Trabecular bone architecture in female renal allograft recipients-- assessed by computed tomography

BACKGROUND: Osteopenia with decreased bone mineral density (BMD) is a frequent finding in renal allograft recipients. Data concerning the bone architecture in these patients do not exist, however. METHODS: We compared the bone architecture of 33 randomly assigned women (age 49 +/- 12 years), who had received renal allografts 5.6 +/- 5.3 years before the investigation, with 74 women (age 50 +/- 14 years) who were admitted for osteodensitometry. All patients underwent single-energy computed tomography (SEQCT) and a midvertebral high-resolution tomography with computer-assisted analysis of the trabecular vertebral body architecture. RESULTS: Progressive alteration of bone architecture was associated with increasing vertebral height loss of the vertebral body. Height reduction of a vertebral body of more than 15% was associated with a significantly lower BMD (-2.3 +/- 0.8 versus -1.1 +/- 1.1 standard deviations below normal BMD), a lower trabecular bone area (13 +/- 8% versus 42 +/- 22%) and a lower trabecular diameter (1.4 +/- 0.5 mm versus 2.2 +/- 0.8 mm) compared to recipients without height reduction. In comparison to a matched group of patients with similarly reduced BMD (1.1 +/- 1.2 versus 1.2 +/- 1.1 SD below normal BMD), renal allograft recipients showed a lower number of trabecular plates (5.6 +/- 3.1 versus 7.0 +/- 3.7) and a smaller intertrabecular surface (54 +/- 116 mm versus 75 +/- 138 mm). CONCLUSIONS: Alterations of bone architecture in renal allograft recipients were associated with progressive vertebral height loss. Despite similar bone mineral density, differences of bone architecture could be observed between renal allograft recipients and patients with osteoporosis.      

Gene Probe Analysis in an Informative Family with Multiple Endocrine Neoplasia Syndrome Type 2A (MEN 2A). Improvement in Carrier Risk Estimation

Gene probe analysis of the MEN 2A locus on chromosome 10 hasbeen undertaken using the markers TB10.163, RBP 3 and TB14.34in a large kindred with familial medullary thyroid carcinomas,with or without phaeochromocytomas or primary hyperparathyroidism.A maximum LOD score of 2.97 gave strong evidence of close linkagewith zero recombination. For 12 members of the family so far not known to be affectedby any form of the disease the estimated risk of carrying thegene has been considerably decreased in all but one, whose riskhas been greatly increased.     

Heterogeneity of human red cell autoantibodies assessed by isoelectric focusing

Human red cell (RBC) autoantibodies may be the products of a single lymphocyte clone or of a restricted number of clones. For insight into the clonal distribution of human RBC autoantibodies, serum fractions from 28 individuals with various forms of autoimmune hemolytic anemia (AHA) and two nonanemic individuals with positive direct antiglobulin tests were separated by isoelectric focusing (IEF), and RBC binding in each fraction was quantitated with a solid-phase radioimmunoassay. IEF fractions of serum from normal volunteers and patients with nonimmune hemolytic anemia served as controls. These studies indicate that RBC antibodies are found in a restricted number of IEF fractions in sera from some patients with immune hemolytic anemia. IEF fractions containing RBC-binding activity vary among patients with idiopathic AHA, and distinct patterns of binding activity are found in serum from some patients with AHA associated with alphamethyldopa and procainamide or with B-cell immunoproliferative diseases. These findings suggest that the mechanism leading to autoantibody production may differ among patients with the various forms of immune hemolytic anemia.     

Expression of phosphorylcholine-specific B cells during murine development

The TEPC 15 (T15) clonotype, a putatively germline antibody specificity, does not appear in the neonatal B-cell repertoire until approximately 1 wk of age. This report extends this observation by the demonstration that (a) the T15 clonotype follows similar kinetics of appearance in germfree as well as conventionally-reared mice; (b) maternal influences and genetic background play a minor role in the development of the T15 clonotype since CBFI neonates raised by C57BL/6 or BALB/c mothers acquire the T15 clonotype at the same time in ontogeny as BALB/c neonates; (c) the lack of phosphorylcholine (PC)-specific B cells shortly after birth is reflected in a dearth of PC-binding cells in the neonate as well; and (d) no PC-specifc B cells are found in 19-day fetal liver or in bone marrow until 7 days of life, coincident with their appearance in the spleen. These findings, along with a previous report that PC-specific splenic B cells are tolerizable as late as day 10 after birth, confirm the invariant, late occurrence of the T15 clonotype and support a highly- ordered, rigorously predetermined mechanism for the acquisition of the B- cell repertoire. The results are discussed in light of other studies on the ontogeny of B-cell specificity, and in terms of the implications on the mechanism by which antibody diversity is generated.     

An empirical evaluation of the performance of antibody identification tasks

Four empirical studies were conducted for better understanding of the nature of problem-solving activities by medical technologists and medical technology students when performing antibody identification tasks. The results indicated the importance of strategies that ensure the collection of converging evidence, as these strategies protect against the fallibility of commonly used heuristics and against errors due to simple slips. The results also indicate that not only do students make significant numbers of errors, but so do practicing technologists. In one of the studies covering a 1-year period, for instance, a group of 16 technologists made a total of 41 errors in 1057 cases. On the basis of these findings, several alternatives are proposed to reduce errors.     

Polymorphonuclear leukocyte heterogeneity in neonates and adults

We have used a mouse monoclonal antibody (31D8) to determine whether differences in neutrophil (PMN) subpopulations might help explain decreased PMN chemotaxis in neonates compared with that of adults. 31D8 has been shown to bind heterogeneously to adult PMNs. Approximately 80% of the PMNs that strongly bind 31D8 (31D8 "bright") are the same cells that depolarize and migrate chemotactically when stimulated with the chemoattractant N-formyl-methionylleucylphenylalanine, while the 20% that weakly bind 31D8 fail to similarly respond. All neonatal PMNs bound 31D8 heterogeneously. There was a smaller population of 31D8 "bright" cells in neonates at birth (76% +/- 6%, n = 45) compared with that of neonates at three to 15 days of age (82% +/- 5%, n = 10, P less than 0.002) and both were smaller than that of adults (88% +/- 4%, n = 45, P less than 0.001 and P less than 0.001). Neonatal cord PMNs, which traversed a micropore filter in a modified Boyden chemotaxis chamber in the presence of a chemoattractant, had an increased percentage of 31D8 "bright" cells (89% +/- 7%) than did PMNs which remained above the filter (82% +/- 7%, n = 10, P = 0.034). PMN chemotaxis was less in neonates at birth (32.7 +/- 4.5 micron) than at three to six days of age (36.8 +/- 11.3 micron) and both were decreased compared with that of adults (69.1 +/- 12.4 micron, P less than 0.001 and P less than 0.001). These findings indicate that decreased PMN chemotaxis in neonates may be due in part to a smaller PMN subpopulation of highly motile cells.     

Kidney transplant outcomes are related to tacrolimus,mycophenolic acid and prednisolone exposure in the first week

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.     

Severe perinatal thrombosis in double and triple heterozygous offspring of a family segregating two independent protein S mutations and a protein C mutation

Molecular genetic and phenotypic analyses were performed in a highly unusual case of combined protein S and protein C deficiency manifesting in a family in which a child had died perinatally from renal vein thrombosis. Antenatal diagnosis in a second pregnancy was initially performed by indirect restriction fragment length polymorphism (RFLP) tracking using a neutral dimorphism within the PROS gene and served to exclude severe protein S deficiency. Am umbilical vein blood sample at 22 weeks gestation showed isolated protein C deficiency. This pregnancy proceeded to a full-term delivery without thrombotic complications. Molecular genetic analysis of the PROC and PROS gene segregating in the family then yielded one PROC gene lesion in the father and two PROS gene lesions, one in each parent. These lesions were shown to segregate with the respective deficiency states through the family pedigree. Analysis of DNA from paraffin-embedded liver tissue taken from the deceased child showed the presence of both PROS mutations, as well as the PROC mutation. Genotypic analysis of the second child showed a PROC mutation, but neither PROS mutation consistent with its possession of normal protein S levels and a low/borderline protein C level. Antenatal diagnosis was then performed in a third pregnancy by direct mutation detection. However, although the fetus carried only the paternal PROS and PROC gene lesions, the child developed renal thrombosis in utero. It may be that a further genetic lesion at a third locus still remains to be defined. Alternatively, the intrauterine development of thrombosis in this infant could have been caused, at least in part by a transplacental thrombotic stimulus arising in the protein S-deficient maternal circulation. This analysis may, therefore, serve as a warning against extrapolating too readily from genotype to phenotype in families with a complex thrombotic disorder.