Tacrolimus Pharmacokinetics and Dose Monitoring After Lung Transplantation for Cystic Fibrosis and Other Conditions

In cystic fibrosis (CF), absorption of tacrolimus through the gastrointestinal tract may be impaired due to fat malabsorption. The aim of this pilot study was to compare tacrolimus pharmacokinetics and inter- and intrasubject variability of exposure in stable lung transplant recipients with and without CF, and to determine the best single-time predictors of exposure. The study included 11 lung transplant recipients with CF and 11 without CF who received tacrolimus twice daily. Blood samples were obtained predose and at 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8 and 12 h postdose on 3 separate days within 1 week. Tacrolimus pharmacokinetics and inter- and intrasubject variability of exposure were similar in the two groups, though exposure-per-milligram-dose was approximately 50% lower in CF patients. Tacrolimus trough concentration did not accurately predict the area under the concentration curve (AUC(0-12)), but the concentration measured 3 h postdose (C(3)) was tightly correlated with the AUC(0-12) in both CF (r(2)= 0.86) and non-CF (r(2)= 0.92) patients. In summary, patients with CF have a higher tacrolimus oral clearance, but nonsignificant differences in short-term inter- and intrasubject variability of exposure compared to patients without CF. C(3) is tightly correlated with AUC(0-12) in lung transplant recipients with and without CF.     

Lateral femoral condyle osteochondral fracture caused by a patella luxation: advantages and disadvantages of PLA fixation

A lateral patella luxation is occasionally complicated by an (osteo)chondral fracture. These fractures are usually located at the inferomedial part of the patella. In this case report we describe an osteochondral fracture of the lateral femoral condyle after a dislocation of the patella. The latter is a more severe injury because it involves an important weight bearing part of the knee joint. Refixation of the osteochondral fracture should be pursued. Various surgical techniques using nonresorbable materials have been described. We describe the advantages and disadvantages of refixation with biodegradable pin fixation for an osteochondral fracture caused by a patellaluxation.     

Coronary stenting for coronary artery narrowing in a heart transplant recipient

Transplant atherosclerotic coronary disease remains the leading cause of death in heart transplant recipients. We report the first case of coronary stent implantation in a heart graft for epicardial focal stenosis. Due to the lower rate of restenosis after stenting in the native coronary artery, we suggest that coronary stenting be considered an acceptable, first intention therapeutic option instead of angioplasty alone whenever possible.     

Hereditary neuropathy with liability to pressure palsies in childhood.

Four children, index cases of families in which autosomal dominant neuropathy with liability to pressure palsies (HNPP) was diagnosed, are presented. Only one child was admitted for evaluation of an acute peroneal palsy, three presented with other symptoms. Polyneuropathy was diagnosed in all four children, in one of their parents and in some sibs. On inquiry, one child and several members of the four families had experienced transient palsies before. Morphological studies of the sural nerves showed frequently large tomacula and a neuropathic process of segmental de- and remyelination, and axonal degeneration. Attention is drawn to the atypical presentation without pressure palsies of HNPP.     

International round robin tests on the measurement of carbon in diesel exhaust particulates

Object: Diesel soot has been recognized as probably carcinogenic to humans. Elemental carbon (also called black carbon) in soot is considered at the moment as the most significant surrogate to be measured for assessing the exposure to this pollutant. Its analysis is done by combustion in an oven and determination of the CO₂ formed, after elimination of the organic fraction of the soot by heating and/or by solvent extraction. The analysis allows determination of both fractions of the soot: “elemental carbon” (EC) and organic carbon␣(OC). The sum of EC and OC is called TC (total carbon). Method: An informal European coordination group organized two round robin tests on filter samples collected from diluted diesel emissions. The first round (RRT1) was performed on 13 different samples analyzed by ten laboratories. The range of loading was 2.5 to 150 μg/cm² of EC. No evaluation of the precision within laboratories could be made since each laboratory gave only one result per sample. Therefore a second round (RRT2) was organized with two samples and a blank filter sent in several portions to 11 laboratories. It should be stressed that each laboratory used its own method and that no standardization was planned at this stage. Results: Results of RRT1 showed that the coefficient of variation between laboratories decreased with higher loading and was around 10% to 15% for EC above about 20 μg/cm². Dispersion of the results varied and it appeared that the way OC is removed from the soot is probably the most important factor of influence. The correlation between the laboratories was good as a whole but some systematic differences could be detected. Besides the different techniques to remove the organic carbon, the pretreatment of the filter by HCl (either as a vapor or as a solution) to remove the inorganic carbonates (potential interference sources), is probably also a significant factor of influence in the dispersion of the results between laboratories. It is not yet clear from these results whether the “environmental” laboratories give different results from the “occupational” laboratories, but it is clear that their objectives differ since for the “environmentalists”, EC is not a specific marker of diesel immissions, in contrast to the “occupationalists”. Conclusion: It can be concluded that, although significant differences exist between laboratories they can be attributed mainly to the narrow distribution of the results within a single laboratory, and that the overall agreement of the results for EC and TC is fairly good. These results obtained with pure diesel engine emissions, should be complemented by field samples, but they have already achieved relevant findings in the performance of the procedures used to assess exposure to diesel soot. Received: 30 December 1996 / Accepted: 21 February 1997     

Predominance of hospital deliveries among children with acute lymphocytic leukemia: speculations about neonatal exposure to fluorescent light

Dutch Childhood Leukemia Study Group, Erasmus University Medical School     

Preliminary evaluation of a fuzzy logic-based automatic quantitative analysis in myocardial SPECT.

This study validates a new quantitative myocardial perfusion SPECT software. METHODS: The processing starts with the extraction of the morphologic skeleton of the left ventricular myocardium from reconstructed transverse sections. Fuzzy logic is used to decide whether a pixel belongs to the myocardium and any perfusion defect is filled according to a truncated bullet model. The resulting image is partitioned in 18 isovolumetric sectors. Sex-matched normal limits, criteria of abnormality for rest (201)Tl and (99m)Tc-labeled perfusion tracers, reproducibility studies, and detection of coronary artery disease were developed and validated in an overall population of 343 patients. The sex- and tracer-matched means and SDs of a normal response were calculated in 93 male and 93 female patients with a <5% likelihood of coronary artery disease. Reproducibility measurements and assignment of different sectors of the myocardium to a specific coronary were performed from data collected in 49 and 60 patients, respectively. The accuracy of the detection of a coronary artery occlusion was assessed in 48 patients who also underwent coronary angiography. RESULTS: The intra- and interoperator reproducibility of the sectorial activity was high with a linear regression coefficient of 0.97 and a SD of the difference measurement at 4.4% and 3.8%, respectively. Overall sensitivity and specificity for the detection of occluded coronary artery were 90% and 80%, respectively. For the detection of left anterior descending, left circumflex, and right artery coronary occlusion, sensitivity was 92%, 75%, and 92.5%, respectively, and specificity was 75%, 78%, and 90%, respectively. CONCLUSION: The new quantitative myocardial perfusion SPECT software appears to be a very helpful program for the objective analysis of perfusion tracer distribution in myocardial SPECT and a very accurate tool in the detection and localization of coronary artery occlusion.     

ATP release from human airway epithelial cells studied using a capillary cell culture system

Epithelial release of adenosine triphosphate (ATP), an important autocrine and paracrine signalling molecule, is acutely mechanosensitive and therefore difficult to study. We describe here a novel preparation that minimizes mechanical and metabolic perturbations, and use it to examine ATP secretion by epithelial cells. The Calu-3 cell line derived from human airway sub-mucosal glands was cultured in a hollow fibre bioreactor on porous capillaries that were perfused by a re-circulating medium pump. Cells became polarized and cultures were stable for > 5 months, as evidenced by microscopy and lactate production (≈250 μg (10⁸ cells)⁻¹ day⁻¹). Elevating apical flow rate 5-fold increased ATP secretion from ≈200 to 6618 fmol min⁻¹. Reducing apical osmolarity by 25–43 % also increased ATP secretion, which then declined spontaneously to a plateau rate that persisted as long as hypotonic perfusion was maintained. Release deactivated rapidly after shear and osmotic stresses were terminated, and was not associated with detectable cell lysis. Lowering apical [Ca²⁺] to increase connexin hemichannel permeability also stimulated ATP release and increased secretion during both hyposmotic and shear stress; however, the connexin 43 blocker flufenamic acid inhibited shear-induced ATP release only in low-Ca²⁺ solution, and therefore another secretory pathway may operate with physiological (i.e. m m ) calcium. Regardless of the mechanism, the present results quantify ATP responses to mechanical and osmotic stimuli and demonstrate the usefulness of capillary cultures for studying epithelial secretion.     

Reference values for nucleosides and nucleobases in cerebrospinal fluid of children

Disturbances in the metabolism of purines and pyrimidines in neurologically affected patients can be reflected by aberrant concentrations of nucleosides and nucleobases in cerebrospinal fluid (CSF). However, normal values, especially for children at different ages, are lacking. We collected 1000 specimens of CSF from subjects ranging in age from newborn to 18 years, who were undergoing a diagnostic lumbar puncture for several clinical indications. Of these, 78 samples could be used retrospectively as a reference according to our criteria. The analyses were performed with a modified HPLC procedure. None of the substances shows age-dependency except uridine and uric acid. Uridine increases with age, and uric acid increases with age in boys older than 12 years.