Genomewide Association Study of Tacrolimus Concentrations in African American Kidney Transplant Recipients Identifies Multiple CYP3A5 Alleles.

We previously reported that tacrolimus (TAC) trough blood concentrations for African American (AA) kidney allograft recipients were lower than those observed in white patients. Subtherapeutic TAC troughs may be associated with acute rejection (AR) and AR-associated allograft failure. This variation in TAC troughs is due, in part, to differences in the frequency of the cytochrome P450 CYP3A5*3 allele (rs776746, expresses nonfunctional enzyme) between white and AA recipients; however, even after accounting for this variant, variability in AA-associated troughs is significant. We conducted a genomewide association study of TAC troughs in AA kidney allograft recipients to search for additional genetic variation. We identified two additional CYP3A5 variants in AA recipients independently associated with TAC troughs: CYP3A5*6 (rs10264272) and CYP3A5*7 (rs41303343). All three variants and clinical factors account for 53.9% of the observed variance in troughs, with 19.8% of the variance coming from demographic and clinical factors including recipient age, glomerular filtration rate, anticytomegalovirus drug use, simultaneous pancreas-kidney transplant and antibody induction. There was no evidence of common genetic variants in AA recipients significantly influencing TAC troughs aside from the CYP3A gene. These results reveal that additional and possibly rare functional variants exist that account for the additional variation.

Archaeal fructose-1,6-bisphosphate aldolases constitute a new family of archaeal type class I aldolase.

Fructose-1,6-bisphosphate (FBP) aldolase activity has been detected previously in several Archaea. However, no obvious orthologs of the bacterial and eucaryal Class I and II FBP aldolases have yet been identified in sequenced archaeal genomes. Based on a recently described novel type of bacterial aldolase, we report on the identification and molecular characterization of the first archaeal FBP aldolases. We have analyzed the FBP aldolases of two hyperthermophilic Archaea, the facultatively heterotrophic Crenarchaeon Thermoproteus tenax and the obligately heterotrophic Euryarchaeon Pyrococcus furiosus. For enzymatic studies the fba genes of T. tenax and P. furiosus were expressed in Escherichia coli. The recombinant FBP aldolases show preferred substrate specificity for FBP in the catabolic direction and exhibit metal-independent Class I FBP aldolase activity via a Schiff-base mechanism. Transcript analyses reveal that the expression of both archaeal genes is induced during sugar fermentation. Remarkably, the fbp gene of T. tenax is co-transcribed with the pfp gene that codes for the reversible PP(i)-dependent phosphofructokinase. As revealed by phylogenetic analyses, orthologs of the T. tenax and P. furiosus enzyme appear to be present in almost all sequenced archaeal genomes, as well as in some bacterial genomes, strongly suggesting that this new enzyme family represents the typical archaeal FBP aldolase. Because this new family shows no significant sequence similarity to classical Class I and II enzymes, a new name is proposed, archaeal type Class I FBP aldolases (FBP aldolase Class IA).

Isotypes and IgG subclasses of anti-Fab antibodies in human immunodeficiency virus-infected hemophilia patients.

We reported recently that anti-Fab autoantibodies of the IgG isotype are associated with the decrease of helper/inducer (CD4+) lymphocytes in human immunodeficiency virus-infected (HIV+) hemophilia patients with acquired immunodeficiency syndrome (AIDS) or AIDS-related complex (ARC). In the present study we investigated the subclass distribution of IgG-anti-Fab autoantibodies, and whether anti-Fab antibodies of the IgA and IgM isotypes also are associated with the development of AIDS. Sera of HIV+ patients with AIDS had significantly higher IgA-anti-Fab activity than HIV+ patients with ARC (p < 0.02), HIV+ patients without AIDS/ARC (p < 0.0001), HIV-negative (HIV-) patients (p < 0.001), or healthy controls (p < 0.0001). An inverse association was found between IgA-anti-Fab activity and CD4+ cell counts (r = -0.396, p < 10(-6)). In contrast, no association of CD4+ cell counts was observed with IgM-anti-Fab. However, IgM-anti-Fab was significantly increased in patients with thrombocytopenia. We found a significant association between IgA-anti-Fab activity and serum neopterin concentrations (r = 0.310, p < 10(-5)). IgG-anti-Fab activity was detected mainly in the IgG3 fraction, although in HIV+ patients with AIDS/ARC various IgG subclasses were present. Affinity-purified anti-Fab antibodies isolated from sera of AIDS patients bound to rgp120-preincubated CD4+ cells of a healthy individual, supporting our hypothesis that anti-Fab antibodies and free circulating gp120 molecules are involved in the elimination of uninfected CD4+ cells. Removal of anti-Fab autoantibodies from the circulation by immune adsorbance might be a useful approach in the treatment of AIDS.

Pretransplant serum IgA concentration and IgA-anti-Fab autoantibody activity as prognostic indicators of kidney graft survival.

IgA concentration and IgA-anti-Fab autoantibody activity were tested in pretransplant sera of 308 kidney graft recipients. Recipients with a serum IgA concentration of 2 g/l or greater had a 1-year graft survival rate of 83%, compared with a 68% rate in recipients with serum IgA of less than 2 g/l (P < 0.005). Serum IgA concentration and IgA-anti-Fab autoantibody activity were significantly associated (r = 0.38, P < 0.0001). Recipients with a high pretransplant IgA-anti-Fab activity had a significantly better graft survival rate (81%) than patients with low pretransplant IgA-anti-Fab (67%, P < 0.025). When IgA-anti-Fab and serum IgA were considered together, 137 recipients with high IgA-anti-Fab and high serum IgA had a 86% 1-year graft survival rate, which was significantly better than the 63% survival rate in patients with low IgA-anti-Fab and low serum IgA (P < 0.0005). The pretransplant serum IgA level and IgA-anti-Fab autoantibody activity were excellent predictors of kidney graft outcome.

[Psychosocial management in pediatric oncology--presentation of a cooperative team model]. / Psychosoziale Versorgung in der pädiatrischen Onkologie--Darstellung eines Arbeitsgruppenmodells.

This article presents a psychosocial patient-care program for pediatric cancer patients and their families. The program, initiated within the framework of a "cooperative team model", represents a new organisational form of cooperation between somatic and psychosomatic medicine that has been virtually untested in the filed of internal medicine. The advantages of this form lie in the improved availability of the families involved and the inherent possibilities of appropriate and effective assistance in overcoming the burdens of the illness and the treatment. Comparison with a liaison model showed a 3-times higher mean contact quota per patient/family. Problems which can be expected through implementation as well as related conflicts are discussed. Basic rules are formulated which must be followed if successful interdisciplinary cooperation is to be achieved. Areas of responsibility and activity are described for members of the psychosocial team (psychologists, social workers, visiting nurses) and a basis for documentation is illustrated using the evaluating results. The working concept behind an integrated psychosocial care system includes, as its basis, accompanying support to the involved families within the framework of general psychosocial care in which all of the members of the entire oncological team take part. As required, the special capabilities of the various psychosocial professions can then be brought to bear according to their functions and competence (psychosocial counselling and therapy, social-service counselling, medical and nursing care). Due to the conditions, inherent in the situation resulting from the illness and treatment, basic conceptional positions and attitudes become apparent that are of importance of psychosocial work is to be successful in a pediatric oncology ward.