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↗

PubMed1999

Peritrophins of adult dipteran ectoparasites and their evaluation as vaccine antigens.

Several peritrophins of larvae of Lucilia cuprina (sheep blowfly) have demonstrated potential as vaccine antigens, and some have been characterised and cloned. These proteins are tightly associated with the peritrophic matrix, a chitinous tube or sac lining the lumen of the gut of most insects. The peritrophins require strong denaturants for their removal from peritrophic matrix. We now report the preliminary characterisation of peritrophins of the adult stage of L. cuprina and Haematobia irritans exigua (buffalo fly). Similar SDS-PAGE profiles were obtained for proteins extracted in SDS or urea from isolated adult peritrophic matrices of both species. Radioiodination of urea-extracted peritrophins improved sensitivity, indicating numerous proteins of 15-75 kDa. Direct radioiodination of L. cuprina peritrophic matrix preferentially labelled high molecular weight complexes and proteins of 80-90 kDa. Two-dimensional gel analyses of a urea extract of adult L. cuprina peritrophic matrix revealed that most proteins were moderately acidic. Antibodies produced against SDS-extracted peritrophins, or against sonicated peritrophic matrices of these two flies were crossreactive. The sera also appeared to recognise SDS-extracted components of Triton X-100 treated and washed adult peritrophic matrix of the mosquito, Aedes vigilax (Skause). This profile altered as the peritrophic matrix matured. In concordance with extracts from the adult L. cuprina and H.i. exigua peritrophic matrices, proteins in the 50-75 kDa region were immunodominant. The vaccine potential of the peritrophins of these Diptera were examined following vaccination of cattle and rabbits with adult H.i. exigua or L. cuprina peritrophins. When the adult life stages of H.i. exigua or two mosquitoes, A. vigilax and A. aegypti (Linnaeus), were fed on the sera or blood of vaccinated hosts, there were no detrimental effects to any life cycle stages of these Diptera.

Aedes↗

PubMed1999

Beyond breast-feeding.

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Breast Feeding↗

PubMed1999

Comparison of cefuroxime axetil and amoxicillin/clavulanate in the treatment of acute bacterial sinusitis.

This double-masked, multicenter, randomized clinical trial compared the efficacy and tolerability of cefuroxime axetil and amoxicillin/clavulanate in the treatment of acute bacterial maxillary sinusitis. A total of 263 patients with acute bacterial maxillary sinusitis were randomly assigned to receive 10 days of treatment with either cefuroxime axetil 250 mg twice daily (n = 132) or amoxicillin/clavulanate 500/125 mg 3 times daily (n = 131). Patients' responses to treatment were assessed once during treatment (6 to 8 days after the start of treatment), at the end of treatment (1 to 3 days posttreatment), and at follow-up (26 to 30 days after cessation of treatment). Clinical success, defined as cure or improvement, was equivalent in the cefuroxime axetil and amoxicillin/ clavulanate groups at the end-of-treatment and follow-up assessments. Patients in both groups showed improvements in symptoms of acute sinusitis at the during-treatment visit. Treatment with amoxicillin/clavulanate was associated with a significantly higher incidence of drug-related adverse events than treatment with cefuroxime axetil (29% vs 17%), primarily reflecting a higher incidence of gastrointestinal adverse events (23% vs 11%), particularly diarrhea. Two patients in the cefuroxime axetil group and 8 patients in the amoxicillin/clavulanate group withdrew from the study due to adverse events (P = 0.06). These results indicate that cefuroxime axetil 250 mg twice daily is as effective as amoxicillin/clavulanate 500 mg 3 times daily in the treatment of acute sinusitis and produces fewer gastrointestinal adverse events. cefuroxime axetil, amoxicillin/clavulanate, acute sinusitis.

Acute Disease↗

PubMed1999

Biochemical monitoring of treatment for galactosaemia: biological variability in metabolite concentrations.

Red cell galactose 1-phosphate (Gal-1-P) concentrations and urinary galactitol excretion have been suggested as biochemical indices of dietary compliance in classical transferase-deficient galactosaemia. We report our experience of measuring both in 32 patients over 0-10.9 years (median 3.45). A total of 438 blood specimens for Gal-1-P and 383 urine specimens for galacitol assay were received; 317 pairs of specimens were collected at the same time. Concentrations of both analytes fell rapidly over the first 2-3 months following dietary intervention, to mean (geometric SD) levels of 225 (1.60) mumol/L red cells for Gal-1-P and 388 (1.19) mumol/mmol creatinine for galactitol. Concentrations then fell exponentially over the next 7-8 years, with times to half-disappearance of 6.3 years for Gal-1-P and 6.4 years for galactitol, to levels of 104 (1.58) and 193 (1.36) respectively in patients aged over 10 years. Concentrations of both analytes were independent of the presence of the common Q188R mutation. Mean intra- and inter-individual coefficients of variation (CV) across the range of values studied were 36% and 61% for Gal-1-P, and 37% and 42% for galactitol. Analytical CVs were 3.6% for Gal-1-P and 5.5% for galactitol, indicating that the major source of variability is biological. The correlation coefficient between Gal-1-P and galactitol in paired samples overall was 0.33; the regression equation being [Galactitol] = 0.84[Gal-1-P] + 176. Serial measurements of both Gal-1-P and galactitol may be valuable in monitoring galactosaemia, but high intra-individual biological variability limits their usefulness. Standardization of sample collection times may improve this. Further work is needed to assess the predictive values of both analytes for long-term outcome.

Adolescent↗

PubMed1999

False negative thiosulphate screening test in a case of molybdenum cofactor deficiency.

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Asphyxia↗

PubMed1999

Childhood vulval pemphigoid: a clinical and immunopathological study of five patients.

We describe five girls with vulval pemphigoid: two had bullous pemphigoid confined to the vulva and three had cicatricial pemphigoid. They demonstrate a spectrum of severity from localized disease to extensive vulval scarring necessitating long-term immunosuppressive therapy and surgical correction. The age at onset of their disease ranged between 6 and 13 years. All presented with vulval discomfort and erosions. Three had oral lesions, two perianal and one eye and cutaneous involvement. Two girls with only vulval lesions and one with vulval and oral lesions responded well to topical steroids. In two, systemic treatment with prednisolone and dapsone or azathioprine was required. The diagnosis was made on the basis of histology and immunofluorescence (IF). All had positive direct IF with IgG and C3. Indirect IF demonstrated circulating IgG binding to the basement membrane zone in four, with dermal or epidermal binding on salt-split skin substrate. Immunoblotting revealed antibodies to the BP230 and BP180 antigens. Immunoelectron microscopy in the child with dermal binding IgG and BP180 and BP230 on immunoblotting showed labelling at the lamina densa-lamina lucida interface adjacent to hemidesmosomes.

Adolescent↗

PubMed1999

A comparison of the expression of known basement membrane components with the linear IgA disease antigens using the novel substrate cylindroma.

Linear IgA disease (LAD) is characterized by IgA basement membrane zone autoantibodies. Immunofluorescence, immunoblotting and immunoelectron microscopy studies have established the complexity and heterogeneity of the target antigens. We have studied the expression of the LAD antigens by cylindroma, a benign epithelial tumour that secretes abundant basement membrane, using 57 LAD sera categorized by indirect immunofluorescence on intact and salt-split skin. The expression of known components of hemidesmosomes, the anchoring filaments, extracellular matrix and the anchoring fibrils could be differentiated and were compared with the expression of the LAD antigens. The results showed that the LAD sera bound to the cylindroma tumour in two distinctive patterns. Thirty-three sera were positive on cylindroma. Twenty-seven sera bound to the basement membrane around the tumour clusters and the islets within the clusters in a thin linear band that was occasionally discontinuous. This was similar to the pattern observed with antibodies to the hemidesmosome components, the alpha6beta4 integrin and the bullous pemphigoid antigens BP230 and BP180. This pattern was observed with sera that bound to the epidermal (11) and the dermal (3) aspects of split skin or were negative (11), and with one serum which bound only to intact skin. Seven sera, all binding to the dermal aspect of split skin, bound the tumour cluster basement membrane in a thick band that was identical in appearance to that seen with antibodies to collagen VII; however, binding to the islets was either identical to collagen VII or similar but differentiated with double staining. Some sera were negative on cylindroma. Using fluorescence overlay antigen mapping we demonstrated colocalization of some epidermal-associated LAD target antigens with known hemidesmosome proteins, and colocalization of some dermal-associated LAD target antigens with anchoring fibril components. The results using cylindroma as substrate suggest that LAD autoantibodies may react with three or more target antigens. We propose from the results of this study that the autoantibodies in LAD target multiple antigens associated with hemidesmosomes and anchoring fibrils.

Adult↗

PubMed1999

Serum soluble transferrin receptor and the prediction of marrow aspirate iron results in a heterogeneous group of patients.

Serum soluble transferrin receptor (sTfR) concentration has been evaluated in the diagnosis of iron deficiency in otherwise healthy individuals and in patients with rheumatoid arthritis, but has not been studied in a general population of patients with complicated clinical presentations. In this study, 145 anaemic patients with a variety of medical conditions undergoing diagnostic bone marrow aspiration for any reason were tested by a complete blood count, a panel of biochemical tests to evaluate iron status, bone-marrow aspirate iron stain, and serum sTfR concentration. Sixteen per cent lacked stainable iron in the marrow aspirate. All biochemical parameters differed significantly between patients with or without stainable marrow iron. The sTfR assay was significantly more sensitive but less specific than other iron status assays in identifying the absence of stainable iron. Logistic regression analysis demonstrated that only sTfR and ferritin contributed independently to the prediction of marrow iron status. Serum ferritin alone was highly specific but insensitive. A decision algorithm combining serum ferritin and sTfR was as sensitive as TfR and as specific as serum ferritin. The measurement of serum sTfR, especially in conjunction with serum ferritin, is a valuable addition to the existing methods for predicting the results of marrow aspirate iron stains.

Adolescent↗

PubMed1999

Carbohydrate-deficient transferrin is a useful marker for the detection of chronic alcohol abuse.

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Alcoholism↗

PubMed1999

Does class switching contribute to remission in bullous pemphigoid?

A correlation between the titre of circulating IgG autoantibodies and disease activity has been difficult to demonstrate in bullous pemphigoid. We postulate that isotype switching from "inflammatory" IgG1 to "blocking" IgG4 subclass antibodies might contribute to disease remission. We studied 16 patients with bullous pemphigoid, 3 patients with cicatricial pemphigoid and 2 patients with epidermolysis bullosa acquisita at different stages of the disease. The titres of IgG subclass and total IgG basement membrane zone autoantibodies were correlated with clinical activity. Ten of the 16 bullous pemphigoid patients went into remission. The total IgG autoantibody levels showed variable changes. IgG1 autoantibody decreased in 7 patients (3 were unchanged) and IgG4 autoantibody increased in 9 patients. The 6 patients with clinical activity did not show such changes in IgG1 and IgG4 autoantibodies. Similar results were observed with the other bullous diseases. Our data suggest that isotype switching from "inflammatory" IgG1 to "blocking" IgG4 antibody correlates with improvement in bullous pemphigoid.

Aged↗

PubMed1999

Modelling the relationship between peripheral blood pressure and blood volume pulses using linear and neural network system identification techniques.

The relationships between peripheral blood pressure and blood volume pulse waveforms can provide valuable physiological data about the peripheral vascular system, and are the subject of this study. Blood pressure and volume pulse waveforms were collected from 12 normal male subjects using non-invasive optical techniques, finger arterial blood pressure (BP, Finapres: Datex-Ohmeda) and photoelectric plethysmography (PPG) respectively, and captured to computer for three equal (1 min) measurement phases: baseline, hand raising and hand elevated. This simple physiological challenge was designed to induce a significant drop in peripheral blood pressure. A simple first order lag transfer function was chosen to study the relationship between blood pressure (system input) and blood volume pulse waveforms (system output), with parameters describing the dynamics (time constant, tau) and input-output gain (K). Tau and K were estimated for each subject using two different system identification techniques: a recursive parameter estimation algorithm which calculated tau and K from a linear auto-regressive with exogenous variable (ARX) model, and an artificial neural network which was trained to learn the non-linear process input-output relationships and then derive a linearized ARX model of the system. The identification techniques allowed the relationship between the blood pressure and blood volume pulses to be described simply, with the neural network technique providing a better model fit overall (p < 0.05, Wilcoxon). The median falls in tau following the hand raise challenge were 26% and 31% for the linear and neural network based techniques respectively (both p < 0.05, Wilcoxon). This preliminary study has shown that the time constant and gain parameters obtained using these techniques can provide physiological data for the clinical assessment of the peripheral circulation.

Adult↗

PubMed1999

Effects of epinephrine and amrinone on contractility and cyclic adenosine monophosphate generation of tumor necrosis factor alpha-exposed cardiac myocytes.

OBJECTIVE: This study utilized an in vitro neonatal rat cardiac myocyte assay to evaluate potential differences in the response of TNF-alpha-exposed myocytes to stimulation with the adrenergic agent, epinephrine, and the phosphodiesterase III inhibitor, amrinone. DESIGN: Contractility was assessed by measuring the maximum extent of the contraction of electrically paced neonatal rat cardiac myocytes in tissue culture using a closed-loop video tracking system. Myocytes were incubated in control or media containing TNF-alpha (50 ng/mL) for 20 mins and were then stimulated with increasing concentrations of either epinephrine (0.1 to 100 ng/mL) for 15 mins or amrinone lactate (0.25 to 10 microg/mL) for 20 mins. MEASUREMENTS AND MAIN RESULTS: Compared with control myocytes, TNF-alpha-exposed myocytes stimulated with increasing concentrations of epinephrine demonstrated a decreased peak augmentation of contractility (p<.0001 analysis of variance). This decrease was paralleled by a decrease in epinephrine-stimulated generation of cyclic AMP, as measured by enzyme-linked immunoassay (p = .05 polynomial regression). In contrast, increasing concentrations of amrinone produced increased peak augmentation of contractility (p = .003 analysis of variance) in TNF-alpha-exposed cardiac myocytes (relative to controls). However, this increase was not reflected by increased amrinone-stimulated generation of cyclic AMP relative to control myocytes not exposed to TNF-alpha (p = NS polynomial regression). CONCLUSIONS: Our data suggest that TNF-alpha induces a defect in beta-adrenergic signal transduction and catecholamine-stimulated contractility in neonatal rat cardiac myocytes. In addition, TNF-alpha augments the inotropic response of myocardial tissue to phosphodiesterase inhibitors through a mechanism independent of cyclic AMP generation. Phosphodiesterase inhibitors such as amrinone may be found to exert significant inotropic effects in catecholamine-refractory septic shock with myocardial depression and other conditions of inflammatory myocardial dysfunction.

Amrinone↗