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Biomedical subjects

G Hardy

Publications and source records attributed to G Hardy.

At least 19 recordsLinked to original sources
PubMed2005

6-tioguanine monitoring in steroid-dependent patients with inflammatory bowel diseases receiving azathioprine.

BACKGROUND: 6-Thioguanine (6-tioguanine) nucleotides are the active metabolites of azathioprine. AIM: The aim of the study was to evaluate the rate of clinical remission without steroids in steroid-dependent Crohn's disease and ulcerative colitis patients receiving azathioprine, the medium- and long-term efficacy and the predictive factors of clinical response when monitoring 6-tioguanine. METHODS: Steroid-dependent Crohn's disease and ulcerative colitis patients receiving either azathioprine or not (treated later with a daily dose of 2.5 mg/kg) were prospectively included. 6-tioguanine was monitored at 1 and 2 months and every 3 months thereafter for 1 year. The azathioprine dose was adapted to reach a 6-tioguanine level of >250 pmol/8 x 10(8) red blood cells. Thiopurine methyltransferase genotype/phenotype was evaluated in some patients. RESULTS: A total of 106 patients were prospectively included (70 Crohn's disease, 36 ulcerative colitis). The clinical remission rate without steroids in patients receiving azathioprine, in intention-to-treat analysis, was 72% and 59% at 6 and 12 months, respectively. The remission rate was significantly higher in patients with 6-tioguanine >250 pmol/8 x 10(8) RBC (86% and 69% at 6 and 12 months, respectively; P < 0.01). No significant difference was observed between Crohn's disease and ulcerative colitis patients whether treated by azathioprine or not on inclusion. In the univariate analysis, the absence of Crohn's disease stenosis, a 6-tioguanine level >250 pmol/8 x 10(8) RBC, and an increase of erythrocyte mean corpuscular volume were the factors predictive of a favourable clinical response. In the multivariate analysis, only a 6-tioguanine level of >250 pmol/8 x 10(8) red blood cells was a predictive factor of favourable clinical remission. CONCLUSIONS: Clinical remission without steroids is significantly more likely when monitoring 6-tioguanine so as to reach a level of >250 pmol/8 x 10(8) red blood cells in steroid-dependent Crohn's disease and ulcerative colitis patients receiving azathioprine (86% and 69% at 6 and 12 months, respectively).

Adolescent↗
PubMed2005

5-lipoxygenase expression and activity in aorta from streptozotocin-induced diabetic rats.

We previously reported an activation of the 5-lipoxygenase pathway in aorta from streptozotocin-induced diabetic rats. The aim of this study was to investigate whether this activation was associated with an increased expression of 5-lipoxygenase, an increased cysteinyl leukotriene (CysLT) production in response to arachidonic acid or calcium ionophore A23187 and/or a hypersensitivity of the aorta to CysLTs in streptozotocin-induced diabetic rats. In aorta from diabetic and control rats, reverse transcriptase-PCR and western blot analysis with a specific 5-lipoxygenase antibody provided evidence for the presence of 5-lipoxygenase in aorta. However, the expression of 5-lipoxygenase was not significantly different between diabetic and control rats. Challenge by A23187 (10 microM) and arachidonic acid (10 microM and 0.1 mM) with or without A23187 (10 micromol/l) induced a significant increase of CysLT release (measured by enzyme immunoassay) that was in the same range in aorta from control and diabetic rats. In contrast, aortas from diabetic rats showed a greater sensitivity to LTC4 and LTD4 contractile effects. These data suggested that the activation of the 5-lipoxygenase pathway previously reported in streptozotocin-induced diabetic rats could be explained by an augmented sensitivity to CysLTs of the diabetic aorta.

Animals↗
PubMed2005

Assessing psychological well-being: a holistic investigation of NHS employees.

A substantial body of research has investigated the effects of work on the psychological well-being of employees. However, there has been little assessment of the ways in which workplace factors (such as job demands, working conditions, inter-personal relations and workplace change) interact with personal factors (such as work-life balance, family circumstances, key personality traits or demographic characteristics) to affect psychological health. This article reports findings from a study which aimed to construct and test a comprehensive model of the influences on employee well-being within the UK National Health Service (NHS). The results show that psychological well-being is influenced by a complex array of personal, environmental and work factors. A key finding is that there are clear associations between workplace change and well-being and between work-life (im)balance and well-being. These effects appear to be independent of one another and therefore require separate attention from managers and employers.

Data Collection↗
PubMed2004

Evidence of thymic reconstitution after highly active antiretroviral therapy in HIV-1 infection.

OBJECTIVES: We aimed to provide evidence of thymic reconstitution after highly active antiretroviral therapy (HAART) in HIV-1 infected patients and to correlate this with the restoration of peripheral naïve T cells. METHODS: Positron emission tomography (PET) enables definitive evidence of thymic activity, indicating functional potential. In this case study, a single patient who initiated HAART demonstrated reconstitution of the naïve T-cell pool and underwent thymic PET scans at baseline and 2 and 6 months following initiation of therapy. Two patients who failed to demonstrate such reconstitution acted as controls. These patients (mean age 27 years) had chronic HIV infection with low CD4 T-cell counts (mean 82, range 9-160 cells/microL blood). Increased function of the thymus visualized by PET was correlated with phenotypic changes in CD4 and CD8 T cells in the periphery measured by flow cytometry, and with numbers of recent thymic emigrants measured by quantification of the numbers of T-cell receptor excision circles (TRECs) in peripheral cells. RESULTS: In one patient, clear correlations could be drawn between visible activity within the thymus, as measured by increased [F18]fluorodeoxyglucose (FDG) uptake, and regeneration of naïve CD4 (CD45RA/CD62L) T cells, increased numbers of CD4 T cells, controlled viraemia and increased numbers of recent thymic emigrants. A second patient displayed no increase in peripheral CD4 count and no increase in thymic activity. The third patient elected to stop therapy following the 2-month time point. CONCLUSIONS: The use of PET suggests that thymic activity may increase after HAART, indicating that the thymus has the potential to be functional even in HIV-1 infected persons with low CD4 T-cell counts.

Adult↗
PubMed2001

Immune responses and reconstitution in HIV-1 infected individuals: impact of anti-retroviral therapy, cytokines and therapeutic vaccination.

Most patients with chronic HIV-1 infection lack functional CD4(+) and CD8(+) HIV-1-specific T cells with proliferative and cytolytic capacity, respectively. This is despite being able to produce intracellular cytokines in response to viral antigens. Protease inhibitor (PI)-based highly active anti-retroviral therapy (HAART) is unable to completely eradicate virus and fails to enable total restoration of immunity including induction of anti-HIV-1 responses. We have taken novel approaches towards the treatment of chronic HIV-1 disease with the aim of instigating long-term non-progressor status and depletion of virus reservoirs. HIV-1-specific CD4(+) and CD8(+) T cell responses were measured following the administration of cytokines, during therapeutic vaccination, and following treatment interruption (TI) or drug therapy change. Administration of cytokines, with or without therapeutic vaccination, in HAART treated patients, improved both CD4(+) and CD8(+) HIV-1-specific T cell responses even in late-stage disease. Virus-specific T cell responses were also seen during TI or when transient viraemia was apparent, and following therapy change from a PI- to a non-nucleoside-based HAART regimen. Reconstitution of HIV-1-specific immune responses was found to be transient and reversal to the previous anergic state was rapid. Viral reservoirs in the latently infected resting CD4(+) T cells, on follicular dendritic cells of germinal centers or even in infected thymic epithelium may be involved in clonal suppression and anergy. These may present major obstacles to the maintenance of HIV-1-specific responses and the eventual eradication of HIV-1.

AIDS Vaccines↗
PubMed2001

Degradation of dehydroascorbic acid in parenteral nutrition mixtures.

The degradation of ascorbic acid (AA) stored in parenteral nutrition (PN) regimens is initially by oxidation, catalysed by trace elements, in particular copper. After prolonged storage the concentration of AA remains relatively constant, with little variation, due to the lack of available oxygen. The initial degradation product is dehydroascorbic acid (DHAA). This is generated in an anaerobic environment, and is hypothesised to degrade by hydrolysis. It is the purpose of this investigation to ascertain the effect of temperature and trace elements on the anaerobic degradation of DHAA, and to identify the kinetics of the reaction. A stability-indicating reversed-phase HPLC assay was used. The column contained C(18) reverse-phase packing (Luna), mean diameter 5 microm. The column dimensions were 15 cm long with an internal diameter of 0.4 cm. The mobile phase consisted of methanol: phosphate buffer (pH 7.8: 0.067 mol dm(-3)) at a ratio of 40: 60 (v/v) and also included Cetrimide (mixed alkyltrimethylammonium bromide) (0.05 mol dm(-3)) as an ion pair reagent. The flow rate was 0.7 ml min(-1) and detection was by ultra-violet light absorption at 278 nm. This assay was used to monitor the degradation rate of DHAA in PN mixtures with and without trace elements over a range of temperatures (5-35 degrees C). Results indicated a first order reaction that was temperature-dependent but trace elements independent.

Dehydroascorbic Acid↗
PubMed2001

Circadian rhythmicity of whole-blood glutathione in healthy subjects.

OBJECTIVES: Physiologic rhythms of antioxidants have been the subject of considerable interest in recent years. Physiologically, it is known that 24-h variability in whole-blood glutathione (GSH) could depend on various factors, such as meal composition, protein dietary content, meal-related hormonal modifications, and stress. Experiments were conducted to determine if the circadian variations previously observed in hepatic concentrations of reduced glutathione in animals also occurred in healthy volunteers. METHODS: The circadian periodicity of whole-blood glutathione was explored. All parameters were measured enzymatically at 4-h intervals over a 24-h period. RESULTS: Circadian rhythms were not found. The rhythms peak for glutathione content occurred at 9 h with a small peak at 21 h. The nadir occurred at 17 h and 1 h. CONCLUSION: These data show that despite this wide distribution of glutathione throughout the day we could not find any significant intertime variability.

Adult↗
PubMed2001

Detection and quantification of HIV-1 specific CD4 helper and CD8 cytotoxic cells: their role in HIV-1-infected individuals and vaccine recipients.

There is a strong link between virus specific CD8 T-cell function and the efficiency of regulatory CD4 helper T cells. Controlling viraemia in HIV-1-infected individuals requires the maintenance of strong CD4 and CD8 T-cell responses. These responses should be elicited by prophylactic vaccination and by postexposure immunotherapy. This review will examine the methods that are available for the detection and quantification of HIV-1 specific CD4 and CD8 T-cell responses. We will also discuss the methods that should be used to identify these responses in HIV-1-infected individuals, seropositive recipients of immunotherapy and seronegative vaccinees. Finally, we will give examples of how responses observed in vitro relate to those known to occur in vivo.

AIDS Vaccines↗
PubMed2001

Candidate vaccines for immunotherapy in HIV.

In this short article we review the immunopathology of HIV infection and delineate the kinds of immune responses seen in acute infection and in long-term nonprogression that are understood to be necessary if the host is to maintain long-term control of the virus. In this context we discuss the potential promise of therapeutic vaccination in HIV infection.

AIDS Vaccines↗
PubMed2001

Practical implications of nutritional support during continuous renal replacement therapy.

Continuous blood membrane interactions during continuous renal replacement therapy cause bioincompatibility and low grade inflammatory reactions with potentially adverse consequences on protein metabolism and immunocompetence. In designing a nutritional program for patients receiving this treatment, these adverse metabolic effects, especially the loss of nutritional substrates, must be considered. This review provides a practical overview of nutritional support in acute renal failure, including assessment techniques, determination of nutrient needs, and appropriate intervention for patient support.

Acute Kidney Injury↗
PubMed2001

Phosphate supplementation for hypophosphataemia and parenteral nutrition.

Routine detection and treatment of acute hypophosphataemia is important in intensive care unit and many other hospitalized patients, but metabolic bone disease and hypophosphataemia are still experienced as a result of parenteral nutrition. A significantly common problem that faces the compounding pharmacist when formulating parenteral nutrition regimens is the difficulty associated with the successful avoidance of calcium phosphate precipitation. Although incorporation of the normal calcium and phosphate requirements into regimens for metabolically stable adults is usually achievable, it can prove impossible in paediatric and neonatal mixtures when using the standard inorganic sources that are currently licensed for use in the UK and USA. In other countries, where organic compounds are routinely available, this problem does not exist.

Bone Diseases↗
PubMed2001

Cysteinyl leukotrienes modulate angiotensin II constrictor effects on aortas from streptozotocin-induced diabetic rats.

Angiotensin II (Ang II) is a vasopressor peptide involved in the pathogenesis of cardiovascular diseases associated with diabetes mellitus. We have previously reported that the 5-lipoxygenase-derived products, particularly the cysteinyl leukotrienes (CysLTs), are involved in Ang II-induced contraction. In this study, we demonstrated that CysLTs contribute to the contraction elicited by Ang II in isolated aortas from streptozotocin-induced diabetic (SS) rats but not from insulin-treated diabetic rats, fructose-fed rats, or control rats. In an organ bath, pretreatment with the 5-lipoxygenase inhibitor (AA861, 10 micromol/L) reduced by 37.6+/-8.2% and 30.1+/-10.9% the Ang II-induced contractions in intact and endothelium-denuded aortic rings, respectively, from SS rats. In contrast, the CysLT(1) receptor antagonist (MK571, 1 micromol/L) or the dual CysLT(1)/CysLT(2) receptor antagonist (BAY-u9773, 0.1 micromol/L) did not affect Ang II-induced contraction. In addition, Ang II induced a 6.2+/-1.5-fold increase in CysLT release through the stimulation of the Ang II type 1 receptor. Furthermore, the urinary excretion of leukotriene E(4) was increased in SS rats (leukotriene E(4), 13.7+/-2.9 ng/24 h [SS rats, n=10] versus 1.5+/-0.5 ng/24 h [control rats, n=6]; P<0.0004). These data suggest the activation of the 5-lipoxygenase pathway in SS rats and the involvement of 5-lipoxygenase-derived products, particularly the CysLTs, in Ang II-induced contraction in aortas from SS rats through stimulation of CysLT receptors different from the well-characterized CysLT(1) or CysLT(2) receptor.

Angiotensin II↗
PubMed2001

Process research in understanding and applying psychological therapies.

OBJECTIVES: Research on the process of psychological therapy aims to demonstrate how therapy works, partly to increase understanding, but primarily to increase effectiveness by pointing to the crucial ingredients which effect change. This paper aims to demonstrate some of the reasons why process research should be undertaken in the attempt to increase therapeutic effectiveness. METHODS: A model of scientific inquiry suggests three broad types of process research: (1) studies which describe behaviours and processes occurring within therapy sessions (exploratory studies); (2) studies which investigate the links between specific psychotherapy processes and treatment outcome (hypothesis testing); (3) studies which examine the links between specific psychotherapy processes and theories of change (theory development). Using this typology, we describe key aspects of process research: what it is; what has been studied; the limitations of existing research. RESULTS: Descriptive studies have deepened understanding of the therapeutic process; however, a large number of reliable process-outcome links have been hard to establish. Comparative studies have been rare. Studies which are linked to models of change and which attempt to track therapist responsiveness are more complex and have been more promising. Most studies are beset by methodological difficulties. CONCLUSIONS: There are a number of promising future research possibilities and methods. Despite methodological challenges, the field is developing and research is encouraging. We argue that process research has a significant place in advancing our understanding of the complexity of therapeutic change, and hence in facilitating theory development and effective therapeutic interventions.

Cognitive Behavioral Therapy↗