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Biomedical subjects

Paul Tam

Publications and source records attributed to Paul Tam.

10 recordsLinked to original sources
PubMed2006

Effect of peritoneal dialysis on renal morphology and function.

BACKGROUND: Results of clinical studies suggest that peritoneal dialysis (PD) is less harmful to the residual renal function than haemodialysis. However, we have no objective data describing the potential injuring effect of PD to kidney. We studied in rats after unilateral nephrectomy changes in renal structure and function after 12 weeks exposure to standard, glucose-based PD fluid. METHODS: One month after removing one kidney PD catheters were implanted in rats and during the following 12 weeks, twice a day, animals were infused with 20 ml of 3.9% glucose dialysis fluid containing high concentration of glucose degradation products. Rats not infused with the dialysis fluid served as control (CON). At the beginning and after 12 weeks of the study renal creatinine clearance, urinary excretion of albumin, N-acetyl-beta-glucosaminidase (NAG) and cytokines were measured. Concentration of malondialdehyde (MDA), advanced glycation end products (AGEs) and monocyte chemoattractant protein-1 (MCP-1) were measured in serum samples. Morphology of the kidneys was evaluated in the light microscope. RESULTS: After 12 weeks exposure to the dialysis fluid serum MDA, AGEs and MCP levels were increased as compared with CON by 80%, P < 0.002, 29%, P < 0.05 and 71%, P < 0.005, respectively. Renal clearance of creatinine was comparable in both groups, but urinary excretion of albumin was increased by 55% in control group and by 160% in the studied group, P < 0.001; whereas urinary excretion of NAG was not changed in control group but increased by 125% in the studied group, P < 0.01. Increase of the remnant kidney's weight was higher (+77%, P < 0.01) in the CON group, but accumulation of the extramesangial matrix in glomeruli and collagen in the peritubular space was stronger in the studied group by 69%, P < 0.0001 and 274%, P < 0.0001, respectively. CONCLUSION: Chronic exposure of rats to the glucose-based dialysis fluid causes morphological changes in the renal glomeruli similar to diabetic nephropathy. Albuminuria increases what may accelerate progression of the kidney damage.

Animals↗
PubMed2006

Bone mineral density and its correlation with clinical and laboratory factors in chronic peritoneal dialysis patients.

The aim of this study was to assess the clinical and laboratory correlations of bone mineral density (BMD) measurements among a large population of patients on chronic peritoneal dialysis (PD). This cross-sectional, multicenter study was carried out in 292 PD patients with a mean age of 56 +/- 16 years and mean duration of PD 3.1 +/- 2.1 years. Altogether, 129 female and 163 male patients from 24 centers in Canada, Greece, and Turkey were included in the study. BMD findings, obtained by dual-energy X-ray absorptiometry (DEXA) and some other major clinical and laboratory indices of bone mineral deposition as well as uremic osteodystrophy were investigated. In the 292 patients included in the study, the mean lumbar spine T-score was -1.04 +/- 1.68, the lumbar spine Z-score was -0.31 +/- 1.68, the femoral neck T-score was -1.38 +/- 1.39, and the femoral neck Z score was -0.66 +/- 1.23. According to the WHO criteria based on lumbar spine T-scores, 19.2% of 292 patients were osteoporotic, 36.3% had osteopenia, and 44.4% had lumbar spine T-scores within the normal range. In the femoral neck area, the prevalence of osteoporosis was slightly higher (26%). The prevalence of osteoporosis was 23.3% in female patients and 16.6% in male patients with no statistically significant difference between the sexes. Agreements of lumbar spine and femoral neck T-scores for the diagnosis of osteoporosis were 66.7% and 27.3% and 83.3% for osteopenia and normal BMD values, respectively. Among the clinical and laboratory parameters we investigated in this study, the body mass index (BMI) (P < 0.001), daily urine output, and urea clearance time x dialysis time/volume (Kt/V) (P < 0.05) were statistically significantly positive and Ca x PO(4) had a negative correlation (P < 0.05) with the lumbar spine T scores. Femoral neck T scores were also positively correlated with BMI, daily urine output, and KT/V; and they were negatively correlated with age. Intact parathyroid hormone levels did not correlate with any of the BMD parameters. Femoral neck Z scores were correlated with BMI (P < 0.001), and ionized calcium (P < 0.05) positively and negatively with age, total alkaline phosphatase (P < 0.05), and Ca x P (P < 0.01). The overall prevalence of fractures since the initiation of PD was 10%. Our results indicated that, considering their DEXA-based BMD values, 55% of chronic PD patients have subnormal bone mass-19% within the osteoporotic range and 36% within the osteopenic range. Our findings also indicate that low body weight is the most important risk factor for osteoporosis in chronic PD patients. An insufficient dialysis dose (expressed as KT/V) and older age may also be important risk factors for osteoporosis of PD patients.

Absorptiometry, Photon↗
PubMed2005

Overexpression of soluble TRAIL induces apoptosis in human lung adenocarcinoma and inhibits growth of tumor xenografts in nude mice.

Recombinant adeno-associated virus 2/5 (rAAV2/5), a hybrid rAAV-2 with AAV-5 capsid, seems to be a very efficient delivery vector for the transduction of the lung adenocarcinoma cell line A549. Infection of the A549 cell line with a rAAV2/5 vector encoding the extracellular domain of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL, amino acids 114-281) resulted in secretion of soluble TRAIL (sTRAIL) and induction of apoptosis in these cells. rAAV2/5-sTRAIL mediated delivery and stable expression of sTRAIL resulted in the presence of the trimeric form of sTRAIL in sera of nude mice that were implanted with s.c. or orthotopic A549 tumors. The rAAV2/5-sTRAIL transduction of the tumors resulted in a statistically significant reduction in tumor growth and prolonged survival of the tumor-bearing animals. Primary cell culture, histologic examination of the tumors, and serum analyses showed the absence of detectable TRAIL-induced toxicity in normal tissues including the liver. The successful inhibition of lung cancer growth and the absence of detectable toxicity suggest a putative role for rAAV2/5-sTRAIL(114-281) in the therapy of lung cancer.

Adenocarcinoma↗
PubMed2005

Glucose degradation products (GDP's) and peritoneal changes in patients on chronic peritoneal dialysis: will new dialysis solutions prevent these changes?

As peritonitis rates are declining, the rate of technique failure due to ultrafiltration failure and inadequate solute removal is becoming more important. The failure of the peritoneal membrane to provide adequate dialysis increases with longer duration on PD and correlates with the structural changes in the peritoneal membrane. The exact mechanism responsible for these structural changes is unclear. Conventional PD fluids with glucose as the osmotic agent and more importantly the glucose degradation products (GDP) generated during the heat sterilization of these solutions seems to be responsible for inducing many of these changes in the peritoneum. GDP's in addition to causing structural and functional alterations of the peritoneal cells is also a leading cause of advanced glycation end-products (AGE) production. There is evidence to suggest that the GDP's and AGE's are not limited to the peritoneal cavity and the membrane. They have been shown to get deposited in the vascular walls. In addition they also interact with receptors on endothelial cells and smooth muscle. Thus they could contribute to the vascular dysfunction similar to that seen in diabetes. Formation of GDP's can be reduced and even be avoided with the use of newer "biocompatible" solutions by sterilizing the glucose and the buffer in separate chambers. These newer solutions have been shown to have several local and systemic advantages over the conventional PD solutions. It remains to be seen whether their chronic use from the start of peritoneal dialysis will prevent the development of peritoneal damage thus allowing these patients to remain on this modality for longer periods.

Animals↗
PubMed2005

Canadian randomized trial of hemoglobin maintenance to prevent or delay left ventricular mass growth in patients with CKD.

BACKGROUND: This randomized clinical trial is designed to assess whether the prevention and/or correction of anemia, by immediate versus delayed treatment with erythropoietin alfa in patients with chronic kidney disease, would delay left ventricular (LV) growth. Study design and sample size calculations were based on previously published Canadian data. METHODS: One hundred seventy-two patients were randomly assigned. The treatment group received therapy with erythropoietin alfa subcutaneously to maintain or achieve hemoglobin (Hgb) level targets of 12.0 to 14.0 g/dL (120 to 140 g/L). The control/delayed treatment group had Hgb levels of 9.0 +/- 0.5 g/dL (90 +/- 5 g/L) before therapy was started: target level was 9.0 to 10.5 g/dL (90 to 105 g/L). Optimal blood pressure and parathyroid hormone, calcium, and phosphate level targets were prescribed; all patients were iron replete. The primary end point is LV growth at 24 months. RESULTS: One hundred fifty-two patients were eligible for the intention-to-treat analysis: mean age was 57 years, 30% were women, 38% had diabetes, and median glomerular filtration rate was 29 mL/min (0.48 mL/s; range, 12 to 55 mL/min [0.20 to 0.92 mL/s]). Blood pressure and angiotensin-converting enzyme inhibitor/angiotensin receptor blocker use were similar in the control/delayed treatment and treatment groups at baseline. Erythropoietin therapy was administered to 77 of 78 patients in the treatment group, with a median final dose of 2,000 IU/wk. Sixteen patients in the control/delayed treatment group were administered erythropoietin at a median final dose of 3,000 IU/wk. There was no statistically significant difference between groups for the primary outcome of mean change in LV mass index (LVMI) from baseline to 24 months, which was 5.21 +/- 30.3 g/m2 in the control/delayed treatment group versus 0.37 +/- 25.0 g/m2 in the treatment group. Absolute mean difference between groups was 4.85 g/m2 (95% confidence interval, -4.0 to 13.7; P = 0.28). Mean Hgb level was greater in the treatment group throughout the study and at study end was 12.75 g/dL (127.5 g/L in treatment group versus 11.46 g/dL [114.6 g/L] in control/delayed treatment group; P = 0.0001). LV growth occurred in 20.1% in the treatment group versus 31% in the control/delayed treatment group (P = 0.136). In patients with a stable Hgb level, mean LVMI did not change (-0.25 +/- 26.7 g/m2), but it increased in those with decreasing Hgb levels (19.3 +/- 28.2 g/m2; P = 0.002). CONCLUSION: This trial describes disparity between observational and randomized controlled trial data: observed and randomly assigned Hgb level and LVMI are not linked; thus, there is strong evidence that the association between Hgb level and LVMI likely is not causal. Large randomized controlled trials with unselected patients, using morbidity and mortality as outcomes, are needed.

Adult↗
PubMed2004

Normalization and analysis of cDNA microarrays using within-array replications applied to neuroblastoma cell response to a cytokine.

The quantitative comparison of two or more microarrays can reveal, for example, the distinct patterns of gene expression that define different cellular phenotypes or the genes that are induced in the cellular response to certain stimulations. Normalization of the measured intensities is a prerequisite of such comparisons. However, a fundamental problem in cDNA microarray analysis is the lack of a common standard to compare the expression levels of different samples. Several normalization protocols have been proposed to overcome the variabilities inherent in this technology. We have developed a normalization procedure based on within-array replications via a semilinear in-slide model, which adjusts objectively experimental variations without making critical biological assumptions. The significant analysis of gene expressions is based on a weighted t statistic, which accounts for the heteroscedasticity of the observed log ratios of expressions, and a balanced sign permutation test. We illustrated the use of the techniques in a comparison of the expression profiles of neuroblastoma cells that were stimulated with a growth factor, macrophage migration inhibitory factor (MIF). The analysis of expression changes at mRNA levels showed that approximately 99 genes were up-regulated and 24 were reduced significantly (P <0.001) in MIF-stimulated neuroblastoma cells. The regulated genes included several oncogenes, growth-related genes, tumor metastatic genes, and immuno-related genes. The findings provide clues as to the molecular mechanisms of MIF-mediated tumor progression and supply therapeutic targets for neuroblastoma treatment.

Gene Expression Profiling↗
PubMed2004

A cross-sectional immunosurveillance study of anti-EPO antibody levels in CRF patients receiving epoetin alfa in 5 Ontario Renal Centers.

BACKGROUND: Epoetin alfa (Eprex*; Johnson & Johnson, Manati, PR) has been used successfully to correct the anemia of chronic renal failure for more than 12 years. Anti-erythropoietin (anti-EPO) antibodies have been reported in a small number of patients, resulting in a blood disorder, pure red cell aplasia (PRCA). To evaluate the utility of a large-scale anti-EPO antibody screening program in patients with chronic kidney disease (CKD) administered epoetin alfa, a study involving 5 large renal centers in southern Ontario, Canada, was conducted. METHODS: More than 1,500 hemodialysis, peritoneal dialysis, and predialysis patients were screened for the prevalence of anti-EPO antibodies by means of a radioimmunoprecipitation (RIP) assay. Serum samples were drawn and shipped to PPD Development (Richmond, VA) for the immunoprecipitation assay. Serum EPO levels also were measured. All samples that tested positive or borderline for antibodies were sent to MDS Pharma Services (Montreal, Canada) for the neutralization assay. RESULTS: Of 1,531 samples tested, 1 patient tested low-positive and 3 borderline results were detected by means of RIP. PRCA previously was diagnosed in the patient with the low-positive antibody level; the patient was treated with cyclosporine and currently is being administered epoetin alfa with good response. The 3 patients with borderline antibody results manifested no clinical signs of PRCA. Neutralization assays performed on all 4 serum samples were negative for anti-EPO antibodies. CONCLUSION: Results from this surveillance study show that the prevalence of antibody to EPO in patients with CKD administered epoetin alfa in 5 Canadian renal centers is low, and the value of a large-scale antibody screening program for PRCA cannot be justified.

Aged↗
PubMed2004

Serum levels of prostate-specific antigen and vitamin D in peritoneal dialysis patients.

Measuring the free:total ratio of prostate-specific antigen (f/t-PSA) can improve the specificity of single-serum PSA values, distinguishing between benign prostatic hyperplasia (BPH) and prostatic carcinoma (PCa) in men over the age of 50. Additionally, clinical trials have shown that dihydroxyvitamin D3 can slow the rate of PSA rise in PCa patients. However, little is known regarding the applicability of those findings in men undergoing chronic peritoneal dialysis (CPD). In the present study, we investigated the prevalence of increased serum PSA levels among CPD patients and correlated those values with serum levels of vitamin D [25-hydroxyvitamin D3 and 1,25-dihydroxyvitamin D3]. We undertook a cross-sectional study of 71 male CPD patients without a known history of prostate cancer from 24 centers in Canada, Greece, and Turkey. All of the patients were more than 50 years of age. In these patients, we measured serum concentrations of PSA, free PSA (f-PSA), total PSA (t-PSA), prostate alkaline phosphatase (PAP), 25-hydroxyvitamin D3, 1,25-dihydroxyvitamin D3, and intact parathyroid hormone (iPTH). We recorded serum PSA levels < 4 ng/mL in 62 patients (87.3%, group A) and levels > 4 ng/mL in 9 patients (12.7%, group B). The f/t-PSA ratio was < 0.25 in 16 patients (22.5%). Group B patients were older than those in group A (median: 73 years vs. 65 years, p < 0.01) and had a lower body weight (median: 66.5 kg vs. 76.7 kg, p < 0.05). We observed no statistically significant difference between the two groups for serum 1,25-dihydroxyvitamin D3 (median: 9.8 ng/mL vs. 10.1 ng/mL) or 25-hydroxyvitamin D3 (8 ng/mL vs. 8.2 ng/mL) levels. Also, we observed no correlation between vitamin D levels and f/t-PSA, but iPTH levels were significantly higher in group A (200.5 pg/mL vs. 61.2 pg/mL, p < 0.04). Also, serum PAP levels correlated significantly with PSA (r = 0.49, p = 0.01) and with f-PSA (r = 0.56, p = 0.000). Our results showed no clear relationship between vitamin D and serum levels of PSA or-of f/t-PSA in PD patients. However, further studies are needed to better define the uses of these PSA markers in PD patients because, in such patients, other relevant factors might be implicated in their predictive value.

Aged↗