Search PubMed⌕ Search

Biomedical subjects

G J Becker

Publications and source records attributed to G J Becker.

At least 55 records · Page 3Linked to original sources
PubMed1998

Suppression of the humoral immune response by mycophenolate mofetil.

BACKGROUND: No conventional immunosuppressive agent preferentially inhibits antibody production. Studies in experimental animals and in human cells in vitro suggested mycophenolate mofetil (MMF) might have such an effect. If this was the case in vivo it could have significant implications in terms of both MMF toxicity and the rational design of immunotherapeutic regimens. METHODS: Subjects were renal transplant recipients (25 patients treated with prednisolone, cyclosporine and azathioprine, and 13 treated with prednisolone, cyclosporine and MMF) and 20 normal controls. The three groups received influenza vaccination, and the antibody response to it was measured 4-6 weeks later using a standard haemagglutination assay. RESULTS: MMF profoundly suppressed the humoral immune response to influenza vaccination when added to prednisolone and cyclosporine. This effect could be seen when comparing the rise in the mean titre of antibody after vaccination. It was also reflected in the number of patients mounting responses deemed to be clinically protective by either demonstrating a 4-fold rise in titre or an increase in titre to > or = 40. CONCLUSIONS: Suppression of the humoral immune response by MMF has implications for the design of immunization protocols to protect the immunosuppressed, and raises the possibility that MMF use may be accompanied by more or different infections than complicate more conventional immunosuppression. More importantly, consideration should be given to harnessing the relatively specific effect of MMF on antibody production to treat antibody-mediated diseases.

Adolescent↗
PubMed1998

Dynamic gadolinium DTPA-enhanced magnetic resonance of intravascular stents.

RATIONALE AND OBJECTIVES: Magnetic resonance contrast enhancement depends on the timing of image acquisition. Human trials have demonstrated efficacy of renal artery stents on salvage of renal function. This study assessed the ability of dynamic gadolinium (Gd)-DTPA administration to demonstrate renal and iliac artery stent patency compared to conventional angiography as the gold standard. METHODS: Seven subjects with eight stents referred for angiography underwent dynamic magnetic resonance studies, all with renal artery stenting. All were examined with conventional angiography and after dynamic Gd-DTPA infusion. Coronal magnetic resonance images were acquired using a GE Signa 1.5 T magnet (fast spoiled gradient echo; echo time = 4.2 ms; repetition time = 68-150 ms; flip angle = 75 degrees) 0 to 600 seconds after 0.1 mmol/Kg Gd-DTPA intravenous bolus injection during sequential breath-hold acquisitions 13 to 32 seconds each. RESULTS: All eight stents were visualized with 100% accurate patency documentation. CONCLUSIONS: Fast spoiled gradient echo magnetic resonance imaging with bolus Gd-DTPA administration can provide adequate time and spatial resolution to demonstrate arterial stent patency.

Aged↗
PubMed1998

Evolution of tubulointerstitial fibrosis in experimental renal infection and scarring.

Renal tubulointerstitial fibrosis may result from a loss of tubulointerstitial volume, which produces a disproportionate increase in the density of matrix. This study examines the relationship between fibrogenesis and collapse in scar formation after experimental renal infection. Escherichia coli were inoculated into the renal cortex of Sprague Dawley rats, with saline substituted in a control group. Glomerular, tubular, and interstitial profile areas were determined. Density of glomerular profiles was used as a measure of tubulointerstitial collapse. Collagen type I, III, and IV expression was examined by in situ hybridization and immunohistochemistry. Myofibroblasts were identified by alpha smooth muscle actin immunohistochemistry, and matrix metalloproteinase-1 (MMP-1) and MMP-2 were localized with appropriate antisera. Acute interstitial edema was followed by increasing density of glomerular profiles, paralleled by loss of interstitial volume and progressive tubular atrophy. Glomerular profile area remained unchanged. Density of glomerular profiles was not temporally related to myofibroblast accumulation. Procollagen alpha 1(I), alpha 1(III), and alpha 1(IV) transcription was focal, spatially related but temporally ordered. Collagen I, III, and IV immunostaining was increased from days 3, 24, and 100, respectively (P < 0.05 versus day 0 and day 100 saline). However, when corrected for glomerular density, collagen I immunostaining decreased between days 24 and 100, whereas collagen III and IV no longer differed from day 0. MMP staining within the lesion was confined to occasional interstitial and epithelial cells throughout. It is concluded that in this model, contraction and collapse of the tubulointerstitial parenchyma has a greater influence than new collagen production on final fibrotic density.

Analysis of Variance↗
PubMed1997

Myofibroblast involvement in chronic transplant rejection.

BACKGROUND: Chronic rejection remains the major cause of late graft failure. We studied the renal tissue of 10 renal transplant patients with chronic rejection in whom biopsies had been performed at various time points over a 15-year posttransplant period to ascertain whether myofibroblasts (MF) have a role in this process. METHODS: Biopsies were grouped into five categories with respect to time after vascular anastomosis: 0 (n=10); 1 day to 3 months (n=7); 6-24 months (n=5); 36-72 months (n=7); and >72 months (n=5). A control group consisted of patients who had undergone routine biopsies at 0 (n=10), 3 (n=10), 12 (n=6), 60 (n=5), and >60 months (n=6) with no rejection. MF were identified by morphology and alpha-smooth muscle actin immunostaining. T cells and macrophages (MF) were identified using an antisera to CD3 and CD68, respectively. Collagen III deposition was similarly quantified by immunohistochemistry. Interstitial fractional area was measured by point counting. RESULTS: At all time points studied beyond time 0, there were significant increases in interstitial fractional area, collagen III staining, MF, and T-cell staining in patients with chronic rejection compared with the controls. Staining for alpha-smooth muscle actin increased with time in conjunction with worsening fibrosis and collagen deposition. CONCLUSIONS: In this study, MF were a major component of the interstitial infiltrate of the 10 patients with chronic transplant rejection. Abnormal persistence of these cells in the interstitium is one of the events that contributes to pathologic scarring of the kidney.

Actins↗
PubMed1997

Large, rapid skeletal changes after parathyroidectomy.

We report dramatic increases in spine and hip bone mineral density six weeks following parathyroidectomy in renal patients. We have previously reported a cross-sectional association between parathyroidectomy and higher axial bone mineral density in dialysis patients. Large axial increases in bone mineral density after surgery for primary hyperparathyroidism have been recorded by others at one year postoperatively. Bone mineral density was recorded before and six weeks after parathyroidectomy. Scans were performed at the lumbar spine, hip and non-dominant radius. Values were expressed as Z-scores (standard deviations from the mean of an age- and gender-matched reference population). Large increases in lumbar were spine and femoral neck bone mineral density seen at six weeks post parathyroidectomy. Median increases were 0.57 (p = 0.006) and 0.26 (p = 0.039) Z-score units for these sites, respectively. Individual six-week increases were as large as 1.3 Z-score units at the spine and 1.0 Z-score units at the femoral neck. No significant cohort change was detected at the forearm but individual forearm changes were highly variable. Several mechanisms to explain these large rapid increases can be postulated. These include: mineralization of osteoid and/or contraction of the remodeling space. The changes illustrate the extent to which the skeleton is capable of rapid and profound change in mineral content. Our findings emphasize that the skeleton is a heterogeneous organ and that bone density should be measured at multiple skeletal sites.

Absorptiometry, Photon↗
PubMed1996

Angiotensin-converting enzyme inhibition in nondiabetic progressive renal insufficiency: a controlled double-blind trial.

Angiotensin-converting enzyme inhibitors delay progression of renal disease in different animal models of nephropathy. We tested this treatment modality in 70 hypertensive patients with severe renal disease of various etiologies. We report a double-blind study of the effect of 5 mg enalapril once daily compared with placebo in patients with nondiabetic severe chronic renal impairment (plasma creatinine 2.8 to 6.8 mg/dL; mean creatinine clearance 15 mL/min/1.73 m2) followed for up to 2 years. Efficacy parameters were the slopes of 51Cr-EDTA clearance, reciprocal of plasma creatinine, creatinine clearance, and the effect on urinary protein excretion. Thirty-one patients completed 2 years of treatment (12 in the enalapril group and 19 in the placebo group). Two patients died from nonrenal causes (one patient each in the enalapril and placebo groups), 16 patients commenced dialysis (seven in the enalapril group and nine in the placebo group), and eight patients were discontinued due to adverse events (five in the enalapril group and three in the placebo group). Eleven patients were discontinued because they were noncompliant, uncooperative, or moved (nine in the enalapril group and two in the placebo group). Two enalapril-treated patients were dropped from the study due to protocol deviations. Importantly, the statistical approach in this study evaluated all patients, regardless of the duration of treatment. A mixed-effects linear model and intention to treat analysis, taking into account the number of observations per patient, indicated that enalapril significantly reduced the rate of deterioration of renal disease: glomerular filtration rate (P = 0.038), reciprocal of plasma creatinine (P = 0.017), or creatinine clearance (P = 0.031). The renal protective effects of enalapril were shown to be in addition to its antihypertensive effect when blood pressure was held constant. Proteinuria was reduced by enalapril (P = 0.007) and was slightly increased in the placebo-treated patients (P = 0.051). The difference between these two groups was highly significant (P = 0.002). In conclusion, enalapril retarded the progression of chronic renal failure, as assessed by changes in glomerular filtration rate, creatinine clearance, and 1/plasma creatinine, and reduced proteinuria in patients with nondiabetic severe chronic renal insufficiency.

Adolescent↗
PubMed1996

Prevalence and risk factors for osteopenia in dialysis patients.

Dialysis patients are at risk for low bone mineral density (BMD) consequent of hyperparathyroidism, 1,25-dihydroxyvitamin D deficiency, previous immunosuppression, chronic acidosis, secondary amenorrhea, and chronic heparin and aluminum exposure. We wanted to determine the prevalence and distribution of osteopenia and the influence of risk factors for osteopenia in dialysis patients. Dual energy x-ray absorptiometry was used to record BMD at the lumbar spine (LS), hip, and nondominant forearm. Results were expressed as Z-scores (standard deviations from the mean of a healthy age- and gender-matched reference population). Osteopenia was defined as a Z-score worse than -2. In the 250 dialysis patients studied, the prevalence of osteopenia at the LS, femoral neck (FN) and ultradistal radius (UD) was 8%, 13% and 20%, respectively. The median Z-scores at these sites were all significantly different from the healthy reference population median of 0 and were 0.29 (P = 0.008), -0.67 (P < 0.001), and -1.01 (P < 0.001), respectively. Previous transplantation was associated with as much as a one Z-score lower BMD at the FN (P = 0.0069) and UD (P = 0.0011) and a marginally significant reduction at the LS (P = 0.0777). Previous parathyroidectomy was associated with a markedly higher LS BMD (P = 0.0001) and a higher BMD at the FN (P = 0.0017) but not the UD (P = 0.3691). A history of secondary amenorrhea was associated with a lower FN BMD (P = 0.0047) but not a significantly lower BMD at the LS (P = 0.0978) or UD (P = 0.2327). In hemodialysis patients without a history of transplantation, parathyroidectomy, or secondary amenorrhea, there was no correlation between Z-score at any site and duration of dialysis. Thus, osteopenia in dialysis patients occurs in both axial and appendicular sites and sites of compact and cancellous bone. It is more common with previous transplantation and secondary amenorrhea, whereas a history of parathyroidectomy is associated with increased BMD. No relationship was found between BMD and duration of hemodialysis, which suggests that important changes in BMD occur during the predialysis stage of chronic renal failure.

Absorptiometry, Photon↗
PubMed1996

The significance of focal and segmental hyalinosis and sclerosis (FSHS) and nephrotic range proteinuria in IgA nephropathy.

Between 1971 and 1991, 845 patients were diagnosed as having IgA glomerulonephritis on renal biopsy performed. These patients were followed for a mean period of 53 months post biopsy (range 0-336 months). By the end of follow up 147 (17%) of patients have developed chronic renal failure (Cr > 0.2 mmol/l) or end-stage renal failure. Presenting creatinine > 0.12 mmol/l, hypertension, nephrotic range, age > 40 years and male gender, all correlated strongly on univariate analysis with the development of chronic renal failure or kidney disease (all p < 0.0001). However, a number of patients developing chronic renal failure or end-stage renal failure already had renal impairment (creatinine > 0.12 mmol/l at presentation). A separate comparison was performed of patients presenting with creatinine < 0.12 mmol/l and either developing chronic failure or end-stage renal failure within 5 years of biopsy (n = 18) and those with creatinine still < 0.12 mmol/l after 5 years follow up (n = 186). Of the 18 patients who deteriorated 6 (35%) were nephrotic at presentation and 9 (56%) had focal hyalinosis and sclerosis on renal biopsy. This compared with 5 (3%) patients with nephrotic range proteinuria and 16 (10%) patients with focal hyalinosis and sclerosis among the 186 patients who did not deteriorate (p < 0.0001). The sensitivity and specificity of the presence of either or both factors in predicting deterioration was calculated at 65% and 87% respectively. Thus in patients with normal renal function at presentation the presence of nephrotic range or focal hyalinosis and sclerosis are strong predictors of adverse clinical outcome.

Adult↗
PubMed1995

Metastatic endophthalmitis in dialysis patients.

Metastatic bacterial endophthalmitis is a rare but devastating complication of septicaemia. We present 3 recent cases occurring in dialysis patients. Septicaemic dialysis patients seem particularly prone to staphylococcal endophthalmitis which developed in the face of therapeutic serum concentrations of appropriate antibiotics in all 3 cases. Prompt treatment, including consideration of intravitreal antibiotics, is required if vision is to be preserved. Early signs of endophthalmitis should be actively sought in septicaemic dialysis patients, as they are easily overlooked.

Adult↗
PubMed1995

Interstitial myofibroblasts in IgA glomerulonephritis.

We examined renal biopsy specimens from patients with mesangial IgA glomerulonephritis (n = 25; plasma creatinine 0.05-0.30 mmol/l) to ascertain whether the myofibroblast has a role in progressive renal interstitial fibrosis. Myofibroblasts were identified by morphology and alpha smooth muscle actin (alpha-SMA) immunostaining at the light and electron microscope level. Results were related to staining for interstitial leukocytes and collagen III. A control group consisted of 6 normal renal transplant donors from whom biopsy specimens were taken at the time of vascular anastomosis. The fractional volume of interstitial alpha-SMA staining was greater in patients with mesangial IgA glomerulonephritis than in the control group (17.2 vs. 1.3%; p < 0.001). alpha-SMA staining was increased in areas of interstitial fibrosis with prominent periglomerular and peritubular distribution. Ultrastructural studies established that alpha-SMA staining in the renal interstitium was intracellular, cytoplasmic, and confined to myofibroblast-like cells and processes. The alpha-SMA expression correlated with fractional volume of tubular atrophy/dilation (r = 0.79, p < 0.001), interstitial connective tissue (r = 0.66, p < 0.001), leucocytes (r = 0.72, p < 0.005), and collagen III (r = 0.71, p < 0.001). Staining correlated with renal function at the time of biopsy (r = 0.64, p < 0.005) and after 2 years of follow-up (r = 0.77, p < 0.01). In conclusion, cells with a myofibroblast-like phenotype have a significant role in the progression of tubulointerstitial injury.

Actins↗
PubMed1995

Interstitial myofibroblasts in experimental renal infection and scarring.

We have examined the temporal and spatial distribution of myofibroblast-like cells, a phenotype with fibroblast and smooth muscle features, in an experimental model of renal infection. Escherichia coli organisms (10(5)) were inoculated directly into the renal cortex of Sprague-Dawley rats weighing 270 g. Saline was substituted in a control group. The animals were sacrificed at five time points up to day 24 (E. coli n = 8, controls n = 3 each interval). Myofibroblasts were identified by morphology and immunohistochemistry for alpha smooth muscle actin (alpha-SMA) and compared with staining for monocytes (ED-1), collagen III, and bromodeoxyuridine incorporation. Histological changes included a focal lesion in E. coli infected animals. Interstitial alpha-SMA staining was confined to spindle-shaped cells resembling myofibroblasts. The percent fractional area of alpha-SMA staining in the lesion increased from 0.12 +/- 0.09 at day 1 to 20.0 +/- 7.1 at day 3 (p < 0.005), decreasing progressively to 2.0 +/- 2.6 by day 24. This paralleled bromodeoxyuridine incorporation in myofibroblasts: 0.4 +/- 0.5 cells/0.25 mm2 at day 1, 105.0 +/- 36.3 at day 3, and 2.6 +/- 2.2 cells/0.25 mm2 at day 24. ED-1-positive cells increased from 374 +/- 200/0.25 mm2 at day 1 to 894 +/- 88 at day 3 (p < 0.01), declining to 230 +/- 108/0.25 mm2 by day 24. Intracellular collagen III and alpha-SMA stainings were colocalized at day 3. The fractional area of collagen III increased by day 24 (p < 0.05). In conclusion, myofibroblasts accumulate transiently during renal interstitial fibrosis and are derived at least in part from local proliferation.(ABSTRACT TRUNCATED AT 250 WORDS)

Actins↗
PubMed1994

Evaluating peer reviews. Pilot testing of a grading instrument.

OBJECTIVE: To measure the reliability and preliminary validity of a grading instrument for editors to evaluate the quality of peer reviews. DESIGN: The consecutive sample design included 53 reviews of 23 manuscripts. Reviews were systematically assigned to interrater reliability (n = 41; power greater than 0.90 to detect a difference of greater than one point) and preliminary criterion-related validity (n = 12) subsamples. Content validity was closely examined. SETTING: Nonclinical. PARTICIPANTS: Three graders evaluated reliability. One individual examined content validity and two editors tested preliminary criterion-related validity. INTERVENTION (INSTRUMENT)--Attributes reflecting two basic dimensions, review content and format, were identified and scored (values are possible points/percent contribution): timeliness, 3/21%; grade sheet, 1/7%; etiquette, 1/7%; sectional narratives, 3/21%; citations, 2/14%; narrative summary, 2/14%; and insights, 2/14%. A scoring guide was provided. MAIN OUTCOME MEASURES: Statistical analyses used to test the interrater reliability of the total score included the intraclass correlation coefficient and analysis of variance with the expectation to uphold the null hypothesis. Kendall's coefficient of concordance was used to test preliminary criterion-related validity. RESULTS: The intraclass correlation coefficient was .84 (P < .001) and a lack of difference between mean scores was demonstrated by analysis of variance (P = .46). Content validity was confirmed and preliminary criterion-related validity was indicated (Kendall's coefficient of concordance = .94, P = .038). CONCLUSIONS: The instrument is reliable. Content validation has been completed, and further criterion-related validation is warranted.

Evaluation Studies as Topic↗
PubMed1994

Triple immunosuppression with subsequent prednisolone withdrawal: 6 years' experience in paediatric renal allograft recipients.

Thirty-four children (< or = 15 years of age) with end-stage renal failure received 39 renal allografts between 1985 and 1991 and were treated with cyclosporin A (CyA), azathioprine and low-dose prednisolone (PNL). We aimed to withdraw PNL by 6 months after transplantation. Median duration of follow-up was 2 years 4 months (range 0.1 month to 6 years 4 months). There were no deaths. Crude graft survival for living-related grafts (n = 9) was 100%, although only 1 patient has been followed for > 2 years. For cadaveric grafts (n = 30), 1- and 5-year actuarial graft survivals were 90% and 79% respectively. At 12 months posttransplant, the median (range) glomerular filtration rate for all patients was 63 (19-109) ml/min per 1.73 m2 (n = 25) and at 5 years was 48 (17-64) ml/min per 1.73 m2 (n = 9). Complications observed included rejection episodes which occurred after discontinuation of PNL. Long-term (after 12 months), 28% of patients remain on PNL. Hypertension was present in more than 50% of patients. Severe CyA nephrotoxicity was not seen. Catch-up growth as determined by the change (delta) in mean height standard deviation score (Ht-SDS) was noted at 1 year [delta SDS/year = +0.60; P < 0.001 (n = 18)] and at 2 years [delta SDS/year = +0.27; P < 0.01 (n = 16)] in pre-pubertal patients. The median Ht-SDS at 2 years for pre-pubertal children was -0.71 SD and growth velocity did not improve thereafter.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗