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Biomedical subjects

G Lindop

Publications and source records attributed to G Lindop.

15 recordsLinked to original sources
PubMed2001

A proinflammatory role of IL-18 in the development of spontaneous autoimmune disease.

Serum from patients with systemic lupus erythematosus (SLE) contained significantly higher concentrations of IL-18 than normal individuals. MRL/lpr mice, which develop spontaneous lupus-like autoimmune disease, also had higher serum levels of IL-18 than wild-type MRL/++ mice. Daily injections of IL-18 or IL-18 plus IL-12 resulted in accelerated proteinuria, glomerulonephritis, vasculitis, and raised levels of proinflammatory cytokines in MRL/lpr mice. IL-18-treated MRL/lpr mice also developed a "butterfly" facial rash resembling clinical SLE. In contrast, MRL/lpr mice treated with IL-18 plus IL-12 did not develop a facial rash. The facial lesion in the IL-18-treated mice showed epidermal thickening with intense chronic inflammation accompanied by increased apoptosis, Ig deposition, and early systemic Th2 response compared with control or IL-12 plus IL-18-treated mice. These data therefore show that IL-18 is an important mediator of lupus-like disease and may thus be a novel target for therapeutic intervention of spontaneous autoimmune diseases.

Adult↗
PubMed1999

Modulation of autoimmune disease in the MRL-lpr/lpr mouse by IL-2 and TGF-beta1 gene therapy using attenuated Salmonella typhimurium as gene carrier.

We have investigated the effects of interleukin-2 (IL-2) and transforming growth factor-beta (TGF-beta) gene therapy on the progress of autoimmune disease in MRL-lpr/lpr mice, a murine model of systemic lupus erythematosus (SLE). These mice have uncontrolled proliferation of T cells, an impaired response to T cell mitogen and produce autoantibodies against nuclear antigens, including DNA. Immune complexes formed by these autoantibodies are believed to cause glomerulonephritis and vasculitis in lupus mice and human SLE. Since there is an imbalance of cytokine production in both SLE patients and lupus mice, we examined the effects of cytokine gene therapy on the progression of autoimmune disease in MRL-lpr/lpr mice. The mice were treated orally with a non-pathogenic strain of Salmonella typhimurium bearing the aroA-aroD- mutations and carrying the murine genes encoding IL-2 and TGF-beta. The bacteria synthesise and slowly release the cytokines in vivo. Our results show that, contrary to expectation, TGF-beta gene therapy produced no improvement in pathology and generally had opposite effects to those of IL-2. IL-2 gene therapy restored the defective T cell proliferative response to mitogen and suppressed the autoantibody response, glomerulonephritis and growth of lymphoid tumours.

Animals↗
PubMed1998

Neuroendocrine cell hyperplasia in colonic tissue used for long term augmentation cystoplasty.

A case is described of neuroendocrine cell hyperplasia in intravesical colonic mucosa, implanted previously during augmentation cystoplasty. The patient was a 28 year old man born with posterior urethral valves, a non-functioning right kidney, and a poorly functioning dilated left kidney. The hyperplasia consisted of pure neuroendocrine acini and tubules within the lamina propria, separate from the normal intestinal glands. Adjacent intraepithelial colonic neuroendocrine cells were increased diffusely. Rectal biopsy and previous biopsies of intravesical colonic tissue contained normal neuroendocrine cell populations. Implantation of gut segments into the urinary tract predisposes to late neoplasia, but there is only one report of carcinoid tumour in uroenteric tissue. Intestinal neuroendocrine cell hyperplasia usually occurs diffusely rather than as aggregates, except when associated with adjacent carcinoid tumour. Both diffuse and nodular hyperplasia were present in this case, with an unusual and striking morphology. This is the first report of neuroendocrine cell hyperplasia in gastrointestinal tissue implanted into the urinary tract; this raises the possibility of a risk of late carcinoid tumour in uroenteric segments.

Adult↗
PubMed1996

The role of interleukin 12 and nitric oxide in the development of spontaneous autoimmune disease in MRL/MP-lpr/lpr mice.

MRL/MP-lpr/lpr (MRL/lpr) mice develop a spontaneous autoimmune disease. Serum from these mice contained significantly higher concentrations of nitrite/nitrate than serum from age-matched control MRL/MP-+/+ (MRL/+), BALB/c or CBA/6J mice. Spleen and peritoneal cells from MRL/lpr mice also produced significantly more nitric oxide (NO) than those from the control mice when cultured with interferon (IFN) gamma and lipopolysaccharide (LPS) in vitro. It is interesting to note that peritoneal cells from MRL/lpr mice also produced markedly higher concentrations of interleukin (IL) 12 than those from MRL/+ or BALB/c mice when cultured with same stimuli. It is striking that cells from MRL/lpr mice produced high concentrations of NO when cultured cells from MRL/+ or BALB/c mice. The enhanced NO synthesis induced by IFN-gamma/LPS was substantially inhibited by anti-IL-12 antibody. In addition, IL-12-induced NO production can also be markedly inhibited by anti-IFN-gamma antibody, but only weakly inhibited by anti-tumor necrosis factor alpha antibody. The effect of IL-12 on NO production was dependent on the presence of natural killer and possibly T cells. Serum from MRL/lpr mice contained significantly higher concentrations of IL-12 compared with those of MRL/+ or BALB/c control mice. Daily injection of recombinant IL-12 led to increased serum levels of IFN-gamma and NO metabolites, and accelerated glomerulonephritis in the young MRL/lpr mice (but not in the MRL/+ mice) compared with controls injected with phosphate-buffered saline alone. These data, together with previous finding that NO synthase inhibitors can ameliorate autoimmune disease in MRL/lpr mice, suggest that high capacity of such mice to produce IL-12 and their greater responsiveness to IL-12, leading to the production of high concentrations of NO, are important factors in this spontaneous model of autoimmune disease.

Animals↗
PubMed1996

A case of neonatal Bartter's syndrome.

We describe a child with a neonatal presentation of Bartter's syndrome. Unlike infants previously described with a similar clinical presentation, the urinary excretion rate of prostaglandin E2 in this child was similar to normal children and Tamm-Horsfall protein was distributed normally in the thick ascending limb of the loop of Henle. The child failed to respond to indomethacin alone, but thrived after the addition of the angiotensin converting enzyme inhibitor, captopril.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1989

Plasma renin levels in patients with thoracic neuroblastoma.

Plasma renin levels are elevated in neuroblastoma as in nephroblastoma patients. Unlike nephroblastoma, the active component appears to predominate. Patients with thoracic neuroblastoma produce high levels of renin by the tumour, which thus excludes an ischaemic aetiology as the source.

Humans↗
PubMed1986

The relative importance of glucocorticoids and mineralocorticoids in the development of adrenal regeneration hypertension in rats.

The adrenocortical tissue which regenerates after adrenal enucleation, and contralateral uninephrectomy and adrenalectomy, resembles histologically zona fasciculata tissue which normally synthesises glucocorticoids. However, increases in blood pressure after enucleation (adrenal regeneration hypertension-ARH] were preceded by a rise in exchangeable body sodium similar to that found with mineralocorticoid-induced hypertension (e.g. DOC/salt rat model). Glucocorticoid involvement in ARH rats was tested, firstly by infusing dexamethasone into control and ARH rats to see whether ACTH suppression would lower blood pressure by reducing adrenocortical activity and, secondly, by infusing dexamethasone into rats with intact adrenals to see whether conditions for ARH (i.e. uninephrectomy and/or saline consumption) pre-disposed rats to the hypertensinogenic properties of glucocorticoids. Low-dose dexamethasone infusions (10 micrograms/day for 5 days) in ARH rats did not affect blood pressure but in control animals caused a significant (P less than 0.01) increase from 128 +/- 3 to 151 +/- 5 mmHg. Corticosterone, 18-hydroxycorticosterone and deoxycorticosterone plasma concentrations were suppressed in both groups by dexamethasone treatment; plasma renin concentrations were lower in ARH rats than in controls. Uninephrectomy or 1% NaCl as drinking fluid did not affect the blood pressure rise induced by sc infusion of 10 micrograms dexamethasone/day for 14 days in rats with intact adrenals. The temporal relationship between blood pressure changes and exchangeable body sodium in ARH rats resembles that in mineralocorticoid-induced hypertension. Glucocorticoid, unlike mineralocorticoid, induced hypertension is not affected by a reduction in renal mass or increased sodium intake.

Adrenal Cortex↗
PubMed1983

Similar blood pressure but different outcome in rats with DOC and post-DOC hypertension.

It is uncertain whether increased arterial pressure alone or increased arterial pressure combined with some other factor is responsible for the development of malignant-phase hypertension. Our object was to test this comparing two groups of rats with hypertension of different mechanism but of similar duration and degree. Two experiments were done in hypertensive rats. In the first blood pressure was measured in the tail, in the second by intra-arterial catheter and pressure transducer. In the first, hypertension was produced in 30 male Sprague-Dawley rats by unilateral nephrectomy followed by thrice-weekly injections of deoxycorticosterone (12.5 mg) and substitution of 1% NaCl and 0.2% KCl for their drinking water. After four weeks 28 rats survived and systolic blood pressure had risen to 220 mmHg. The survivors were paired by blood pressure and randomly allocated either to continued DOC and salt or to a regime in which DOC was stopped and tap-water was substituted for the NaCl-KCl solution (post-DOC rats). Blood pressure remained similar in the two groups thereafter, but in every case it was the DOC-salt animal of the pair which died first. Fibrinoid arteriolar lesions of malignant-phase hypertension were significantly commoner in DOC-salt animals and, before death, they had more pronounced features of microangiopathic haemolytic anaemia. The second experiment was the same in design as the first except that two weeks after randomization the similarity of blood pressure was confirmed by measurement of intra-arterial pressure in eight pairs of DOC-salt and post-DOC rats. We conclude that increased arterial pressure is not the only factor influencing development of malignant-phase hypertension.

Animals↗
PubMed1981

Angiotensin-induced myocardial necrosis and renal failure in the rabbit: distribution of lesions and severity in relation to plasma angiotensin II concentration and arterial pressure.

Angiotensin II was infused into conscious rabbits at various doses from 0.001 to 0.5 microgram . kg-1 . min-1 for 24 h, and caused multifocal myocardial necrosis, renal tubular necrosis and acute renal failure. The myocardial necroses were found principally in the left ventricle; only at the highest doses of angiotensin II were right ventricular lesions present. The endocardium was not involved and no arterial or arteriolar lesions were seen. Mean arterial plasma angiotensin II concentration during angiotensin infusion was closely correlated with the increase in arterial pressure, the height of the plasma urea at the end of the infusion and the severity of the induced myocardial lesions. The myocardial necroses could be a consequence of the induced hypertension, or a direct effect of angiotensin II, or a combination of effects, although their predominance in the left ventricle suggests high systemic arterial pressure is an important factor. Cardiac lesions were observed with plasma angiotensin II concentrations only some 2 to 3 fold normal values; it is therefore possible that similar myocardial abnormalities might occur as a result of rises in endogenous renin, for example, in experimental or clinical renovascular hypertension.

Acute Kidney Injury↗
PubMed1975

Lithium induced nephrogenic diabetes insipidus: changes in plasma vasopressin and angiotensin II.

Nephrogenic diabetes insipidus associated with high basal levels of plasma arginine vasopressin developed in a patient during lithium therapy. Fluid deprivation was accompanied by an increase in the concentration in peripheral venous plasma of vasopressin and angiotensin II, a rise in plasma osmolality and a modest rise in urine osmolality. Infusion of arginine vasopressin produced comparable levels of plasma vasopressin to those found during fluid deprivation, with no overall change in plasma angiotensin II and little change in urine volume or osmolality. It is suggested that angiotensin II may be responsible for the difference in ability to concentrate urine under these two conditions. Following death by self-poisoning, renal histology revealed distinct structural changes in the distal tubules: such lesions have not previously been described in man and it is suggested that the occurrence of nephrogenic diabetes insipidus while on lithium therapy may be related to tubular damage.

Adult↗