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Biomedical subjects

M J Dillon

Publications and source records attributed to M J Dillon.

At least 19 recordsLinked to original sources
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

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

Childhood vasculitis.

Vasculitis can and does occur in childhood. Apart from the relatively common vasculitides (Henoch-Schönlein purpura, Kawasaki disease and in world wide terms Takayasu disease) there are a number of important but comparatively rare disorders affecting children. These include macroscopic and microscopic polyarteritis, cutaneous polyarteritis, Wegener's granulomatosis, Churg-Strauss syndrome, primary angiitis of the central nervous system, hypersensitivity angiitis, hypocomplimentaemic urticarial vasculitis, vasculitis associated with various connective tissue disorders and vasculitis associated with conditions such as Behçets syndrome, familial Mediterranean fever and Cogan's syndrome. Distinguishing these conditions from other disorders is often difficult and requires clinical acumen and appropriate investigative procedures. With modern therapeutic agents, it is possible to implement appropriate therapy but in spite of this, there remains a not inconsequential morbidity and mortality.

Child↗
PubMed1997

Autosomal recessive polycystic kidney disease: long-term outcome of neonatal survivors.

Autosomal recessive polycystic kidney disease causes renal and hepatic dysfunction in childhood. We describe the clinical outcome of 52 children with this diagnosis born between 1950 and 1993. Currently 23 are alive, 24 dead and 5 have been lost to follow-up; 1 has been dialysed and 7 transplanted. Life-table analysis of the patients surviving the 1st month of life revealed an actuarial renal survival of 86% at 1 year and 67% at 15 years. The probability of requiring anti-hypertensive treatment was 39% at 1 year and 60% at 15 years of age. Bleeding from gastro-oesophageal varices occurred in 8 patients at a mean age of 12.5 years, and was preceded by haematological evidence of hypersplenism in 6 of them. The study indicates a relatively good prognosis for patients with this condition who survive the neonatal period and emphasises the importance of early detection and appropriate management of systemic and portal hypertension.

Adolescent↗
PubMed1997

The diagnosis of renovascular disease.

Renovascular disease is an important cause of remediable hypertension in childhood. Specific diagnostic procedures currently available to investigate affected children include Doppler and computed duplex sonography, angiotensin converting enzyme (ACE) inhibitor sensitisation of radionuclide imaging, captopril-stimulated plasma renin activity, hypotensive responses to ACE inhibitor, renal vein renin measurements, renal angiography and magnetic resonance angiography. Carbon dioxide digital subtraction angiography and computerised tomographic and spiral angiography are also available and may play an important future role in such evaluations. Utilising this array of procedures it is usually possible to define the anatomical and functional status of the renal vasculature and be guided towards the most appropriate therapeutic manoeuvres.

Child↗
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

Rare vasculitic syndromes.

Vasculitis can and does occur in childhood. Apart from the common vasculitides (Henoch-Schönlein purpura, hypersensitivity angiitis and Kawasaki disease) there are a number of important but comparatively rare disorders affecting children. These include macroscopic and microscopic polyarteritis, cutaneous polyarteritis, Wegener's granulomatosis, Churg-Strauss syndrome, primary angiitis of the central nervous system, hypocomplimentaemic urticarial vasculitis, vasculitis associated with various connective tissue disorders, Takayasu's disease and vasculitis associated with conditions such as Behcet's syndrome, familial Mediterranean fever and Cogan's syndrome. Distinguishing these conditions from other disorders is often difficult and requires clinical acumen and appropriate investigative procedures. With modern therapeutic agents it is possible to implement appropriate therapy but in spite of this, there remains a not inconsequential morbidity and mortality.

Arteritis↗
PubMed1996

Endothelial dysfunction late after Kawasaki disease.

BACKGROUND: Kawasaki disease (KD) is a systemic vasculitis of childhood with widespread vascular endothelial damage in the acute stage. Long-term complications, such as myocardial infarction and death, are recognized, but the extent and nature of late vascular abnormalities that might predispose to these events have not been studied. METHODS AND RESULTS: We used high-resolution ultrasound to study endothelial function in the brachial artery of 20 patients 5 to 17 years after acute KD (median, 11 years) and compared findings with those in 20 age- and sex-matched control subjects. Vascular responses to reactive hyperemia (with flow increase leading to endothelium-dependent dilation) and to sublingual glyceryl trinitrate (GTN; endothelium-independent dilation) were recorded. The relationship between endothelium-dependent vascular responses and features of the endothelium acute illness was examined. There was no difference in baseline vessel diameter, degree of reactive hyperemia, or response to GTN between patients and control subjects. In contrast, flow-mediated dilation was markedly reduced in KD patients compared with control subjects (3.1% versus 9.4%; P < .001). Late endothelium-dependent responses were not related to features of the acute illness. CONCLUSIONS: Abnormalities of systemic endothelial function are present many years after resolution of acute KD, even in patients without detectable early coronary artery involvement. Because this may be an important factor in the genesis of late vascular complications, long-term follow-up of all patients with KD is indicated.

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

Craniometaphyseal and craniodiaphyseal dysplasia, head and neck manifestations and management.

Craniometaphyseal and craniodiaphyseal dysplasia are rare genetic disorders of bone due to modelling errors of long bones and skull bones. These syndromes present with multiple ENT symptomatology from an early age. The diagnostic distinction can now be made radiologically by serial skeletal survey which is important for prognosis. We review the clinical, radiological, computed tomography (CT) scan, otological, audiological and histopathological findings in two cases with craniodiaphyseal, and two cases with craniometaphyseal dysplasia, and report our experiences of medical and surgical treatment to date. In the craniodiaphyseal dysplasia, the hearing abnormality progressed from an initial conductive to a mixed loss on serial audiometric follow up. Temporal bone CT scans showed narrowing of the middle ear cavity, internal auditory meatus, and facial nerve canal at the geniculate ganglion. Benefits from choanal stenosis surgery, craniofacial remodelling and dacrocystorhinostomy were shortlived. Calcitriol therapy with a low calcium diet did not alter the clinical course of progression in our cases. The underlying defect, causing net bone formation in these phenotypically similar syndromes, appears to be different when based on the differing biochemical responses to calcitriol and bone biopsy findings. Increased numbers of osteoblasts were found in bone biopsies from both cases with craniodiaphyseal dysplasia. Early recognition is crucial in these conditions as therapy directed at the underlying bony defect has the best chance of success if initiated in infancy.

Adult↗
PubMed1996

Normal levels of soluble E-selectin, soluble intercellular adhesion molecule-1 (sICAM-1), and soluble vascular cell adhesion molecule-1 (sVCAM-1) decrease with age.

sE-selectin, sICAM-1, sVCAM-1 and von Willebrand factor (vWF) were assayed in 238 samples in a longitudinal study of 81 normal children from 9.5 to 15.5 years old. Multilevel modelling was used to quantify changes with age. sE-selectin, sICAM-1 and sVCAM-1 all fell significantly over the age range (by 17%, 16%, and 10%, respectively). In contrast, levels of vWF were not age-dependent. Our findings highlight the need for age-matched controls when studying cell surface adhesion molecules in disease groups, and may imply developmental changes in expression of these molecules and their shedding from the cell surface.

Adolescent↗
PubMed1996

Localisation of pseudohypoaldosteronism genes to chromosome 16p12.2-13.11 and 12p13.1-pter by homozygosity mapping.

Pseudohypoaldosteronism type 1 (PHA1, OMIM 264350) is a rare Mendelian disorder characterised by end-organ unresponsiveness to mineralocorticoids. Most steroid hormone insensitivity syndromes arise from mutations in the corresponding receptor, but available genetic evidence is against involvement of the mineralocorticoid receptor gene, MLR, in PHA1. A complete genome scan for PHA1 genes was undertaken using homozygosity mapping in 11 consanguineous families. Conclusive evidence of linkage with heterogeneity was obtained with a maximum two-locus admixture lod score of 9.9. The disease locus mapped to chromosome 16p12.2-13.11 in six families and to 12p13.1-pter in the other five families. The two chromosomal regions harbour genes for subunits of the amiloride-sensitive epithelial sodium channel: SCNN1B and SCNN1G on 16p and SCNN1A on 12p. Liddle's syndrome of hypertension and pseudoaldosteronism has been shown to arise from mutations in SCNN1B and SCNN1G. These results strongly suggest that PHA1 and Liddle's syndrome are allelic variants caused by mutations in genes encoding subunits of this sodium channel. These genes are of broad biological interest both in relation to sodium and water homeostasis in mammals and by virtue of their homology to the mec genes of Caenorhabditis elegans involved in mechanosensitivity and neuronal degeneration.

Chromosome Mapping↗
PubMed1996

Retrospective study of plasma exchange in patients with idiopathic rapidly progressive glomerulonephritis and vasculitis.

A retrospective study of 48 patients was conducted to evaluate the efficacy of plasma exchange in children with idiopathic rapidly progressive glomerulonephritis (IRPGN), and renal or non-renal vasculitis. All patients were followed up at a single centre over a 15 year period. Treatment consisted of corticosteroids and/or cytotoxic agents. Plasma exchange was used in all patients because of severe renal involvement and/or clinical deterioration. One hundred per cent of patients with renal vasculitis who started plasma exchange within one month of disease onset and 58% of cases with IRPGN had significant improvement in renal function. No relapses of vasculitis were observed after treatment with plasma exchange in patients with renal and non-renal vasculitis. The results suggest that plasma exchange associated with immunosuppressive treatment could be of benefit in cases of IRPGN or vasculitis in terms of both renal and extrarenal recovery.

Adolescent↗
PubMed1996

Antiphospholipid syndrome presenting as episodic limb ischaemia.

A child presented with ischaemic episodes of his left leg from the age of 2 months. He was found to have raised anticardiolipin antibodies so was started on low dose aspirin. At a three year follow up he was asymptomatic with a normal anticardiolipin antibody level while taking aspirin daily, probably for life.

Acute Disease↗