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Biomedical subjects

D A Price

Publications and source records attributed to D A Price.

At least 55 records · Page 3Linked to original sources
PubMed2001

Salt intake and non-ACE pathways for intrarenal angiotensin II generation in man.

Angiotensin-converting enzyme (ACE) plays a crucial role in the generation of angiotensin II (Ang II) via conversion from angiotensin I (Ang I). There has been substantial recent interest in non-ACE pathways of Ang II generation in the heart, large arteries, and the kidney. In the case of the human kidney, studied when in balance on a low-salt diet, the renal haemodynamic response to Ang II antagonists substantially exceeds the renal response to ACE inhibitors (ACE-I), suggesting that about 30-40% of Ang II-generation occurs via non-ACE pathways. In this study, we examined the relative contribution of non-ACE pathways, by comparing the response to candesartan and to captopril at the top of the dose-response in normal humans when in balance on a low-salt, as well as a high-salt, diet. As anticipated on a low-salt diet, the increase in renal plasma flow (RPF) in response to candesartan (165+/-14 mL/min/1.73 m2) significantly exceeded the response to captopril (118+/-12 mL/min/1.73 m2; p<0.01). In subjects studied on a high-salt diet, the response to candesartan (97+/-20 mL/min/1.73 m2) also significantly exceeded the response to captopril on the same diet(30+/-15 mL/min/1.73 m2; p<0.01). This remarkable response to candesartan in subjects on a high-salt diet,when compared with the response to captopril,suggests that non-ACE-dependent Ang II generation was influenced less than the classical renal pathway with an increase in salt intake, so that the percentage of Ang II generated via the non-ACE pathway rose to the 60-70% range.

Adult↗
PubMed2000

Early highly active antiretroviral therapy for acute HIV-1 infection preserves immune function of CD8+ and CD4+ T lymphocytes.

Highly active antiretroviral therapy (HAART) has been advocated for the management of primary HIV-1 infection without clear understanding of its immunological effects. Here, we demonstrate that early use of HAART during primary infection preserves HIV-specific CD8(+) T cells physically and functionally while HIV-specific T cell help is sustained. We also show that even transient administration of HAART at seroconversion can preserve HIV-specific immunity. In contrast, delayed initiation of HAART is associated with a progressive loss of HIV-specific CD8(+) T cells and absent HIV-specific T cell help. These results imply that HIV-specific T help is damaged during primary HIV-1 infection. Early drug treatment, which preserves this immunity, also preserves HIV-specific CD8(+) T cells. These results have implications for understanding the early pathogenesis of HIV-1 infection and suggest that acute HIV infection should be treated aggressively and as early as possible.

Amino Acid Sequence↗
PubMed2000

Peptide cotransmitter release from motorneuron B16 in aplysia californica: costorage, corelease, and functional implications.

Many neurons contain multiple peptide cotransmitters in addition to their classical transmitters. We are using the accessory radula closer neuromuscular system of Aplysia, which participates in feeding in these animals, to define the possible consequences of multiple modulators converging on single targets. How these modulators are released onto their targets is of critical importance in understanding the outcomes of their modulatory actions and their physiological role. Here we provide direct evidence that the partially antagonistic families of modulatory peptides, the myomodulins and buccalins, synthesized by motorneuron B16 are costored and coreleased in fixed ratios. We show that this release is calcium-dependent and independent of muscle contraction. Furthermore, we show that peptide release is initiated at the low end of the physiological range of motorneuron firing frequency and that it increases with increasing motorneuron firing frequency. The coordination of peptide release with the normal operating range of a neuron may be a general phenomenon and suggests that the release of peptide cotransmitters may exhibit similar types of regulation and plasticity as have been observed for classical transmitters. Stimulation paradigms that increase muscle contraction amplitude or frequency also increase peptide release from motor neuron B16. The net effect of the modulatory peptide cotransmitters released from motorneuron B16 would be to increase relaxation rate and therefore allow more frequent and/or larger contractions to occur without increased resistance to antagonist muscles. The end result of this modulation could be to maximize the efficiency of feeding.

Action Potentials↗
PubMed2000

Incidence of diabetes mellitus and impaired glucose tolerance in children and adolescents receiving growth-hormone treatment.

BACKGROUND: Growth hormone (GH) contributes to insulin resistance, but whether children treated with GH are at increased risk of diabetes has not been established. We undertook a retrospective analysis of data from an international pharmacoepidemiological survey of children treated with GH to find out the incidence of impaired glucose tolerance and types 1 and 2 diabetes mellitus. METHODS: Reports to the survey of abnormal glucose metabolism were investigated and classified. The incidence and age-distribution of type 1 diabetes were compared with values from a model of reference data. The incidence of type 2 diabetes was compared with data from two reports of children not treated with GH. FINDINGS: 85 (0.36%) of 23333 children were reported with abnormal glucose metabolism. After investigation, 43 had confirmed glucose disorders (11 with type 1 diabetes, 18 with type 2 diabetes, and 14 with impaired glucose tolerance). The incidence and age at diagnosis of type 1 diabetes in children treated with GH did not differ from expected values. The incidence of type 2 diabetes was 34.4 cases per 100000 years of GH treatment which was six-fold higher than reported in children not treated with GH. Type 2 diabetes did not resolve after GH therapy was stopped. INTERPRETATION: GH treatment did not affect the incidence of type 1 diabetes mellitus in any age group. We postulate that the higher than expected incidence of type 2 diabetes mellitus with GH treatment may be an acceleration of the disorder in predisposed individuals.

Adolescent↗
PubMed2000

Effect of ACE inhibition on pressor, renal vascular, and adrenal responses to infusion of angiotensin I in normal subjects eating a low-salt diet.

To examine the influence of angiotensin-converting enzyme (ACE) on pressor, renal vascular, and adrenal responses during angiotensin I (Ang I) infusion, we studied 10 normotensive, healthy men. Each was in balance with a 10-mEq sodium, 100-mEq potassium intake and was studied before and during ACE inhibition with enalapril. Ang I (3, 10, and 30 ng/kg/min) was infused in each subject. Then ACE inhibition was instituted with enalapril for 3 days, which induced the anticipated fall in blood pressure, plasma Ang II, and aldosterone concentration, and rise in renal plasma flow. During ACE inhibition only the 30-ng/kg/min Ang I dose raised plasma Ang II levels. There was a spectrum, however, in the end-organ response to Ang I during ACE inhibition. Responses of plasma aldosterone concentration and blood pressure were in excellent accord with the reduction in Ang II formation. On the other hand, responses of the renal blood supply were substantially less inhibited than anticipated. Under the conditions of this study, ACE inhibition led to nonuniform changes in the response to exogenous Ang I, suggesting intrarenal conversion of Ang I to Ang II.

Adolescent↗
PubMed2000

Monitoring serum insulin-like growth factor-I (IGF-I), IGF binding protein-3 (IGFBP-3), IGF-I/IGFBP-3 molar ratio and leptin during growth hormone treatment for disordered growth.

OBJECTIVE: Serum IGF-I levels are monitored during GH replacement treatment in adults with GH deficiency (GHD) to guide GH dose adjustment and to minimize occurrence of GH-related side-effects. This is not routine practice in children treated with GH. The aim of this study was to evaluate changes in (1) serum IGF-I, IGFBP-3 and IGF-I/IGFBP-3 molar ratio, and (2) serum leptin, an indirect marker of GH response, during the first year of GH treatment in children with disordered growth. DESIGN: An observational prospective longitudinal study with serial measurements at five time points during the first year of GH treatment was carried out. Each patient served as his/her own control. PATIENTS: The study included 31 patients, grouped as (1) GHD (n = 20) and (2) non-GHD (Turner syndrome n = 7; Noonan syndrome n = 4), who had not previously received GH treatment. MEASUREMENTS: Serum IGF-I, IGFBP-3 and leptin levels were measured before treatment and after 6 weeks, 3 months, 6 months and 12 months of GH treatment, with a mean dose of 0.5 IU/kg/wk in GHD and 0.7 IU/kg/wk in non-GHD groups. IGF-I, IGFBP-3 and the calculated IGF-I/IGFBP-3 molar ratio were expressed as SD scores using reference values from the local population. RESULTS: In the GHD group, IGF-I SDS before treatment was lower compared with the non-GHD (-5.4+/-2.5 vs. -1.8+/-1.0; P<0.001). IGF-I (-1.8 SDS +/- 2.2) and IGFBP-3 (-1.1 SDS +/- 0.6) levels and their molar ratios were highest at 6 weeks and remained relatively constant thereafter. In the non-GHD group, IGF-I levels increased throughout the year and were maximum at 12 months (0.3 SDS +/- 1.4) while IGFBP-3 (1.1 SDS +/- 0.9) and IGF-I/IGFBP-3 molar ratio peaked at 6 months. In both groups, IGF-I SDS and IGF-I/IGFBP-3 during treatment correlated with the dose of GH expressed as IU/m2/week (r-values 0. 77 to 0.89; P = 0.005) but not as IU/kg/week. Serum leptin levels decreased significantly during GH treatment in the GHD (median before treatment 4.0 microg/l; median after 12 months treatment 2.4 microg/l; P = 0.02) but not the non-GHD (median before treatment 3.0 microg/l; median after 12 months treatment 2.6 microg/l). In the GHD group, serum leptin before treatment correlated with 12 month change in height SDS (r = 0.70, P = 0.02). CONCLUSIONS: The pattern of IGF-I, IGFBP-3 and their molar ratio during the first year of GH treatment differed between the GHD and non-GHD groups. Calculation of GH dose by surface area may be preferable to calculating by body weight. As a GH dose-dependent increase in serum IGF-I and IGF-I/IGFBP-3 may be associated with adverse effects, serum IGF-I and IGFBP-3 should be monitored routinely during long-term GH treatment. Serum leptin was the only variable that correlated with first year growth response in GHD.

Adolescent↗
PubMed2000

A conceptual framework to guide the development of self-directed, lifelong learning in problem-based medical curricula.

CONTEXT: The information explosion and continual changes in the means of accessing information have reinforced the importance of preparing graduates to direct their own learning throughout their careers. Increasingly, medical schools are turning to problem-based curricula to develop in graduates the capacity to 'self-direct' further learning. PROBLEM: Experience shows that, to achieve this goal, there needs to be consistency in interpretation of the goal and faculty-wide agreement about the way the problem-based curriculum fosters self-direction. SUGGESTED SOLUTION: This paper describes the conceptual framework developed by the Graduate School of Medicine, The University of Queensland, to guide the achievement of self-directed, lifelong learning in a graduate entry, problem-based curriculum. IMPLICATIONS: It may be useful for others who are experiencing difficulties with implementing problem-based curricula, and for those who are contemplating changing to problem-based models.

Clinical Competence↗
PubMed2000

Short-term changes in growth and urinary growth hormone, insulin-like growth factor-I and markers of bone turnover excretion in healthy prepubertal children.

Childhood growth is a non-linear process. To assess whether there is a biochemical correlate of non-linear growth, we have measured free pyridinoline (fPYR) and deoxypyridinoline (fDPYR) excretion in seven healthy prepubertal children, aged 6.1-7.7 years. To examine the link between short-term growth and hormone output, urinary growth hormone (uGH) and insulin-like growth factor-I (uIGF-I) were also measured. Height and weight were measured and a timed overnight urine was collected three times per week from September to July, with results expressed as a weekly change in height (Dheight(w)) or weight (Dweight(w)), and as weekly average hormone or bone marker excretion (uGH(w), uIGF-I(w), fPYR(w), fDPYR(w)). Subject specific SD scores (SDS) were derived for each variable.Dheight(w)and Dweight(w)did not correlate to uGH(w), uIGF-I(w), fPYR(w)or fDPYR(w). Dheight(w)SDS was weakly but significantly correlated to fPYR(w)SDS (r = +0.16;P<0.05) and fDPYR(w)SDS (r = +0.15;P<0.05). The percentage of high frequency (2-4 weeks) variation in uGH(w)excretion, as defined by time series analysis, was correlated with the mean uIGF-I(w)(r = +0.81;P<0.05), which in turn was significantly reduced (92 +/- 38 vs 120 +/- 47 ng;P<0.001) during periods of slow growth (Dheight(w)< 0.05 cm/week). We conclude that in normal children the amount of urinary fPYR, fDPYR, GH and IGF-I does not provide a direct biochemical correlate of growth from week to week. However good growth is associated with a relative increase in fPYR and fDPYR excretion, while poor growth is associated with reduced IGF-I excretion, which in turn is influenced by the temporal secretory pattern of GH over 2-4 weeks.

Amino Acids↗
PubMed2000

Effect of angiotensin II antagonist eprosartan on hyperglycemia-induced activation of intrarenal renin-angiotensin system in healthy humans.

We have previously reported that hyperglycemia in healthy human subjects increased the renal vasodilator response to the angiotensin-converting enzyme inhibitor captopril. This observation raised intriguing possibilities relevant to the pathogenesis of nephropathy in patients with diabetes mellitus. To ascertain whether the effect of captopril was indeed mediated by a reduction in angiotensin II (Ang II) formation, we performed another study in which an Ang II antagonist, eprosartan, was used in place of captopril. Nine healthy subjects were studied in high sodium balance (ie, sodium intake 200 mmol/d). On the first day, the subjects received 600 mg eprosartan orally, and renal plasma flow (RPF) and glomerular filtration rate (GFR) were measured. Glucose was infused intravenously on the second and third study days to increase plasma glucose to a level below the threshold for glycosuria ( approximately 8.8 mmol/L). Eprosartan at a dose of 600 mg or placebo was administered randomly on the second or third study day 1 hour after initiation of glucose infusion. RPF increased (by 76+/-7 mL. min(-1). 1.73 m(-2), P<0.01) in response to sustained moderate hyperglycemia and then increased further (by 147+/-15 mL. min(-1). 1. 73 m(-2), P<0.01) when eprosartan was administered during hyperglycemia. Eprosartan, conversely, did not affect RPF and GFR in normoglycemic subjects. GFR was not affected by either hyperglycemia or eprosartan. Neither plasma renin activity nor plasma Ang II concentration changed during hyperglycemia, suggesting that the hormonal responses responsible for the enhanced renal vasodilator response to eprosartan occurred within the kidney. The enhancement of the renal vasodilator effect of eprosartan during hyperglycemia is consistent with activation of the intrarenal renin-angiotensin system.

Acrylates↗
PubMed2000

Renal hemodynamic and hormonal responses to the angiotensin II antagonist candesartan.

The development of very specific blockers for the angiotensin II type 1 (AT(1)) receptor made it possible to examine the contribution of angiotensin II to normal control mechanisms and disease with a specificity beyond what ACE inhibitors could provide. In the present study, we explored the contribution of angiotensin II to 2 renal mechanisms: renal hemodynamics and the short feedback loop, in which angiotensin II acts as a determinant of renin release. To make that comparison, we studied healthy volunteers in balance on a 10-mmol sodium intake to activate the renin system. Our goal was to compare the relation between the dose of candesartan, an AT(1) receptor blocker, and the renal hemodynamic and hormonal responses. A second goal was to ascertain the relation between time after candesartan administration and the peak response. Twelve healthy subjects (mean age 33+/-2.3 years) in low-sodium balance were administered candesartan in 4-, 8-, 16-, and 32-mg doses. Candesartan produced a dose-related increase in renal plasma flow, with the maximum vasodilator response at 16 mg (142+/-13 mL. min(-1). 1.73 m(-2)) occurring during the first 4 hours after the dose. Likewise, candesartan caused a dose-related rise in plasma renin activity, with 32 mg as the dose producing the greatest response at 4 and 24 hours after administration. The peak plasma renin activity achieved in this study (15.3+/-1.6 ng. L(-1). s(-1); 55.0+/-5.6 ng angiotensin I. mL(-1). h(-1)) was found at the 4- to 8-hour interval after dosing in a subset of subjects (n=5) who received the 16-mg dose 4 hours earlier than the other subjects. On the basis of the difference in the relation between dose and response and the relationship between time after drug administration and response, the determinants of the renal hemodynamic and hormonal response can be said to differ. The remarkable rise in plasma renin activity after candesartan is substantially larger than that in earlier studies with ACE inhibition, providing additional evidence for non-ACE-dependent angiotensin II generation in the kidney.

Adult↗
PubMed2000

Prediction of long-term response to recombinant human growth hormone in Turner syndrome: development and validation of mathematical models. KIGS International Board. Kabi International Growth Study.

It has become common practice to apply GH treatment in short Turner syndrome patients with the objective of promoting growth. The variability in response and the high costs of this treatment demand the individualization and optimization of therapy. Based on 686 prepubertal Turner patients from the Kabi International Growth Study (KIGS; Pharmacia & Upjohn, Inc. International Growth Database), we undertook a multiple regression analysis of height velocity (centimeters per yr) by using various parameters of potential relevance. Derived prediction models for the first 4 yr of GH treatment were validated with 76 additional KIGS patients and 81 patients from Tuebingen, Germany. Among the 6 predictors identified, the most influential variable for first year growth response was the natural log (ln) of the weekly GH dose. The first year growth response was also correlated with age and distance between height and target height (SD score; both negative) and body weight SD, number of GH injections per week, and oxandrolone treatment given additionally (positive). The first year model explains 46% of the variability, with 1 SD of 1.26 cm. For the second to fourth years, 5 predictors were identified: height velocity during previous years, weekly GH dose (ln), weight SD, oxandrolone therapy (all positive), and age (negative). These models explained 32%, 29%, and 30% of the variability, respectively, with SD scores of 1.1, 1.0, and 1.0 cm, respectively. When the models were applied to the other cohorts, no significant difference was noted between observed and predicted responses. Although the parameters used in our models do not entirely explain the variability in the growth response in Turner syndrome, the parameters themselves were clinically relevant to our present understanding and proved to be of high precision. Some of the tested markers, such as karyotype, do not contribute to the growth response. These variables make the models practical and suitable for planning beneficial and cost-effective therapy.

Anabolic Agents↗
PubMed2000

Cytotoxic T lymphocyte responses to human immunodeficiency virus: control and escape.

Effective preventive and therapeutic intervention in individuals exposed to or infected with human immunodeficiency virus (HIV) depends, in part, on a clear understanding of the interactions between the virus and those elements of the host immune response which control viral replication. Recent advances have provided compelling evidence that cytotoxic T lymphocytes (CTLs) constitute an essential component of protective antiretroviral immunity. Here, we review briefly the significance of this work in the context of previous studies, and outline the mechanisms through which HIV evades CTL activity.

Animals↗
PubMed2000

Blunted suppression of plasma renin activity in diabetes.

We have documented, contrary to expectation, that the renin-angiotensin-aldosterone system (RAAS) is stimulated normally by restriction of sodium intake inpatients with Type 2 diabetes mellitus (DM) and hypertension. Conversely, plasma renin activity (PRA)is suppressed less than in normal subjects by a high-salt diet in these patients. Increasing plasma angiotensin II (Ang II) concentration through intravenous Ang II infusion also suppresses renin release, via the short feedback loop. In this study, we sought to ascertain whether the limited renin suppression in Type 2 diabetes mellitus via high-salt intake is a unique defect or part of a more generalised abnormality of PRA suppression. We studied 38 patients with Type 2 DM and hypertension, 158 hypertensive control patients, and 61 normotensive controls. All patients were studied while in metabolic balance on a 10 mEq sodium (Na) diet. The response to the Ang II infusion at 3 ng/kg/min for 45 minutes was measured. We found that PRA fell significantly in normal subjects, from 4.0 +/- 0.33 to 2.5 +/- 0.23 ngAngI/ml/hr (p=0.0056). In patients with essential hypertension, the Ang II infusion also led to a fall in PRA from 3.51 +/- 0.23 to 2.76 +/- 0.17 ng Angl/ml/hr(p=0.014). In patients with DM, despite a similar basal PRA (3.7 +/- 0.40 ng AngI/ml/hr), the infusion of Ang II did nor influence PRA significantly (3.43 +/- 0.42ng AngI/ml/hr; p > 0.77), though these patients had the most robust mean arterial pressure response. Our data are in complete accord with the concept of high intrarenal Ang II in DM and suggest lower systemic Ang II despite comparable PRA.

Adult↗
PubMed1999

Specificity of CTL interactions with peptide-MHC class I tetrameric complexes is temperature dependent.

Tetrameric peptide-MHC class I complexes ("tetramers") are proving invaluable as reagents for characterizing immune responses involving CTLs. However, because the TCR can exhibit a degree of promiscuity for binding peptide-MHC class I ligands, there is potential for cross-reactivity. Recent reports showing that the TCR/peptide-MHC interaction is dramatically dependent upon temperature led us to investigate the effects of incubation temperature on tetramer staining. We find that tetramers rapidly stain CTLs with high intensity at 37 degrees C. We examine the fine specificity of tetramer staining using a well-characterized set of natural epitope variants. Peptide variants that elicit little or no functional cellular response from CTLs can stain these cells at 4 degrees C but not at 37 degrees C when incorporated into tetramers. These results suggest that some studies reporting tetramer incubations at 4 degrees C could detect cross-reactive populations of CTLs with minimal avidity for the tetramer peptide, especially in the tetramer-low population. For identifying specific CTLs among polyclonal cell populations such as PBLs, incubation with tetramers at 37 degrees C improves the staining intensity of specific CTLs, resulting in improved separation of tetramer-high CD8+ cells. Confocal microscopy reveals that tetramers incubated at 37 degrees C can be rapidly internalized by specific CTLs into vesicles that overlap with the early endocytic compartment. This TCR-specific internalization suggests that coupling of tetramers or analogues with toxins, which are activated only after receptor internalization, may create immunotoxins capable of killing CTLs of single specificities.

Body Temperature↗
PubMed1999

IFN-gamma exposes a cryptic cytotoxic T lymphocyte epitope in HIV-1 reverse transcriptase.

The proteasome, an essential component of the ATP-dependent proteolytic pathway in eukaryotic cells, is responsible for the degradation of most cellular proteins and is believed to be the main source of MHC class I-restricted antigenic peptides for presentation to CTL. Inhibition of the proteasome by lactacystin or various peptide aldehydes can result in defective Ag presentation, and the pivotal role of the proteasome in Ag processing has become generally accepted. However, recent reports have challenged this observation. Here we examine the processing requirements of two HLA A*0201-restricted epitopes from HIV-1 reverse transcriptase and find that they are produced by different degradation pathways. Presentation of the C-terminal ILKEPVHGV epitope is impaired in ME275 melanoma cells by treatment with lactacystin, and is independent of expression of the IFN-gamma-inducible proteasome beta subunits LMP2 and LMP7. In contrast, both lactacystin treatment and expression of LMP7 induce the presentation of the N-terminal VIYQYMDDL epitope. Consistent with these observations we show that up-regulation of LMP7 by IFN-gamma enhances presentation of the VIYQYMDDL epitope. Hence interplay between constitutive and IFN-gamma-inducible beta-subunits of the proteasome can qualitatively influence Ag presentation. These observations may have relevance to the patterns of immunodominance during the natural course of viral infection.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1999

Cytotoxic T lymphocytes, chemokines and antiviral immunity.

Evidence that CD8+ CTLs produce chemokines following engagement of viral antigens, and that MIP-1alpha is required for an inflammatory response to virus challenge, suggests that these molecules are key elements in the generation of effective antiviral immunity. Here, David Price and colleagues argue that the antigen-dependent release of chemokines by CTLs provides an elegant mechanism linking localization, amplification and coordination of the antiviral immune response to specific recognition of infected host cells beyond the confines of the lymphoid system.

Animals↗
PubMed1999

Antagonism of cytotoxic T-lymphocyte activation by soluble CD8.

The CD8 co-receptor is important in the differentiation and selection of class I MHC-restricted T cells during thymic development, and in the activation of mature T lymphocytes in response to antigen. Here we show that soluble CD8alphaalpha receptor, despite an extremely low affinity for MHC, inhibits activation of cytotoxic lymphocytes by obstructing CD3 zeta-chain phosphorylation. We propose a model for this effect that involves interference of productive receptor multimerization at the T-cell surface. These results provide new insights into the mechanism of T-cell activation and evidence that CD8 function is exquisitely sensitive to disruption, an effect that might be exploited by molecular therapeutics.

CD3 Complex↗