Search PubMed⌕ Search

Biomedical subjects

A J Howie

Publications and source records attributed to A J Howie.

At least 55 records · Page 3Linked to original sources
PubMed1997

Association of vasculitic glomerulonephritis with membranous nephropathy: a report of 10 cases.

BACKGROUND: The concomitant occurrence of a vasculitic glomerulonephritis and membranous nephropathy in the same patient is unusual. We report data on 10 patients with this unusual combination. METHODS: Ten patients (nine males/one female; median age 63.5 years, range 30-70 years) presented between 1981 and 1995 with: acute renal failure (n = 3), nephrotic syndrome (n = 4), non-nephrotic range proteinuria and renal insufficiency (n = 3). The median serum creatinine at presentation was 296 mumol/l (range 65-1749 mumol/l). One patient had a vasculitic transformation from membranous nephropathy 5 years after the original presentation, coincident with an acute deterioration of renal function requiring dialysis; in all other patients the two glomerular disorders were seen together at presentation. Treatment was with oral prednisolone and cyclophosphamide (eight patients), of whom one also had plasma exchange; and oral prednisolone and azathioprine (one patient). Specific immunosuppressive treatment was withheld in one patient with histological evidence of chronic renal damage. Sera from four patients out of nine tested were positive for ANCA. RESULTS: After a median follow-up of 3.5 years (range 2 months-10 years), renal function had improved in three patients and remained stable in two. Two patients required renal replacement therapy. Three patients had died: one was ANCA-negative and died of a systemic vasculitis, and the other two died of sepsis. CONCLUSION: Membranous nephropathy complicated by a vasculitic glomerulonephritis: (1) has a more aggressive clinical course than membranous nephropathy alone, (2) appears to have an association with ANCA, (3) should be considered in those patients with an accelerated decline in renal function, and (4) may respond to treatment with immunosuppressive drugs.

Adult↗
PubMed1997

Focal segmental necrotizing glomerulonephritis in rheumatoid arthritis.

We report ten patients with rheumatoid arthritis (RA) who developed a focal segmental necrotizing glomerulonephritis (FSNGN) and extracapillary proliferation typical of vasculitic glomerulonephritis. Five patients also had extrarenal vasculitis. Renal presentation was with renal impairment (n = 9) (median creatinine 726 mumol/l, range 230-1592 mumol/l), microscopic haematuria (n = 8) and proteinuria (n = 10). Nine patients were seropositive for rheumatoid factor and nine had bone erosions. Serum from four of five patients tested by indirect immunofluorescence was positive for antineutrophil cytoplasmic antibody (ANCA) with perinuclear staining. Only three patients had penicillamine or gold therapy. Treatment was with prednisolone and cyclophosphamide (six patients, two of whom were also plasma-exchanged), prednisolone and azathioprine (two patients) and prednisolone alone (two patients). There was a marked improvement in renal function in eight patients. Two patients with dialysis-dependent renal failure recovered renal function, although in one patient this was transient and she required further dialysis 4 months later. Two other patients progressed to dialysis at 3 months and 1 year respectively. Four patients died, one remains dialysis-dependent, and four continue to have good renal function at 5 year follow-up (median creatinine 148.5 mumol/l, range 120-193 mumol/l). One patient was lost to follow-up at 5 years. FSNGN should be considered in all patients with RA and renal impairment, proteinuria and/or microscopic haematuria. This diagnosis appears to be more likely in patients with clinical extrarenal vasculitis, bone erosions or who are seropositive. In these cases, an urgent renal biopsy is indicated.

Adult↗
PubMed1997

Controlled trial of pulse versus continuous prednisolone and cyclophosphamide in the treatment of systemic vasculitis.

Although cyclophosphamide and prednisolone are effective in treating systemic vasculitis, the optimum treatment regimes and duration of treatment are unknown. We randomized 54 patients aged 15-70 years (median 57.5 years) with systemic vasculitis (classical polyarteritis n = 8, microscopic polyarteritis n = 17, Wegener's granulomatosis n = 29) to treatment with either pulse cyclophosphamide and prednisolone (PCYP) (n = 24) or continuous oral and prednisolone and cyclophosphamide, with the latter followed after a median of 3 months (range 1.5-10 months) by azathioprine (CCAZP) (n = 30). Patients on CCAZP were more likely to develop leucopenia (13/30) than patients on PCYP, (7/24) although the difference was not significant. The numbers of infective episodes during follow up were comparable in the two groups at 1.7/patient for PCYP and 1.66/patient for CCAZP. Overall, 26/30 patients (87%) treated with CCAZP developed treatment-related toxicity, as did 17/24 patients (71%) treated with PCYP. After a median follow-up of 40.4 months (range 0.7-64.8), there was no difference in the frequency of deaths (PCYP 5, CCAZP 4), relapses (PCCYP 7, CCAZP 8), treatment failures (PCYP 4, CCAZP 4), improvement in disease activity scores or renal function. Survival at three years was 77% in patients treated with PCYP, and 90% in patients on CCAZP (p = 0.38). There was a tendency towards increased toxicity in patients treated with the continuous regimen.

Adolescent↗
PubMed1997

Immunodetection of 11 beta-hydroxysteroid dehydrogenase type 2 in human mineralocorticoid target tissues: evidence for nuclear localization.

11 beta-Hydroxysteroid dehydrogenase (11 beta HSI) is an enzyme complex responsible for the conversion of hormonally active cortisol to inactive cortisone; two isoforms of the enzyme have been cloned and characterized. Clinical observations from patients with the hypertensive syndrome apparent mineralocorticoid excess, recently explained on the basis of mutations in the human 11 beta HSD2 gene, suggest that it is the 11 beta HSD2 isoform that serves a vital role in dictating specificity upon the mineralocorticoid receptor (MR). We have raised a novel antibody in sheep against human 11 beta HSD2 using synthetic multiantigenic peptides and have examined the localization and subcellular distribution of 11 beta HSD2 in mineralocorticoid target tissues. The immunopurified antibody recognized a single band of approximately 44 kDa in placenta, trophoblast, and distal colon. In kidney tissue, two bands of approximately 44 and 48 kDa were consistently observed. No signal was seen in decidua, adrenal, or liver. Immunoperoxidase studies on the mineralocorticoid target tissues, kidney, colon, and parotid gland indicated positive staining in epithelial cells known to express the MR: respectively, renal collecting ducts, surface and crypt colonic epithelial cells, and parotid duct epithelial cells. No staining was seen in these tissues in other sites. The intracellular localization of 11 beta HSD2 in kidney and colon epithelial cells was addressed using confocal laser microscopy. Parallel measurements of 11 beta HSD2 and nuclear propidium iodide fluorescence on sections scanned through an optical section of approximately 0.1 micron indicated significant 11 beta HSD2 immunofluorescence in the nucleus. In human kidney, colon, and salivary gland, 11 beta HSD2 protects the MR from glucocorticoid excess in an autocrine fashion. Furthermore, within these tissues, 11 beta HSD2, which had been considered to be a microsomal enzyme, is also found in the nucleus, suggesting that the interaction between the MR and aldosterone or cortisol is in part a nuclear event.

11-beta-Hydroxysteroid Dehydrogenases↗
PubMed1996

Hypertension in the syndrome of apparent mineralocorticoid excess due to mutation of the 11 beta-hydroxysteroid dehydrogenase type 2 gene.

BACKGROUND: 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD) catalyses the interconversion of hormonally active cortisol to inactive cortisone and is vital for dictating specificity for the mineralocorticoid receptor. Thus, in patients with congenital deficiency of 11 beta-HSD (the syndrome of apparent mineralocorticoid excess, AME), cortisol and not aldosterone acts as a mineralocorticoid, resulting in hypertension and hypokalaemia with suppression of the renin-angiotensin-aldosterone axis. Two isoforms of human 11 beta-HSD have been described, but it is the NAD-dependent type 2 isoform (11 beta-HSD2), first characterised in placental tissue, that is expressed in the mineralocorticoid target tissues, kidney and colon. We have analysed the 11 beta-HSD2 gene as a candidate gene in explaining the molecular basis of AME. METHODS: By exon-specific PCR-amplification of the 11 beta-HSD2 gene in a consanguineous kindred with AME, we found a point mutation (C1228T) in two affected siblings, and also in placental DNA obtained from a stillbirth pregnancy. FINDINGS: The mutation in exon 5 of the 11 beta-HSD2 gene resulted in a premature stop site at codon 374 instead of a normal arginine (R374X), with the deletion of 32 aminoacids from the C-terminus of the 11 beta-HSD2 enzyme protein. Both parents, who are phenotypically normal, are heterozygote for the C1228T mutation in keeping with an autosomal recessive form of inheritance. NAD-dependent 11 beta-HSD activity was severely attenuated in the stillbirth placenta compared with control placental tissue, and no 11 beta-HSD immunostaining was observed in this placenta with antisera derived against a C-terminal 11 beta-HSD2 peptide sequence. INTERPRETATION: AME is due to a mutation in the 11 beta-HSD2 gene, and is an example of human hypertension arising from a single gene defect.

11-beta-Hydroxysteroid Dehydrogenases↗
PubMed1996

Effect of RS61443 in combination with leflunomide or FK506 on rat heart allograft survival.

Mycophenolate Mofetil (RS61443) is a potent inhibitor of de novo purine synthesis and lymphocyte proliferation. It is known to prevent ongoing rejection and even reverse established rejection, alone and in combination with, cyclosporin. We investigated whether RS61443 in combination with leflunomide (Lef) or FK506 (FK) could prolong allograft survival in a rat heart model, since combination therapy might help to overcome drug toxicity. Abdominal heart grafting was performed from DA to LEW rats (250 g) and RS61443, 10 mg/kg or 30 mg/kg monotherapy or combination treatment (RS 10 mg/kg with Lef 5 mg/kg or FK 0.5 mg/kg) was begun orally at transplantation and continued daily until the ninth posttransplant (post-Tx) day. Ventricular motion was graded daily and rejection was defined as lack of contractions, confirmed by histology. Results were analysed using non-parametric tests. A two-tail P value < 0.05 was considered significant. RS at 10 mg/kg was ineffective and all grafts were rejected under immunosuppression between 5 and 6 post-Tx day, whereas RS at 30 mg/kg was immunosuppressive for as long as it was given. The combinations of RS at 10 mg/kg with either Lef at 5 mg/kg or FK at 0.5 mg/kg were immunosuppressive in the majority of cases, for as long as they were given. However, the combination of RS at 10 mg/kg with FK at 0.5 mg/kg was attendant with graft vein anastomosis rupture (3/5). The combination of RS with Lef was clinically therapeutic for as long as it was given; grafts were rejected 3-4 days after withdrawing immunosuppression. The combination of RS with FK resulted in over-immunosuppression, leading to graft vein anastomosis non-healing and rupture within 5 days of grafting; histology demonstrated evidence of bacterial infection with complete destruction of the vein wall. These data suggest that the combination of RS with Lef or FK in subtherapeutic doses might be a potentially promising strategy for combination therapy in solid organ transplantation.

Animals↗
PubMed1996

Detection of myocardial infarction by immunohistological staining for C9 on formalin fixed, paraffin wax embedded sections.

AIMS: To evaluate an immunohistological stain for complement component C9 as a method of detecting early myocardial infarction and to compare this with (1) an enzyme histochemical method and (2) conventional histological staining. METHODS: (1) Eight hearts taken at necropsy were stained using the nitroblue tetrazolium/phenazine methosulphate method and an immunohistological stain for C9. (2) Twenty five hearts from cases of suspected or confirmed myocardial infarction and 25 from cases without conventional evidence of infarction were stained for C9 and by haematoxylin and eosin. RESULTS: (1) The histochemical method indicated myocardial necrosis in five hearts and the C9 method in seven, all of which had clinical evidence of myocardial damage or a reason for it. The histochemical method required fresh myocardium, was difficult to use and was difficult to interpret. (2) Of 25 hearts with suspected or confirmed infarction, 24 were stained by the C9 method. Staining with haematoxylin and eosin showed infarction in 16 of these, all with infarcts at least 24 hours old; the other eight had clinical evidence of infarction less than 24 hours old. The heart not stained by C9 was from a patient who, on review, had no evidence of infarction. Of the 25 control hearts, none had infarction on staining with haematoxylin and eosin, but three were stained by the C9 method. These three were from patients with septicaemia or another reason for myocardial damage. CONCLUSIONS: The immunohistological method for C9 is a simple, reliable and sensitive method for the detection of early myocardial necrosis that could be used on formalin fixed, paraffin wax embedded necropsy material. This had advantages over a histochemical method and conventional staining with haematoxylin and eosin.

Adult↗
PubMed1996

Interactions between renal tubules and interstitium.

Renal tubules and interstitium have close physiological associations. Changes in both are often seen in renal disease. Damaged tubules can attract inflammatory cells and stimulate interstitial fibrosis, but do not always do so. Interstitial inflammation can damage tubules and can also stimulate fibrosis, and is probably always initiated by tubular events. Interstitial and tubular abnormalities are closely associated with changes in renal excretory function, but tubular events are more important. A main determinant of the outcome of renal disease is whether tubules can recover, not the extent of interstitial changes. If tubules are atrophic, they will not recover and renal function will be permanently impaired.

Extracellular Space↗
PubMed1996

Glomerular vascular cell adhesion molecule-1 expression in renal vasculitis.

AIMS: To study the expression of cell adhesion molecules in the renal biopsy specimens of patients with systemic vasculitis and Henoch-Schönlein purpura (HSP); to correlate this with the severity of glomerular inflammation. METHODS: Renal biopsy specimens obtained from eight patients with untreated systemic vasculitis (four with Wegener's granulomatosis and four with microscopic polyarteritis), eight with HSP and nine controls (four with normal histopathology and five with thin glomerular basement membrane disease) were stained using the alkaline phosphatase anti-alkaline phosphatase method with monoclonal antibodies directed against intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) and E-selectin. RESULTS: Biopsy specimens of normal kidneys expressed ICAM-1 in glomerular endocapillary cells, Bowman's capsule epithelium, interstitial cells and interstitial vascular endothelium, and VCAM-1 in Bowman's capsule epithelium, proximal tubular epithelium and interstitial vascular endothelium. No staining with antibody directed against E-selectin was seen in any of the biopsy specimens. Biopsy specimens of patients with a vasculitic glomerulonephritis (segmental necrotising glomerulonephritis) expressed VCAM-1 in glomerular endocapillary cells (four of eight patients with systemic vasculitis; two of eight patients with HSP). In patients with a systemic vasculitis glomerular VCAM-1 expression was associated with a more severe renal lesoin (44, 50, 60, and 65% of glomeruli involved) than in those not showing glomerular VCAM-1 expression (3, 3, 11, and 39% of glomeruli involved). CONCLUSION: Expression of VCAM-1 by glomerular endocapillary cells in renal biopsy specimens raises the possibility that recruitment of VLA-4 bearing leucocytes may contribute to glomerular injury in Wegener's granulomatosis and microscopic polyarteritis.

Adolescent↗
PubMed1996

Renal effects of metabolic acidosis in the normal rat.

Metabolic acidosis causes renal growth and proteinuria, and may contribute to the progression of CRF. This study assessed the effects of HCI-induced acidosis on the structure and function of normal kidneys. Acidosis was induced in 12 rats by dietary HCl. After 2 weeks, acidotic animals had higher kidney/body weight ratios (0.47 +/- 0.10 vs. 0.35 +/- 0.10 g%, p < 0.001) and higher kidney protein content (123 +/- 3 vs. 111 +/- 4 mg/kidney, p < 0.05) than controls, but tubular nuclear densities were lower, suggesting tubular hypertrophy. Acidotic animals developed tubular proteinuria (16.4 +/- 2.6 mg/day after 2 weeks of acidosis vs. 2.9 +/- 0.3 mg/day at baseline; p < 0.001), and the pattern of immunohistochemical staining for Tamm-Horsfall protein suggested tubular injury. These data suggest that a tubulotoxic effect of metabolic acidosis may contribute to the progression of CRF.

Acidosis↗
PubMed1996

'Benign' essential hypertension and kidney damage: a histopathologist's view.

The kidney is damaged in people with hypertension and clinical renal disorders. The damage may be explained by chronic renal ischaemia, but there is no rigorous proof that hypertension damages a previously normal kidney. Indeed there are ideas that the kidney is abnormal from the start in hypertensive people.

Humans↗
PubMed1995

Detection of human 11 beta-hydroxysteroid dehydrogenase isoforms using reverse-transcriptase-polymerase chain reaction and localization of the type 2 isoform to renal collecting ducts.

11 beta-Hydroxysteroid dehydrogenase (11 beta-HSD), responsible for the interconversion of hormonally active cortisol to inactive cortisone, dictates specificity for the mineralocorticoid receptor (MR) in the distal nephron and colon. Two isoforms of human 11 beta-HSD have been cloned, an NADP(H)-dependent (type 1) dehydrogenase/oxo-reductase enzyme, and a high-affinity NAD-dependent (type 2) unidirectional dehydrogenase. Using the reverse-transcriptase polymerase chain reaction (RT-PCR) amplification of RNA extracted from human adult tissues, type 1 11 beta-HSD mRNA was found in decidua, placenta, liver, lung, spleen, kidney medulla, cerebellum and pituitary, but was absent in kidney cortex, sigmoid and rectal colon, salivary gland and thyroid. In contrast, type 2 11 beta-HSD mRNA was found only in placenta and in the classical mineralocorticoid target tissues, kidney cortex, kidney medulla, sigmoid and rectal colon, salivary gland, and colonic epithelial cell lines (AAC1 and RGC28). In situ hybridization studies of renal cortex, cortico-medullary junction and medulla using a 35S-labeled antisense cRNA probe for type 2 human 11 beta-HSD, revealed specific localization of type 2 11 beta-HSD mRNA expression exclusively to renal cortical and medullary collecting ducts. Type 1 and type 2 isoforms of human 11 beta-HSD are expressed in a distinct tissue-specific fashion, in keeping with the proposed differences in their physiological roles. Type 2 11 beta-HSD is found predominantly in mineralocorticoid target tissues where it serves to protect the MR in an autocrine fashion.

11-beta-Hydroxysteroid Dehydrogenases↗
PubMed1995

Pathogenesis of segmental glomerular changes at the tubular origin, as in the glomerular tip lesion.

Segmental abnormalities at the glomerulo-tubular junction, or tip changes, are a common and early feature in several experimental and human renal disorders. Scanning and transmission electron microscopic study of an experimental model, Lewis rats given anti-glomerular basement membrane antibodies, showed that at 5 days there were monocytes/macrophages in glomerular capillary loops next to the tubular origin, with abnormalities of visceral epithelium, including prolapse of groups of these cells into the tubular origin. At 12 days, there was contact and adhesion between glomerular capillary loops and Bowman's capsule. Transmission electron microscopic study of human renal biopsies showed that the human tip changes resembled the later lesions seen in rats, with intracapillary foam cells confirmed by immunohistological study to be monocytes/macrophages. These findings show that abnormalities of the glomerular tuft precede adhesion to Bowman's capsule and that the earliest changes recognized by light microscopy in human renal biopsies are relatively late in their natural history, meaning at least several days old. Prolapse of visceral epithelial cells into the tubular origin may explain the characteristic site of tip changes.

Animals↗
PubMed1995

Anti-epithelial (anti-A549) antibodies: their nature, specificity and relevance to transplantation.

Several studies have addressed the possible importance of anti-epithelial cell antibodies in kidney transplantation using the A549 cell line as an in vitro model. In this paper we report our results using for the first time an enzyme-linked immunosorbent assay (ELISA) to detect the anti-A549 cell antibodies. Sera from 129 kidney transplant patients were tested for IgM anti-epithelial cell antibodies directed against the A549 cell line prior to transplantation; only three sera were positive (2.3%). 101 of these patients were then followed-up post-transplantation; sera were collected routinely at 2, 6 and 12 weeks and at the time of rejection episodes. All samples were also tested for cytomegalovirus (CMV) IgM antibodies. Sixteen patients developed anti-A549 IgM antibodies, and there was no correlation with acute graft rejection. Anti-epithelial antibodies showed no binding to sections of normal kidney or biopsies of rejected kidneys. Eleven patients were positive for anti-CMV IgM antibodies. In nine cases both IgM anti-A549 and IgM anti-CMV antibodies were found, which was a highly significant association (p < 0.001). Analysis of A549 cellular proteins by immunoblotting gave evidence for the presence of CMV polypeptides in the cell lysate. Electron-microscopic examination of A549 cell preparations revealed intracellular particles which were compatible in size with CMV. Polymerase chain reaction analysis confirmed the presence of a specific CMV DNA sequence in A549 cells of several batches from different sources. Our data strongly suggest that the A549 cell line used in several published reports is infected with CMV and that in the majority of cases the anti-A549 'anti-epithelial' antibodies found in renal transplant patients are anti-CMV antibodies.

Adolescent↗
PubMed1995

Measurement of proliferation in renal biopsy specimens: evidence of subclinical tubular damage in the nephrotic syndrome.

BACKGROUND: Proliferating cells can be detected in histological material in various ways. This investigation was to study the feasibility and usefulness of application of proliferation markers to routine renal biopsy specimens. METHODS: One hundred and thirteen renal biopsies fixed in formalin and embedded in paraffin were studied immunohistologically using antibody MIB 1, which recognises the Ki-67 antigen. Twenty-two biopsies were also immunostained with antibody PC10 against proliferating cell nuclear antigen. RESULTS: PC10 stained nuclei in all biopsies, including those that were negative with MIB 1. MIB 1 stained nuclei in endocapillary sites to various extents, and there was an average of less than one stained endocapillary nucleus per glomerulus in biopsies with IgA nephropathy and IgM nephropathy, conventionally regarded as types of proliferative glomerulonephritis. Glomerular extracapillary nuclei were stained by MIB 1 in vasculitic disorders and at the site of tip changes. MIB 1 also stained nuclei in the arterial intima, especially in vascular rejection, and in interstitial tissues, correlating with renal excretory function. Tubular nuclei stained by MIB 1 were common in biopsies from patients with renal impairment and in a group with the nephrotic syndrome, in many of whom renal function was normal. CONCLUSIONS: The main conclusions are that (1) immunohistological markers of proliferation can be applied to routine renal biopsy material; (2) PC10 appears to overestimate proliferation compared with MIB 1; and (3) there is evidence of subclinical tubular damage in the nephrotic syndrome, shown by increased tubular proliferation without clinical renal impairment. This observation seems not to have been made previously.

Antibodies, Monoclonal↗
PubMed1995

An optical practice based diabetic eye screening programme.

In many cases, blindness due to diabetic retinopathy can be prevented provided treatment with laser photocoagulation is used at the correct time. A screening programme is required to identify cases of sight threatening retinopathy. An optical practice based diabetic eye screening programme has been established in Dorset. The optometrist undertaking the examination is paid a fee. The findings are recorded on a coded form and sent to the hospital diabetologist who recalls positive cases. Seventy-six optical practices have joined the scheme and 3224 patients have been screened in the first 6 months (Dorset population 655,000). In the Poole area (population 230,000), 1922 patients were screened and 129 (6.7%) were recalled in 6 months. Outcome of 3 months screening, identified 59 recalls. Referral to the opthalmologist was made in 15 cases for potentially sight threatening retinopathy, 14 cases were followed in the diabetic clinic for significant background retinopathy, and 24 cases were returned to the annual screening in the optical practices. Six cases where the patients either failed or were unable to attend were reviewed by the GP. An optical practice based diabetic eye screening programme has been successful in screening a large number of patients.

Diabetic Retinopathy↗
PubMed1995

Tamm-Horsfall protein in reflux nephropathy.

The distribution of Tamm-Horsfall protein, the main protein in normal urine, was studied immunohistologically in the kidneys of 70 pigs with unilateral vesico-ureteric reflux but without outflow obstruction. Strains of Escherichia coli were inoculated in the bladder. Inflammatory changes of reflux nephropathy (chronic pyelonephritis) were found in 52 pigs. There were extra-tubular deposits of Tamm-Horsfall protein in the kidneys of only 26 pigs. These deposits were small, increased in prevalence as the size of inflamed areas increased, and were not associated with deposits of the protein in glomeruli. These findings suggest that escape of Tamm-Horsfall protein from tubules and backwash into glomeruli are not major features of low pressure reflux nephropathy, unlike the findings in outflow obstruction of the lower urinary tract. There was no evidence that a reaction to Tamm-Horsfall protein was important in the pathogenesis of reflux nephropathy.

Animals↗