Amyloid (type AA) in a patient with hypogammaglobulinemia.
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Agammaglobulinemia↗
Biomedical subjects
G H Neild
Publications and source records attributed to G H Neild.
Ultrastructural pathology of experimental Ebola haemorrhagic fever virus infection.
The organs of monkeys infected with Ebola haemorrhagic fever were examined by light and electron microscopy during the acute stage of the disease. The virus caused focal coagulative necrosis in the liver, spleen, kidney, lung and testis and widespread mild vascular damage. In the brain there was intense congestion, with erythrocyte 'sludging', but no inflammatory reaction. There was significant injury to the microvasculature in all organs. Virus replicated in endothelial cytoplasm causing focal necrosis, separation of tight junctions and detachment from basement membranes. These changes were associated with oedema and haemorrhage, but though contributing to the hypovolaemic shock were not sufficiently extensive to account for the severity of vascular collapse. Renal involvement was also clinically important. Some renal cellular injury was caused by direct virus invasion of glomerular endothelium and tubular epithelium, but much tubular damage was probably due to ischaemia resulting from thrombosis in the peritubular capillaries. The virus also replicated in lymphocytes and monocytes and in interstitial cells of the testis. Since particles were not found in seminiferous epithelium, the degeneration of spermatogonia and spermatocytes was probably secondary to ischaemia.
Animals↗
Pathophysiology of shock and hemorrhage in a fulminating viral infection (Ebola).
Eleven rhesus monkeys were monitored intensively during experimental infection with Ebola virus. Prominent neutrophilia with left shift and lymphopenia were the earliest abnormalities and were statistically significant by day 4 (P less than .02 and P less than .01, respectively). By day 4 falls in platelet counts were not statistically significant, whereas in vitro platelet aggregation was markedly depressed, progressing rapidly to complete failure by the time of maximum illness. Intraplatelet protein studies suggested this event was the result of in vivo activation and degranulation. Coagulation cascade defects were mainly in the intrinsic system and were surprisingly mild, with no evidence of selective consumption or production deficit of factor VII or VIII. When the possibility of indirectly mediated damage to endothelium possibly by a nonspecific immune response was examined, weight loss was less severe in drug-treated monkeys, and all had detectable plasma prostacyclin metabolites, but there was no improvement in survival.
Animals↗
Glomerular thrombi in renal allografts associated with cyclosporin treatment.
We have found glomerular capillary thrombi or afferent arteriolar thrombosis in eight renal biopsy specimens from seven renal allograft recipients. All patients were receiving cyclosporin and prednisolone. Biopsies were performed either routinely one and four weeks after transplantation or during periods of renal dysfunction. None of the patients whose biopsy material contained glomerular thrombi was considered, in retrospect, to have been undergoing rejection at the time of biopsy. Thrombi consisted of finely granular material partially obstructing glomerular capillaries. By light microscopy the staining characteristics of the thrombi were compatible with platelet-fibrin aggregates, and this was confirmed by immunoperoxidase examination. Such thrombi have not previously been seen in biopsy material from patients treated with prednisolone and azathioprine, except rarely associated with acute vascular injection. In none of these patients was there haematological evidence of the haemolytic uraemic syndrome as has been reported in bone marrow recipients treated with cyclosporin.
Adult↗
Platelet involvement in the nephritis of acute serum sickness in rabbits: protection by dipyridamole and FUT-175.
In the acute serum sickness model in rabbits, we investigated platelet release of 5-HT, platelet surface immunoglobulins, and platelet aggregation in response to ADP, together with the effect of dipyridamole and the Clr antagonist FUT-175. The immune release of 5-HT from platelets occurred between 4 and 6 days after injection of bovine serum albumin (BSA), before immune elimination and proteinuria, but coincident with the appearance of immune complexed BSA in the circulation. Nevertheless, platelet turnovers were not detectably accelerated. Treatment with dipyridamole 50 mg/kg/24 h prevented the release of 5-HT and inhibited proteinuria, glomerular hypercellularity and immune complexes in the glomeruli. Using the Clr antagonist FUT-175, similar abrogation of the disease was obtained. We conclude that in the nephritis of acute serum sickness in rabbits, some of the immune release from platelets may be the result of immune complex binding to the platelet, perhaps through the receptor for C3b.
Adenosine Diphosphate↗
Severe systemic vascular necrosis in cyclosporin-treated rabbits with acute serum sickness.
Rabbits given acute serum sickness (ASS) and treated with cyclosporin A (CyA) developed a severe, systemic vascular injury, which was not similar to that normally seen in ASS. Thirty-three NZW rabbits received a single intravenous injection of 250 mg/kg bovine serum albumen (BSA) with or without endotoxin (5 micrograms/kg), on day 0. Groups of rabbits were given intramuscular CyA as follows: 15 mg/kg/day from day -2 to +8, or 25 mg/kg/day from day -2 to +3 or day 0 to 5. Muscular arteries of the heart and splanchnic organs developed an arterial injury in which there was extensive fibrinoid necrosis of the vessel wall but little or none of the mononuclear cell reaction that is normally associated with the arteritis of ASS. A microvascular injury also occurred which led to interstitial haemorrhage in the gastric mucosa and multi-focal necrosis in the heart and liver. These lesions were seen with equal frequency in all groups of rabbits with serum sickness who received CyA, irrespective of whether they also received endotoxin. We suggest that CyA altered the host inflammatory response to the injury initiated by the BSA-anti-BSA immune complexes and this led to enhanced vascular injury. The inhibition by CyA of the perivascular cellular reaction suggests that this reaction may be mediated by T lymphocytes. This model should provide further insight into the pathogenesis of arteritis, as well as the mechanisms of cyclosporin toxicity.
Animals↗
Vasculitis affecting the kidney: presentation, histopathology and long-term outcome.
Fifty-three patients who by clinical and/or histological criteria were judged to have vasculitis affecting the kidney were reviewed. Patients with systemic lupus or Schönlein-Henoch purpura were excluded. Segmental necrotising glomerulitis was taken as a manifestation of vasculitis ('microscopic polyarteritis'). Those patients in whom vasculitis was confined to glomerular capillaries were compared with those who in addition had vascular lesions outside the glomeruli. The two groups were found to have identical clinical features. Clinical presentation was predominantly extrarenal, and exclusively renal in only two. Three patients were classified histologically as Wegener's granulomatosis, four had malignant tumours and two relapsing polychondritis. Hepatitis B surface antigen was absent in all of 37 patients tested. Renal disease presented with microscopic haematuria and minor proteinuria in the majority (32) but 16 patients presented with rapid deterioration of renal function, including seven with anuria. Histologically 42 patients showed segmental necrotising glomerulitis ('microscopic polyarteritis'), six diffuse proliferative glomerulonephritis,and in five only minor or ischaemic glomerular changes were present. Crescents were found in 41/42 of those with segmental necrotising glomerulitis, nd involved more than 50 per cent of glomeruli in 15 patients. Immunohistochemical studies were generally negative except the fibrin. Electron microscopy showed no evidence of immune deposits in necrotising glomerulitis, but these were present in 2/6 patients with diffuse proliferative glomerulonephritis. Overall prognosis was poor, 35 patients having died, 20 early in the course of the disease and 15 later. Oligoanuria and extensive crescent formation were adverse signs. Survivals were 54, 38 and 34 per cent at one, five and 10 years respectively. Of those who survived the initial illness, 12 were stable with apparently inactive disease, whilst 16 continued to show clinical signs of activity and required treatment. A variety of treatments was employed including oral and intravenous corticosteroids, immunosuppressive agents, anticoagulants; only one patient was treated by plasmapheresis. It is difficult to draw any firm conclusions as to the efficacy of treatment and survival rates remain unsatisfactory.
Acute Disease↗
Glomerular thrombosis and cortical infarction in cyclosporin-treated rabbits with acute serum sickness.
Rabbits given acute serum sickness (ASS) and treated with cyclosporin A (CyA) developed glomerular capillary thrombosis and cortical infarction, lesions not seen in unmodified ASS. Thirty-three NZW rabbits received a single intravenous injection of 250 mg/kg bovine serum albumen (BSA) with or without endotoxin (5 micrograms/kg) on day 0. Groups of rabbits were given intramuscular CyA as follows: 15 mg/kg from day -2 to +8, or 25 mg/kg/day from day -20 to +3 or day 0 to 5. Signs of this renal injury were haematuria, transient proteinuria, glycosuria and oliguria and they occurred during the rapid phase of antigen elimination when immune complexes were being formed. Seventeen of the 33 rabbits developed glomerular capillary thrombi and 11 of 17 also had glomerular and tubular infarction. Electron microscopic examination showed that these lesions were associated with severe endothelial injury and platelet-fibrin-leucocyte thrombi. These changes were more severe in the groups given 25 mg/kg. The lesions were not seen in untreated rabbits and ASS, nor in normal rabbits given equivalent doses of CyA alone. A strikingly similar renal lesion has been seen in patients receiving CyA following bone marrow transplantation, and also in the haemolytic uraemic syndrome. The model we describe may be valuable for the study of the mechanisms of endothelial injury and thrombosis in the kidney.
Animals↗
Case 15-1983: Hodgkin's disease and focal glomerulosclerosis.
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Adult↗
Effect of Cyclosporin A on prostacyclin synthesis by vascular tissue.
NZW rabbits with acute serum sickness given Cyclosporin A (CyA) 25 mg/kg/day develop glomerular capillary thrombosis similar to that seem in the haemolytic uraemic syndrome (HUS). Bone marrow recipients treated with CyA may also develop a similar renal lesion associated with a haemolytic uraemic-like syndrome. In the HUS, impaired production of prostacyclin by vascular tissue may be found and has been associated with a lack of a plasma factor which stimulates prostacyclin synthesis. We therefore examined, in six normal rabbits, treated with CyA 25 mg/kg for five days, the ability of plasma from treated and untreated rabbits to stimulate prostacyclin synthesis from normal rabbit aortic rings. Plasma from untreated rabbits produced 21.5 +/- 6.9 ng 6-keto PGF1 alpha/ml/mg wet weight aorta (mean +/- SEM). However, the ability of plasma from CyA-treated rabbits to stimulate prostacyclin production was profoundly reduced. This was apparent within 24 hours of starting and persisted for seven days after therapy was stopped: mean of values from all rabbits bled from start of therapy until seven days after therapy stopped was 3.7 +/- 0.5 ng/ml/mg. We suggest that the renal complications of CyA therapy are related to a failure of normal vascular prostacyclin synthesis due to lack of a prostacyclin-stimulating plasma factor.
Animals↗
Haematological and biochemical monitoring of Ebola infection in rhesus monkeys: implications for patient management.
Patients with severe viral infections such as Lassa or Ebola may be denied adequate laboratory investigations because of justifiable fears among laboratory staff. This study in monkeys was designed to provide comprehensive haematological and biochemical monitoring in a contained environment during all stages of Ebola infection. Marked neutrophilia, depletion of lymphocytes, and early failure of platelet aggregation preceded a consumption coagulopathy with a microangiopathic haemolytic anaemia, thrombocytopenia, and failure of prostacyclin production by vascular endothelium. Liver dysfunction was moderate but in conjunction with the dehydration and hypoalbuminaemia could be expected to precipitate renal failure and shock. It seems reasonable to anticipate successful patient support with a patient management isolator and treatment with platelet transfusions, fresh frozen plasma, and possibly prostacyclin when haemostasis is defective during this otherwise self-limiting illness.
Animals↗
Cyclosporin A inhibits acute serum sickness nephritis in rabbits.
The effect of the immunosuppressive agent cyclosporin A (Cy A) on the renal injury in acute serum sickness was examined in rabbits. Serum sickness was induced in 23 untreated NZW rabbits by a single intravenous injection of bovine serum albumin (BSA) 250 mg/kg with E. coli endotoxin (5 micrograms/kg): BSA was eliminated after 8.6 +/- 0.16 days (mean +/- s.e. (mean]; proteinuria occurred in 19 (84%) and glomerular proliferation in 20 (87%) rabbits. When Cy A (15 or 25 mg/kg) was given daily by intramuscular injection, starting either 2 days before or at the time of induction of acute serum sickness, proteinuria was profoundly reduced and glomerular proliferation was inhibited. Even when rabbits were first treated with Cy A (25 mg/kg) 5 days after the induction of disease proteinuria and glomerular proliferation were similarly inhibited. When the treated animals were compared with controls there were no differences in the following: time to elimination of BSA, amount or size of circulating immune complexes, fall in serum C3 at immune elimination, or deposition of immune reactants in the glomeruli. These results show that Cy A inhibits the renal injury of acute serum sickness and indicate that T cells may play a role in mediating the nephritis in this condition.
Acute Disease↗
Rapidly progressive glomerulonephritis with extensive glomerular crescent formation.
Thirty-nine patients with severe crescentic glomerulonephritis and rapidly progressive renal failure were reviewed. Nineteen patients had a focal necrotizing glomerulonephritis, they usually presented with signs of multi-system disease, and eight had histologically-proven microscopic polyarteritis. A second group of 20 patients presented with an acute nephritic syndrome, often with nephrotic features, and had only minor prodromal symptoms. Renal biopsy material showed various forms of proliferative glomerulonephritis in addition to crescents. The most important prognostic feature at admission was renal function: only four of 21 patients who required dialysis recovered any renal function. The prognosis was worse for those with necrotizing glomerulonephritis, of whom two-thirds had oliguria on admission. All patients who were not oliguric, and some with oliguria, were treated with high doses of corticosteroids, usually accompanied by azathioprine and anticoagulants. Seventeen of 18 patients who were not oliguric initially retained or regained renal function, although three subsequently went into renal failure, and three others died of non-renal causes. At the most recent review, 25 of the 39 patients were either dead (16 patients) on dialysis or transplanted (nine patients). Ten were alive with diminished renal function, one had normal renal function but persisting proteinuria, and three were well. Prompt treatment may have contributed to these favourable results in a very severe disease.
Adolescent↗
Cortical infarction in rabbits with serum sickness following Cyclosporin A therapy.
Rabbits given acute serum sickness (ASS) and treated with Cyclosporin A (CyA) developed glomerular capillary thrombosis and cortical infarction. These lesions were associated with severe endothelial injury and platelet-fibrin-leucocyte thrombi. They were not seen in untreated rabbits with ASS, nor in normal rabbits given CyA alone in equivalent doses. A similar renal lesion has been reported in patients receiving CyA following bone marrow transplantation.
Animals↗
Effects of high-dose i.v. steroid (pulse) therapy on acute serum sickness in rabbits.
We investigated the effect of high doses (50 mg/kg/day) of i.v. methylprednisolone ("pulses") on a model of acute serum sickness in rabbits, using bovine serum albumen as antigen and endotoxin as an adjuvant. The pulses were given on 2 consecutive days at one of the following times during antigen elimination: Days 1 and 2, Days 5 and 6, and Days 8 and 9. Methylprednisolone did not alter antibody production, or the size of circulating immune complexes. Pulses given at any period inhibited the fibrinoid necrosis associated with arteritis, but did not otherwise lessen the histopathological changes. Pulses given on Days 1 and 2 or at the end of immune elimination on Days 8 and 9 increased proteinuria and haematuria, and tended to increase histopathological changes, whereas pulses given at the onset of immune elimination on Days 5 and 6 in contrast reduced haematuria, but had a variable effect on proteinuria and organ damage. In this model high-dose steroids produced no consistent amelioration of the disease, apart from reduced fibrinoid necrosis, and at some times there was a tendency for the disease to be exacerbated.
Animals↗
Coeliac disease: a graft-versus-host-like reaction localised to the small bowel wall?
In coeliac disease, gluten, or one of its fractions, combines with a gut-wall macrophage or lymphocyte to form a lymphoid cell which is recognised by the host as foreign. It is proposed that this cell, rather than being eliminated as the target of a cell-mediated attack by the host, becomes autonomous and initiates a graft-versus-host (GvH)-like reaction. The reaction is largely confined to the gut wall and its associated lymphoid tissue. The severe cachexy and the peripheral lymph-node and splenic atrophy may be explained as features of chronic GvH disease. or a "runting" syndrome. Untreated coeliac disease may lead to lymphomatous transformation indistinguishable from the lymphoma of experimental chronic GvH disease
Animals↗
The long-term outcome of idiopathic membranous nephropathy.
Thirty-five consecutive patients with renal biopsy appearances of idiopathic membranous nephropathy, who were initially studied between 1960 and 1969, were reevaluated in 1979 to determine (a) the long-term outcome of idiopathic membranous nephropathy, and (b) whether any clinical or biopsy features at onset would permit prediction of long-term outcome. After fifteen years, actuarial analysis showed that approximately half the patients would be in remission; the rest dead or on dialysis/transplantation programs. Entry into renal failure, in those who ran this course, started at three years after diagnosis and continued steadily for at least another ten years. Likewise, remission was seen as early as one year from onset, but patients were still going into remission after thirteen years of proteinuria. No feature in the glomeruli predicted outcome, but interstitial and vascular changes were seen more frequently in those whose disease persisted or worsened. No onset feature predicted a poor outcome reliably, but younger patients did better than older, and all three children with initial macroscopic hematuria went into remission.
Adolescent↗
Penicillamine induced membranous glomerulonephritis.
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Adult↗