801 Ostrum St
Bethlehem PA 18015
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Restricted differentiation potential of progenitor cell populations obtained from the equine superficial digital flexor tendon (SDFT). - Journal of orthopaedic research : official publication of the Orthopaedic Research Society
The aim of this study was to characterize stem and progenitor cell populations from the equine superficial digital flexor tendon, an energy-storing tendon with similarities to the human Achilles tendon, which is frequently injured. Using published methods for the isolation of tendon-derived stem/progenitor cells by low-density plating we found that isolated cells possessed clonogenicity but were unable to fully differentiate towards mesenchymal lineages using trilineage differentiation assays. In particular, adipogenic differentiation appeared to be restricted, as assessed by Oil Red O staining of stem/progenitor cells cultured in adipogenic medium. We then assessed whether differential adhesion to fibronectin substrates could be used to isolate a population of cells with broader differentiation potential. However we found little difference in the stem and tenogenic gene expression profile of these cells as compared to tenocytes, although the expression of thrombospondin-4 was significantly reduced in hypoxic conditions. Tendon-derived stem/progenitor cells isolated by differential adhesion to fibronectin had a similar differentiation potential to cells isolated by low density plating, and when grown in either normoxic or hypoxic conditions. In summary, we have found a restricted differentiation potential of cells isolated from the equine superficial digital flexor tendon despite evidence for stem/progenitor-like characteristics.Â© 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.
Dermoscopy, reflectance confocal microscopy and histopathology of a melanoma in situ from an individual homozygous for GSTP1*105Val/MC1R*92Met. - The Australasian journal of dermatology
Glutathione S-transferase 1 is an enzyme involved in the detoxification of reactive oxygen species, and the rs1695*Val polymorphism has been proposed as a melanoma-associated variant with significant effect. We report a case of malignant melanoma in an individual homozygous for the rs1695*Val variant and discuss the non-invasive and histopathological tools used in diagnosis.Â© 2014 The Australasian College of Dermatologists.
Molecular analysis of common polymorphisms within the human Tyrosinase locus and genetic association with pigmentation traits. - Pigment cell & melanoma research
We have compared the melanogenic activities of cultured melanocytes carrying two common TYR alleles as homozygous 192S-402R wild-type, heterozygous and homozygous variant. This includes assays of TYR protein, DOPAoxidase activity, glycosylation and temperature sensitivity of protein and DOPAoxidase levels. Homozygous wild-type strains on average had higher levels of TYR protein and enzyme activity than other genotypes. Homozygous 402Q/Q melanocytes produced significantly less TYR protein, displayed altered trafficking and glycosylation, with reduced DOPAoxidase. However, near wild-type TYR activity levels could be recovered at lower growth temperature. In a sample population from Southeast Queensland, these two polymorphisms were present on four TYR haplotypes, designated as WT 192S-402R, 192Y-402R and 192S-402Q with a double-variant 192Y-402Q of low frequency at 1.9%. Based on cell culture findings and haplotype associations, we have used an additive model to assess the penetrance of the ten possible TYR genotypes derived from the combination of these haplotypes.Â© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
A differential impact of mycophenolic acid, prednisolone, and tacrolimus exposure on sCD30 levels in adult kidney transplant recipients. - Therapeutic drug monitoring
Soluble CD30 (sCD30) has been associated with rejection and graft loss in kidney transplantation, leading to the suggestion that sCD30 might be a useful biomarker to adjust immunosuppressant medication dosing. However, there has been minimal study of the influence of individual immunosuppressive drugs on sCD30 levels.To evaluate the influence of mycophenolic acid (MPA), prednisolone, and tacrolimus exposure on sCD30 levels in adult kidney transplant recipients.The sCD30 levels were measured pretransplant and 30 days posttransplant. Area under the concentration-time curve (AUC) for each drug was estimated on day 30 using validated, multiple regression-derived limited sampling strategies.One hundred twenty-five subjects were included. Median (interquartile range) sCD30 levels were lower on day 30 posttransplant compared with pretransplant [10.7 (3.7-20.1) pg/mL versus 66.5 (46.0-95.1) pg/mL; P < 0.0001]. On univariate analyses, day 30 sCD30 levels were negatively correlated with MPA exposure and positively correlated with tacrolimus exposure. Using multivariate logistic regression, higher tacrolimus exposure was independently associated with higher day 30 sCD30 levels (2.2 change in odds for an SD increase in tacrolimus AUC 0-12, P = 0.01; 5.5 change in odds for an SD increase in tacrolimus predose concentration, P < 0.0001). In contrast, MPA and total and free prednisolone exposures were not independently associated with sCD30 levels.The sCD30 levels are significantly reduced in the presence of combination immunosuppression but are differentially affected by different immunosuppressant agents. More research is required before introduction of sCD30 measurement into clinical practice can be considered.
Ethnic differences in creatinine kinetics in a New Zealand end-stage kidney disease cohort. - Nephrology (Carlton, Vic.)
Recent data have suggested that glomerular filtration rate (GFR) is better predicted in New Zealand (NZ) MÄori and Pacific People using the equations for Black people that predict higher GFR for any given serum creatinine. We hypothesized that this might be due to a higher rate of creatinine generation in NZ MÄori and Pacific People.To compare creatinine kinetics between different ethnic groups in a cohort of NZ peritoneal dialysis patients.In this retrospective single-centre observational study, creatinine kinetics in 181 patients were determined from timed serum samples, peritoneal dialysate and urine collections between 1 October 2004 and 31 July 2011. Ethnicity was classified as Asian, NZ European, NZ MÄori and Pacific People.A total of 799 samples from 181 patients were analysed: 194 in Asians, 127 in NZ Europeans, 268 in NZ MÄori, 207 in Pacific People. Pacific People had the highest serum creatinine and lean body mass, and the highest creatinine generation rate at 1349 mg/day, compared with 1049 for Asians, 1186 for NZ Europeans and 1094 for NZ MÄori (Pâ€‰=â€‰0.0001). After adjustment for confounding factors, Pacific People had a greater creatinine generation by 140 mg/day compared with NZ Europeans (Pâ€‰=â€‰0.047).Pacific People on peritoneal dialysis in NZ have higher serum creatinine, lean body mass and creatinine generation than other ethnic groups. This is consistent with previous observations that equations for predicting GFR in Black people may have increased accuracy in some Australasian non-White non-Asian populations.Â© 2013 The Authors. Nephrology Â© 2013 Asian Pacific Society of Nephrology.
NR1I2 polymorphisms are related to tacrolimus dose-adjusted exposure and BK viremia in adult kidney transplantation. - Transplantation
Pregnane X, encoded by the gene NR112, is a nuclear receptor whose primary role is to promote the detoxification and clearance of drugs and other foreign compounds from the body.The aim of this study was to analyze associations between NR1I2 polymorphisms, immunosuppressant drug exposure, and clinical outcomes in adult kidney transplant recipients.Exposures to tacrolimus, mycophenolic acid, and total and free prednisolone were estimated at month 1 posttransplant using validated multiple regression-derived limited sampling strategies.In the 158 subjects studied, median (interquartile range) dose-adjusted exposure to tacrolimus was significantly higher in individuals carrying the NR1I2 8055T variant allele, when compared with exposure in wild-type individuals [20 (14, 22) Î¼gÂ·h/L/mg versus 15 (9, 24) Î¼gÂ·h/L/mg; P =0.0007]. Using multivariable logistic regression, NR1I2 8055T carrier status was independently predictive of higher dose-adjusted tacrolimus exposure (P=0.0005). Moreover, BK viremia was seen significantly more frequently in NR1I2 8055T allele carriers compared with wild-type individuals (38% vs 18%, P=0.005) and possession of the NR1I2 8055T allele imposed significantly higher odds of BK viremia (adjusted odds ratio, 2.76 [95% confidence interval, 1.33-7.73]; P=0.006). No significant difference in geometric mean peak BK viral replication titer was observed between 8055T carriers and noncarriers. No NR1I2 SNP or haplotype was significantly, independently associated with total or free prednisolone or MPA exposure.These data demonstrate an impact of pregnane X receptor polymorphisms on tacrolimus pharmacokinetics. Association of the 8055T allele with BK viremia suggests clinically significant "overimmunosuppression" in individuals with this genotype.
Clinical pharmacokinetics and pharmacodynamics of prednisolone and prednisone in solid organ transplantation. - Clinical pharmacokinetics
Prednisolone and prednisone are integral components of induction and maintenance immunosuppressive regimens in solid organ transplantation. The pharmacokinetics of these agents are extremely complex. Prednisolone is the active drug moiety while prednisone is both a pro-drug and inactive metabolite of prednisolone. Within the dosage range used in transplantation, prednisolone and prednisone exhibit concentration-dependent non-linear pharmacokinetics when parameters are measured with reference to total drug concentration. Dose dependency disappears when free (unbound) prednisolone is measured. Altered organ function, changing biochemistry and use of a number of concomitant medicines in transplantation appear to lead to pharmacokinetic differences in transplant recipients compared with other patient groups. Greater than threefold variability in dose-adjusted exposure to total prednisolone in transplant recipients is evident. Time post-transplant, hepatic and renal dysfunction, patient age, sex, bodyweight, serum albumin concentration, concomitant medication exposure, various disease states and genetic polymorphisms in metabolic enzymes and drug transporters have sometimes been associated with prednisolone pharmacokinetic variability. The clinical impact of corticosteroid therapy on the disposition of ciclosporin, tacrolimus and sirolimus and the impact of different immunosuppressant therapy combinations on prednisolone exposure needs to be further elucidated. Patient response patterns to prednisolone are consistent with delayed and indirect mechanisms of corticosteroid action involving modification of nuclear transcription and protein synthesis. Many adverse effects have been linked with prednisolone and prednisone therapy, but not all of these have been investigated thoroughly in transplant populations. Dyslipidaemia, growth restriction, diabetogenesis, hypertension and cataracts are well studied toxicities. Evidence is less clear for prednisolone-induced osteonecrosis, obesity and hypertriglyceridaemia. There have been some reports of a relationship between prednisolone pharmacokinetics and incidence of acute rejection, Cushing's syndrome and adverse cardiovascular and metabolic events. Dosing of prednisolone and prednisone in transplantation is typically empirical and varies significantly across transplant centres. Currently, authoritative guidelines are conflicting in their opinions regarding corticosteroid avoidance and early discontinuation in adult kidney transplantation. Overall, data suggest the promise of corticosteroid-free immunosuppression in paediatric patients. Further investigation of the pharmacokinetics and pharmacodynamics of prednisolone and prednisone in transplant recipients based on new chromatography assay techniques and free drug measurement, population pharmacokinetic/pharmacodynamic modelling approaches, genetic testing and larger studies in patients on modern day immunosuppressant protocols may lead to better individualization of corticosteroid therapy in the future.
Kidney transplant outcomes are related to tacrolimus, mycophenolic acid and prednisolone exposure in the first week. - Transplant international : official journal of the European Society for Organ Transplantation
This study analysed associations between tacrolimus, mycophenolic acid (MPA) and prednisolone exposures on day 4 and month 1 post kidney transplant and clinical outcomes. Area under the concentration-time curve (AUC) for each drug was estimated using validated multiple regression-derived limited sampling strategies. Multivariate logistic regression was used to associate drug exposure with clinical outcomes. One hundred and twenty subjects were studied. Between-subject variability in dose-adjusted exposure to each medication was high. Both day 4 tacrolimus and MPA exposures were independently predictive of delayed graft function (2.6 change in odds for a standard deviation (SD) increase in tacrolimus AUC(0-12) , P = 0.02; 0.23 change in odds for a SD increase in MPA AUC(0-12) , P = 0.02). Both day 4 MPA and total prednisolone exposures were independently predictive of rejection (0.20 change in odds for a SD increase in MPA AUC(0-12) , P = 0.04; 0.40 change in odds for a SD increase in total prednisolone AUC(0-6) , P = 0.03). Lowest tertile exposure to all three immunosuppressant medications imposed significantly higher odds of rejection [adjusted odds ratio 34.2 (95% CI 4.1, 284.4), P = 0.001]. This study highlights the importance of achieving early target exposure and suggests a potential role for individualized initial dosing or early therapeutic monitoring of all three immunosuppressive agents.Â© 2012 The Authors. Transplant International Â© 2012 European Society for Organ Transplantation.
A limited sampling strategy for the simultaneous estimation of tacrolimus, mycophenolic acid and unbound prednisolone exposure in adult kidney transplant recipients. - Nephrology (Carlton, Vic.)
The aim of this study was to develop a limited sampling strategy (LSS) for the simultaneous estimation of exposure to tacrolimus, mycophenolic acid and unbound prednisolone in adult kidney transplant recipients.Tacrolimus, mycophenolic acid and unbound prednisolone area under the concentration-time curve profiles from 0 to 12 h post dose (AUC(0-12)) were collected from 20 subjects. Multiple linear regression analyses were performed to develop a LSS enabling the simultaneous estimation of exposure to all three drugs. Median percentage prediction error and median absolute percentage prediction error were calculated via jackknife analysis to evaluate bias and imprecision.LSS showed superior ability to predict exposure compared with single concentration-time points. A LSS incorporating concentration measurements at 0.5 h (C(0.5)), 2 h (C(2)) and 4 h (C(4)) post dose displayed acceptable predictive ability for all three drugs.This LSS may serve as a useful research tool for further investigation of the utility of concentration monitoring of these medications.Â© 2011 The Authors. Nephrology Â© 2011 Asian Pacific Society of Nephrology.
The impact of surgical approach and urinary diversion on patient outcomes in pediatric pyeloplasty. - The Journal of urology
Recent comparisons of the impact of the surgical approach on pediatric pyeloplasty outcomes have generally incorporated a form of internal ureteral drainage. We hypothesized that the surgical approach does not affect outcomes in children who undergo unstented pyeloplasty and stenting offers no long-term benefit in those with pediatric pyeloplasty.After receiving institutional review board approval we examined the records of all children who underwent initial pyeloplasty from December 2001 to December 2009. We compared unstented and stented pyeloplasties, and each surgical approach in the unstented group.During the study period 367 pyeloplasties were performed, including 231 unstented and 136 stented procedures. When comparing unstented to stented pyeloplasties, there was no difference in the complication or failure rate. Of unstented pyeloplasties 71, 67 and 93 were done using a transperitoneal laparoscopic approach, a flank approach and dorsal lumbotomy, respectively. There were 5 failures, of which 2 were laparoscopic, 2 used a flank approach and 1 used dorsal lumbotomy (p = 0.51). A total of 31 patients, including 10 treated with a laparoscopic approach, 3 with a flank approach and 18 with dorsal lumbotomy (p = 0.02), required second procedures, of which 24 were temporary drainage for a urine leak. Univariate analysis of factors associated with secondary procedures in the unstented pyeloplasty group showed that only surgical approach was significant (p = 0.05).In pediatric pyeloplasty there is no significant difference in outcome between stented and unstented repairs. In unstented repairs complications may vary by surgical approach. Regardless of the approach unstented pyeloplasty is safe and effective in the pediatric population.Copyright Â© 2011 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.
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801 Ostrum St Bethlehem, PA 18015
801 Ostrum St Dept. Of Emergency Medicine
240 Union Station Plz Dr. Hadi Ghazzouli-Dental Clinic
801 Ostrum St Department Of Internal Medicine