Biomedical subjects
Publications and source records attributed to J Michael.
Thirteen patients with end-stage renal disease aged 70 years have been successfully treated by chronic dialysis treatment. Despite many problems associated with the elderly, a good quality of life was achieved.
Antibody responses against pneumococcal capsular antigens and tetanus toxoid were measured in 14 patients with chronic renal failure who were managed by continuous ambulatory peritoneal dialysis (CAPD) or haemodialysis (HD) and in eight healthy controls. IgG antipneumococcal responses were predominantly of the IgG2 and to a lesser extent IgG1 subclasses, while the IgG response against tetanus toxoid was largely IgG1 with smaller amounts of IgG4 and IgG3. The post-immunisation serum levels of IgG1 and IgM antibody against both antigens were significantly reduced in the uraemic patients compared with controls (P less than 0.05). All the uraemic patients had normal levels of IgG, IgA and IgM in the serum, but elevated levels of IgG3 prior to immunisation. The mechanisms responsible for the asymmetric depression of antibody responses in uraemia are unclear and may account in part for the increased susceptibility to infection in these patients.
102 episodes of continuous ambulatory peritoneal dialysis (CAPD) peritonitis were studied prospectively during a 288-day period at The Queen Elizabeth Hospital, Birmingham. Organisms were isolated from 76% of the episodes, with coagulase-negative staphylococci, being the most commonly encountered organism (55%). Initial treatment consisted of intraperitoneal vancomycin and ceftazidime with subsequent adjustment on the basis of antibiotic sensitivities. With this regimen, 83% of the positive cultures became negative by 72 h, 9.8% of cases relapsed and removal of the CAPD catheter was necessary in 8 patients (7.8%). Overall, 92% of cases were cured. No adverse drug reactions were seen. This combination of antibiotics appears effective and safe in the treatment of CAPD peritonitis.
In 153 consecutive renal allograft recipients whose initial immunosuppression was prednisolone and azathioprine, 41 developed acute rejection episodes that were not reversed by 5-9 g of intravenous methylprednisolone. Renal histology showed cellular rejection in ten patients, vascular rejection in 12, and mixed cellular and vascular rejection in 16. Thirty-one patients were converted to cyclosporin in the first month post-transplant and ten in the second month. At the time of conversion, 20 patients were dialysis dependent and in the remainder the mean serum creatinine was 353 mumol/l (range 139-548 mumol/l). Renal function improved in 31 patients after conversion. Ten patients lost their grafts, of whom seven were on dialysis. There were no deaths and the 1-year graft survival was 75%. These data suggest that conversion from azathioprine to cyclosporin because of steroid-resistant rejection is an effective and safe strategy in patients whose initial immunosuppression is prednisolone and azathioprine.
Four patients with well-documented severe recurrent painful sickle cell crises received 12-month courses of self-administered minidose heparin (5000-7500 units every 12 hours). Patients were evaluated weekly or bi-weekly for symptoms and signs of sickle crises. The observations were compared with identical observations during 12 months off heparin (control). Prior to starting heparin, baseline laboratory values were established, including hematocrits, platelet counts, and plasma coagulation factors. Bone density was evaluated by radiologic measurement of metacarpal cortical width and by forearm transmission osteodensitometry. Laboratory values were repeated at each visit; bone density was reevaluated every 6 months. At each visit clinical status for the preceding 1-2 weeks was classified as: no pain (I), minor pain controllable by non-prescription medications (II), pain requiring office or emergency room admissions for parenteral narcotics (III), hospitalized for about 3 days for pain crisis (IV). One patient completed a single 2-year cycle; one patient completed 2 cycles (followed 4 years), and 2 patients have undertaken 3 cycles (followed greater than or equal to 6 years). No treatment-related complications occurred requiring discontinuation of heparin. Thrombocytopenia was not observed. There was no evidence of progressive osteopenia. All patients improved while receiving heparin; 1 moderately, 3 markedly. Cumulative data (8.7 patient years on heparin, 12 control years) revealed a 73% reduction in days of hospitalization per year and 74% reduction in hours spent in emergency rooms per year during heparin administration. Pretreatment pain patterns recurred when heparin was discontinued.
Polyethylene glycol (PEG, 4%)-precipitated macromolecular IgG isolated from the sera of 20 patients with systemic lupus erythematosus (SLE) and 15 control subjects was analyzed for its IgG isotype concentration by single radial immunodiffusion. PEG precipitates from SLE sera had higher mean levels of IgG1, IgG2 and IgG3 and lower IgG4 than PEG precipitates isolated from normal sera although only the IgG2 levels were significantly different. Using an anti-complementary assay there was a significant correlation between the ability of parent sera to fix complement and the absolute levels of PEG precipitable IgG1, IgG2 and IgG3. These data suggest that the ability of immune complexes in the sera of patients with SLE to fix complement is dependent on their IgG subclass composition.
The effect of 'scavengers' of reactive oxygen products (ROPs) was studied in the heterologous phase of anti-glomerular basement (anti-GBM) nephritis induced in rats. Glomerulonephritis was induced by the intravenous administration of sheep anti-GBM antibody (5 mg/100 g) to rats on day 0. The intraperitoneal administration of superoxide dismutase (SOD) 30 mg/kg/day or 150 mg/kg/day leads to a significant reduction in proteinuria on day 1 and also on day 3 in animals given SOD 30 mg/kg/day. Proteinuria was not significantly reduced by the intraperitoneal administration of inactivated SOD (150 mg/kg/day). In rats given polyethylene glycol coupled catalase (PEG-catalase) intraperitoneally at a dose of 10,000 iu/kg/day and 100,000 iu/kg/day proteinuria was lower than in rats with unmodified anti-GBM nephritis. These differences were significant on day 1 (P less than 0.05) in rats given PEG-catalase 100,000 iu/kg/day and on days 3 and 5 in rats treated with either dose of PEG-catalase (P less than 0.01). These data suggest a role for superoxide anion and hydrogen peroxide, or a product of their interaction such as hydroxyl radical, in glomerular injury induced by anti-GBM antibody.
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Fourteen immunosuppressed patients with Pneumocystis carinii infection presented in two clusters that were separated by 2 years. The diagnosis in all cases was made early by alveolar lavage with cytology. The first group of seven patients was immunosuppressed with cyclophosphamide or azathioprine and prednisolone. All recovered with high dose co-trimoxazole. The second group of seven patients was on prednisolone and cyclosporin A. Despite identical treatment three patients died and a further two who survived lost their grafts from rejection. Our data suggest that cyclosporin A adversely affects the prognosis from Pneumocystis carinii infection and raises the question of prophylactic co-trimoxazole in these patients. The clustering of Pneumocystis carinii infection suggests the possibility of nosocomial transmission although in this study we were unable to implicate person-to-person spread of infection.
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The effect of the nephrotic syndrome induced by puromycin aminonucleoside (PA) in rats on specific antibody responses to 2,4 dinitrophenyl (DNP) conjugated to either spider crab haemocyanin (MSH), a T cell-dependent antigen, or hydroxyethyl starch (HES), a T cell-independent type 2 antigen were studied. The serum IgG anti-DNP levels following immunization with both antigens were reduced in nephrotic animals compared with controls while IgM anti-DNP antibody titres were higher. The half-life of IgG anti-DNP antibodies passively transferred into non-immunized nephrotic rats was markedly reduced while the half-life of anti-DNP antibodies of the IgM class was comparable to that in controls. Low serum IgG and elevated IgM levels were seen in nephrotic animals compared to controls. Antibody-forming cells specific for DNP were demonstrated by immunohistology on rat spleens and the numbers of both IgG and IgM-producing cells were found to be significantly increased (P less than 0.05) in nephrotic animals in response to both DNP-HES and DNP-MSH. These data indicate that in nephrotic rats the alteration seen in the serum immunoglobulin levels is not attributable to reduced antibody production but increased catabolism of serum IgG antibodies.
In a telescoped model of antiglomerular basement membrane (GBM) antibody induced nephritis, Lewis strain rats were injected in the footpad with rabbit IgG on day 0 and then given a single intravenous injection of rabbit anti-rat GBM antibody on day 5. Proteinuria developed within 24 h and renal histology 7 days later showed a focal or diffuse proliferative glomerulonephritis. In this study rats treated as above were given Cyclosporin A (CyA) 20 mg/kg daily by intraperitoneal injection from day 0 or from day 5. Rats given CyA plus anti-GBM antibody developed extensive glomerular infiltration with polymorphs and glomerular thrombosis, lesions not seen with unmodified anti-GBM nephritis or in rats who received CyA alone. The mechanism by which CyA given prior to or at the onset of immunological insult in this model worsens glomerular injury is unclear.
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Secretory granule-enriched fractions prepared from isolated rat islets of Langerhans, previously labeled in culture for 18 h with [3H]leucine, have been lysed and separated into pH 5.4 soluble and insoluble fractions by zonal sucrose gradient centrifugation. A high proportion of both labeled and immunoreactive rat insulins I and II were recovered in the insoluble granule core fraction in the expected ratio of approximately 60/40, respectively. Essentially equivalent amounts of the rat C-peptides on a molar basis were recovered in the granule supernatant fractions. The proportion of labeled proinsulin in the granule core fraction was less than 2% relative to insulin, while the soluble fraction contained about 8%, which probably arose mainly from disrupted proinsulin-rich noncrystalline prosecretory vesicles. Electron microscopic examination of the granule core fraction revealed large numbers of well preserved crystalline cores exhibiting typical dimensions and regular internal spacings of normal mature rat beta-granule inclusions. These results provide direct biochemical evidence that the beta-granules are nonuniform in composition with the insulin contained mainly in a crystalline state in the electron-dense central inclusions while the C-peptide is dissolved in the fluid bathing the crystalline hormone. The significance of this structural organization of the beta-granule is discussed.
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1. The nephrotic syndrome was induced in inbred female Wistar rats by the intravenous injection of puromycin aminonucleoside (PA) (5 mg/100 g body weight). 2. One group (n = 12) received superoxide dismutase (SOD) (15 mg/kg body weight), a second group (n = 12) received polyethylene glycol coupled catalase (PEG-catalase) (5000 i.u./kg body weight) and the third (n = 9) saline (150 mmol/l NaCl) via the intraperitoneal route, in addition to the PA. 3. SOD and PEG-catalase reduced the 24 h urine protein on days 8 and 15 compared with unmodified puromycin treated animals and this difference was significant on day 15 for SOD (P less than 0.05) and for PEG-catalase (P less than 0.01). Glomerular filtration rate, as measured by the creatinine clearance, was lower in the PEG-catalase group but did not differ significantly from the saline treated group. 4. These data suggest that superoxide anion and hydrogen peroxide, or their reaction products, are involved in the glomerular injury of puromycin nephropathy.