Search PubMed⌕ Search

Biomedical subjects

K Clarke

Publications and source records attributed to K Clarke.

At least 91 records · Page 5Linked to original sources
PubMed1996

Thrombopoietic effects of pegylated recombinant human megakaryocyte growth and development factor (PEG-rHuMGDF) in patients with advanced cancer.

BACKGROUND: Pegylated recombinant human megakaryocyte growth and development factor (PEG-rHuMGDF) is a potent stimulator of megakaryocyte colony formation and platelet production. It is likely to be useful in the management of severe thrombocytopenia. To determine its clinical activity and safety, we gave it to patients with advanced cancer before chemotherapy. METHODS: Patients were randomly assigned to receive either PEG-rHuMGDF or placebo in a three to one ratio. PEG-rHuMGDF was given at a dose of 0.03, 0.1, 0.3, or 1.0 microgram/kg body weight. The study drug or placebo were administered daily by subcutaneous injection for up to 10 days or until a target platelet count was reached. FINDINGS: 17 patients, median age 59 years, received either PEG-rHuMGDF (13 patients) or placebo (four patients). PEG-rHuMGDF produced a dose-dependent increase in platelet counts. Patients given placebo. 0.03, and 0.1 microgram/kg of PEG-rHuMGDF had median increases in platelet counts of 16%, 12%, and 39%. Those receiving 0.3 and 1.0 microgram/kg of PEG-rHuMGDF had an increase in blood platelets of between 51% and 584%. Platelets rose from day 6 of PEG-rHuMGDF administration and continued to rise after stopping the drug. The platelet count peaked between days 12 and 18 and remained above 450 x 10(9)/L for up to 21 days. There were no alterations in white-blood-cell count or haematocrit, and low toxicity. Platelets taken from patients during PEG-rHuMGDF administration and at the time of peak platelet count were morphologically and functionally normal. INTERPRETATION: The potency with which PEG-rHuMGDF stimulates platelet production and its low toxicity indicate that this is likely to be a useful agent for the management of thrombocytopenia.

Dose-Response Relationship, Drug↗
PubMed1996

The beta/alpha peak height ratio of ATP. A measure of free [Mg2+] using 31P NMR.

From 31P NMR measurements made in vitro at 38 degrees C, I = 0.25, pH 5. 75-8.5, and calculated free [Mg2+] from 0 to 5 mM, we show that, within the physiological range of cytosolic free [Mg2+] from 0.25 to 1.5 mM, the chemical shift difference between the alpha- and beta-ATP resonances, deltaalphabeta, changes by only 0.6 ppm. Consequently, we developed new formalisms from known acid and Mg2+ dissociation constants by which the observed chemical shift of Pi, deltaPi, and the peak height ratio of the beta- and alpha-ATP resonances, hbeta/alpha, could be related to free [Mg2+] by simultaneous solution of: [equation: see text] We found that hbeta/alpha changed 2.5-fold as free [Mg2+] varied from 0.25 to 1.5 mM, providing a more sensitive and accurate measure of free cytosolic [Mg2+]. In working rat heart perfused with glucose, free [Mg2+] was 1.0 +/- 0.1 from hbeta/alpha and 1.2 +/- 0.03 from measured [citrate]/[isocitrate] but 0.51 +/- 0.1 from deltaalphabeta. Addition of ketone bodies to the perfusate decreased free [Mg2+] estimated from hbeta/alpha to 0.61 +/- 0.02 and 0.74 +/- 0.11 by [citrate]/[isocitrate] but the estimate from deltaalphabeta was unchanged at 0.46 +/- 0.04 mM. Such differences in estimated free [Mg2+] alter the apparent Keq of the creatine kinase reaction and hence the estimated cytosolic free [SigmaADP].

Adenosine Triphosphate↗
PubMed1996

Prenatal cocaine delays astroglial maturation: immunodensitometry shows increased markers of immaturity (vimentin and GAP-43) and decreased proliferation and production of the growth factor S-100.

Exposure to cocaine during fetal development has been demonstrated to produce a variety of brain and behavioral changes. Cocaine is a potent releaser of a variety of neurotransmitters, such as serotonin, which act as developmental signals. Since serotonin plays an important role in astroglial maturation, migration, and growth factor production (e.g. S-100 beta), we proposed that these properties of astroglial cells will be altered in a brain prenatally exposed to cocaine. To observe cocaine's effects on astroglial development, we performed immunocytochemical analyses of a variety of developmental protein makers including BrdU, Gap-43, vimentin, and S100 beta. Our results demonstrate that prenatal cocaine administration produces decreased cell proliferation as measured by BrdU staining, retarded neurite outgrowth as ascertained by increased Gap-43 immunoreactivity, increased density of vimentin-positive radial glial cells, and diminished tissue S100 beta immunoreactivity. Overall, these results suggest that cocaine delays astroglial development. This delay would have profound effects on neuronal development and outgrowth and, thus, development of the entire brain.

Age Factors↗
PubMed1996

Ability of FGFs to promote the outgrowth and proliferation of limb mesoderm is dependent on IGF-I activity.

IGF-I and members of the FGF family have been implicated in the reciprocal interactions between the apical ectodermal ridge (AER) and underlying subridge mesoderm that are required for outgrowth of the developing limb bud. Several FGFs are expressed by the AER and appear to mediate its outgrowth and patterning effects on the subridge mesoderm. IGF-I is expressed by the subridge mesoderm that is growing out in response to the AER, and exogenous IGF-I can promote the outgrowth of the subridge mesoderm in the absence of the AER. Maintenance of IGF-I expression by the subridge mesoderm is dependent on the AER. Here we report that exogenous FGF-2 and FGF-4 can substitute for the AER in maintaining IGF-I expression by the posterior subridge mesoderm of the chick limb bud. Furthermore, we have found that neutralizing antibodies against IGF-I inhibit the ability of FGFs to promote the outgrowth and proliferation of the posterior subridge mesoderm cultured in the absence of the AER. These results indicate that FGFs secreted by the AER maintain IGF-I expression by the subridge mesoderm, and that the ability of FGFs to promote the outgrowth and proliferation of limb mesoderm is dependent on IGF-I activity. Interestingly, however, the ability of FGFs to maintain the expression of the homeobox containing gene Msx-1 by the subridge mesoderm is not dependent on IGF-I activity.

Animals↗
PubMed1996

The role of platelet growth factors in cancer therapy.

The use of myeloid growth factors has markedly reduced the complications of chemotherapy-induced neutropenia, however, abrogation of severe thrombocytopenia remains a major clinical problem. Platelet transfusions remain the standard method of preventing or treating thrombocytopenia but are associated with a variety of complications and are a limited resource. A number of cytokines have been clinically investigated for their thrombopoietic activity, the most promising of which is the recently cloned ligand to the hematopoietic growth factor receptor, c-Mpl. The c-Mpl ligand, also referred to as thrombopoietin, megakaryocyte growth and development factor (MGDF) and megapoietin, is a potent lineage-specific agent that promotes growth and maturation of megakaryocytes and their progenitors. It holds promise for clinical use in the treatment of iatrogenic or disease-associated bone marrow failure states and possibly in syndromes of excessive platelet consumption. Early clinical trials assessing the safety and activity of recombinant human MGDF are now underway.

Blood Platelets↗
PubMed1996

Appropriateness of admission and the last 24 hours of hospital care in medical wards in an east London teaching group hospital.

OBJECTIVE: To assess the rates of inappropriateness of admission and last day of care on adult medical wards in an east London hospital, to identify associations with any inappropriateness and to assess what services need to be improved or provided if patients assessed as "inappropriate" are to be more appropriately placed in the future. DESIGN: From the patients' medical notes, nursing notes and ward charts, a trained reviewer with nursing and university qualifications collected concurrent information about each patient's first 24 hours as an in-patient and about the last 24 hours of care preceding discharge. Patients were also interviewed before discharge and 7-10 days after discharge, and their health status and level of satisfaction about the discharge process assessed. SETTING: The three adult medical wards at the Homerton Hospital in Hackney, east London. This hospital is within the St Bartholomew's Hospital Teaching Hospital Group. SUBJECTS: The case-notes of a random sample of 625 adult in-patients were reviewed. END POINTS: Appropriateness of admission and last day of care. MAIN OUTCOME MEASURES: The main instrument used was the Appropriateness Evaluation Protocol (AEP). This is an instrument devised to assess the appropriateness of adult patient admission to, and specific days of care in, acute hospital beds through case-note review against a structured set of criteria. RESULTS: The study presented here reported that 31% of in-patient admissions to adult medical wards in an east London hospital were inappropriate, and also that 66% of the last days of stay were inappropriate. CONCLUSIONS: There is clearly considerable room for improvement in relation to cooperation between service providers in order to maximise efficient bed use. Delays due to waiting for medications from pharmacy, and the combination of more "inappropriate" cases wanting help from social services after discharge with the fact that many of them were still in hospital because they were waiting for these services to be organized, suggest that inappropriateness could be reduced through increased efficiency or increased provision in these areas. The study reported here is unique in its inclusion of patient interview data.

Adult↗
PubMed1996

Is a high glycogen content beneficial or detrimental to the ischemic rat heart? A controversy resolved.

A high glycogen level may be beneficial to the ischemic heart by providing glycolytic ATP or detrimental by increasing intracellular lactate and protons. To determine the effect of high glycogen on the ischemic myocardium, the glycogen content of Langendorff-perfused rat hearts was either depleted or elevated before 32 minutes of low-flow (0.5 mL/min) ischemia with Krebs-Henseleit buffer with or without 11 mmol/L glucose, followed by 32 minutes of reperfusion with buffer containing 11 mmol/L glucose. 31P nuclear magnetic resonance spectra were acquired sequentially throughout. Further experiments involved early reperfusion or the addition of HOE 694, a Na+-H+ exchange inhibitor, during reperfusion. When glucose was supplied throughout ischemia, no ischemic contracture occurred, and postischemic recovery of contractile function was highest, at 88% of preischemic function. In the absence of glucose, normal-glycogen hearts underwent ischemic contracture at 5 minutes, had an end-ischemic pH of 6.87, and recovered to 54%, whereas in high-glycogen hearts, contracture was delayed to 13 minutes, the end-ischemic pH was 6.61, and functional recovery decreased to 13%. Contracture onset coincided with the decrease in glycolysis, which occurred as glycogen became fully depleted. Functional recovery in the high-glycogen hearts increased to 89% when reperfused before contracture and to 56% when reperfused in the presence of HOE 694. Thus, during brief ischemia in the high-glycogen hearts, ischemic glycogen depletion and contracture were avoided, and the hearts were protected from injury. In contrast, during prolonged ischemia in the high-glycogen hearts, glycogen became fully depleted, and myocardial injury occurred; the injury was exacerbated by the lower ischemia pH in these hearts, leading to increased Na+-H+ exchange during reperfusion. The contradictory findings of past studies concerning the effect of high glycogen on the ischemic myocardium may thus be due to differences in the extent of glycogen depletion during ischemia.

Adenosine Triphosphate↗
PubMed1996

An audit into the use of intravascular contrast media in Scotland. The Audit Committee of the Scottish Radiological Society and the Scottish Standing Committee of the Royal College of Radiologists.

A survey was conducted into the use of intravascular contrast media within Scotland during 1993-4 auditing the period from April 1992 to March 1993. The first phase of the study examined the use of low osmolar contrast media and high osmolar contrast media and this obtained a 100% response rate. All users were found to adhere to Royal College of Radiologists guidelines, but as an incidental finding, only 87% recorded adverse reactions and a separate register was not always maintained. A second follow-up questionnaire was issued to examine specifically the recording of adverse reactions. A 96% response rate was obtained. Although all departments recorded adverse reactions in some form, only 13% kept a separate register. Recommendations are made that all departments should maintain a separate adverse reaction register and that there should be standardisation of the grading of reactions. Annual returns to a central body are also recommended.

Contrast Media↗
PubMed1995

The role of Na+/K+ ATPase activity during low flow ischemia in preventing myocardial injury: a 31P, 23Na and 87Rb NMR spectroscopic study.

An increase in intracellular Na+ during ischaemia has been associated with myocardial injury. In this study, we determined whether inhibition of Na+/K+ ATPase activity contributes to this increase and whether Na+/K+ ATPase activity can be maintained by provision of glucose to perfused rat hearts during low flow, 0.5 ml/min, ischemia. We used 31P NMR spectroscopy to determine changes in myocardial energetics and intracellular and extracellular volumes. 23Na NMR spectroscopy, with DyTTHA3- present as a shift reagent, was used to measure changes in intracellular Na+ and 87Rb NMR spectroscopy was used to estimate Na+/K+ ATPase activity from Rb+ influx rates, Rb+ being an NMR-sensitive congener of K+. In hearts provided with 11 mM glucose throughout ischemia, glycolysis continued and ATP was twofold higher than in hearts without glucose. In the glucose-hearts, Rb+ influx rate was threefold higher, intracellular Na+ was fivefold lower at the end of ischemia and functional recovery during reperfusion was twofold higher. We propose that continuation of glycolysis throughout low flow ischemia allowed maintenance of sufficient Na+/K+ ATPase activity to prevent the increase in intracellular Na+ that would otherwise have led to myocardial injury.

Animals↗
PubMed1995

Is lactate-induced myocardial ischaemic injury mediated by decreased pH or increased intracellular lactate?

The detrimental effect of exogenous lactate during ischaemia on post-ischaemic contractile function may be mediated either by a lactate-induced intracellular H+ load or by an increase in intracellular lactate. To distinguish between these two mechanisms, isolated rat hearts were perfused with lactate or pyruvate during low flow ischaemia, the rationale being that both would decrease H+ efflux via lactate/H+ cotransport and lead to decreased pH, but only exogenous lactate would decrease lactate efflux and lead to increased intracellular lactate. 31P NMR spectra were acquired sequentially while hearts were subjected to 32 min low flow (0.5 ml/min) ischaemia and 32 min reperfusion. During ischaemia, hearts were perfused with Krebs-Henseleit buffer containing 11 mM glucose (controls) or 11 mM glucose plus either 10 mM lactate or 10 mM pyruvate. Reperfusion of all hearts was with buffer containing only glucose. Intracellular volume, estimated to be 0.52 ml/heart using 31P NMR spectroscopy with phosphonate space markers, did not change under any of the ischaemic conditions during the protocol. Control and pyruvate hearts recovered approximately 85% of pre-ischaemic contractile function, but there was no recovery of function in lactate hearts. This lack of recovery correlated with a 57% loss of ATP during ischaemia, which was significantly greater (P < 0.001) than the 41% loss of ATP in control and pyruvate-perfused hearts. End-ischaemic intracellular pH was 6.60 in both lactate-perfused and control hearts, but significantly lower (P < 0.05) at pH 6.43 in pyruvate-perfused hearts. Both exogenous pyruvate and lactate should have decreased H+ efflux, however the higher pH in the lactate-perfused hearts could be explained by a 60% inhibition of glycolysis, determined by measurement of myocardial lactate production. Thus, the intracellular pH during ischaemia does not necessarily predict the extent of myocardial injury. We propose that lactate-induced damage is a consequence of increased intracellular lactate leading to inhibition of glycolysis, presumably via an increased NADH/NAD ratio. This study highlights the important role of glycolysis in the ischaemic rat heart.

Animals↗
PubMed1995

Referral patterns within Scotland to specialist oncology centres for patients with testicular germ cell tumours. The Scottish Radiological Society and the Scottish Standing Committee of the Royal College of Radiologists.

Details of 1123 patients registered in Scotland between 1983 and 1990 for testicular cancer under the Scottish Cancer Registration Scheme were obtained and compared with registrations within the five Scottish oncology centres. Some registration discrepancies were identified. Twenty-eight cancer registrations (2.5%) were coded to the wrong site, 29 patients seen at oncology centres had no cancer registration and 14 cancer registrations had the wrong histology. Five hundred and twenty-seven patients with testicular non-seminomatous germ cell tumours (NSGCT) and 567 with testicular seminoma were identified. Referral rates to specialist oncology centres for testicular germ cell tumours were measured by period and health board area of residence. For the whole study period 92% of NSGCT and 93% of seminoma patients were referred to specialist centres for treatment. Referral rates for different health board areas of residence were not significantly different. This study shows that within Scotland the majority of patients with testicular NSGCT and seminoma are referred to specialist centres, and suggests referral rates of around 92% are underestimates. Access is not related to area of residence.

Cancer Care Facilities↗
PubMed1995

A Scottish national audit of current patterns of management for patients with testicular non-seminomatous germ-cell tumours. The Scottish Radiological Society and the Scottish Committee of the Royal College of Radiologists.

A detailed casenote review was performed on all 65 patients registered with testicular non-seminomatous germ cell tumours (NSGCT) during 1989 under the Scottish Cancer Registration Scheme. Details of management at presentation and 2 years following diagnosis were recorded and analysed. In a small number of patients an unacceptable delay in diagnosis was noted. Variation was found in the frequency and type of investigations performed on patients placed on surveillance, types of chemotherapy regimens used and numbers of patients entered into trials. Three per cent of patients had a biopsy of the contralateral testis and 27% of patients defaulted from clinic attendance. Considerable variation in the management of testicular NSGCT in Scotland has been identified. The introduction of management guidelines should result in a more consistent approach to the care of these patients. Support, both financial and psychological, may reduce the unacceptable rate of default.

Adolescent↗
PubMed1995

A Scottish national mortality study assessing cause of death, quality of and variation in management of patients with testicular non-seminomatous germ-cell tumours. The Scottish Radiological Society and the Scottish Standing Committee of the Royal College of Radiologists.

A detailed casenote review was performed on 55 patients registered with testicular non-seminomatous germ cell tumours (NSGCT) between 1983 and 1988 under the Scottish Cancer Registration Scheme and who had died by 1992. Details of all aspects of clinical management relating to their NSGCT and death details were extracted and summarised. An assessment was made on whether the patients' management had been optimal. An analysis of 5 year survival rates by the five Scottish oncology centres demonstrated significant differences between centres (range 70.4-94.2; chi 2 = 14.46, d.f. = 4, P = 0.006). Some patients in all centres were assessed as having received suboptimal treatment, but two centres performed less well than the other three. There is a suggestion that the number of patients treated suboptimally decreases with increasing number of patients seen, but this does not reach statistical significance.

Adolescent↗