Representative sample of rheumatoid synovium: a morphometric study.

The synovium from 11 patients with rheumatoid arthritis, who were undergoing joint surgery, was assessed using histological and morphometric techniques. Histological examination confirmed previous reports that the intensity of the cellular reaction varied throughout the synovium, and the morphometric method reflected this variability sensitively. The method was shown to be reproducible and allowed areas of similar cellular density to be defined. From these defined areas a total of 2.5 mm2 of synovium equivalent to 12 fields at x250 required analysis to reflect the variation in the cellular reaction. It would be feasible to collect this amount of material using an arthroscope.

Morphometric comparison of synovium from patients with osteoarthritis and rheumatoid arthritis.

Synovium was collected from 15 patients who were undergoing joint surgery. Two groups were defined by clinical diagnosis: patients with primary osteoarthritis (n = 4); and those with rheumatoid arthritis (n = 11). The synovium was studied using histological and morphometric techniques. In agreement with previous studies, no histological features specific for either diagnosis were found. A previously validated morphometric method was used to estimate the cellular density of randomly picked fields within defined areas of synovium. The mean nuclear density of cellularity of comparable areas of synovium was significantly different between these two disease states, but the mean nuclear density between individual representative samples within each clinical group was homogeneous. The morphometric analysis of lymphocyte subsets showed that within the upper synovial region and cellular aggregates in osteoarthritis, the distribution of T cells expressing the CD4 and CD8 antigen was the same. In rheumatoid arthritis CD8 cells predominated in the upper synovial region and CD4 cells in the cellular aggregates. Plasma cells were rarely found in osteoarthritic synovia, but were common in rheumatoid arthritis, with IgG-producing plasma cells predominating. Morphometric studies of representative synovial samples may help to improve histological diagnosis and our understanding of pathological mechanisms.

Post meningococcal acute glomerular nephritis.

A case of meningococcal meningitis is described in which 10 days later there developed the histological lesions of acute exsudative proliferative glomerular nephritis without proteinuria, hematuria, hypertension or salt and water retention. The relationship between structural and functional changes in the kidney in glomerular nephritis is discussed in the light of these findings.

SLE nephritis: an ultrastructural immunogold study to evaluate the relationship between immune complexes and the basement membrane components type IV collagen, fibronectin and heparan sulphate proteoglycans.

The nature of immune complexes and their relationship to the normal glomerular basement membrane (GBM) components type IV collagen, fibronectin, and heparan sulphate proteoglycans (HSPG) have been examined in the glomeruli of 7 cases of systemic lupus erythematosus (SLE) glomerulonephritis using an ultrastructural immunogold technique. In paraformaldehyde-fixed, Lowicryl resin-embedded tissue, the electron-dense deposits contained IgG, IgM, IgA, and C3 whether they were subepithelial, intramembranous, subendothelial, or mesangial and there was no particular relationship between the class of immunoglobulin and site of immune complex localization within the glomerulus. The normal GBM components type IV collagen, fibronectin, and HSPG were found within all the glomeruli, but did not have the same distribution. Type IV collagen and fibronectin were found predominantly on the inner aspect of the GBM and diffusely throughout the more central regions of the mesangial matrix. By contrast the HSPG was seen mainly on the outer aspect of the GBM and at the periphery of the mesangial matrix. In none of the cases were GBM antigens localized within the electron-dense deposits, results which suggest that autoantibodies to these GBM components may not play a role in the development of the glomerulonephritis.

Rhabdomyolysis and acute renal failure in chronic alcoholics with myopathy, unrelated to acute alcohol ingestion.

Rhabdomyolysis leading to acute renal failure necessitating hemodialysis is described in three chronic alcoholics. In each case an acute medical or surgical event, but not alcoholic intoxication, was implicated. Renal biopsies demonstrated acute tubular necrosis with intraluminal deposits consisting of Tamm-Horsfall protein and myoglobin. After recovery all three patients were demonstrated to have proximal muscle weakness with similar electromyographic abnormalities but nerve-conduction was impaired in only two. Muscle biopsies showed mixed, but predominantly type II fiber atrophy and reduced muscle phosphorylase levels. In the one patient tested the lactate response to forearm muscle ischemia was abnormal. It is postulated that chronic alcoholics may be predisposed to rhabdomyolysis and acute renal failure following acute medical and surgical stress as well as acute alcohol abuse. The muscle damage in these patients may be due to impaired intra cellular glycogen metabolism.

Myopathy in acquired partial lipodystrophy.

We describe two women with acquired partial lipodystrophy, one with significant myopathic symptoms and signs. Muscle biopsy of deltoid and quadriceps was performed in each case. The light microscopy findings were of type 1 and type 2 fibre hypertrophy, with an increase in intracytoplasmic fat in both cases. Electron microscopy showed normal fibres, with accumulations of electron-lucent fat droplets between the myofibrils. The cause of the lipodystrophies is uncertain, but myopathy may be a feature, and muscle biopsy studies may help in further defining the syndrome.

Crystal deposition in the knee and great toe joints of asymptomatic gout patients.

Crystal deposition in asymptomatic knee and first metatarsophalangeal (MTP) joints has been studied in 31 patients with previously proven gout. All had had clinical gout in their MTP joints but their knee joints had never been the site of acute gout. Knee arthroscopy was performed permitting synovial membrane inspection, photography and biopsy. Crystalline material was seen in 9 knees (28%) and confirmed histologically as monosodium urate (MSU) in 4 (12.5%). Synovial fluid analysis on 26 samples using a polarizing light microscope demonstrated MSU crystals in 4 (12.5%) and calcium pyrophosphate dihydrate (CPPD) in 2 (6%). Fluid aspirated from 27 of the metatarsophalangeal joints revealed MSU crystals in 14 (52%) and no CPPD crystals.

Testosterone deficiency myopathy.

Testosterone is recognized to have a positive effect on nitrogen balance and muscle development in hypogonadal men, but significantly myopathy secondary to testosterone deficiency has been reported only rarely. We describe a patient who presented with a myopathy associated with testosterone deficiency, and who demonstrated a significant functional and myometric response to treatment.

Terminal changes in mice experimentally infected with Borrelia duttoni.

The terminal changes following Borrelia duttoni infection in mice consisted of disseminated intravascular coagulation with associated depression in temperature, and in white cell and platelet counts with the development of a positive limulus lysate test. Apart from thrombosis and haemorrhage, similar changes were found in mice given cyclophosphamide prior to infection. The results suggest that neither intravascular coagulation nor immune complex formation are major factors in causing death in borreliosis.

Hydronephrosis: prevention by restoration of urinary concentrating ability using desamino-8D-arginine vasopressin (DDAVP) in Brattleboro rats.

Male Brattleboro rats with hereditary diabetes insipidus (BDI) were lifetime-treated with the vasopressin V2 receptor agonist desamino-8D-arginine vasopressin (DDAVP), given daily in the drinking fluid. The DDAVP-treated adult male BDI rats drank 34 +/- 6 ml/24 h (mean +/- s.e.m.) and excreted urine volumes of 22 +/- 5 ml/24 h compared with their age-matched untreated controls of 142 +/- 12 and 115 +/- 7 ml/24 h respectively. There was no significant difference between the mean body weights of chronically DDAVP-treated BDI rats (198 +/- 9 g) and untreated animals (207 +/- 9 g). Morphometry of sections of kidney confirmed extensive hydronephrosis in the right kidneys of the control untreated Brattleboro rats only. This was quantified as the area of pelvis expressed as a percentage of total cross-sectional area of kidney (17 +/- 3 compared with 5 +/- 1% in the chronically DDAVP-treated rats; P less than 0.002). Medium-term treatment of adult BDI rats with DDAVP reduced daily fluid output towards normal rat values but hydronephrosis was still present. These observations indicate that the restoration of fluid balance in adult BDI rats by treatment from conception with DDAVP may be an important factor in preventing the development of hydronephrosis in these animals.

Cytochemistry of the tubular aggregates found in hepatocytes of interferon-treated suckling mice.

Administration of mouse interferon to neonatal mice induces the formation of tubular aggregates within hepatocytes. These aggregates are composed of networks of small tubules which are continuous with the granular endoplasmic reticulum. The tubules are bounded by trilaminar unit membranes and exhibit glucose-6-phosphatase activity. These features suggest that the tubular aggregate is an interferon-induced alteration of the endoplasmic reticulum.

Proteinuria in rheumatoid arthritis--drug-induced or amyloid?

Over a 5-year period 325 patients with rheumatoid arthritis received treatment with gold (162) or D-penicillamine (163). Thirty-eight (11.7%) developed proteinuria, which persisted in 10 patients; renal biopsies in these 10 patients revealed 6 cases of amyloid disease. These 6 cases illustrate the importance of investigation of rheumatoid patients developing proteinuria even when they are receiving potentially nephrotoxic drugs.

Ultrastructural immunogold studies of heparan sulphate proteoglycan in normal human glomeruli and glomerulonephritis.

The distribution of heparan sulphate proteoglycans (HSPG) has been investigated in normal human glomeruli, membranous glomerulonephritis, mesangial IgA disease, and anti-glomerular basement membrane disease. HSPG was localized using anti-bovine HSPG antibody and 10 nm gold-labelled secondary antibody on paraformaldehyde-fixed, Lowicryl K4M resin-embedded kidneys. HSPG was present in all glomeruli and there was a zonation of its distribution in that it was predominantly on the epithelial aspect of the glomerular basement membrane (GBM) and mesangium with little in the central regions of the mesangial matrix. In the cases of immune complex glomerulonephritis, no HSPG was found in the electron-dense deposits. These findings contrast with our previous studies using the same technique in which type IV collagen and fibronectin were found predominantly on the endothelial aspect of the GBM.

Myopathy in HIV infection: the role of zidovudine and the significance of tubuloreticular inclusions.

Muscle biopsies were obtained from 33 consecutive HIV-infected patients with symptoms suggestive of muscle disorder. Twenty-three patients had clinical evidence of myopathy; 18 of these had been taking zidovudine (AZT) for between 8 and 28 months, and were found to have a multifocal necrotizing myopathy with little or no inflammation. However, the remaining five clinically myopathic patients, who had never received AZT or had stopped treatment at least 5 months earlier, had either a necrotizing myopathy which appeared indistinguishable for that seen in patients taking the drug, or an inflammatory myopathy. The 10 clinically non-myopathic patients showed no significant histological abnormalities. Tubuloreticular inclusions (TRI), in capillary endothelial cells, were found in all clinically myopathic cases but were not seen in five out of ten clinically non-myopathic cases. We suggest that AZT causes a myopathy only when an underlying HIV-related inflammatory myopathy is present. The drug appears to substantially reduce the inflammatory reaction in the muscle, but this may recur when the drug is stopped. The appearance of TRI may be the first manifestation of HIV activity in muscle.

Dialysis-associated amyloid: systemic or local?

Dialysis-associated amyloidosis has been classified as one of the local amyloidoses. To test this, we examined post-mortem tissue from 14 long-term haemodialysis patients, ten with dialysis arthropathy and four without arthropathy. Tissue was obtained from the shoulder, knee, or hip joints and the following organs: brain, kidney, liver, heart, lung, spleen, and rectum. Congo-red stain was used to identify amyloid deposits and these were characterised further using an indirect immunoperoxidase technique with antibodies to beta 2-M, prealbumin, serum amyloid A protein, and kappa and lambda light chains. All patients with arthropathy had large deposits of beta 2-M amyloid in the articular tissues. In contrast to this, systemic amyloid deposits were only found in four patients and were small and mainly confined to vessel walls. The four patients without joint symptoms had no evidence of systemic or articular amyloidosis. In addition, subcutaneous fat aspirations were carried out in 13 patients with dialysis arthropathy and 12 without arthropathy. Amyloid deposits were only found in two patients with arthropathy. Our results show that dialysis-associated amyloidosis has a predilection for deposition in articular tissues, and that systemic deposits are infrequent, small, and mainly confined to vessel walls. The discrepancy between our post-mortem series and case reports describing large systemic deposits may be due to differences in patient susceptibility.

Immunoelectron microscopic studies of immune complex deposits and basement membrane components in IgA nephropathy.

The relationship between the immune complex deposits of mesangial IgA nephropathy and the basement membrane components, type IV collagen and fibronectin, has been investigated by an indirect immunogold technique in four cases of mesangial IgA disease. Using paraformaldehyde-fixed, Lowicryl K4M resin-embedded kidney, IgA, IgM and C3 were localized in the mesangial electron-dense deposits with 10 and 20 nm gold-labelled secondary antibodies. In the same glomeruli, type IV collagen and fibronectin were rarely present within the electron-dense deposits, although both were distributed throughout the remainder of the mesangial matrix with the exception of the subepithelial regions. These two components were also present within the glomerular basement membrane and localized mainly on the endothelial aspect. A similar distribution of the basement membrane components was seen in a control kidney processed in the same way. This technique gives reproducible results and has demonstrated for the first time the relationship between the mesangial immune complex deposits of mesangial IgA nephropathy and the basement membrane components of the matrix in which they are found.

Relationship of precipitating antibodies to soluble cellular antigens and histologically defined renal lesions in systemic lupus erythematosus.

Antibodies to nuclear ribonucleoprotein (nRNP), Sm, SS-A, and SS-B, were studied by a quantitative immunodiffusion technique in 48 patients with systemic lupus erythematosus (SLE). There was no correlation between the presence or titre of antibodies to any of these antigens and clinically apparent renal disease. However, among 34 patients who had renal biopsies antibodies to nRNP, Sm, and/or SS-A were seen in all 8 patients with membranous glomerulonephritis. Low-titre antibodies (less than 1:4) were seen in 3 out of 7 patients with diffuse proliferative glomerulonephritis. Longitudinal studies in 4 patients who had serial biopsies indicated that the association between serological and histological findings was maintained for prolonged periods. In 2 patients whose biopsy pattern changed, antibodies to nRNP, Sm, and SS-A antedated the development of membranous nephritis.

Dialysis arthropathy: amyloid or iron?

The clinical, biochemical, radiological, and pathological features in five cases of dialysis arthropathy were analysed. All patients were receiving long term haemodialysis and had had multiple blood transfusions. The arthropathy affected both large and small joints, was predominantly bilateral, and in all cases was associated with the carpal tunnel syndrome. In some instances joint pain was exacerbated during dialysis. In four cases the serum ferritin concentration was raised. Radiological examination showed a few juxta-articular cysts and erosions but most affected joints looked normal. All synovial tissue examined showed amyloid, which stained immunohistochemically for beta 2 microglobulin. Large amounts of iron were present in synovial tissue from affected joints. It is suggested that the deposits of iron, rather than amyloid, in synovial tissue may be the cause of the arthropathy. Iron may be derived locally as a result of haemarthrosis or it may be a manifestation of systemic iron overload.