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Biomedical subjects

S J Harper

Publications and source records attributed to S J Harper.

At least 55 records · Page 3Linked to original sources
PubMed1994

Low antibody affinity restricted to the IgA isotype in IgA nephropathy.

Antibody affinity affects the handling and behaviour of immune complexes, and experimental studies have shown that animals which produce predominantly low-affinity antibody are prone to immune complex deposition resulting in glomerulonephritis. In order to investigate the potential role of antibody affinity in the pathogenesis of IgA nephropathy, affinity of both IgA and IgG antibody isotypes during secondary response to systemic immunization with tetanus toxoid was studied in 20 patients with IgA nephropathy. Patients with IgA nephropathy produced IgA antibodies of significantly lower affinity than controls (P < 0.001), whereas IgG antibody affinities were similar. Contrasting with controls, patients' IgA antibody affinity was inversely related to antibody concentration, with higher responders producing large amounts of low-affinity antibody. IgG antibody affinity increased with time, and maturation of IgG antibody affinity was similar in both controls and patients. IgA affinity in controls decreased with time, and this lack of IgA affinity maturation may explain the relative unimportance of IgA in normal systemic immunity. This temporal decrease in IgA affinity was not observed in patients with IgA nephropathy. The production of low-affinity IgA in IgA nephropathy may provide an explanation for the predominant deposition of IgA in this disease.

Adolescent↗
PubMed1994

Influence of nifedipine on interstitial fibrosis in renal transplant allografts treated with cyclosporin A.

AIMS: To compare the degree of interstitial fibrosis in renal transplant biopsy specimens from immunosuppressed patients using conventional doses of cyclosporin with and without calcium channel blockade with a combination of low dose cyclosporin and azathioprine; to correlate the degree of interstitial fibrosis with the glomerular filtration rate. METHODS: A single blind histomorphometric assessment was done of cortical interstitial volume fraction from biopsy specimens taken intraoperatively and at one, six, and 12 months after transplantation from three prospectively randomised groups of patients: (A) conventional dose cyclosporin; (B) conventional dose cyclosporin plus nifedipine; (C) low dose cyclosporin plus azathioprine. RESULTS: Interstitial volume increased with time in all groups. No differences in interstitial volume were present at operation or at one month, but at six months interstitial volume was significantly less in group B than group A (p < 0.001) or group C (p < 0.05). More grafts failed in group A than group B leaving only small numbers for comparison at 12 months. At 12 months the differences persisted but did not reach significance. These results strongly reflected the clinical findings, where glomerular filtration rate was significantly lower in group A than groups B or C at six and 12 months; no differences in glomerular filtration rate were found at one month. In a direct comparison glomerular filtration rate showed a significant negative correlation with interstitial volume fraction. CONCLUSIONS: These findings suggest that calcium channel blockade with nifedipine slows the development of interstitial fibrosis in renal transplant recipients treated with cyclosporin. When clinical data are considered, it is suggested that calcium channel blockade may have a mitigating effect on the long term nephrotoxic effects of cyclosporin and should be considered as adjunctive treatment in patients requiring this immunosuppressant following renal transplantation.

Azathioprine↗
PubMed1994

Neurite outgrowth stimulated by L1 requires calcium influx into neurons but is not associated with changes in steady state levels of calcium in growth cones.

L1, NCAM and N-cadherin are cell adhesion molecules (CAMs), present on neuronal growth cones, which promote cell-contact dependent axonal growth by activating a second messenger pathway in neurons that requires calcium influx through L- and N-type calcium channels. In the present study we show that two of these CAMs, (L1 and N-cadherin) can stimulate neurite regeneration from axotomised adult dorsal root ganglion (DRG) neurons cultured in vitro and that this response can be fully inhibited by agents that block or negate the effect of calcium influx into the neurons. However although the response required calcium influx into neurons, it was not associated with an increase in the steady state levels of calcium in neuronal growth cones. These results suggest that small localised changes, or increases in the rate of calcium cycling, in growth cones and/or filopodia, are more important for regulating axonal growth than changes in the steady-state level of calcium.

3T3 Cells↗
PubMed1994

Glomerular disease as a cause of isolated microscopic haematuria.

Microscopic haematuria is a common clinical finding, with reported prevalences of up to 22%. The role of renal biopsy in the investigation of this condition is still debated. Currently urological investigation including cystourethroscopy is often regarded as adequate. We investigated 165 patients (94 male, 71 female; mean age 37.5 years, range 10-71) referred with isolated microscopic haematuria, using renal biopsy and cystourethroscopy. All patients were normotensive with normal serum creatinine, no proteinuria, sterile urine and a normal IVU. Renal biopsy abnormalities were found in 77/165 (46.6%): IgA nephropathy (49), global or segmental mesangial proliferative glomerulonephritis without IgA deposits (16), thin membrane nephropathy (7), vascular changes suggestive of hypertension (3), interstitial nephritis (1), and membranous nephropathy (1). Only five abnormalities were found on cystourethroscopy (cystitis 3, urethral stricture 1, bladder stone 1). Two patients with cystitis also had IgA nephropathy. Biopsy abnormalities were commonest under the age of 20 (69.2%), but 40% of biopsies were abnormal even in the seventh decade of life. Because renal biopsy abnormalities are very frequent in patients with isolated haematuria, renal biopsy is indicated in patients over 45 years of age if renal imaging and cystoscopy are normal. In those under 45 years, renal biopsy should replace cystoscopy as the investigation to follow normal renal imaging.

Adolescent↗
PubMed1993

Neurite outgrowth of spinal neurons on tissue sections of embryonic muscle is largely integrin dependent.

Embryonic chick spinal neurons have been cultured over sections of human foetal muscle to determine which cell adhesion molecules present in embryonic muscle are important in promoting neurite outgrowth. Using blocking antibodies against the major cell adhesion molecules, neural cell adhesion molecule (NCAM), N-cadherin and the beta 1 subunit of the integrins, neurite outgrowth was significantly blocked only by anti-integrin antibodies. In addition other agents that block neurite outgrowth stimulated by NCAM, N-cadherin and L1, such as the calcium channel antagonists verapamil and omega-conotoxin and pertussis toxin which inactivates G-proteins also had no effect. This suggests that in this culture system integrins are able to promote neurite outgrowth whereas NCAM and N-cadherin are not.

Animals↗
PubMed1993

Systemic and mucosal IgA responses to systemic antigen challenge in IgA nephropathy.

IgA nephropathy (IgAN) is characterized by the deposition of glomerular IgA. The source of the deposited IgA is not known, but both the mucosal and systemic IgA systems have been implicated. In order to investigate mucosal and systemic antibody production to systemic antigen challenge in IgAN, 20 patients and 20 controls where immunized with tetanus toxoid (TT). While patients with IgAN responded with a similar serum IgG, IgA, IgA1, and IgA2 antibody response to controls, they did, however, produce more IgA1 antibodies relative to IgA2 (P < 0.05). No salivary IgA antibody response was observed to systemic immunization in controls; however, there was a significant IgA response to TT in the saliva of patients with IgAN. IgA antibodies were produced in vitro by Epstein Barr virus (EBV)-transformed peripheral blood lymphocytes (PBLs) obtained from control blood only when taken shortly (1 or 2 weeks) after immunization. Patients with IgAN produced significantly more IgA anti-TT positive cultures than controls and for a longer period (P < 0.01) after immunization. In contrast, IgG anti-TT was produced in EBV-transformed cultures at all time points, but with no difference between IgAN and controls in the proportion of IgG producing cultures. These results demonstrate increased IgA antibody production in both the systemic and mucosal IgA systems following systemic immunization in IgAN and suggest an abnormal overlap between the two systems in IgAN.

Adolescent↗
PubMed1993

Elevation of IgA in IgA nephropathy is localized in the serum and not saliva and is restricted to the IgA1 subclass.

Glomerular deposits in IgA nephropathy (IgAN) are predominantly IgA1 but their origin is not known. Previous studies have analysed serum or saliva IgA, but not in the same patients. To investigate whether IgA and IgA subclass anomalies occur in IgAN at both mucosal and systemic sites, blood and saliva from 20 patients and 20 age- and sex-matched controls were studied. Patients with IgAN had significantly increased serum IgA (P < 0.002), and this elevation was restricted to the IgA1 subclass. Serum IgA1 was also increased significantly (P < 0.001) but IgA2 was not. By contrast salivary IgA, IgA1, and IgA2 did not differ significantly from the controls. These results demonstrate that the elevated serum IgA is predominantly IgA1 and is likely to be of systemic origin. Further studies should consider the bone marrow as a potential source of the elevated IgA1.

Adolescent↗
PubMed1993

The pathogenic role of immunoglobulin A polymers in immunoglobulin A nephropathy.

Circumstantial evidence that pIgA has a key role in glomerular injury of IgAN is now strong. Although the answers to the questions posed in this review are necessarily incomplete, they do indicate that (1) pIgA is a major component of mesangial IgA. (2) circulating pIgA is increased and this pIgA is particularly enhanced during acute hematuric relapses of IgAN. As well as true J-chain-positive pIgA, other macromolecular IgA species may circulate, including CIC, rheumatoid factors and complexes with fibronectin. (3) pIgA appears not to be derived from the mucosal lamina propria and may originate in the marrow and/or tonsil which may be unduly stimulated as a result of impaired oral tolerance. (4) Abnormalities of IgA production control are several, including genetic and cellular influences. Little is yet known about abnormalities specific for pIgA, although antigen-driven pIgA responses appear exaggerated and prolonged. In addition, pIgA enhancement may be due to activation of polyclonal antigen-independent antibody production of low affinity. (5) There is some evidence that pIgA has an enhanced capacity to bind to mesangial cells and induce injury compared to mIgA. (6) As yet, it is unclear whether pIgA has particular effects on mesangial cell activity and the induction of progressive injury. While steady progress continues in the understanding of the role of pIgA in the immunopathogenesis of IgAN, the design of therapeutic strategies based on such understanding still remains a considerable way off.

Glomerular Mesangium↗
PubMed1993

Deficiency of IgG subclass antibody response to tetanus toxoid associated with high serum IgA levels in IgA nephropathy.

In order to investigate IgG subclass response in IgA nephropathy (IgAN), 20 patients and 20 age and sex matched controls were systemically immunized with tetanus toxoid (TT). Nineteen/20 controls and 19/20 IgAN made a serum IgG anti-TT response of similar magnitude. However, significantly more patients with IgAN had undetectable amounts of at least one IgG subclass antibody to this antigen than controls (7/19 IgAN, 1/19 controls, p < 0.05). All individuals with an IgG subclass anti-TT deficiency lacked IgG1 and/or IgG4. Two patients made no IgG3 anti-TT (as well as no IgG1 and IgG4 anti-TT) but all individuals who responded to TT made IgG2 anti-TT. Total IgG subclass levels in IgAN did not differ from controls and no patient with IgAN had a total IgG subclass deficiency. Total serum IgA was significantly raised in IgAN (p < 0.002) and 6/7 IgAN with an IgG anti-TT subclass deficiency had a serum IgA level of over 3.2 milligrams compared to only 2/12 IgAN with no IgG subclass anti-TT deficiency (p < 0.01). The association of high serum IgA levels with IgG subclass deficiency to TT may be due to an abnormality in switching from IgG to IgA production in IgAN, or a manifestation of a defect of immunoregulation analogous to that proposed in IgA deficiency.

Adult↗
PubMed1993

Effect of renal function on the pharmacokinetics and pharmacodynamics of trandolapril.

1. The pharmacokinetics and pharmacodynamics of a single dose of trandolapril, an angiotensin converting enzyme (ACE) inhibitor with an active metabolite, trandolaprilat, which is in part further metabolised prior to renal elimination, were evaluated in 31 subjects with a wide range of renal function (creatinine clearance 4-112 ml min-1 1.73 m-2). 2. The pharmacokinetics of trandolapril were unaffected by differences in renal function. 3. In contrast, there was a close correlation between the renal clearance (0-96 h) of trandolaprilat and creatinine clearance (r = 0.95, P = 0.0001). The maximum plasma concentration of trandolaprilat, and the area under the concentration curve (0-96 h) correlated inversely with creatinine clearance (r = -0.59, P < 0.001; and r = -0.61, P < 0.001 respectively). 4. Significant changes in plasma trandolaprilat concentrations were seen only in patients with creatinine clearances of 30 ml min-1 1.73 m-2 or less, suggesting that a dose reduction in trandolapril might be advisable in severe renal impairment. 5. However, the majority of parameters of ACE inhibition were unrelated to creatinine clearance, although area under the curve for ACE inhibition (0-336 h) showed a weak negative correlation (r = -0.49, P < 0.01). Similarly, weighted mean changes in blood pressure were not influenced by renal function. 6. Therefore, while the pharmacokinetic parameters of trandolaprilat correlated with creatinine clearance, pharmacodynamic measurements (ACE inhibition and blood pressure changes) in general showed no such relationship, indicating that dose adjustment of ACE inhibitors in renal impairment should be based on pharmacokinetic results only in conjunction with pharmacodynamic data.

Adult↗
PubMed1992

Specific cytogenetic abnormalities and k-ras mutation in two new human colorectal-adenoma-derived cell lines.

Two new human epithelial cell lines from sporadic colorectal adenomas designated S/RR and S/BR are reported. Both cell lines have extended growth capacities in vitro, reaching passages 38 and 40 respectively and show no sign of senescence. S/RR and S/BR cell lines have retained the ability to differentiate in vitro, as shown by mucin production from goblet-like cells. S/BR was derived from a large colonic tubular villous adenoma (3 to 4 cm), whereas S/RR was derived from a small rectal adenoma (< 1 cm), and may represent a relatively early-stage adenoma. The parent S/RR cell line has given rise to a clonogenic variant, designated S/RR/Cl, which also has shown no sign of senescence and has currently reached passage 43. Both the S/BR and the S/RR cell lines had mutations in codon 12 of the K-ras gene, while retaining one normal allele. The presence of this mutation, particularly in the cell line S/RR derived from a small adenoma, is consistent with ras mutation being a relatively early event in colorectal carcinogenesis and is perhaps involved in the ability of the adenoma cells to progress and to give rise to an immortal cell line in vitro. The clonal derivatives of the S/RR cells have an isochromosome 1q and abnormalities of chromosome 13 which include an isochromosome 13q. The S/BR cells have a deletion on the short arm of chromosome 1 and trisomy 7. The common abnormality for S/RR and S/BR cells involves chromosome 1. The involvement of different chromosomes in the 2 cell lines also suggests different pathways for malignant progression of the premalignant adenoma cells.

Adenoma↗
PubMed1992

A single human colonic adenoma cell line can be converted in vitro to both a colorectal adenocarcinoma and a mucinous carcinoma.

In a previous study, using a chemical carcinogen, we converted in vitro a non-tumorigenic cell line derived from a human colorectal diploid adenoma, designated PC/AA, into a tumorigenic cell line which, when inoculated into athymic nude mice, produced progressively growing adenocarcinomas. We now report that continuous in vitro passage of the PC/AA adenoma cell line resulted in its spontaneous transformation to a mucinous carcinoma with a modal karyotype of 51, XY, +i(Iq), +8, +9, +13, +i(13q), -21, +mar. These studies show that a single adenoma can be converted along 2 independent pathways, giving rise to either a mucinous carcinoma or an adenocarcinoma, and provide further experimental evidence for the adenoma-carcinoma sequence. Cytogenetic changes which occur along both pathways to tumorigenicity include abnormalities of chromosome I and multiple copies of chromosome 13. These abnormalities may be important in tumour development and progression in colorectal carcinogenesis.

Adenocarcinoma↗
PubMed1992

Nifedipine improves immediate, and 6- and 12-month graft function in cyclosporin A (CyA) treated renal allograft recipients.

To investigate the effect of oral nifedipine, a calcium channel blocker known not to modify cyclosporin A (CyA) pharmacokinetics, on immediate transplant function and CyA nephrotoxicity, 68 adult renal transplant recipients were pre-operatively randomized to one of three regimes: A (high-dose CyA, initial dose 17 mg/kg per day, maintenance dose 7 mg/kg per day); B (regime A plus oral nifedipine); C low-dose CyA, initial dose 10 mg/kg per day, maintenance 4 mg/kg per day plus azathioprine 1 mg/kg per day). All three groups received identical steroid regimes. Calcium channel blockers of all types were avoided in groups A and C. Delayed graft function (dialysis dependence by day 4) was seen least frequently in group B (P < 0.02). Group B had improved graft function at 6 months compared with group A, identified by differences in serum creatinine (P < 0.05), GFR (P < 0.01) and ERPF (P < 0.05). Similar differences in serum creatinine (P < 0.05) and GFR (P < 0.05) were also identified at 12 months. Group C also had better 6- and 12-month GFR values than group A (P < 0.05 each). The three groups did not differ in donor or recipient age, HLA matching, ischaemic or anastomosis times, frequency of early rejection or whole-blood CyA levels. These results indicate that nifedipine significantly improves immediate and medium-term graft function.

Adult↗
PubMed1992

Increased and prolonged production of specific polymeric IgA after systemic immunization with tetanus toxoid in IgA nephropathy.

IgA nephropathy (IgAN) is a chronic form of glomerulonephritis which is characterized by the deposition in the glomerular mesangium of polymeric IgA (pIgA), the source of which is unknown. In order to investigate the production of pIgA in IgAN, patients were immunized systemically with tetanus toxoid (TT). Two weeks after immunization patients and controls responded to TT with an IgA response of similar magnitude. HPLC separation of sera showed that patients with IgAN produce significantly more pIgA anti-TT than controls (7.7 versus 2.88 arbitrary units; P less than 0.04). At this time, 33% of serum IgA anti-TT produced by patients with IgAN was polymeric, compared with 21% produced by controls (P less than 0.02). Monomeric IgA (mIgA) anti-TT levels were similar in both groups. Four weeks after immunization the proportion of pIgA anti-TT in controls and patients was significantly reduced from the 2 week level (from 21% to 0%, P less than 0.02 for controls; and from 33% to 8%, P less than 0.001, for patients). Only four out of 12 controls had any detectable pIgA anti-TT at this time compared with nine out of 10 patients with IgAN (P less than 0.05), and IgAN patients produced proportionally more pIgA anti-TT than did controls (median 8%, interquartile ranges (IQR) 4-10% versus 0% IQR 0-3%; P less than 0.01). HPLC analysis under acid conditions did not alter the pattern of pIgA and mIgA anti-TT, suggesting that the high molecular weight IgA fraction was not due to complexes. These data indicate that circulating pIgA results (at least in part) from a systemic response to antigen, which may be exaggerated in IgAN.

Adolescent↗
PubMed1992

Simultaneous in situ hybridisation of native mRNA and immunoglobulin detection by conventional immunofluorescence in paraffin wax embedded sections.

AIMS: The development of a technique for simultaneous in situ hybridisation for native mRNA and conventional immunofluorescence for cytoplasmic antigens in routine pathology specimens. METHODS: Cocktails of synthetic deoxyoligonucleotides coding for immunoglobulin J chain and kappa light chain were 3' end labelled enzymatically with digoxigenin using terminal deoxynucleotidyl transferase. Native mRNA sequences were "unmasked" using proteolytic digestion with proteinase K and hybrid detection was achieved with an alkaline phosphatase labelled anti-digoxigenin antibody. Alkaline phosphatase was visualised with Fast red/naphthol AS-MX phosphate. Fluorescein isothiocyanate (FITC) conjugated anti-isotype antibodies were used simultaneously at the detection stage to identify the isotype production by individual plasma cells in endoscopic duodenal biopsy specimens. RESULTS: The IgA plasma cells of the lamina propria were identified by immunofluorescence and hybrids were detected in the anticipated plasma cell population by Fast red visualisation. The reaction product was visible in bright field or ultraviolet illumination which allowed FITC and Fast red labels to be visualised together under ultraviolet light at 490 nm. Dual labelled cells were clearly visible. Morphology was well preserved throughout. CONCLUSIONS: This technique permits the demonstration of specific mRNA species in cells expressing immunoglobulin. It combines all the advantages of non-radioactive synthetic oligonucleotide probes and conventional immunofluorescence techniques in routine formol-saline fixed and paraffin wax embedded sections with good retention of morphology.

Antigens↗
PubMed1992

Delayed psyllium allergy in three nurses.

The use of psyllium has been associated with various allergic reactions. Three nurses at the Prescott Veterans Affairs Medical Center had differing degrees of psyllium allergy. The reactions ranged from sneezing to chest congestion and wheezing. Two nurses were available for skin testing, and both had a positive wheal reaction. Psyllium allergic reactions have been reported rarely in the literature; however, they may be more prevalent than previously realized.

Allergens↗