, promoting practitioners' listening and enquiring skills, and increasing the 'visibility' and availability of staff. Further research should also explore gender and age differences in perceptions of the lay-practitioner relationship.

Adolescent↗
PubMed2001

Phase I study of topoisomerase I inhibitor exatecan mesylate (DX-8951f) given as weekly 24-hour infusions three of every four weeks.

Exatecan mesylate (DX-8951f) is a topoisomerase I inhibitor that has increased solubility and antitumor activity compared with other topoisomerase I inhibitors. The purpose of this study was to establish a safe dose of DX-8951f given as a weekly 24-h infusion 3 of every 4 weeks. DX-8951f was administered as a 24-h continuous infusion in escalating doses. Twenty-seven patients were treated with 81 courses of the drug. Dose-limiting toxicities included neutropenia, thrombocytopenia, and inability to administer all three doses in the first cycle. In minimally pretreated patients, a dose of 0.8 mg/m(2) was tolerable. In patients who were heavily pretreated, a slightly lower dose, 0.53 mg/m(2), was tolerated without any severe toxicities. Nonhematological toxicities were mild and consisted of mild diarrhea, asthenia, mild nausea, and constipation. Pharmacokinetic parameters could be well described with a one-compartment model in most patients, although the application of the one-compartment model probably resulted in an underestimated elimination half-life. In conclusion, the recommended Phase II dose for DX-8951f administered as a weekly 24-h infusion on a 3-of-4 week schedule is 0.8 mg/m(2) in minimally pretreated patients and 0.53 mg/m(2) in patients who are heavily pretreated.

Aged↗
PubMed2000

An exploration of the epistemological intricacies of using qualitative data to develop a quantitative measure of user views of health care.

Nurse researchers are increasingly combining qualitative and quantitative methods in order to understand more fully the world of research subjects. Qualitative data are often used to explore the subjective meanings behind survey responses and to develop quantitative measures and scales. Insights from qualitative data help researchers to design instruments which are more sensitive to respondents' meanings and interpretations. The aim of this paper is to highlight the epistemological and methodological complexities involved in this enterprise through drawing on our own experience of developing an instrument to examine person-centredness in health care from a qualitative study of dissatisfaction. The intricacies of this project relate to: epistemological continuity and inconsistency; research roles; reflexivity; confirmation; and completeness. Through discussing the literature around integrating methods, we suggest that researchers could be assisted in their attempts to develop conceptually sound quantitative measures by extending the concept of reflexivity (used in qualitative research) to the quantitative components of mixed method studies. This would aid conceptual clarity by making explicit the social, cultural, and political construction of knowledge, and would also encourage researchers to reflect upon the ethical and political consequences of their research.

Adolescent↗
PubMed2000

DX-8951f: summary of phase I clinical trials.

Exatecan mesylate (DX-8951f) is a new hexacyclic camptothecin analogue with favorable attributes compared to topotecan and CPT-11, including watersolubility, greater potency against topoisomerase I, lack of esterase-dependent activation, broad antitumor activity, and low cross-resistance against MDR-1 overexpressing tumors. In preclinical studies, the compound demonstrated a favorable toxicology profile with hematologic dose-limiting toxicity and moderate gastrointestinal toxicity, linear pharmacokinetics, P450 hepatic metabolism (CYP3A4 and CYP1A2), and predominately fecal excretion. The results of six U.S. and European phase I clinical trials as well as two Japanese studies are presented including total DX-8951 and lactone DX-8951 pharmacokinetics. The toxicity profile was similar for all schedules of administration. Hematologic toxicity was dose-dependent and reversible. Neutropenia was dose-limiting in minimally pretreated patients, whereas neutropenia and thrombocytopenia were dose-limiting in heavily pretreated patients. Non-hematologic toxicity included moderate gastrointestinal toxicity (nausea, vomiting > diarrhea), transient elevation of hepatic transaminases, asthenia, and alopecia. Two cases of acute pancreatitis not predicted by preclinical toxicology were also observed. Antineoplastic activity was detected in several solid tumor types: non-small cell lung cancer, extrapulmonary small cell cancer, colorectal cancer, hepatocellular cancer, and sarcoma. Antitumor activity was seen in CPT-11 and topotecan-resistant tumors. Pharmacokinetics were linear within the dose range tested. A pharmacokinetic/pharmacodynamic model predictive of DX-8951f-induced neutropenia in individual patients was developed. The daily x5, every 3-week schedule with the drug administered as a 30-minute intravenous infusion was selected for future phase II clinical trials based on its superior antitumor activity.

Animals↗
PubMed2000

DX-8951f, a hexacyclic camptothecin analog, on a daily-times-five schedule: a phase I and pharmacokinetic study in patients with advanced solid malignancies.

PURPOSE: To assess the feasibility of administering DX-8951f (exatecan mesylate), a water-soluble, camptothecin analog, as a 30-minute intravenous infusion daily for 5 days every 3 weeks, determine the maximum-tolerated dose (MTD) and pharmacokinetic (PK) behavior of DX-8951f, and seek preliminary evidence of anticancer activity. PATIENTS AND METHODS: Patients with advanced solid malignancies were treated with escalating doses of DX-8951f. After three patients were treated at the first dose level, doses were to be escalated in increments of 100%, using a single patient at each dose level unless moderate toxicity was observed. The MTD, defined as the highest dose level at which the incidence of dose-limiting toxicity did not exceed 20%, was calculated separately for minimally pretreated (MP) and heavily pretreated (HP) patients. The PK and excretory profiles of DX-8951, the anhydrous form of DX-8951f, were also characterized. RESULTS: Thirty-six patients were treated with 130 courses of DX-8951f at six dose levels ranging from 0.1 to 0.6 mg/m(2)/d. Brief, noncumulative neutropenia was the most common toxicity observed. Severe myelosuppression (neutropenia that was protracted and/or associated with fever and/or severe thrombocytopenia) was consistently experienced by HP and MP patients at doses exceeding 0.3 and 0.5 mg/m(2)/d, respectively. Nonhematologic toxicities (nausea, vomiting, and diarrhea) were also observed, but these effects were rarely severe. Objective antitumor activity included partial responses in one patient each with platinum-resistant extrapulmonary small-cell and fluoropyrimidine- and irinotecan-resistant colorectal carcinoma, and minor responses in patients with prostate, hepatocellular, thymic, primary peritoneal, and irinotecan-resistant colorectal carcinomas. The PKs of total DX-8951 were linear and well fit by a three-compartment model. CONCLUSION: The recommended doses for phase II studies of DX-8951f as a 30-minute infusion daily for 5 days every 3 weeks are 0.5 and 0.3 mg/m(2)/d for MP and HP patients, respectively. The characteristics of the myelosuppressive effects of DX-8951f, paucity of severe nonhematologic toxicities, and antitumor activity against a wide range of malignancies warrant broad disease-directed evaluations of DX-8951f on this schedule.

Adult↗
PubMed1999

Differentiation of normal and abnormal airway protection during swallowing using the penetration-aspiration scale.

Accidental loss of food or liquids into the airway while eating or drinking is perhaps the most clinically significant consequence of dysphagia. Although videofluoroscopic recording of swallowing is the current gold standard for identifying and determining remediation for aspiration, results are generally described in descriptive terms, thus limiting information and lending to errors of interpretation. We previously published an 8-point scale to quantitate selected aspects of penetration and aspiration conveying depth of airway invasion and whether or not material entering the airway is expelled (Rosenbek et al., 1996, Dysphagia 11:93-98). The present study defines the distribution of the Penetration-Aspiration Scale scores in healthy normal subjects of different genders and ages. The scale was also used with two groups of patients known to have significant dysphagia relative to stroke or head and neck cancer. Significant differences found among groups are discussed.

Adult↗
PubMed1999

Understanding dissatisfied users: developing a framework for comprehending criticisms of health care work.

Recent government proposals have underlined the importance of ascertaining users' views of health care. Traditionally these have been obtained through satisfaction surveys. However, researchers argue that the focus of attention should now shift to exploring dissatisfaction because it highlights more clearly any problems in lay-practitioner relationships. Research has shown that dissatisfaction is a complex social construct which is underpinned by a range of values, beliefs, attitudes and experiences. The aim of this paper is to provide insights into the meaning of dissatisfaction by exploring how dissatisfied users attribute cause, responsibility and blame for their untoward experiences. Forty-one people were identified from a household survey of user views as experiencing problems with their health care. They were interviewed in depth, and a grounded theory approach was used to construct a framework inductively from their accounts. This identified a number of normative expectations through which health work was routinely criticized; these included respondents casting aspersions on the professional integrity of health care practitioners and preserving their own moral identity through demonstrating competence, knowledge, rationality, reasonableness and concern for others. Moreover, it is argued that these patterns help practitioners to understand how dissatisfied users' perceive subsequent health care encounters.

Adolescent↗
PubMed1999

Seeing the wood for the trees: defining the forgotten concept of patient dissatisfaction in the light of patient satisfaction research.

Studies of patient satisfaction are regarded by many as the most important way to obtain patients' views. To date, relatively few studies have focussed specifically on dissatisfaction. Concerns have been expressed about the validity of the concept of satisfaction. Dissatisfaction, however, has received little attention since it has been assumed to be the opposite of satisfaction and thus already defined. Therefore a series of assumptions have also been made about dissatisfaction, which may or may not compromise its validity or usefulness. The aim of this review is to clarify the concept of dissatisfaction by examining what studies of patient satisfaction can and cannot tell us about dissatisfaction; identifying assumptions; and finally by suggesting how research might best be oriented to accommodate the complexity of patient experiences.

Attitude to Health↗
PubMed1998

The meaning of patient satisfaction: an explanation of high reported levels.

The social policy background to the proliferation of patient satisfaction surveys is a desire for increased patient representation and participation. Within this context, it is assumed that satisfaction surveys embody patients' evaluations of services. However, as most surveys report high satisfaction levels, the interpretation of satisfaction as the outcome of an active evaluation has been called into question. The aim of this study is to identify whether and how service users evaluate services. This was made possible through unstructured in-depth interviews with users of mental health services and through more structured discussion around their responses on a patient satisfaction questionnaire (CSQ 18B) whose psychometric properties has been well documented. Twenty-nine people with current or recent contact with mental health services within the British National Health Service were interviewed. The data revealed that service users frequently described their experiences in positive or negative terms. However, the process by which these experiences were transformed into "evaluations" of the service was complex. Consequently, many expressions of "satisfaction" on the CSQ 18B hid a variety of reported negative experiences. An explanation for this lack of correspondence is outlined.

Bias↗
PubMed1998

Frequency-range discriminations: special and general abilities in zebra finches (Taeniopygia guttata) and humans (Homo sapiens).

The acoustic frequency ranges in birdsongs and human speech can provide important pitch cues for recognition. Zebra finches and humans were trained to sort contiguous frequencies into 3 or 8 ranges, based on associations between the ranges and reward. The 3-range task was conducted separately in 3 spectral regions. Zebra finches discriminated 3 ranges in the medium and high spectral regions faster than in the low region and discriminated 8 ranges with precision. Humans discriminated 3 ranges in all 3 spectral regions to the same modest standard and acquired only a crude discrimination of the lowest and highest of 8 ranges. The results indicate that songbirds have a special sensitivity to the pitches in conspecific songs and, relative to humans, have a remarkable general ability to sort pitches into ranges.

Acoustic Stimulation↗
PubMed1995

Pfcrk-1, a developmentally regulated cdc2-related protein kinase of Plasmodium falciparum.

A gene encoding a novel cdc2-related protein kinase has been identified in Plasmodium falciparum, using degenerate oligonucleotides designed to hybridise to regions that are conserved in members of the cdc2 gene family. This gene, called Pfcrk-1, is located on chromosome 4. It is most closely related to the p58GTA gene family, members of which are negative regulators of cell growth in vertebrates. Pfcrk-1 is developmentally regulated, as indicated by stage-specific accumulation of mRNA in gametocytes.

Amino Acid Sequence↗
PubMed1990

Detection and measurement of simulated early rheumatoid lesions of the hand using digital subtraction radiography.

The ability of digital subtraction radiography, a new technique to detect and quantify small bone lesions, is demonstrated. Discrete lesions in the metacarpals of cadaver hands simulated erosive bone loss. Radiographs made before and after removal of bone were digitized and subtracted. Density changes on subtraction images were determined, and bone loss was estimated by an automatic procedure that compared changes in radiographic density with a calibration wedge included in the radiographs. Comparison of estimated bone loss with the weight of bone removed showed reproducible detection and measurement of bone lesions as small as 4.6 mg, a size undetectable using current radiographic methods. Subtraction radiographs of bone chips overlaid on the hand of a volunteer indicated detection limits were similar in vivo. This technique enhanced the radiographic visibility of erosive lesions and thus has the potential to improve the detection of subtle bone changes in clinical settings.

Arthritis, Rheumatoid↗