Biomedical subjects

D A Price

Publications and source records attributed to D A Price.

At least 73 records · Page 4Linked to original sources

PubMed1999

Relationship between serum and urinary insulin-like growth factor-I through childhood and adolescence: their use in the assessment of disordered growth.

OBJECTIVE: Serum insulin-like growth factor-I (sIGF-I) measurement as an index of growth hormone status has become a common test in the investigation of disordered growth. IGF-I may also be measured in the urine. The aims of this study were to investigate the correlation between serum and urinary IGF-I in normal children and compare their use in the evaluation of growth disorders. DESIGN: Normal ranges for serum and urinary IGF-I were devised from a cross-sectional study of normal schoolchildren. These were then used to assess the sensitivity and specificity of serum and urinary IGF-I in the diagnosis of childhood GH deficiency. PATIENTS: A cohort of 333 (M = 156, F = 177) healthy schoolchildren aged 5-19 years were recruited and data previously collected from 22 growth hormone deficient (GHD) and 47 short normal (SN) children were compared with those of the normal children. MEASUREMENTS: Height, weight and pubertal status were assessed in all children. Serum IGF-I (sIGF-I) (n = 305) and total amount of urinary IGF-I excreted overnight (TuIGF-I) (n = 205) were measured by RIA using excess IGF-II to block the interference of IGFBPs. RESULTS: Serum IGF-I was loge transformed and overall levels (geometric mean +/- 1 tolerance factor) were higher in females than males (F: 569 (329, 985) micrograms/l; M: 398 (227, 696) micrograms/l). LogeIGF-I correlated with age (F: r = +0.76, P < 0.001, M: r = +0.71, P < 0.001) and was significantly affected by both sex and Tanner stage of puberty (TS) (both P < 0.001). The distribution of TuIGF-I was normalized by performing a square root transformation (square root of TuIGF-I). square root of TuIGF-I was correlated with age (F: r = +0.36, P < 0.001; M: r = +0.5, P < 0.001) and was significantly affected by TS (P < 0.001). In both sexes there was a highly significant correlation between logeIGF-I and square root of TuIGF-I (F: r = +0.39, P < 0.001; M: r = +0.41, P < 0.001). Using the third centile of our normal ranges as a cut off to identify GHD, sIGF-I had a sensitivity of 82% and specificity of 62%, whereas TuIGF-I had a sensitivity of 18% and specificity of 79%. CONCLUSIONS: This study demonstrates that although urinary IGF-I has no place in the diagnosis of growth disorders, in normal children there is a highly significant relationship between serum and urinary IGF-I with levels of each changing in a similar manner through childhood and adolescence. Thus, TuIGF-I could be used as a valid surrogate for sIGF-I in the physiological assessment of the relationship between IGF-I status and the normal growth process.

Adolescent↗

PubMed1999

A lesson from the introduction of a problem-based, graduate entry course: the effects of different views of self-direction.

OBJECTIVES: Difficulties in the early years of a new curriculum are to be expected as staff and students come to terms with new structures, and with different approaches to teaching and learning. During the first year of implementation of the Graduate Medical Course at the Graduate School of Medicine, The University of Queensland, we experienced our share of 'teething troubles'. One source of difficulty was different interpretations of the concept of 'self-directed learning' as it was to be applied in the new course. This paper presents an analysis of the effects of these differences on the development of the curriculum. DESIGN: An orientation programme was designed to introduce students to staff, facilities and the PBL process. SETTING: The University of Queensland. SUBJECTS: Problem-based learning (PBL) tutors, medical students. RESULTS: The overall effect was to place in jeopardy the achievement of student self-direction and commitment to lifelong learning as a goal of the course. To counter the undesirable effects of different interpretations, we have developed a conceptual framework to promote an agreed understanding of the meaning of self-direction, and to guide review and further development of the curriculum. A further paper describes the framework. CONCLUSIONS: Consistency in interpretation of key concepts is an important factor in the success of problem-based curricula.

Adult↗

PubMed1999

Renal response to captopril reflects state of local renin system in healthy humans.

BACKGROUND: Heightened activity of the renin-angiotensin system has been linked to the development of both essential hypertension and diabetic nephropathy. Blunting of the renal vasoconstrictor response to Ang II, specifically when it is corrected by angiotensin converting enzyme (ACE) inhibition, is a feature which we have employed as a marker for activation of the intrarenal RAS. In this study we tested the hypothesis that variation in the renal vasodilator response to ACE inhibition in healthy humans reflected the variation in angiotensin-mediated renal vasoconstriction provoked by a low-salt diet. METHODS: We studied 20 healthy people (ages 19 to 57; 15 males) who were in balance on a low sodium diet. Ang II was infused for 45 minutes (3 ng/kg/min), followed by 25 mg captopril and a repeat Ang II infusion; PAH clearance was measured at the end of each interval. RESULTS: All subjects responded to captopril with a rise in renal plasma flow (range 43 to 242, mean 118 + 12 ml/min/1.73 m2). Individual vasodilator response to captopril was a strong inverse predictor of the precaptopril vasoconstrictor response to Ang II (P = 0.006, r = -0.59). There was a stronger, positive correlation of the vasodilator response to captopril and enhancement of Ang II responsiveness after captopril (r = 0.57). Plasma renin activity was significantly correlated with captopril response among the large responders (P = 0.003; r = 0.83), but not at all among those with little response. CONCLUSION: These results suggest substantial variation in angiotensin-mediated control of the renal circulation in healthy individuals on a low sodium intake. Variation in the vasodilator response to captopril, correlated with responses to Ang II, provides a measure of that control.

Adult↗

PubMed1999

Regular fluctuations in growth hormone (GH) release determine normal human growth.

Growth hormone (GH) is the principal hormone associated with growth through childhood, but in a normal child the amount of GH secretion does not appear to be critical in the generation of normal growth rates. We have assessed the relationship between growth and urinary GH (uGH) output in a longitudinal study of 29 healthy prepubertal schoolchildren (13 male, 16 female; age 5.7-7.8 years) over 1 year. Height and uGH were measured three times a week. Individual height velocity curves were derived using non-linear regression. Growth was expressed in terms of the total increment over the year (DeltaHt, cm), height velocity standard deviation score (HVSDS) and the average size of individual growth spurts. Urinary GH data (ng) were expressed as a weekly average. Mean uGH did not correlate with stature or growth over the year. However, the coefficient of variation of uGH was correlated with height standard deviation score (HtSDS, r = 0.38, P< 0.05), while the relative constancy of short-term change in uGH (coefficient of incremental change, DeltaINC) was inversely correlated with DeltaHt (r = - 0.44) and HVSDS (r = - 0.42, both P< 0.05) but not with HtSDS. DeltaINC was also inversely correlated with the average size of individual growth spurts derived from the height velocity curves (r = - 0.45, P< 0.05). Using time series analysis to identify rhythms in uGH excretion, a positive correlation was found between the magnitude of rhythms of a period of 2 to 4 weeks and HtSDS (r = 0.40, P< 0.05). These data demonstrate that variability in GH is a more important determinant of normal childhood growth rate than the amount of GH alone. Stature is correlated to the overall variability in GH release, while increment in height and the magnitude of individual growth spurts are influenced by the constancy of the GH profile. This would imply that once the GH dose has been replaced in GH deficiency, optimal growth could only be achieved by varying the pattern of GH administration.

Adolescent↗

PubMed1999

Predicting the response to recombinant human growth hormone in Turner syndrome: KIGS models. KIGS International Board. Kabi International Growth Study.

A mathematical model for predicting the growth response in patients with Turner syndrome who received growth hormone (GH) therapy was developed by analysing data from KIGS, the Pharmacia & Upjohn International Growth Database. A model for year 1 of GH therapy explained 46% of the variability of the growth response, with GH dose being the most important of the predictors of height velocity. In years 2-4 of therapy, height velocity during the previous year was the most important predictor, suggesting that an individual's initial response to GH may determine the height outcome of treatment. Additional predictors of height velocity in years 1-4 of GH therapy included age (negative), weight SDS and additional treatment with oxandrolone. The predictions in all 4 years were highly accurate, as indicated by the low error SDs. However, relatively low predictive power (R) during years 2-4 of treatment suggests the models are missing other parameters that would explain more of the variability of the growth response. These growth prediction models could help clinicians to design individualized treatment regimens, provide realistic expectations of therapy outcomes, and adjust treatment on the basis of detected differences between observed and predicted height velocities.

Body Height↗

PubMed1999

A decade of growth hormone treatment in girls with Turner syndrome in the UK. UK KIGS Executive Group.

Fifteen per cent of children treated with growth hormone (GH) are receiving treatment for Turner syndrome, but few results are available on final height in the UK. In this study, data were obtained from the UK KIGS database for 485 girls with Turner syndrome who were treated from 1986, allowing an audit of practice and outcome over 10 years. Over the decade, the mean age of starting growth hormone treatment fell from 10.4 to 8.5 years and the starting dose increased from 0.55 to 0.95 IU/kg/week. The frequency of injections increased from three to six or seven/week. Some girls received suboptimal doses, which also differed depending on whether they were based on weight or surface area. To assess what height gain might be expected at final height, all 52 girls who were prepubertal at the start of treatment, which continued for four years or more, and who had reached final height or had a growth velocity < 2 cm/year were selected. Their mean gain in final height was 5.2 cm and the GH dose was 0.78 IU/kg/week over 5.8 years. Final height gain correlated significantly with duration of treatment, total dose received, and first year response, which itself related to starting dose. This audit shows a changing pattern of treatment over the past decade, which in many instances has been inadequate. When treatment starts before puberty and continues through to final height, with a dose of 30 IU/m2/week in six or seven injections, a mean increase in final height of 5 cm or more would be expected.

Adolescent↗

PubMed1999

Hyperglycemia and angiotensin-mediated control of the renal circulation in healthy humans.

Type 1 and type 2 diabetics have an enhanced renal vasodilator response to angiotensin-converting enzyme (ACE) inhibition despite suppressed plasma renin activity (PRA), indicating possible activation of the intrarenal renin angiotensin system. To investigate the role of hyperglycemia, we evaluated the renal hemodynamic response to ACE inhibition in 9 healthy subjects in high-salt balance after steady-state hyperglycemia (8.4+/-1 mmol/L) was achieved via intravenous glucose administration. Renal plasma flow (RPF) and glomerular filtration rate (GFR) responses to captopril and to angiotensin II (Ang II) were measured as paraminohippuric acid and inulin clearances. Hyperglycemia produced a significant increase in RPF of 117 mL. min-1. 1.73 m-2 after 90 minutes but not GFR. Administration of captopril at a dose of 25 mg during glucose infusion led to an increase in RPF of 173+/-24 mL. min-1. 1.73 m-2 (P<0.01) but did not significantly change RPF in the absence of hyperglycemia (7+/-21 mL. min-1. 1.73 m-2). Captopril did not alter GFR in the presence or absence of hyperglycemia. Ang II infusion during hyperglycemia decreased RPF by 45+/-16 mL. min-1. 1. 73 m-2, and this was significantly enhanced by captopril (-98+/-26 mL. min-1. 1.73 m-2, P<0.05). In contrast, there was no enhancement of the vasoconstrictor response to Ang II in the absence of hyperglycemia. PRA did not change with hyperglycemia. Enhancement of renal vasodilation during hyperglycemia by captopril without alteration of PRA suggests activation of the intrarenal renin angiotensin system.

Adult↗

PubMed1999

Derivation and validation of a mathematical model for predicting the response to exogenous recombinant human growth hormone (GH) in prepubertal children with idiopathic GH deficiency. KIGS International Board. Kabi Pharmacia International Growth Study.

Postmarketing surveillance studies of recombinant human GH therapy, such as the Kabi Pharmacia International Growth Study (KIGS; Pharmacia & Upjohn, Inc., International Growth Database), have accumulated extensive data concerning the characteristics and growth outcomes of children with various causes of short stature. These data provide an opportunity to analyze the factors that determine responsiveness to GH and allow the development of disease-specific growth prediction models. We undertook a multiple regression analysis of height velocity (centimeter per yr) with various patient parameters of potential relevance using data from a cohort of 593 prepubertal children with idiopathic GH deficiency (GHD) from the KIGS database. Our aim was to produce models that would have practical utility for predicting prepubertal growth during each of the first 4 yr of GH replacement therapy. These models were validated by a prospective comparison of predicted and observed growth outcomes in an additional 3 cohorts of prepubertal children with idiopathic GHD: 237 additional KIGS patients, 29 patients from the Australian OZGROW study, and 33 patients from Tubingen, Germany. The most influential variable for first year growth response was the natural log (ln) of the maximum GH response during provocation testing, which was inversely correlated with height velocity. The first year growth response was also inversely correlated with chronological age and height SD score minus midparental height SD score. First year growth was positively correlated with body weight SD score, weekly GH dose (ln), and birth weight SD score. Two first year models were developed using these parameters, 1 including and 1 excluding the maximum GH response to provocative testing. The former model explained 61% of the response variability, with a SD of 1.46 cm; the latter model explained 45% of the variability, with a SD of 1.72 cm. The two models gave similar predictions, although the model excluding the maximum GH response to testing tended to underpredict the growth response in patients with very low GH secretory capacity. For the second, third, and fourth year growth responses, 4 predictors were identified: height velocity during the previous year (positively correlated), body weight SD score (positively correlated), chronological age (negatively correlated), and weekly GH dose (ln; positively correlated). The models for the second, third, and fourth year responses explained 40%, 37%, and 30% of the variability, respectively, with SDs of 1.19, 1.05, and 0.95 cm, respectively. When the models were applied prospectively to the other cohorts, there were no significant differences between observed and predicted responses in any of the cohorts in any year of treatment. The fourth year response model gave accurate prospective growth predictions for the fifth to the eighth prepubertal years of GH treatment in a subset of 48 KIGS patients. Analyses of Studentized residuals provided further validation of the models. The parameters used in our models do not explain all of the variability in growth response, but they have a high degree of precision (low error SDs). Moreover, the parameters used are robust and easily accessible. These properties give the models' practical utility as growth prediction tools. The availability of longitudinal, disease-specific models will be helpful in the future for enabling growth-promoting therapy to be planned at the outset, optimized for efficacy and economy, and individualized to meet treatment goals based on realistic expectations.

Child↗

PubMed1999

The paradox of the low-renin state in diabetic nephropathy.

Although diabetic nephropathy is often a low renin state, the renin system appears to be implicated in its pathogenesis. In this study, it was hypothesized that the low plasma renin activity (PRA) is misleading, masking and perhaps reflecting an activated intrarenal renin system. PRA and renal vascular responses (inulin and para-aminohippurate clearance) to graded doses of an angiotensin II (AngII) antagonist, irbesartan, were assessed in eight healthy volunteers and 12 patients with type 2 diabetes mellitus and nephropathy on a 10 mmol Na intake, to activate the renin system. Basal PRA was suppressed in type 2 diabetes mellitus compared with the healthy subjects (0.58 +/- 0.14 versus 1.58 +/- 0.28 ng/L per s, mean +/- SEM; P < 0.01). Despite the low PRA, renal perfusion rose more in response to irbesartan in type 2 diabetes mellitus (714 +/- 83 to 931 +/- 116 ml/min; P = 0.002) than normal (624 +/- 29 to 772 +/- 49 ml/min; P = 0.008). The youngest patients were hyperfiltrating and showed the largest rise in renal plasma flow in response to irbesartan, whereas renal plasma flow rose less and GFR fell in patients with low basal GFR. PRA rose in response to irbesartan more gradually in the patients with type 2 diabetes mellitus, but ultimately matched the normal response. To account for the apparent paradox of a heightened renal hemodynamic response to an AngII antagonist in the face of a low PRA in type 2 diabetes mellitus, and the rise in PRA following the AngII antagonist, it is proposed that there is increased intrarenal AngII production in type 2 diabetes mellitus. This increase could account for suppressed circulating renin, the exaggerated renal vasodilator response to irbesartan, and the therapeutic effectiveness of interrupting the renin system in diabetic nephropathy.

Adult↗

PubMed1999

Osmoregulation and FMRFamide-related peptides in the salt marsh snail Melampus bidentatus (Say) (Mollusca: Pulmonata).

The pulmonate snail Melampus bidentatus occupies the high intertidal zone of salt marshes in a nearly terrestrial environment. The hemolymph osmolarity of the snails collected in the field paralleled that of the adjacent water and was affected by the tides and precipitation. The snails initially gained or lost weight when submerged in hypo- or hyperosmotic media, respectively, but returned to their original weight after 24 h. The content of their immunoreactive (IR)-FMRFamide-Related Peptides (FaRPs) was measured in various tissues by radioimmunoassay, and IR-FaRPs were found in every tissue analyzed. The subesophageal part of the central nervous system (CNS) contained more IR-FaRPs than the supraesophageal part, and the kidney and the tissues of the reproductive tract contained more than other peripheral tissues. The levels of IR-FaRPs in the CNS, kidney, and hemolymph were higher in snails that were immersed in higher concentrations of seawater. Many IR neurons are present in all ganglia of the CNS except the pleural ganglia, and IR neurites are extensively distributed within the CNS and its connective tissue sheath. The visceral nerve from the visceral ganglion is immunoreactive and could be seen to innervate the kidney, which contains IR-varicosities. An osmoregulatory role for the FaRPs is suggested.

Animals↗

PubMed1999

The state and responsiveness of the renin-angiotensin-aldosterone system in patients with type II diabetes mellitus.

We have recently reported a combination of renal features that suggests independent angiotensin-mediated control of the renal circulation in the majority of hypertensive patients with type II diabetes. To ascertain whether other tissue elements of the renin-angiotensin-aldosterone system (RAAS) also were activated, we examined the adrenal response to angiotensin II (AngII) infusion on a low salt diet. We assessed also the renin response to the upright position in patients on a low salt diet and renin suppression in patients on a high salt diet. We compared responses in 42 hypertensive patients with type II diabetes (53.1 +/- 1.4 years, mean +/- SEM), 25 healthy controls (52.6 +/- 4.4 years); and 137 essential hypertensives without diabetes (43.3 +/- 1.2 years). A low renin state, defined as a plasma renin activity (PRA) <2.5 ng angiotensin I (AI)/mL/h after 5 to 7 days on a 10-mmol Na diet and 2 h of upright posture, was found in 21% of the essential hypertensives, but in only 14% of patients with type II diabetes. On this diet, PRA increased from 2.7 +/- 0.4 supine to 10.1 +/- 1.3 ng AI/mL/h upon standing in healthy subjects. In patients with type II diabetes, PRA was 3.6 +/- 0.4 and increased to 9.1 +/- 1.0 ng AI/mL/h. On a high salt (200 mmol) diet, healthy subjects showed the expected PRA suppression (0.3 +/- 0.1), but in patients with type II diabetes the PRA was less suppressed (1.2 +/- 0.3 ng AI/mL/h; P = .003). Thus, in most hypertensive patients with type II diabetes the RAAS shows normal activation, but is poorly suppressible. AngII infused intravenously to assess adrenal responsiveness in patients on a low salt diet caused an essentially identical increase in aldosterone concentration in patients with type II diabetes (21.1 +/- 1.7 to 44.0 +/- 5.9 ng/dL) and in essential hypertension (20.6 +/- 1.4 to 43.7 +/- 2.8 ng/ dL). The frequency of nonmodulation assessed as a blunted adrenal response to AngII infusion was identical in type II diabetes (47%) and in essential hypertension (46%) after exclusion of the low renin patients. Thus, at the level of one tissue renin system, the adrenal glomerulosa, responses were unaltered in patients with type II diabetes. The relative unresponsiveness of the renal blood supply to infused AngII in type II diabetes in association with an enhanced renal vasodilator response to angiotensin converting enzyme inhibition probably reflects local, intrarenal actions secondary to the diabetic state. The infrequency of a low renin state, and the inappropriately high renin levels on a high salt intake, provide a rational basis for pharmacologic interruption of the renin system to treat patients with type II diabetes.

Adult↗

PubMed1999

Cytotoxic T lymphocytes and viral evolution in primary HIV-1 infection.

Efforts to develop immune-based therapies for HIV infection have been impeded by incomplete definition of the immunological correlates of protection. Despite many precedents demonstrating that CD8(+) cytotoxic T lymphocytes are key mediators of protective anti-viral immunity in non-human animal models, direct evidence that these effector cells control viral replication in HIV-1 infection has remained elusive. The first part of this paper describes a detailed immunological and genetic study founded on evolutionary considerations. Following infection with HIV-1, virus variants which escaped recognition by autologous cytotoxic T lymphocytes were shown to possess a selection advantage within the host environment. Cytotoxic T lymphocytes therefore exert anti-viral pressure in vivo. This observation provides compelling evidence that cytotoxic T lymphocytes comprise a significant element of anti-retroviral immunity. Subsequently, the quantification of peripheral cytotoxic T lymphocyte frequencies utilizing peptide-(human leucocyte antigen class I) tetrameric complexes is described. Five patients with qualitatively similar immunodominant cytotoxic T lymphocyte responses during symptomatic primary HIV-1 infection were studied longitudinally. Expansions of virus-specific CD8(+) lymphocytes comprising up to 2% of the total CD8(+) T cell population were observed in the acute phase of infection. Antigenic load was identified as an important determinant of circulating HIV-1-specific CD8(+) lymphocyte levels; however, significant numbers of such cells were also found to persist following prolonged therapeutic suppression of plasma viraemia. In addition, an analysis of antigenic sequence variation with time in this case series suggests that the early administration of combination anti-retroviral therapy may limit HIV-1 mutational escape from host cytolytic specificities. The implications of these preliminary data are discussed. The data presented suggest that vaccination protocols should aim to elicit vigorous cytotoxic T lymphocyte responses to HIV-1. Attempts to stimulate polyvalent responses to mutationally intolerant epitopes are likely to be most effective. Optimal management of HIV-1 infection requires an understanding of dynamic host-virus interactions, and may involve strategies designed to enhance cytotoxic T lymphocyte activity following periods of anti-retroviral drug therapy.

Acute Disease↗

PubMed1998

FMRFamide-related peptides, partial serotonin depletion, and osmoregulation in Helisoma duryi (Mollusca: Pulmonata).

Serotonergic neurons were studied by specific histological methods, and neurons containing Phe-Met-Arg-Phe-NH2 (FMRFamide)-related heptapeptides were identified with an antiserum specific for these substances in the central nervous system of the freshwater snail Helisoma duryi. Serotonergic neurons and their axons are present in all of the ganglia (paired buccal, cerebral, pedal, pleural, parietal, and single visceral) and major nerves of the central nervous system. Large neurons containing FMRFamide-related peptide immunoreactivity are located in the left parietal and visceral ganglia, whereas a few small neurons are located in the cerebral and pedal ganglia. Both serotonergic and FMRFamide-related peptide-immunoreactive dendrites and varicosities were observed in the kidney. A second antiserum with high affinity for FMRFamide-related heptapeptides was used to measure the levels of the immunoreactive material in various tissues, and such material was found in every tissue analyzed. When snails were exposed to a medium isosmotic to their hemolymph, the levels of immunoreactive FMRFamide-related peptides increased in the hemolymph, central nervous system, mantle, and kidney. Injection of dihydroxytryptamine, which is known to deplete serotonin content in the snail, also reduced the levels of FMRFamide-related-immunoreactive material in the above tissues. Therefore, serotonin may influence the levels of FMRFamide-related peptides in tissues by regulating the rate of their synthesis, axonal transport, or release. Both serotonin and FMRFamide-related peptides could be involved in osmoregulation.

5,6-Dihydroxytryptamine↗

PubMed1998

Antigen-specific release of beta-chemokines by anti-HIV-1 cytotoxic T lymphocytes.

A major advance in understanding human immunodeficiency virus (HIV) biology was the discovery that the beta-chemokines MIP-1 alpha (macrophage inflammatory protein-1 alpha), MIP-1 beta (macrophage inflammatory protein-1 beta) and RANTES (regulated on activation, normal T-cell expressed and secreted) inhibit entry of HIV-1 into CD4+ cells by blocking the critical interaction between the CCR5 coreceptor and the V3 domain of the viral envelope glycoprotein gp120 [1,2]. CD8+ lymphocytes are a major source of beta-chemokines [3], but the stimulus for chemokine release has not been well defined. Here, we have shown that engagement of CD8+ cytotoxic T lymphocytes (CTLs) with HIV-1-encoded human leukocyte antigen (HLA) class I-restricted peptide antigens caused rapid and specific release of these beta-chemokines. This release paralleled cytolytic activity and could be attenuated by naturally occurring amino acid variation within the HLA class I-restricted peptide sequence. Epitope variants that bound to appropriate HLA class I molecules but failed to stimulate cytolytic activity in CTLs also failed to stimulate chemokine release. We conclude that signalling through the T-cell receptor (TCR) following binding of antigen results in beta-chemokine release from CTLs in addition to cytolytic activity, and that both responses can be abolished by epitope mutation. These results suggest that antigenic variation within HIV-1 might not only allow the host cell to escape lysis, but might also contribute to the propagation of infection by failing to activate beta-chemokine-mediated inhibition of HIV-1 entry.

Chemokine CCL4↗

PubMed1998

The influence of antigenic variation on cytotoxic T lymphocyte responses in HIV-1 infection.

The propensity of HIV-1 for genetic variation, a consequence of error-prone reverse transcription combined with high rates of replication, is thought to contribute to the establishment of persistent infection in the host despite the presence of a vigorous antiviral immune response. Protective immunity to viruses is mediated primarily by cytotoxic T lymphocytes, which recognize viral peptides of 8-11 amino acids bound to major histocompatibility complex class I molecules on the surface of infected cells. In this review we examine the mechanisms by which mutation within peptide antigen-encoding regions of the viral genome enables HIV-1 to evade recognition by virus-specific cytotoxic T lymphocytes. The discussion is relevant to other genetically unstable viruses and more generally to intracellular pathogens of variable antigenicity.

Antigenic Variation↗

PubMed1998

Mortality in patients with congenital adrenal hyperplasia: a cohort study.

OBJECTIVE: To determine mortality in patients with congenital adrenal hyperplasia (CAH) compared with that in the general population. DESIGN: We identified 333 children with CAH, treated at several pediatric endocrinology departments in the United Kingdom since 1964, and monitored their mortality to mid 1996. Standardized mortality ratios were calculated, comparing mortality in the cohort with that in the general population, adjusted for sex, age, and calendar period. RESULTS: All-cause mortality in the cohort was 3 times that expected. Mortality was significantly increased at ages 1 to 4 years (standardized mortality ratio = 18.3) but not at older ages and was significantly increased in patients of Indian-subcontinent ethnicity (standardized mortality ratio = 20.4), particularly in girls. From case notes and death certificates, it appears that most deaths were caused by adrenal crisis, often after infection. CONCLUSIONS: Although survival of patients with CAH has greatly improved since steroid therapy has been used, this disease can still have fatal consequences. The high mortality rate in Indian ethnic girls may well reflect lack of parental acceptance and understanding of the disease, as well as of the action required when their child becomes acutely ill. Better communication with and education of parents of children with CAH, especially those from immigrant ethnic minorities, is important.

Adolescent↗

PubMed1998

Identification and characterization of a myomodulin-like peptide in the leech.

A novel myomodulin-like peptide, GMGALRLamide, has been purified and sequenced from extracts of 1000 medicinal leech nerve cords. Synthetic leech myomodulin-like peptide blocked the specific staining pattern of leech ganglia by the antiserum against Aplysia myomodulin A PMGMLRLamide. Moreover, the synthetic leech myomodulin-like peptide GMGALRLamide showed identical neuronal modulation effect on the giant leech Retzius cell compare to that by the synthetic Aplysia myomodulin A PMGMLRLamide.

Amino Acid Sequence↗

PubMed1998

Development of gastrointestinal beta2-microglobulin amyloidosis correlates with time on dialysis.

Dialysis-associated beta2-microglobulin (beta2m) amyloidosis affects predominantly musculoskeletal tissue, but visceral involvement also occurs. To evaluate the clinical significance and prevalence of gastrointestinal beta2m amyloidosis, we studied hemodialysis patients admitted for gastrointestinal-related complaints. Hemodialysis patients (excluding those with non-beta2m amyloidosis) who were admitted with gastrointestinal complaints from 1984 to 1994 were identified. Gastrointestinal tissues from patients with available autopsy or surgical specimens were examined using hematoxylin and eosin stain, Congo red stain, and beta2m immunostain. Each case was evaluated independently by two pathologists and scored for quantity and location of beta2m amyloid and associated pathology. Of 24 patients, eight (four men and 4 women) had beta2m amyloid deposits within the gastrointestinal tract. Acute clinical presentation ranged from abdominal pain to gastrointestinal bleeding and was not significantly different for patients with or without gastrointestinal beta2m amyloid deposits. However, the mean time on dialysis of 15.3 +/- 5.7 years (range 6-24 years) for patients with gastrointestinal beta2m amyloidosis was significantly greater than that of patients without gastrointestinal beta2m amyloidosis (10.5 +/- 7.0 years, range <1 to 22 years, p < 0.05). Vascular histopathology ranged from mild focal thickening of vessel walls to massive vascular beta2m amyloid deposition with thrombosis. Extravascular beta2m amyloid ranged from mild to severe with marked expansion of the submucosa. Mucosal pathology ranged from none to severe ulceration. The degree of beta2m amyloid and the associated pathology tended to increase in severity with time on dialysis. Gastrointestinal beta2m amyloid deposition is an underappreciated complication of chronic hemodialysis that is significantly associated with increased time on dialysis. Gastrointestinal beta2m amyloidosis should be considered in any patient on hemodialysis 10 years or more who has gastrointestinal symptoms and can be identified in resection specimens as well as some biopsy specimens. Congo red stain and beta2m immunostains may be necessary for sensitive histopathologic evaluation of gastrointestinal beta2m amyloidosis.

Adult↗