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R J Rigby

Publications and source records attributed to R J Rigby.

At least 19 recordsLinked to original sources
PubMed2006

Identification of chromosome intervals from 129 and C57BL/6 mouse strains linked to the development of systemic lupus erythematosus.

Systemic lupus erythematosus is an autoimmune disease in which complex interactions between genes and environmental factors determine the disease phenotype. We have shown that genes from the non-autoimmune strains 129 and C57BL/6 (B6), commonly used for generating gene-targeted animals, can induce a lupus-like disease. Here, we conducted a genome-wide scan analysis of a cohort of (129 x B6)F2 C1q-deficient mice to identify loci outside the C1qa locus contributing to the autoimmune phenotype described in these mice. The results were then confirmed in a larger dataset obtained by combining the data from the C1q-deficient mice with data from previously reported wild-type mice. Both analyses showed that a 129-derived interval on distal chromosome 1 is strongly linked to autoantibody production. The B6 genome contributed to anti-nuclear autoantibody production with an interval on chromosome 3. Two regions were linked to glomerulonephritis: a 129 interval on proximal chromosome 7 and a B6 interval on chromosome 13. These findings demonstrate that interacting loci between 129 and B6 mice can cause the expression of an autoimmune phenotype in gene-targeted animals in the absence of any disrupted gene. They also indicate that some susceptibility genes can be inherited from the genome of non-autoimmune parental strains.

Animals↗
PubMed2006

Mice, humans and haplotypes--the hunt for disease genes in SLE.

Defining the polymorphisms that contribute to the development of complex genetic disease traits is a challenging, although increasingly tractable problem. Historically, the technical difficulties in conducting association studies across the entire human genome are such that murine models have been used to generate candidate genes for analysis in human complex diseases, such as SLE. In this article we discuss the advantages and disadvantages of this approach and specifically address some assumptions made in the transition from studying one species to another, using lupus as an example. These issues include differences in genetic structure and genetic organisation which are a reflection on the population history. Clearly there are major differences in the histories of the human population and inbred laboratory strains of mice. Both human and murine genomes do exhibit structure at the genetic level. That is to say, they comprise haplotypes which are genomic regions that carry runs of polymorphisms that are not independently inherited. Haplotypes therefore reduce the number of combinations of the polymorphisms in the DNA in that region and facilitate the identification of disease susceptibility genes in both mice and humans. There are now novel means of generating candidate genes in SLE using mutagenesis (with ENU) in mice and identifying mice that generate antinuclear autoimmunity. In addition, murine models still provide a valuable means of exploring the functional consequences of genetic variation. However, advances in technology are such that human geneticists can now screen large fractions of the human genome for disease associations using microchip technologies that provide information on upwards of 100,000 different polymorphisms. These approaches are aimed at identifying haplotypes that carry disease susceptibility mutations and rely less on the generation of candidate genes.

Animals↗
PubMed2005

Production of interleukin (IL)-10 and IL-12 by murine colonic dendritic cells in response to microbial stimuli.

Intestinal dendritic cells (DC) are likely to regulate immunity to gut microflora, but little is known about their responses to bacterial antigens. Therefore, DC from normal murine colon were characterized and their cytokine responses to components of Gram-negative and/or Gram-positive bacteria assessed. Cells were obtained by digestion of colonic tissue and contained DC that were identified by flow cytometry as CD11c(+) major histocompatibility complex (MHC) class II(+) cells. Purified DC were obtained by immunomagnetic separation plus cell sorting. DC had the morphology of immature myeloid cells, were endocytically active, expressed low levels of co-stimulatory molecules and stimulated a weak allogeneic mixed leucocyte reaction. Analysis of flow cytometry data by a sensitive subtraction method allowed measurement of production of interleukin (IL)-12 and IL-10 by small numbers of gut DC by intracellular staining. Fewer than 5% of unstimulated DC produced either IL-10 or IL-12. IL-10 production was significantly up-regulated following stimulation with Bifidobacteria longum, but not after exposure to lipopolysaccharide (LPS) or Streptococcus faecium. In contrast, colonic DC produced IL-12 in response to both LPS and B.longum. Thus, colonic DC can produce both IL-12 and IL-10 following bacterial stimulation. Cell wall components from different bacteria stimulate distinct responses and may direct immune responses differentially in the gut.

Animals↗
PubMed2004

Multiple loci are linked with anti-red blood cell antibody production in NZB mice -- comparison with other phenotypes implies complex modes of action.

The New Zealand Black (NZB) mouse strain is a model of autoimmune haemolytic anaemia (AHA) and systemic lupus erythematosus (SLE), characterized by the production of anti-red blood cell (RBC) antibodies and anti-nuclear antibodies (ANA), respectively. A linkage analysis was carried out in an (NZB x BALB/c) F(2) cross in order to identify loci involved in the production of both anti-RBC IgM and IgG antibodies. These regions of linkage were compared with linkage data to ANA from the same cohort and other linkage analyses involving New Zealand mice. Four previously described NZB loci linked to anti-RBC antibodies were confirmed, and eight novel loci linked to this trait were also mapped: five of which were of NZB origin, and three derived from the non-autoimmune BALB/c background. A comparison between loci linked with anti-RBC antibodies and ANA demonstrated many that co-localize, suggesting the presence of genes that result in the general breaking of tolerance to self-antigen. Furthermore, the observation that some loci were associated only with the anti-RBC response suggests an antigen specific mechanism in addition to a general breaking of tolerance. A locus linked with anti-RBC antibodies and ANA on distal chromosome 7 in this cohort is orthologous to one on the q arm of human chromosome 11, a region linked to AHA and ANA in human SLE.

Anemia, Hemolytic, Autoimmune↗
PubMed2001

A retrospective analysis of mycophenolic acid and cyclosporin concentrations with acute rejection in renal transplant recipients.

OBJECTIVES: Although monitoring of cyclosporin (CsA) is standard clinical practice postrenal transplantation, mycophenolic acid (MPA) concentrations are not routinely measured. There is evidence that a relationship exists between MPA area under the concentration-time curve (AUC) and rejection. In this study, a retrospective analysis was undertaken of 27 adult renal transplant recipients. METHODS: Patients received CsA and MPA therapy and had a four-point MPA AUC investigation. The relationship between MPA AUC performed in the first week after transplantation, as well as median trough cyclosporin concentrations, and clinical outcomes in the first month posttransplant were evaluated. RESULTS: A total of 12 patients experienced biopsy proven rejection (44.4%) and 4 patients had gastrointestinal adverse events (14.8%). A statistically significant relationship was observed between the incidence of biopsy proven rejection and both MPA AUC (p = 0.02) and median trough CsA concentration (p = 0.008). No relationship between trough MPA concentration and rejection was observed (p = 0.21). Only 3 of 11 (27%) patients with an MPA AUC > 30 mg x h/L and a median trough CsA > 175 microg/L experienced acute rejection, compared with a 56% incidence of rejection for the remaining 16 patients. Patients who experienced adverse gastrointestinal events had significantly lower MPA AUC (p = 0.04), but median trough CsA concentrations were not significantly different (p = 0.24). Further, 3 of these 4 patients had rejection episodes. CONCLUSIONS: In addition to standard CsA monitoring, we propose further investigation of the use of a 4-point sampling strategy to predict MPA AUC in the first week posttransplant, which may facilitate optimization of mycophenolate mofetil dose at a time when patients are most vulnerable to acute rejection.

Adult↗
PubMed2000

Novel surveillance and cure of a donor-transmitted lymphoma in a renal allograft recipient.

BACKGROUND: In this report we describe a malignant lymphoma of donor origin inadvertently transplanted into two renal allograft recipients, despite standard comprehensive donor screening. The successful clearance of the tumor from both patients and a novel method of surveillance are detailed. METHODS: Initial management consisted of withdrawal of immunosuppression to promote rejection of the allograft and the transplanted tumor in both patients, followed by graft removal. Peripheral blood microchimerism was assessed in both recipients using nested polymerase chain reaction to detect the DYZ3 gene on the Y chromosome (donor male, recipients female). RESULTS: Although microchimerism was detected on day 6 after transplantation and day 1 after explantation, repeat peripheral blood examination at 1, 3, and 6 months after explantation demonstrated no microchimerism. Both patients remain well at 12 months and have been relisted for transplantation. CONCLUSION: Despite inadvertent transplantation of a previously undiagnosed malignancy of donor origin, the recipients' immune response was able to eliminate donor tumor cells after the withdrawal of immunosuppression. Repeated surveillance of peripheral blood from both recipients, using a novel application of the technique of nested polymerase chain reaction to amplify donor DNA, demonstrated no persistence of donor cells, supporting effective eradication of the donor malignancy.

Aged↗
PubMed2000

A comparison of the effects of dialysis and renal transplantation on the survival of older uremic patients.

BACKGROUND: Patients over age 60 constitute half of all new patients accepted into the renal replacement therapy programs in Australia. However, the optimal treatment of their end-stage renal disease remains controversial. The aim of the present study was to compare survival for dialysis and renal transplantation in older patients who were rigorously screened and considered eligible for transplantation. METHODS: The study cohort consisted of 174 consecutive patients over 60 who were accepted on to the Queensland cadaveric renal transplant waiting list between January 1, 1993 and December 31, 1997. Follow-up was terminated on October 1, 1998. Data were analyzed on an intention-to-transplant basis using a Cox regression model with time-varying explanatory variables. An alternative survival analysis was also performed, in which patients no longer considered suitable for transplantation were censored at the time of their removal from the waiting list. RESULTS: There were 67 patients receiving a renal transplant, whereas the other 107 continued to undergo dialysis. These two groups were well matched at baseline with respect to age, gender, body mass index, renal disease etiology, comorbid illnesses, and dialysis duration and modality. The overall mortality rate was 0.096 per patient-year (0.131 for dialysis and 0.029 for transplant, P<0.001). Respective 1-, 3- and 5-year survivals were 92%, 62%, and 27% for the dialysis group and 98%, 95%, and 90% (P<0.01) for the transplant group. Patients in the transplant group had an adjusted hazard ratio 0.16 times that of the dialysis group (95% confidence interval 0.06-0.42). If patients were censored at the time of their withdrawal from the transplant waiting list, the adjusted hazard ratio was 0.24 (95% confidence interval 0.09-0.69). CONCLUSIONS: Renal transplantation seems to confer a substantial survival advantage over dialysis in patients with end-stage renal failure who are rigorously screened and considered suitable for renal transplantation.

Aged↗
PubMed1999

The kinetics of mycophenolic acid and its glucuronide metabolite in adult kidney transplant recipients.

BACKGROUND: Mycophenolic acid kinetics have been reported to vary after renal transplantation, and mycophenolic acid area under the concentration-time curve (AUC) is the best predictor of suppression of graft rejection. METHODS: To determine whether mycophenolic acid kinetics vary after renal transplantation and to examine the potential role of enterohepatic recirculation, we investigated the kinetics of mycophenolic acid and mycophenolic acid glucuronide on days 2, 5, and 28 after transplantation in 10 kidney transplant recipients (male/female ratio, 1.5; mean age, 41.7 +/- 5.0 years) given 1 g mycophenolate mofetil twice a day. To facilitate therapeutic drug monitoring, we examined a limited sampling strategy for estimating 12-hour mycophenolic acid [AUC(0-12)]. RESULTS: The mean +/- SE AUC(0-12) for mycophenolic acid on day 28 was 38.5 +/- 1.6 mg x h/L, with a secondary peak 4 to 8 hours after dosing that was attributable to enterohepatic recirculation. Marked variability was shown in the kinetic profile of mycophenolic acid among patients across the three sampling days. Mycophenolic acid AUC(0-12) was positively predicted by both serum creatinine (P = .01) and serum albumin (P = .03) but not by time after transplantation, body weight, or trough concentration. Limited sampling (at 0, 1, 3, and 6 hours) accounted for 84.1% of the variability in the mycophenolic acid AUC(0-12) data and predicted the AUC(0-12) closely (r2 = 0.954) when evaluated in 10 different kidney transplant recipients. CONCLUSIONS: Mycophenolic acid AUC(0-12) is predicted by serum albumin and creatinine after kidney transplantation, and the AUC(0-12) may be determined during the early posttransplant period while the patient remains hospitalized with use of a limited sampling strategy to facilitate therapeutic drug monitoring.

Adult↗
PubMed1998

Sclerosing peritonitis: the experience in Australia.

BACKGROUND: Sclerosing peritonitis (SP) is a rare but serious complication of peritoneal dialysis (PD). Small-bowel obstruction (SBO) due to encapsulation, dense adhesions, or mural fibrous is characteristic, often associated with peritonitis. The aim of the study was to determine the incidence, clinical features, effect of duration of dialysis, and other possible aetiological factors in severe SP. METHODS: All dialysis units in Australia were surveyed for possible cases up to 1994. Patients were included if there was either surgical or radiological evidence of sclerosing encapsulating peritonitis or SBO with tanned or thickened peritoneum in the absence of other causes of SBO. RESULTS: Fifty-four patients were analysed. The duration of continuous PD was mean 52 +/- 30 months, median 48 months and range 8-127 months. Nineteen cases were diagnosed between 1980 and 1989 and 35 between 1990 and 1994, giving mean annual incidences 1.9 and 4.2 per 1000 PD periods respectively. The overall prevalence was 0.7%, which increased progressively with the duration of PD being 1.9, 6.4, 10.8, and 19.4% for patients on dialysis for > 2, 5, 6 and 8 years respectively. Sclerosing encapsulating peritonitis was diagnosed in 87% of cases, SBO in 92%, and haemoperitoneum in 8%. Peritoneal calcification was present in seven cases, all of which had been on PD > 7 years. Peritonitis was associated with 38% of cases with fungal infection in 7%. Treatment with immunosuppression in five patients appeared to result in a favourable outcome in three. The mortality rate was 56%. CONCLUSION: Severe sclerosing peritonitis is a serious complication of peritoneal dialysis and there is a time dependent increase on CAPD.

Adult↗
PubMed1996

A randomized trial comparing 1.25 mmol/l calcium dialysate to 1.75 mmol/l calcium dialysate in CAPD patients.

BACKGROUND: Effective control of hyperparathyroidism and renal osteodystrophy in CAPD patients requires a combination of calcitriol and calcium carbonate (CaCO3), but is frequently limited by hypercalcaemia. Reducing dialysate calcium (Ca) concentration may overcome this problem, but had not been examined in a controlled trial. METHODS: 45 stable CAPD patients were randomly assigned in a prospective double-blind trial to either a study group (1.25 mmol/l Ca dialysate) or a control group (1.75 mmol/l Ca dialysate) for 12 months. Clinical, biochemical and radiological parameters of secondary hyperparathyroidism were followed. RESULTS: Twenty-three patients did not complete the study due to death (9), transplantation (7) or conversion to haemodialysis (7). Eleven patients in each group completed the study. Mean serum Ca, phosphate, ionized Ca, aluminium, alkaline phosphatase (AP), and bone mineral density (BMD) Z-scores did not differ significantly at any time within or between the two groups. Severe hypercalcaemia was more common in the control group (11 vs. 2, P = 0.027). Mean serum intact parathyroid hormone (PTH) and osteocalcin (OCN) initially rose in the study group relative to controls at 3 months (40 +/- 7 vs 12 +/- 3 pmol/l, P = 0.004, and 33 +/- 5 vs 15 +/- 2 micrograms/l, P = 0.002 respectively), but were not sustained. Median weekly dosages of calcitriol and daily dosages of CaCO3 increased significantly in the study group (O microgram to 1 microgram P = 0.014 and 1260 mg to 2520 mg P = 0.002 respectively), but not in the control group. Supplementary aluminium hydroxide (A1, (OH)3) was required for phosphate control in both study (n = 5) and control patients (n = 4). CONCLUSIONS: Lowering dialysate calcium concentration reduced the frequency of severe hypercalcaemia and allowed prescription of larger quantities of calcitriol and CaCO3. However, in this study it offered no advantage in terms of A1(OH)3 requirement, while bone mass density did and may have initially exacerbated secondary hyperparathyroidism not change.

Aluminum Hydroxide↗
PubMed1995

Effect of OKT3 in steroid-resistant renal transplant rejection.

Between January 1, 1982, and November 1, 1986, 169 cadaver renal graft transplantations were performed at this hospital with CsA as induction therapy. OKT3 was not available in this period. Of these grafts, 15.9% were lost within 6 months, 10.7% from acute rejection (AR). Between November 1, 1986, and October 1, 1992, 483 cadaver renal graft transplantation were performed. Induction therapy included CsA and OKT3 was available. Of these grafts, 8.7% were lost inside 6 months, 3.1% from AR. Of these last 483 grafts, 113 received 125 courses of OKT3. Ten courses were prophylactic, and 115 courses in 103 patients were for rejection resistant to steroid therapy (biopsy proven in all but 2 cases. Ninety-three percent of rejection episodes treated with OKT3 responded, at least initially. Graft survival in OKT3-treated patients was 81%, 77%, and 76% at 6 months, 1 year, and 2 years, respectively. In contrast, graft survival in steroid-resistant rejection during the first period (without OKT3) was 59%, 57%, and 57% at these intervals. There were 8 infective deaths within 6 months in the 113 OKT3-treated patients, compared with 2 in the 343 who did not receive OKT3 (P < 0.001). There were 7 viral deaths in the OKT3 group compared with none in those not receiving OKT3 (P < 0.001). Prophylaxis with oral acyclovir and cotrimoxazole was instituted in October 1990 in OKT3-treated patients and ganciclovir use was increased. Since this change, no further viral deaths have occurred. OKT3 is a very effective antirejection agent, but its use is associated with an increased mortality from viral infections. With appropriate prophylaxis and treatment, however, this mortality can be reduced.

Cyclosporine↗
PubMed1995

Recovery of gastrointestinal function after renal transplantation in a patient with sclerosing peritonitis secondary to continuous ambulatory peritoneal dialysis.

We describe the rapid and dramatic improvement in gastrointestinal function that occurred after successful renal transplantation in a women with severe sclerosing peritonitis secondary to continuous ambulatory peritoneal dialysis (CAPD). We postulate that the antiinflammatory effect of the immunosuppressive agents was the most important factor leading to the patient's recovery.

Adult↗
PubMed1990

Onset of dialysis encephalopathy in cyclosporine-treated renal allograft recipients.

Three patients who developed typical features of dialysis encephalopathy following renal transplantation are presented. No patient had evidence of overt neurological dysfunction pretransplantation. All patients were taking cyclosporine at the time of onset of neurological disease. Two patients died as a result of their neurological condition. The third patient made a satisfactory recovery. Factors responsible for the onset of dialysis encephalopathy in the renal posttransplantation period are discussed. We propose that cyclosporine may have been an important precipitating factor of the neurological syndrome of these patients.

Adult↗
PubMed1989

Selection of ESRD treatment: an international study.

Using the method of paired comparisons, we surveyed nephrologists in three different socioeconomic regions, North Carolina, Southern California, and Australia-New Zealand, to determine their preferences among the major end-stage renal disease (ESRD) treatment modalities. For comparison, we also determined how patients were assigned to the treatment modalities, based on registry data in the regions. Preferences were determined in for six standard ESRD treatment modalities--living related donor (LRD), four-antigen match, LRD two-antigen match, and cadaver (CAD) transplantation; and home peritoneal dialysis (HPD), home hemodialysis (HHD), and facility hemodialysis (FHD)--and for three categories of patients--patients with diabetes, patients over age 60, and patients in general. There was overall agreement in the ranking of treatments by the nephrologists from all three regions for each of the three patient categories; however, significant differences were noted between regions in preferences for certain modalities. Comparison within and between regions revealed striking disparities between preferences and practice. Analysis of these findings provides important insights into the process of ESRD treatment selection and identifies issues that merit further consideration.

Attitude of Health Personnel↗
PubMed1989

Cyclosporin A in the treatment of childhood glomerulonephritis.

Seven children with steroid resistant nephrotic syndrome (focal segmental sclerosis in six, mesangial proliferation in one) were treated with Cyclosporin A for 12 weeks. Five of these children were also resistant to cyclophosphamide. All patients had normal renal function. Cyclosporin was started at 8 mg/kg/day then increased until a trough blood level of 100-300 ng/ml (HPLC) was achieved. Three of the seven patients achieved complete remission, and the other four had a significant reduction in their proteinuria (p less than 0.05). In the three patients who achieved complete remission, relapse of proteinuria occurred within six weeks of ceasing Cyclosporin. All patients experienced some impairment in renal function with mean creatinine clearance decreasing from 129 +/- 19 to 91 +/- 13 ml/min/1.73m2 (p less than 0.05). One child was subsequently treated with Cyclosporin for 12 months. He remains in remission with a repeat renal biopsy showing no evidence of nephrotoxicity. One other child with steroid sensitive minimal change nephrotic syndrome who had severe steroid toxicity was treated with a lower dose (5 mg/kg/day) for 12 months. She remained in remission off steroids, but relapsed 16 weeks after Cyclosporin was ceased. A renal biopsy after 12 months showed no nephrotoxicity. Cyclosporin should be considered in steroid resistant nephrotic syndrome, and in children with minimal change disease who show signs of steroid toxicity and short remission period after cyclophosphamide. Serial renal biopsies are recommended with prolonged therapy.

Child↗