Search PubMed⌕ Search

Biomedical subjects

C D Goonasekera

Publications and source records attributed to C D Goonasekera.

At least 19 recordsLinked to original sources
PubMed2000

Vascular endothelial cell activation associated with increased plasma asymmetric dimethyl arginine in children and young adults with hypertension: a basis for atheroma?

The mechanism behind the development of vascular complications of hypertension in the young human remains unclear. To explore the role of vascular endothelium-generated nitric oxide (a known mediator of leucocyte-platelet-endothelial interactions) in this context, we investigated markers of endothelial activation (soluble vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), P-selectin, E-selectin), and von Willebrand factor and the plasma level of the endogenous nitric oxide inhibitor asymmetric dimethyl arginine (ADMA) in a group of 31 (17 male, mean age 9.4 years) hypertensive and 9 (4 male, mean age 9.1 years) healthy, normotensive children and young adults. We found raised levels of ADMA (mean (SEM) 235 (32) n mol/l) and VCAM-1 (median (range) 1237 (675-2700) ng/ml) in the plasma of hypertensive subjects compared with those of normotensives (ADMA, 103 (7) n mol/l and VCAM-1, 1005 (425-1650) ng/ml, respectively). Furthermore, in hypertensive subjects, higher VCAM-1 concentrations (r = 0.66, p < 0.001) and vWF concentrations (r = 0.37, p = 0.04) were significantly associated with a higher plasma ADMA level. Therefore, an isolated increase in plasma VCAM-1 in hypertensives in association with raised ADMA may signify a selective "non-inflammatory" endothelial activation triggered by endothelial nitric oxide synthase inhibition. Since VCAM-1 is implicated in the origins of atherosclerosis, ADMA may be an important contributory factor in increasing the risk of atheroma formation in hypertensive children and young adults.

Adolescent↗
PubMed1998

Vincristine and focal segmental sclerosis: do we need a multicentre trial?

Over the last 10 years, eight children have received vincristine for the treatment of steroid- and cyclophosphamide-resistant nephrotic syndrome at Great Ormond Street Hospital for Children, London. We present our experience of these eight cases and put forward a case for reassessing the effectiveness of vincristine in this disorder. In our series, two children treated with vincristine achieved complete remission with preserved renal function, including relapses in one. Both had primary steroid- and cyclophosphamide-resistant focal segmental glomerulo sclerosis (FSGS). Of the other cases, four also had primary FSGS, one familial FSGS and one mesangioproliferative glomerulonephritis. We discuss in general the pros and cons of vincristine therapy in nephrotic syndrome versus the cytotoxic agents that are currently used and the differences in clinical features among the responders and non-responders in this small group. In addition, we explore why this may have occurred and summarise the literature over the last 25 years, where vincristine appeared to have been beneficial, especially in secondary forms of nephrotic syndrome associated with malignancy. We conclude that vincristine therapy warrants re-examination as it could be a valuable alternative therapeutic agent in some cases of FSGS with relatively minor side effects.

Child, Preschool↗
PubMed1998

Vascular endothelium and nitric oxide in childhood hypertension.

Vascular endothelium releases nitric oxide (NO), an important vasodilator that is continuously synthesised by the constitutive enzyme, endothelial nitric oxide synthase (NOS). This maintains a constant vasodilator tone which is diminished in adult hypertension, due to reduced endothelium-dependent vascular relaxation, which is NO dependent. In childhood, however, hypertension is often secondary, and normalisation of blood pressure by removal of cause (e.g. renal artery stenosis, catecholamine-producing tumour) suggests reversibility of endothelial dysfunction, if it is present. Raised plasma levels of endogenous inhibitors have been found, especially in children with secondary hypertension due to renal parenchymal and renovascular disease, and may contribute to hypertension by more than just inhibition of vascular NO release; e.g. by reduction of glomerular filtration rate and promotion of salt and water retention. These inhibitors also modulate renin release, which may be of relevance in cardiovascular physiology, and may also interfere with the anti-platelet properties of NO, increasing the likelihood of vascular thrombotic events. NO inhibitors also promote endothelial activation, with increased expression of adhesion molecules that may form seedlings of atherosclerosis. In chronic renal impairment, accumulation of NO inhibitors may contribute to hypertension. Efficient long-session dialysis helps better interdialysis control of blood pressure in these subjects, independent of salt and water removal, suggesting that removal of such vasoactive agents may be important for efficient blood pressure control. There are a few studies assessing NO generation in hypertensive children via plasma nitrite and nitrate, the NO end products, which suggest normal or increased production as opposed to a reduction, perhaps as a compensatory phenomenon. In the treatment of hypertension, nitroprusside and nitrates exert their actions via NO donation. Excessive production of NO (usually via inducible NOS) or excessive administration (nitrovasodilators) can be cytotoxic and may cause hypotension and shock, as in severe sepsis. NOS inhibitors and NO therefore appear to play a crucial role in aetiology, complications and therapy of childhood hypertension.

Child↗
PubMed1998

Reflux nephropathy and hypertension.

Renal scarring associated with vesico-ureteric reflux (VUR), most commonly detected in young children, is associated with a significant risk of developing hypertension in later life. Hypertension in reflux nephropathy contributes significantly to morbidity including deterioration of renal function. The mechanism of onset of hypertension is not clear although abnormalities of the renin-angiotensin system and sodium/potassium ATPase activity have been described in some cases. It is becoming clear that radiologically detectable renal scars or small kidneys may histologically indicate a variety of diagnoses. Prediction of the risk of developing hypertension in individual cases is difficult and therefore regular follow-up remains the only current means of recognising these subjects. Although prevention of renal scar development in children with VUR may offer some benefit in reducing the incidence of hypertension, there is no uniform action that can definitely achieve this, particularly in the very young, before any urinary infection occurs. Primary VUR seems to be a disorder with mendelian dominant inheritance and location of the gene may offer some hope of early identification within certain families. Timely introduction of preventative measures may then be possible even though reservations exist about their effectiveness.

Adult↗
PubMed1998

Performance of a new blood pressure monitor in children and young adults: the difficulties in clinical validation.

The aim of this study was to assess the performance of a new ambulatory blood pressure monitor (Dynapulse 5000A) in children and young adults. The reference methods, i.e. the mercury-Doppler (Hg-D) method of blood-pressure measurement (recommended for less than 5-year-old children by the British Hypertension Society criteria) and the mercury-auscultation (Hg-A) technique (recommended for 5 years and above) were initially compared utilizing 132 concomitant systolic blood pressure (SBP) readings taken among 44 subjects (3 in each) aged 2-30 years. Hg-D over-read SBP above that of the conventional Hg-A by a mean of 5.25 mmHg (95% confidence interval (CI) 4.11, 6.4). This difference in measurement between the two techniques was also significantly (p = 0.01) related to age. [Difference in mmHg = 7.83 (95% CI 5.53, 10.12) -0.30 (95% CI -0.54, -0.07) age in years.] The Dynapulse 5000A was therefore validated only against Hg-D throughout the age range and was undertaken utilizing 468 concomitant resting SBP measurements taken among 59 subjects (supine or sitting) using a 'T' system. The Dynapulse was found to give higher SBP readings (average 13.5 mmHg) than Hg-D sphygmomanometry. Although the differences were not dependent on the age of the child, the pulse rate or the body mass index, there was a significant drift in the differences with time (-0.05 mmHg/day). Repeatability of each of the measurement methods calculated utilizing two or three consecutive recordings taken at 1-min intervals showed that variability between repeated measurements made with the Dynapulse (14.8%) was greater than for Hg-D. Repeatability coefficient of the Hg-D (11.2%) was also less than ideal for a reference method. We conclude that Dynapulse 5000A over-reads SBP above that detected by Hg-D, but cannot be fairly graded by British Hypertension Society criteria due to the inconsistency and poor repeatability of the recommended reference methods.

Adolescent↗
PubMed1998

Reflux nephropathy.

Explore the source record for details and available documents.

Abnormalities, Multiple↗
PubMed1998

15-year follow-up of reflux nephropathy by imaging.

Reflux nephropathy i. e. renal scarring associated with vesico-ureteric reflux and urinary tract infection is primarily a diagnosis based on renal imaging. It is well known to be associated with hypertension and renal failure. This has led to regular long-term follow-up of patients, clinically and radiologically. We report the findings of renal imaging in a cohort of 37 patients with reflux nephropathy 15 or more years after successful surgical correction of vesico-ureteric reflux. The degree of renal scarring had been assessed and recorded at the beginning of the study utilizing a score on the original X-ray films. The scar scores of the current intravenous urography (IVU) imaging underestimate the degree of scarring in 35% of cases when compared with the previously recorded scar scores of the original IVU images suggesting a reduction in the renal scar score in some cases over the years. In the current review, concomitant renal images obtained by IVU and 99mTc dimercapto succinic acid (DMSA) scanning were in agreement for scar scoring in only 50% of cases. The original scar score by IVU or the current scar score by either technique does not correlate with blood pressure, urine albumin excretion or glomerular filtration rate (GFR). We conclude that serial long-term two-dimensional renal imaging in children with damaged kidneys who no longer have vesico-ureteric reflux, does not provide additional information that will alter clinical management. However, the changes in renal volume and echogenicity were not assessed in this study.

Adult↗
PubMed1997

Nitric oxide synthase inhibitors and hypertension in children and adolescents.

OBJECTIVE: To establish the role played by the circulating nitric oxide synthase inhibitors N(G)-monomethyl-L-arginine (L-NMMA), asymmetrical dimethyl arginine (ADMA) and symmetric dimethyl arginine (SDMA) and its association with hypertension of children and adolescents. DESIGN: We measured plasma concentrations of L-NMMA, ADMA and SDMA in 38 hypertensives (median age 7.7 years) and in nine healthy normotensive controls (median age 8.2 years) using high-performance liquid chromatography. In addition, their plasma renin activity was determined. The subjects' glomerular filtration rates were calculated from plasma creatinine and height measurements. To determine the vasoactive potency of the arginine analogues, concentration-response curves were plotted for the responses in isolated endothelium-intact and endothelium-denuded mouse aortic rings that had been pre-contracted by administration of a threshold concentration of phenylephrine. RESULTS: Plasma ADMA and SDMA concentrations in members of the hypertensive group [0.23 +/- 0.03 and 1.37 +/- 0.06 micromol/l, respectively (means +/- SEM)] were significantly higher than those in members of the control group (ADMA 0.10 +/- 0.01 micromol/l and SDMA 1.18 +/- 0.06 micromol/l). Plasma concentrations of L-NMMA were similar in members of the hypertensive (0.21 +/- 0.01 micromol/l) and control (0.18 +/- 0.02 micromol/l) groups. The glomerular filtration rate of the hypertensive group was below normal [70.4 +/- 5.4 ml/min per 1.73 m2 (mean +/- SEM)] and was significantly associated with elevated plasma concentrations of ADMA (r = -0.77, P < 0.001), SDMA (r = -0.38, P = 0.02) and L-NMMA (r = 0.35, P = 0.03). Higher plasma ADMA concentrations were associated with a lower plasma renin activity (r = -0.36, P = 0.04). The vasoactive potencies of ADMA (concentration for half-maximal effect with the endothelium intact 25.4 +/- 7.1 micromol/l) and L-NMMA (concentration for half-maximal effect with the endothelium intact 8.2 +/- 2.9 micromol/l) was significantly (P < 0.05) greater than that of SDMA. Both ADMA and L-NMMA (at 3 micromol/l concentrations) initiated a significant vasocontractile response from baseline (P = 0.03 and P < 0.001, respectively). These effects were absent after the endothelium had been removed. SDMA had no effect. CONCLUSIONS: Plasma ADMA and SDMA levels are increased in hypertensive children. By inference from in-vitro data, ADMA appears to attain sufficient concentrations to produce a significant change in vascular tone and hence might play a role in the pathophysiology of childhood hypertension.

Adolescent↗
PubMed1997

Nitric oxide activity in childhood hypertension.

OBJECTIVES: To investigate nitric oxide (NO) activity in childhood hypertension using nitrite and nitrate (NOx) concentrations in plasma as an index of nitric oxide generation. DESIGN: Cross sectional study. SETTING: Tertiary care paediatric centre and district general hospitals in the UK. PATIENTS: Children attending the above centre for treatment of hypertension. The control subjects were normotensive healthy children attending district general hospitals for minor medical and surgical disorders. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Plasma (P) and urinary (U) NOx concentrations, blood pressure, and glomerular filtration rate. RESULTS: Sixteen normal children (mean age 6.9 years), 13 children with renovascular hypertension (mean age 7.8 years), and 25 children with hypertension associated with renal parenchymal disease (mean age 10.7 years) were studied. Mean (SD) PNOx values of children with hypertension with renovascular disease (15.3 (11.4) mumol/l) and renal parenchymal disease (18.3 (11.4) mumol/l) were significantly above that of normal children (11.9 (5.9) mumol/l) after accounting for age and glomerular filtration rate influences. Higher concentrations of PNOx in normal children were associated with younger age, but not in the children with hypertension. Higher PNOx concentrations were also associated with a lower glomerular filtration rate in normal children and children with hypertension with renal parenchymal disease, but not in the children with hypertension with renovascular disease. UNOx excretion expressed as a ratio against urine creatinine (Ucreat) excretion was not statistically different among the study groups. CONCLUSIONS: PNOx is increased in children with hypertension even after statistical elimination of the glomerular filtration rate and age influences. This suggests a normal or increased NO synthase activity in childhood hypertension in contrast with adults with hypertension in whom it is described as reduced.

Biomarkers↗
PubMed1997

Middle ear surgery under local anaesthesia and sedation.

BACKGROUND: Middle ear surgical procedures such as myringoplasty, stapedectomy and tympanolasty are traditionally performed under general anaesthesia, with induced hypotension. METHODS: We performed middle ear surgery in 73 patients, without induced hypotension, under local anaesthesia with sedation, and assessed feasibility, safety and acceptability. RESULTS: The operating conditions achieved were good and the complications were minor. None required conversion to general anaesthesia. CONCLUSION: Middle ear surgery under local anaesthesia and sedation is safe and feasible. Prospective trials are needed to fully assess the advantages of this technique over general anaesthesia.

Adolescent↗
PubMed1996

15-year follow-up of renin and blood pressure in reflux nephropathy.

BACKGROUND: Beginning in 1978 a cohort of patients with reflux nephropathy first seen at a London Childrens hospital have had 5-yearly follow-ups. This is the fourth (15-year) report from that series. METHODS: Of the original 100 normotensive children with reflux nephropathy 78 were traced for the 15-year study in 1994. Five patients were excluded because of nephrectomy, ten for other reasons, and eight refused to take part, leaving 55. 26 were on oral contraceptives. Supine blood pressure and plasma renin activity (PRA) were measured, and daily sodium excretion was assessed on a sample of overnight urine. FINDINGS: Of the 55 patients (15 male, 40 female, median age 27 years, range 20-31), five had systolic and two had diastolic hypertension. Compared with the 10-year (1988) follow-up there was no change in blood pressure standard deviation scores (SDS) in this cohort. PRA showed an increasing dissociation from controls after 15 years of age and was significantly above that of controls by age 25. Exclusion of the patients on oral contraceptives did not significantly alter the results. The PRA values in 1988 were not individually predictive of the development of hypertension over the ensuing 5 years. INTERPRETATION: Previously, in the long-term study of reflux nephropathy, blood pressure SDS had progressively increased with age. By 15 years blood pressure had levelled out and the PRA, though raised, did not predict the development of hypertension. Oral contraceptive use did not significantly modify the results.

Adolescent↗
PubMed1996

Tubular proteinuria in reflux nephropathy: post ureteric re-implantation.

We studied urine protein excretion in 55 adults with reflux nephropathy (median age 26.9 years) who had had normal blood pressure, renal function and ureteric reimplantation in childhood. Urine retinol binding protein (RBP), N-acetyl-beta-D-glucosaminidase (NAG), albumin, bacteriuria, systolic blood pressure, glomerular filtration rate (GFR), peripheral plasma renin activity (PRA) and the degree of renal scarring were measured in each subject; 20 had bilateral and 35 unilateral renal scarring; 5 were hypertensive and none were in renal failure. Urinary NAG and RBP excretions were significantly greater in the study group than in 34 healthy controls (median age 29.7 years). Within the study group, NAG excretion significantly correlated with PRA (P = 0.02). RBP excretion correlated with PRA, systolic blood pressure and the laterality (bilateral vs. unilateral) of scarring (P < 0.01). Urinary albumin excretion correlated with systolic blood pressure (P = 0.03). We conclude that increased urinary protein, especially NAG and RBP excretion, occur late after ureteric re-implantation in reflux nephropathy independent of GFR. Its association with PRA supports the concept of segmental perfusion and filtration as an important mechanism that may explain the above findings.

Acetylglucosaminidase↗
PubMed1996

Abnormalities of erythrocyte sodium transport in reflux nephropathy.

Hypertension is a complication of reflux nephropathy commonly occurring during adolescence and young adult life. We studied cellular sodium transport in an adolescent cohort with this condition as abnormal sodium transport is a feature of human hypertension. Thirty males and 52 females with reflux nephropathy, (median age 20.3 years) had erythrocyte ouabain sensitive sodium-potassium ATPase (Na/K ATPase) pump site number (Bmax) and red cell sodium concentration (RBC Na+) measured in 1988. Six years later, 55 of those had red cell sodium-lithium counter transport (LCT) measured. On both occasions, their renal function and blood pressure (BP) were determined. Bmax in the study group (median 10.3 nmol/l) was significantly less than that of controls (median 11.45 nmol/l). Nine patients who were diagnosed as having hypertension during the 6 year study period appeared to have a lower Bmax compared with that of normotensives in the group. RBC Na+ and LCT of the study group were not significantly different from that of controls. The Na/K ATPase activity is diminished, and sodium-lithium counter transport is unchanged in reflux nephropathy. Further study is needed to ascertain the link between these observations and the onset of high BP.

Adolescent↗