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Biomedical subjects

P Salmon

Publications and source records attributed to P Salmon.

At least 19 recordsLinked to original sources
PubMed1996

An activated form of Notch influences the choice between CD4 and CD8 T cell lineages.

Notch is a transmembrane receptor that controls cell fate decisions in Drosophila and whose role in mammalian cell fate decisions is beginning to be explored. We are investigating the role of Notch in a well-studied mammalian cell fate decision: the choice between the CD8 and CD4 T cell lineages. Here we report that expression of an activated form of Notch1 in developing T cells of the mouse leads to both an increase in CD8 lineage T cells and a decrease in CD4 lineage T cells. Expression of activated Notch permits the development of mature CD8 lineage thymocytes even in the absence of class I major histocompatability complex (MHC) proteins, ligands that are normally required for the development of these cells. However, activated Notch is not sufficient to promote CD8 cell development when both class I and class II MHC are absent. These results implicate Notch as a participant in the CD4 versus CD8 lineage decision.

Animals↗
PubMed1996

The cytoplasmic domain of CD4 promotes the development of CD4 lineage T cells.

Thymocytes must bind major histocompatibility complex (MHC) proteins on thymic epithelial cells in order to mature into either CD8+ cytotoxic T cells or CD4+ helper T cells. Thymic precursors express both CD8 and CD4, and it has been suggested that the intracellular signals generated by CD8 or CD4 binding to class I or II MHC, respectively, might influence the fate of uncommitted cells. Here we test the notion that intracellular signaling by CD4 directs the development of thymocytes to a CD4 lineage. A hybrid protein consisting of the CD8 extracellular and transmembrane domains and the cytoplasmic domain of CD4 (CD884) should bind class I MHC but deliver a CD4 intracellular signal. We find that expression of a hybrid CD884 protein in thymocytes of transgenic mice leads to the development of large numbers of class I MHC-specific, CD4 lineage T cells. We discuss these results in terms of current models for CD4 and CD8 lineage commitment.

Animals↗
PubMed1996

Characterization of an intronless CD4 minigene expressed in mature CD4 and CD8 T cells, but not expressed in immature thymocytes.

The expression of the CD4 gene undergoes a complex pattern of regulation during T cell development. Results obtained in transgenic mice suggest that a combination of proximal enhancer and a silencer from the CD4 gene is sufficient to obtain a developmentally controlled expression along T cell maturation. We generated transgenic mice expressing the human CD4 cDNA under the control of the human CD4 promoter and the murine CD4 minimal proximal enhancer. No other regulatory sequences, including the silencer, were included. The pattern of expression of this transgene is restricted to mature peripheral T cells, to the only mature heat-stable Ag(HSA)low/- single positive thymocytes, and to some NK cells. Surprisingly, no expression was found in double positive or in immature HSAhigh single positive thymocytes. These results suggest that additional, yet uncharacterized genomic sequences are necessary for CD4 expression in immature thymocytes and that there is a change in transcription factors occurring at the late states of T cell development. Finally, since this is the first combination of regulatory sequences that possess such a T mature specific pattern of expression, it should provide a novel tool to address several immunologic questions or for therapeutic purposes.

Animals↗
PubMed1996

Development of a defined medium fermentation process for physostigmine production by Streptomyces griseofuscus.

Physostigmine is a plant alkaloid of great interest as a therapeutic candidate for the treatment of Alzheimer's disease. Fortunately, this compound is also produced by Streptomyces griseofuscus NRRL 5324 during submerged cultivation. A fermentation process that used chemically defined medium was therefore developed for its production. By means of statistical experimentation, the physostigmine titer was quickly increased from 20 mg/l to 520 mg/l with a culture growth of 19 gl dry cell weight on the shake-flask scale. Further medium optimization resulted in a yield of 790 mg/l in a 23-1 bioreactor using a batch process. A titer of 880 mg/l was attained during scale-up in a 800-1 fermentor by employing a nutrient-feeding strategy. This production represents a 44-fold increase over the yield from the initial process in shake-flasks. The defined-medium fermentation broth was very amenable to downstream processing.

Cholinesterase Inhibitors↗
PubMed1996

The Patient Requests Form: a way of measuring what patients want from their general practitioner.

A consumer-oriented approach to the delivery of health care and an understanding of the processes that influence clinical management decisions require the measurement of what patients seek when they consult their doctor. The present study completed the development of an instrument (the Patient Requests Form) that can quantify the intentions of patients attending their general practitioner. The Patient Requests Form was completed by 410 patients attending two general practices: one in an inner city area, the other in a small town. Principal components analysis revealed that the responses from each sample yielded identical components that described three distinct types of request: (i) for explanation and reassurance, (ii) for emotional support, and (iii) for investigation and treatment. Scales constructed to measure each type of request have high internal consistency while being sufficiently brief to be acceptable to general practice patients. The Patient Requests Form is a novel, convenient method to quantify the intentions of patients when they consult a general practitioner. It permits research into neglected aspects of consultation behaviour, including the factors that influence patients' intentions to seek different kinds of help and GPs' perceptions of these intentions.

Adolescent↗
PubMed1996

The relationship of childhood physical and sexual abuse to adult illness behavior.

A sample of 275 undergraduate subjects reported (i) their history of sexual and physical abuse in childhood and (ii) their health care utilization, somatization, and hypochondriasis as an adult. Physical and sexual abuse were recalled by largely separate groups, physical abuse predominating in males and sexual abuse in females. Both types of abuse were followed by a greater number of hospital admissions and surgical procedures in adulthood. Although sexual, and especially physical, abuse were associated with recall of emotionally disturbed parenting, this could not explain their influence on health care utilization because this was unrelated to parenting. Similarly, although abuse was followed by greater somatization and hypochondriasis, these also were unrelated to health care utilization. Physical and sexual abuse in childhood are risk factors, independent of their association with poor parenting, in the development of separate aspects of adult illness behavior.

Adolescent↗
PubMed1996

Fatigue after major joint arthroplasty: relationship to preoperative fatigue and postoperative emotional state.

Fatigue has been widely assumed to increase after major surgery, and possible physical explanations have been intensively investigated. Nevertheless, existing data are almost exclusively from abdominal surgery and are based on the use of a single visual analogue scale. Moreover, no physical basis has been found. The present study used a more homogeneous surgical model than has been employed hitherto in order to find whether fatigue was related to emotional state. We measured fatigue before and 1 and 7 weeks after major joint arthroplasty in 63 patients, using a questionnaire that separates mental and physical fatigue. Physical function and subjective emotional and somatic state were measured at the same times; optimism was measured preoperatively. Neither mental nor physical fatigue increased after this form of surgery. Mental and physical fatigue each correlated with low positive mood throughout. The best predictor of physical fatigue postoperatively and at follow-up was preoperative physical fatigue. Preoperative mental fatigue and negative mood were independent predictors of mental fatigue postoperatively and at follow-up. Preoperative fatigue also predicted worse subjective emotional and physical state after surgery. These results suggest that fatigue should be regarded as an aspect of emotional distress perioperatively and that complaints of fatigue postoperatively may reflect the tendency to complain of fatigue or negative mood preoperatively rather than being attributable to surgical trauma.

Aged↗
PubMed1996

The measurement of beliefs about physical symptoms in English general practice patients.

A way of measuring patients' beliefs about the origin of their symptoms would allow the investigation of important questions concerning the consultation process and its outcome. The purpose of this study was to develop an instrument that could measure the beliefs about symptoms of patients attending their general practitioner and to demonstrate its utility by comparing beliefs about three types of symptom (respiratory, musculoskeletal and gastrointestinal). Interviews of 150 patients generated items for the belief questionnaire which was then completed by a second sample of 406 general practice patients. Principal components analysis of the responses identified eight readily interpretable belief dimensions: stress; lifestyle; wearing out; environment; internal-structural; internal-functional; weak constitution; concern. Scales were constructed to measure each dimension and the symptom groups were compared. Gastrointestinal symptoms were the most likely to be attributed to internal malfunction and to lifestyle or weak constitution. Musculoskeletal symptoms were more likely to be attributed to structural problems caused by the body wearing out and respiratory symptoms, in contrast, to the influence of the environment. Contrary to prediction, attribution to stress was made equally for the different types of symptom. We have devised a questionnaire, valid specifically for general practice patients, which permits the quantification of beliefs in this setting. The questionnaire could be used in future to track how beliefs respond to medical intervention and how, in turn, beliefs influence illness behaviour.

Adolescent↗
PubMed1996

Is patient-controlled analgesia controlled by the patient?

Using patient-controlled analgesia (PCA) after surgery, a patient can obtain pain-relieving injections of morphine without the direct involvement of a nurse or doctor. The present study was a response to the conventional view that patients value PCA because of the control which it affords them over their own treatment. Twenty-six patients underwent semi-structured interviews postoperatively, shortly after discontinuation of PCA. Responses were examined qualitatively to identify recurring themes in patients' experience of PCA. Negative as well as positive evaluation was found. PCA was only rarely described as a way of gaining control over analgesia and, in general, this was not valued. Instead, PCA was valued as a way to avoid the difficulty of disclosing pain or securing pain relief within the usual nurse-patient relationship. In turn, PCA strained the nurse-patient relationship where it impeded either the patient's or the nurse's wish for the nurse to take responsibility for pain relief. The results showed that the professionally and theoretically constructed concept of PCA as a method of self-control over pain is inconsistent with patients' experience of it.

Adult↗
PubMed1996

Pharmacokinetics and pharmacodynamics of recombinant human interferon-beta in healthy male volunteers.

The pharmacokinetics and pharmacodynamics of recombinant human interferon-beta (rHuIFN-beta 1a) were assessed following administration to 12 healthy male volunteers. Each subject received, in a double-blind, balanced, random-order, crossover sequence, single doses of 6 MIU of rHuIFN-beta 1a (Rebif) i.v., i.m., and s.c. or matching placebo on four occasions separated by washout periods of 1 week. Blood samples were collected at preset times for the measurement of serum IFN-beta levels and of intracellular 2'-5'-oligoadenylate synthetase levels. Blood pressure, sitting heart rate, respiratory rate, oral body temperature, and tolerance were monitored regularly. All administrations of rHuIFN-beta 1a were well tolerated, although about half of the subjects had a flu-like syndrome, as expected. After i.v. bolus injection, the pharmacokinetics of rHuIFN-beta 1a were well described by a classic two-compartment model. Mean total clearance of rHuIFN-beta 1a was about 100 L.h-1. The distribution half-life was 5 min, and the terminal half-life was approximately 5 h. After i.m. or s.c. injection, serum IFN-beta profiles were rather flat, and about one sixth of the administered dose was available systemically. Extent and duration of clinical and biologic effects were independent of the route of administration and of the IFN-beta serum levels. Biologic pharmacodynamic effects persisted even when IFN-beta serum levels had returned to baseline and were still significantly elevated 3 days after a single dose. Because of the independence of the extent and duration of clinical and biologic pharmacodynamic effects from the route of administration and from the IFN-beta serum levels, the s.c route of administration is preferred in indications in which primarily an immunomodulatory action is sought. Predominantly antiviral and antiproliferative activity is enhanced by the i.v. route to provide adequate drug levels at the site of pathology, although its application is limited on practical grounds.

2',5'-Oligoadenylate Synthetase↗
PubMed1996

Patients' experiences of patient-controlled analgesia.

We examined patients' experiences of patient-controlled analgesia by the use of semistructured interviews in 26 patients shortly after discontinuation of the device. The options expressed by the patients were examined qualitatively to identify recurring themes in their experience of patient-controlled analgesia. The areas of interest were analgesia, factors influencing whether the patient pressed the button or not, whether they felt in control and side effects. Negative as well as the expected positive evaluations were found. The negative evaluations reflected problems with nausea and vomiting and inadequate analgesia. No clear strategy for pressing, or not pressing, the button emerged and the principle of control by the patient over their pain relief was not considered important.

Adult↗
PubMed1996

Truncated mammalian Notch1 activates CBF1/RBPJk-repressed genes by a mechanism resembling that of Epstein-Barr virus EBNA2.

The Notch/Lin-12/Glp-1 receptor family participates in cell-cell signaling events that influence cell fate decisions. Although several Notch homologs and receptor ligands have been identified, the nuclear events involved in this pathway remain incompletely understood. A truncated form of Notch, consisting only of the intracellular domain (NotchIC), localizes to the nucleus and functions as an activated receptor. Using both an in vitro binding assay and a cotransfection assay based on the two-hybrid principle, we show that mammalian NotchIC interacts with the transcriptional repressor CBF1, which is the human homolog of Drosophila Suppressor of Hairless. Cotransfection assays using segments of mouse NotchIC and CBF1 demonstrated that the N-terminal 114-amino-acid region of mouse NotchIC contains the CBF1 interactive domain and that the cdc10/ankyrin repeats are not essential for this interaction. This result was confirmed in immunoprecipation assays in which the N-terminal 114-amino-acid segment of NotchIC, but not the ankyrin repeat region, coprecipitated with CBF1. Mouse NotchIC itself is targeted to the transcriptional repression domain (aa179 to 361) of CBF1. Furthermore, transfection assays in which mouse NotchIC was targeted through Gal4-CBF1 or through endogenous cellular CBF1 indicated that NotchIC transactivates gene expression via CBF1 tethering to DNA. Transactivation by NotchIC occurs partially through abolition of CBF1-mediated repession. This same mechanism is used by Epstein-Barr virus EBNA2. Thus, mimicry of Notch signal transduction is involved in Epstein-Barr virus-driven immortalization.

Amino Acid Sequence↗
PubMed1996

Short-term recovery from hip and knee arthroplasty.

There are many studies of long-term recovery from major point arthroplasty, but little is known about the first days and weeks after operation. We measured function, emotional state and life evaluation before arthroplasty and at seven and 50 days after in a consecutive series of 40 hip and 23 knee replacements. Pain was relieved significantly at seven days after hip arthroplasty and even more at 50 days. In knee patients, pain relief was modest and was not apparent until 50 days. Functional ability was much improved by 50 days in hip patients, but hardly changed in knee patients. Positive mood and life satisfaction did not improve in either group. Our findings will help with more accurate information for patients before operation and also in judging the rate of recovery.

Aged↗
PubMed1996

Taking the problem oriented medical record forward.

The problem oriented medical record (POMR) has proved to be very successful in providing a structure that helps doctors record their notes about patients, and view those notes subsequently in a manner that quickly gives them a good understanding of that patients history. This approach has been validated by the American Institute of Medicine. With the increased use of computer systems that implement the POMR by doctors, the limitations of this structure have become apparent, and there is clearly scope for developing the model further to improve the quality of the data recorded, and adding meaning to it. This paper describes some of the limitations of the POMR, and discusses a number of areas in which it may be extended. Crucially, this is done in a manner which is both implementable, and usable. The extensions explored include some types of entity including encounters, episodes and subproblems; and an alternative view-the Timeline. The terminology used for the extensions is clarified. Mechanisms by which these extensions have been implemented are described. Ways in which systems can manage these extensions automatically are suggested. Such implementations are constrained by the need not to allow the demands of the computer to intrude into the patient encounter. They are also constrained by the requirements for reporting by professional and governmental institutions, and by what is pragmatically feasible in software and hardware.

Computer Systems↗
PubMed1995

Stress responsivity in exercisers and non-exercisers during different phases of the menstrual cycle.

It has been suggested that, premenstrually, women are more vulnerable to the effects of stress. It has also been proposed that the fitter the individual is, the less the body responds to, and the more quickly it recovers from, a stressful experience. The present study investigated whether premenstrual sensitivity to a stressful laboratory task would be attenuated in women who exercised. Responses to the task across the menstrual cycle were studied in 20 women who exercised regularly and 20 women who were sedentary. Heart rate and blood pressure as well as subjective mood responses were measured in each of three phases: premenstrual, menstrual and postmenstrual. Exercising and sedentary women differed in sensitivity to stress: heart rate responsivity to stress was less in exercisers, but mood fluctuation was greater. Menstrual cycle phase, by contrast, influenced general levels of heart-rate and mood, but did not affect responsivity to stress or performance. These findings suggest that the menstrual cycle and physical exercise have independent effects on cardiovascular and emotional state.

Adaptation, Psychological↗
PubMed1995

How do women cope with menstrual cycle changes?

Very little is known about how women naturally cope with premenstrual and menstrual symptoms. A sample of 342 women was therefore surveyed to discover how they coped with menstrual cycle changes and how helpful these methods were. Principal components analysis of responses to a specially devised coping checklist revealed four components which corresponded to types of coping distinguished in the literature. These were termed: active-behavioural, active-cognitive, avoidance and menstrual cycle specific. There was no relationship between the extent to which particular coping strategies were used and how helpful they were thought to be. The most popular ways of coping were active-cognitive. The most helpful were active-behavioural and active-cognitive. Further analyses did not show any effect of parity or occupational group on the frequency or helpfulness of the different types of coping; nor was there any association with age. Modest correlations of coping methods with symptom severity emerged.

Adaptation, Psychological↗