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Biomedical subjects

A Shoker

Publications and source records attributed to A Shoker.

At least 19 recordsLinked to original sources
PubMed2006

Prevalence of weight gain in patients with better renal transplant function.

AIMS: This study investigates the association between renal function and change in weight after kidney transplantation. METHODS: Retrospective analyses of 165 transplant patients on maintenance steroids who were followed-up for 6.2 +/- 2.4 years. RESULTS: 101 males and 64 females participated in the study. Results are expressed as mean +/- SD. At the first post-transplant outpatient visit (time 0), BMI was 25.3 +/- 4.8 kg/m2. It increased significantly by 7.7 +/- 10.8% and 10.9 +/- 12.6% at 1 and 5 years. 18 and 29% of patients had a BMI > 30 kg/m2 at times 0 and 5 years, respectively. Thereafter, diminishing glomerular filtration rate (GFR) was associated with the loss of the excess weight. Multivariate analysis showed that GFR, but not age, race, sex, source of graft, number of HLA mismatches or length of dialysis was significant to post-transplant weight gain. 38 patients gained weight > 1 SD above the mean of the population and were designated the high weight gain (HWG) group. 41 patients gained weight < the mean - 1 SD of the population and were designated the low weight gain (LWG) group. GFR in the high and low weight gain groups at time 0 was 71.8 +/- 20.3 ml/min/1.73 m2 and 66.4 +/- 23.1 ml/min/1.73 m2, respectively (p = NS), as compared to 77.4 +/- 23.3 ml/min/1.73 m2 and 61.5 +/- 24.5 ml/min/ 1.73 m2 at 6 months, respectively (p < 0.01) and continued to be significant thereafter (72.7 +/- 17.2 ml/min/1.73 m2 and 58.9 +/- 19.8 ml/min/1.73 m2, p < 0.05 at 6 years). CONCLUSIONS: Patients with relatively better renal transplant function gained more weight, suggesting a pivotal role of improved appetite on weight gain post transplantation. Most of the weight gain occurred during the first year.

Adult↗
PubMed2006

Performance of creatinine clearance equations on the original Cockcroft-Gault population.

BACKGROUND: Prediction of endogenous creatinine clearance by mathematical equations such as the Cockcroft-Gault formula is used in clinical practice in spite of the reported concern for their limited predictability. The aim of this study is to determine whether the measured creatinine clearance can be predicted accurately by a number of published equations including the recently modified Cockcroft-Gault formula = Cockcroft-Gault formula x 1.73 m2/body surface area from the original Cockcroft-Gault population. METHODS: The performance of the mathematical equations in patients with different creatinine clearance and body mass indices was assessed by computing accuracy at different percentiles, bias and precision from the original Cockcroft-Gault data. RESULTS: Refitting the modified formula to the Cockcroft-Gault data gave superior results compared to the original Cockcroft-Gault formula with an overall accuracy in the general and subgroup analysis above 70% agreement within 30% estimate of the measured creatinine clearance. On the other hand, analysis of the other equations, including the original Cockcroft-Gault, demonstrated a limited accuracy to predict creatinine clearance particularly in patients with creatinine clearance below 50 ml/min with an overall accuracy in less than 1/3 of the calculated creatinine clearance within 30% range from the measured creatinine clearance. CONCLUSION: The current creatinine clearance equations and even the original Cockcroft-Gault formula did not accurately predict the measured creatinine clearance. Normalization for body surface area in the original Cockcroft-Gault formula demonstrated more accuracy to estimate creatinine clearance, particularly in patients with diminished renal function and is recommended to physicians who wish to use the Cockcroft-Gault formula in their practice until more credible formulas are developed.

Adult↗
PubMed2003

Improvement of experimental allergic encephalomyelitis (EAE) by thymoquinone; an oxidative stress inhibitor.

UNLABELLED: Experimental Allergic Encephalomyelitis (EAE) is an autoimmune demyelinating disease of the central nervous system that is widely accepted as an animal model for the human multiple sclerosis. Oxidative stress appears to play a role in the onset and progression of EAE. We reasoned that decreasing oxidative stress might ameliorate symptoms and signs of EAE. Thymoquinone is reported to inhibit oxidative stress. One way of decreasing oxidative stress is to induce glutathione (GSH). We tested the impact of Thymoquinone (1 mg/kg, injected at tail vein) in our EAE model. We induced (EAE) in female Lewis rats using myelin basic protein emulsified with complete Freund's adjuvant. 24 animals were placed into three groups: A) Rats with EAE B) EAE rats with concomitant five day injection of Thymoquinone days 1-5, C) EAE rats with five doses of Thymoquinone injected at day 12-17. Twenty-eight days later, animals were sacrificed; spinal cord tissues collected for glutathione (GSH). RESULTS: 63% of animals in group "A" developed hind limb weakness and/or paralysis while 37% developed mild tail weakness, perivascular inflammation and low spinal cord GSH level. 25% of animals in group "B" exhibited mild tail and hind limb weakness and 75% animals had no symptoms, no perivascular inflammation and high spinal cord GSH level. 63% of animals of group "C" showed improving symptoms following Thymoquinone injections, no perivascular inflammation and higher GSH level while 37% of animals showed no symptoms prior and post Thymoquinone injections. Clinical symptoms correlated well with perivascular inflammation and GSH level. Animals received Thymoquinone at day 12-17 had higher GSH level, no perivascular inflammation and no symptoms compared with other groups. CONCLUSION: Thymoquinone inhibited oxidative stress which leads into improvement in our EAE animals. Thymoquinone may have a role in treatment of Multiple Sclerosis.

Animals↗
PubMed2001

Pre-column derivatization high-performance liquid chromatographic method for determination of cysteine, cysteinyl-glycine, homocysteine and glutathione in plasma and cell extracts.

A sensitive high-performance liquid chromatographic method for quantification of sulphydryl and disulfide amino acids in human plasma using ultra violet spectrophotometric detection was developed. Precolumn derivatization with 5,5'-dithio-bis-nitrobenzoic acid (DTNB) and an optional pre-derivatization reaction with dithiothreitol allowed both quantitative reduction of disulfides for measurement of total amino acid levels and the measurement of the reduced forms. A dynamic range of 500 nmol/l-750 micromol/l allowed the major analytes of interest to be quantified in plasma without sample dilution. The assay is a sensitive and precise method for the determination of sulphydryl and disulfide amino acids in plasma and cell extracts.

Cell Extracts↗
PubMed2000

Heightened CD40 ligand gene expression in peripheral CD4+ T cells from patients with kidney allograft rejection.

BACKGROUND: CD40 ligand (CD40L) gene expression is increased in rejecting allograft biopsies. We, therefore, tested the possibility that CD40L gene expression is heightened in peripheral CD4+ T cells during renal allograft rejection. METHODS: CD40L gene expression in peripheral blood CD4+ T cells from two renal transplant groups was measured by quantitative reverse transcription-polymerase chain reaction (RT-PCR). Group 1: 20 patients with excellent renal transplant function; group 2: 25 patients with findings of acute and/or chronic allograft nephropathy (CAN); and group 3 of 12 normal controls. CD4+ cells were isolated by positive selection. The modifying effect of cyclosporine (CsA) and FK506 on CD40L gene expression was further tested in vitro in CD4+ T lymphocytes separated from pokeweed mitogen- (PWM) activated peripheral blood lymphocytes (PBL) preparations. RESULTS: Mean+/-SD expressions of CD40L gene, in aM, in groups 1-3 were as follows: 0.0052+/-0.0094; 0.022+/-0.023 (P=0.0038 vs. group 2); and 0.014+/-0.005. Levels of CD40L gene expression correlated significantly with acute rejection Banff 97 score (R2=0.44, P=0.0004) and severity of intertubular capillary changes (ITCC) (R2=0.33, P=0.011). After in vitro activation, CD40L gene expression increased by approximately 4-fold and the addition of CsA or FK506 diminished CD40L gene expression to a base level. CONCLUSION: Peripheral CD4+ T cell CD40L gene expression increases significantly in acute rejection and CAN and may serve as a non-invasive method to monitor allograft function and determine the biological response to CsA and FK506.

Acute Disease↗
PubMed2000

Intravenous mycophenolate mofetil: safety, tolerability, and pharmacokinetics.

An intravenous (i.v.) formulation of mycophenolate mofetil (MMF; CellCept, Roche Pharmaceuticals, Inc., Palo Alto, CA) that will enable its administration to patients unable to tolerate oral medication is available. Two separate studies, an open-labeled pharmacokinetic (PK) study and a double-blind safety study, were performed. Within 24 h after transplant, 153 (safety study) and 45 (PK study) first or second renal transplant recipients were started on i.v. MMF 1 g Q12h or placebo (used in the safety study only, 2:1 MMF:placebo), given over 2 h via a dedicated peripheral venous catheter. In the safety study, per os (p.o.) MMF (1g Q12h) or placebo was administered, starting within 72 h after transplant, whereas in the PK study, p.o. MMF was started on the evening of day 5. Sequential blood samples obtained on study days 5 (i.v. MMF) and 6 (p.o. MMF) before and up to 12 h after the AM dose were analyzed for mycophenolic acid (MPA) and MPA glucuronide (MPAG) concentrations by high-performance liquid chromatography. The area under the concentration curve (AUC) was calculated using the linear trapezoidal rule. The MPA AUC(0-12) was higher for i.v. MMF than p.o. MMF (40.8 +/- 11.4 microg x h/ mL vs. 32.9 +/- 15, p < 0.001). There were no other significant PK differences for plasma MPA or MPAG. In the safety study (n = 98 i.v. MMF vs. n = 55 placebo), 11 patients (11%, i.v. MMF) and 4 patients (7%, placebo) discontinued their use of the drug because of an adverse event (AE). Overall, AEs were similar between i.v. MMF and placebo. Injection site phlebitis (4%) and thrombosis (4%) were observed only with i.v. MMF. MMF i.v. 1 g twice daily (b.i.d.) should provide efficacy at least equivalent to p.o. MMF without increased toxicity, and it provides an acceptable alternative dose form in the immediate period after transplant.

Administration, Oral↗
PubMed1999

Production of human alloreactive antibodies by uremic sensitized lymphocytes engrafted in severe combined immunodeficient mice.

BACKGROUND: Numerous studies have documented antibody responses to nominal antigens in human peripheral blood lymphocyte (hu-PBL)-severe combined immunodeficient (SCID) mice engrafted with PBL. We suggest, therefore, that engraftment of SCID mice by allosensitized cells produces alloreactive antibodies (allo-Ab). As such, SCID mice can be used as a model to examine the cellular basis of the sustenance of humoral alloresponses. METHODS: C.B-17 SCID mice were engrafted intraperitoneally with PBL from sensitized uremic patients for 5 weeks and classified into the following: group 1, 8 mice engrafted with unactivated cells (n = 5; n = sensitized patients); group 2, 6 mice engrafted with unactivated PBL (n = 3) followed 2 days later by in vivo activation with interleukin-2 (IL-2) and lipopolysaccharide (LPS); group 3, 11 mice engrafted with cells preactivated in vitro with IL-2 and LPS (n = 6); group 4, 9 mice engrafted with cells preactivated with irradiated allogeneic transformed B cells, IL-2, and LPS (n = 5); group 5, 10 mice engrafted with cells preactivated with IL-2, LPS, and HLA class II allopeptides and adjuvant (n = 6); group 6, 8 control mice engrafted with control cells preactivated with IL-2 and LPS. Two weeks later, each group was rechallenged by the same stimuli. Allo-Ab production was measured by the panel-reactive antibody PRA-STAT ELISA method. Results. Allo-Ab was produced in 54.5% of group 3, 43% of group 4; 80% of group 5, and 0% of groups 1, 2, and 6. The ratio of alloreactive positive wells in the allo-Ab-producing PBL-hu-SCID mice to that present in the respective patient's sera was 82%, 52%, and 87% in groups 3, 4, and 5, respectively. Conclusions. The study demonstrates the feasibility of using the hu-PBL-SCID model to study alloreactive memory B-cell function in humans. Discrete HLA-class allopeptides (group 5) appeared more potent allo-Ab producers than allogeneic cells (group 4).

Adjuvants, Immunologic↗
PubMed1998

Safety and tolerability of cyclosporine and cyclosporine microemulsion during 18 months of follow-up in stable renal transplant recipients: a report of the Canadian Neoral Renal Study Group.

BACKGROUND: There has been concern that the increased drug exposure associated with treatment with cyclosporine microemulsion (CsA-ME) would lead to an increase in adverse events. METHODS: The long-term safety and tolerability of conventional cyclosporine (CsA) and CsA-ME were compared in a randomized, multicenter, pharmacoepidemiologic study involving 1097 stable renal transplant patients after 18 months of follow-up. RESULTS: No significant difference was seen in change in serum creatinine or calculated creatinine clearance between the two groups. Episodes of deterioration in renal function (change in serum creatinine > or = 20%) were categorized with the following results for CsA-ME versus CsA, respectively: acute rejection, 4.5% vs. 4.5%; chronic rejection, 8% vs. 11%; CsA nephrotoxicity, 12% vs. 7% (P=0.008); transient changes, 17% vs. 12%; other causes, 4% vs. 6%. During the first 6 months of the study, a transient increase in the incidence of gastrointestinal and neurological adverse events was seen in the CsA-ME group compared with the CsA group. Up to 18 months, patients in the CsA group reported significantly fewer hearing and vestibular disorders, but more cardiovascular problems than those in the CsA-ME group (P=0.035). CONCLUSIONS: Tolerance to CsA and CsA-ME was similar. Renal function over 18 months was not adversely affected by the increased drug exposure with CsA-ME, although there was a transient increase in nephrotoxicity. The frequency of acute and chronic rejection did not change.

Administration, Oral↗
PubMed1997

Absence of irreversible rejection in the presence of warm anti-donor-HLA class I cytotoxic IgG antibody.

Since the initial presentation by Kissmeyer-Nielsen and colleagues [1966] and later by Patel and Terasaki [1969], it has been accepted that renal transplantation should not be performed in the presence of cytotoxic alloreactive antibodies of the IgG fraction performed at room temperature against HLA Class I [Braun 1989] antigens. Such antibodies are feared to induce hyper-acute or accelerated rejection because of the presence of HLA Class I antigens on kidney cells. For this reason, the microlymphocytotoxicity crossmatch (XM test: recipient serum reacted against donor lymphocytes as surrogate for HLA antigens) is now universally used before transplantation [Ting 1983]. A positive XM performed against the recipient T lymphocyte at room temperature after treatment of recipient serum with dithiothreitol (DTT), an agent that removes immunoglobulin M, denotes the presence of cytotoxic alloreactive IgG antibodies against the potential donor HLA class I antigen. Herein, we present the case of a patient who developed positive XM test of the IgG isotype against HLA Class I of the donor antigens performed at room temperature seven days after she received a kidney allograft from her daughter. Although the development of a positive XM was associated clinically with acute rejection, the patient responded remarkably well to anti-rejection therapy and maintained excellent graft function thereafter. Thus, strategies to identify the role played by the different IgG isotypes determined against HLA Class I antigens and their relation to irreversible rejection are needed to differentiate between those potential kidney recipients who may benefit from kidney transplantation in the presence of innocent warm IgG subclass antibodies reactive against HLA Class I antigens and those patients who may not.

Adult↗
PubMed1997

Fate of recurrent acute interstitial cellular rejection in an HLA identical kidney transplant recipient: impact of donor microchimerism.

We and others have shown that the incidence of acute interstitial rejection in HLA identical and non-identical kidney transplantation is similar. Chronic vascular rejection is, however, rare in full matched recipients. In light of the known correlation between previous acute cellular and chronic vascular rejections, lack of chronic rejection in full matched kidney allografts suggest that the immunological basis of acute and chronic rejections are different and/or only high-grade acute cellular rejection leads to chronic vascular rejection. Herein, we present the case of an HLA identical kidney transplant from a male donor to a female recipient who, because of poor compliance, had frequent acute interstitial cellular rejection culminating into chronic interstitial fibrosis with no evidence of vasculopathy or glomerulopathy characteristic of chronic vascular rejection. Donor cells, as examined by the presence of the Y chromosome DNA, were present in the peripheral blood during the most recent acute rejection but not thereafter. These findings support the notion that acute interstitial cellular rejection can lead to interstitial fibrosis but not chronic vasculopathy/glomerulopathy, and that microchimerism did not confer protection against acute cellular rejection.

Adult↗
PubMed1996

A randomized, prospective multicenter pharmacoepidemiologic study of cyclosporine microemulsion in stable renal graft recipients. Report of the Canadian Neoral Renal Transplantation Study Group.

BACKGROUND: The safety, tolerability, and pharmacokinetics of conventional cyclosporine (ConCsA) and cyclosporine microemulsion (MeCsA) were compared under conditions of normal clinical practice in a prospective, randomized, concentration-controlled, pharmacoepidemiologic study. METHODS: Between September 1994 and March 1995, 1097 stable renal transplant recipients in 14 Canadian centers were randomized 2:1 to treatment with MeCsA or ConCsA. Patients were commenced on each study drug at a dose equal to their previous therapy with ConCsA, and the dose was adjusted to maintain predose whole blood cyclosporine concentrations within the therapeutic range established for each center. Prednisone and azathioprine were continued unless dose adjustment was required for clinical reasons. RESULTS: The mean cyclosporine concentration was comparable in both treatment groups at all time points throughout the 6 months of follow-up. The mean dose of cyclosporine was 3.6 mg/kg/day in both treatment groups at entry to the study, and declined by 0.3% and by 2.8% in patients receiving ConCsA and MeCsA, respectively. The nature and severity of adverse events were similar in both treatment groups, but there was a transient increase in neurological and gastrointestinal complications in the group receiving MeCsA within the first month after conversion (P<0.05). Serum creatinine and creatinine clearance did not change in either treatment group throughout the study. Biopsy-proven acute rejection occurred in three patients (0.8%) receiving ConCsA and in seven patients (0.9%) receiving MeCsA, with non-histologically proven acute rejection in an additional three patients (0.8%) receiving ConCsA and five patients (0.6%) receiving MeCsA (P=NS). Serum creatinine rose transiently in 35 patients (9.8%) receiving ConCsA and 138 patients (18.7%) receiving MeCsA (P<0.05) and resolved either spontaneously or after a reduction in the cyclosporine dose. One graft was lost in the MeCsA group due to irreversible rejection, and seven patients died, three in the group receiving ConCsA and four of those receiving MeCsA (P=NS). Absorption of cyclosporine was more rapid and complete from MeCsA than from ConCsA during the first 4 hr of the dosing interval, resulting in almost 40% greater exposure to the drug (P<0.001). There was close correlation between area under the time-concentration curve (AUC) over the first 4 hr of the 12-hr dosage interval and AUC over the entire 12-hr dosage interval for both formulations, making AUC over the first 4 hr a good predictor of total cyclosporine exposure. Using this parameter, patients with low absorption randomized to receive MeCsA showed a marked increase in drug exposure by months 3 and 6, whereas there was no change in those who continued on ConCsA. A limited sampling strategy utilizing samples at the predose and postdose trough levels provided an excellent correlation with drug exposure, particularly for patients receiving MeCsA (r2=0.94 MeCsA vs. r2=0.89 ConCsA). CONCLUSIONS: MeCsA appears to be a safe and effective therapy in stable renal transplant patients and provides superior and more consistent absorption of cyclosporine when compared with ConCsA. Transient toxicity after conversion to MeCsA occurs in some patients, and may reflect the increased exposure to cyclosporine. Use of a limited sampling approach combining trough and 2-hr postdose concentrations may provide an effective way to monitor this exposure.

Adolescent↗
PubMed1996

Pseudohypoaldosteronism with normal blood pressure.

In adults, persistent hyperkalemic distal renal tubular acidosis in the absence of impaired renal function is an unusual abnormality usually associated with the syndromes of aldosterone deficiency or resistance. Herein, we present an adult with a clinical picture consisting of a normal blood pressure of 125/80 mmHg, normal blood volume, and glomerular filtration rate, with hyperkalemic distal renal tubular acidosis. The patent could spontaneously lower her urine pH to less than 5.5. Plasma renin activity was normal. Serum aldosterone level was appropriately elevated for the level of serum potassium. Following alkalinization of the urine, she was able to generate a urinary to blood PCO2 gradient [U-B PCO2] of 55 mmHg, and had a ten fold increased potassium secretion. After salt restriction and furosemide administration, her potassium secretion rate increased only twofold despite correction of he acidosis. The acidosis, as well as the hyperkalemia, was completely corrected after 9-alpha-Fluorohydrocortisone administration. Hydrochlorothiazide corrected the acidosis and hyperkalemia. Collectively, this picture suggests an underlying chloride shunt as the possible pathophysiological mechanism. Our case in unique in that it is not associated with hypertension.

Acidosis, Renal Tubular↗
PubMed1995

Lack of enhanced T-helper cell function in uremic patients with circulating alloreactive antibodies.

Some uremic patients with a history of blood transfusion, pregnancy, and previous transplantation maintain high levels of alloreactive cytotoxic antibodies in the absence of continuous exogenous allogenic stimuli and are thus considered sensitized to the major histocompatibility proteins. To differentiate into antibody-producing cells, B lymphocytes must interact with T-helper (CD4+) cells. Whether ongoing help from these cells is necessary for the B cells to continue producing cytotoxic alloreactive antibodies in these sensitized uremic patients is unknown. To gain insight into the cellular mechanisms that are associated with sustained alloantibody production, T cell activation markers were measured and specific and nonspecific T-helper cell function was studied in three uremic groups with different levels of panel reactive antibodies: 10 patients whose sera reacted to more than 80% of a panel of normal lymphocytes for at least 6 months before the study were highly sensitized, 20 patients whose sera reacted to less than 80% of the panel were moderately sensitized, and 10 nonsensitized patients whose sera did not react to any cell on the panel. The number of total and activated T-helper cells was similar in the highly sensitized and nonsensitized patients. Peripheral blood lymphocyte proliferation in response to plant lectins, soluble OKT3, or alloantigens was similar in the three uremic groups. The spontaneous proliferation of pure T-helper cells and proliferative responses to immobilized OKT3 or alloantigens were also similar in highly sensitized and nonsensitized patients. Alloreactive interleukin-2-producing cell frequencies with pure CD4+ cells as responding cells were 771 +/- 77.9/10(6) cells in highly sensitized, 945 +/- 252/10(6) cells in nonsensitized, and 973 +/- 114/10(6) cells in controls (P = not significant). Panel reactive antibody levels did not correlate with any of the measures of T helper responses. There was a significant decrease of peripheral blood lymphocyte responses to alloantigens and anti-CD3 antibody in all uremic patients as compared with normals, suggesting a dysfunction in accessory cells that was quantitatively similar in sensitized and nonsensitized patients. In spite of the continuous production of alloantibodies by B cells, there is no evidence of either specific or nonspecific enhancement of T-helper cell function in sensitized patients. The absence of T cell immunity to alloantigens suggests that sustained activation of T-helper cells with subsequent interleukin-2 production is not necessary to maintain alloreactive B cell function.

Adult↗
PubMed1988

The sensitized patient. A single center study.

1. In a 20-year period from 1966 to 1986, 650 renal transplants have been performed at the Toronto Western Hospital (University of Toronto). The 10-year actuarial patient survival is 62% and the actuarial graft survival is 35%. 2. A multivariant analysis using the Cox proportional hazard model indicated recipient age, donor source, graft number and time period were factors which independently influenced patient survival and that age and time period were variables which independently effected graft outcome. 3. Sensitization alone, using either peak or current PRA, did not significantly influence graft survival. Sensitization interacting with gender did affect graft survival, which was significantly lower in female patients with a high current PRA. Sensitization interacting with age produced different effects in the younger and older patients. The highly sensitized older patient has a better survival than the highly sensitized younger patient. However, for less sensitized patients the reverse was found; younger patients had a better survival than older patients. Also increasing levels of sensitization correlated with decreased survival in younger patients. 4. Predictive models based on the survivorship analysis of Kalbfleisch and Prentice were constructed to illustrate the impact of these variables on outcome.

Actuarial Analysis↗