Lack of association of the 3'-UTR polymorphism in the NFKBIA gene with Crohn's disease in an Israeli cohort.

BACKGROUND: Crohn's disease (CD) is a chronic inflammatory disease of the gastrointestinal tract associated with dysregulation of the immune response. It is caused by a combination of environmental and genetic factors. Patients with CD have a TH1-type inflammatory response characterized by nuclear factor kappa B (NFkappaB) activation. Mutations in the bacterial pattern recognition receptors NOD2/CARD15 and Toll-like receptor 4 (TLR4) genes, which lead to activation of NFkappaB under normal circumstances, have been associated with increased susceptibility for CD. NFkappaB plays a critical role in the immune response and is down-regulated by NFkappaB inhibitor alpha (NFKBIA). NFKBIA was found to be a susceptibility gene for German CD patients lacking NOD2/CARD15 mutations. MATERIALS AND METHODS: A cohort of 231 Israeli CD patients previously genotyped for the single nucleotide polymorphisms (SNPs) in the CARD15, TLR4 susceptibility genes for CD, was analyzed for the 3'-untranslated region (UTR) SNP of the NFKBIA gene in comparison to 100 healthy ethnically matched controls. We evaluated the contribution of the 3'-UTR SNP in NFKBIA in patients with or without other SNPs in CARD15 to age of onset, disease location, and disease behavior (Vienna classification). RESULTS: We did not identify a significant difference in allele and genotype frequencies between either groups or an effect on phenotype. No interactions were found between NFKBIA and any NOD2. CONCLUSIONS: The contribution of population diversity to susceptibility genes for CD plays an important role in disease-associated variants and is important for better understanding of the pathologic mechanisms of the polymorphism.

Recombinant human erythropoietin reduces allogeneic blood transfusion requirements in patients undergoing major orthopedic surgery.

Blood loss is a significant problem encountered in patients undergoing total joint arthroplasty, and is considered to be one of the factors affecting the outcome of the operation. Traditionally these patients have been treated with blood transfusions. The introduction of recombinant human erythropoietin (rHuEpo) into clinical practice enabled assessment of its effectiveness to decrease the allogeneic blood transfusion requirement (BTR), thus avoiding or minimizing transfusion-related complications. Fifteen patients undergoing total hip replacement (THR, 10 patients) and total knee replacement (TKR, 5 patients) in our institute (from January-April 1997), were studied. After signing an informed consent they received daily s.c. rHuEpo (100 IU/kg for those with hemoglobin (Hb) > 13 g/dl, 300 IU/kg for Hb < 13) during the 10 days prior to surgery and the 4 days following the operation. Allogeneic red blood cell (RBC) transfusions were given as needed. Hb levels were measured on days -10, 0, +1.3 and 7 of the procedure and the BTR was recorded. The results were compared with those of previous patients operated on from January-December 1996. Patients who were eligible for the study but refused to participate served as controls. The mean Hb level in the study group prior to rHuEpo administration (day -10) was 13.41 g/dl, similar to those of the control group (13.47 g/dl on day 0). However, the mean Hb levels in the rHuEpo treated patients on days 0, 1, 3 and 7 were 14.37, 11.09, 10.99, and 11.2 g/dl, respectively. This way compared with the levels of 13.47 (p = 0.016), 9.88 (p = 0.024), 9.60 (p = 0.004) and 9.97 g/dl (p = 0.007) in the control patients. The difference between the rHuEpo treated patients and the control patients was more significant among the THR patients than among the TKR patients. Of the 10 rHuEpo-treated THR patients, only a single patient required one allogeneic blood unit, as compared with 23 units transfused to the 30 control patients. None of the rHuEpo-treated TKR patients required blood transfusion as opposed to 4 units needed by the 11 control patients. In total, only one allogeneic blood unit was required by the study group which way calculated to an average consumption of 0.066 blood unit per person, compared with 27 blood units used by the 41 controls, i.e. 0.66 blood units per person (p < 0.001). In the patients treated, rHuEpo was very well tolerated with no adverse effects.

The effect of short-term dipyrone administration on cyclosporin pharmacokinetics.

BACKGROUND: A large number of drugs have been shown to affect the metabolism of cyclosporin A (CSA) and, since cyclosporin is characterized by a narrow therapeutic range, the consequences of such drug interactions may often be of clinical importance. OBJECTIVE: To evaluate the effect of short-term administration of dipyrone on steady state CSA pharmacokinetics. METHODS: Six kidney- and two heart-transplanted patients on chronic CSA therapy participated in this study, which consisted of two 4-day study periods separated by 3-week washout periods. The patients received, in addition to their usual drugs, dipyrone 500 mg or placebo t.i.d., as identical-looking tablets, and the order of administration was randomized. CSA concentrations were measured in whole blood by means of radio-immunoassay (CYCLO-Trac SP) daily during the study periods and periodically over 24 h on the fourth study day. RESULTS: CSA concentrations over time were reduced after dipyrone (ANOVA, P < 0.01), but statistical significance was noted only at 2, 4, 5 and 10 h after drug intake (P < 0.05). Peak CSA concentration was not altered by dipyrone, but the time required to reach maximal concentration was longer with dipyrone treatment than with the placebo (3.8 +/- 2.6 h vs 2.1 +/- 0.6 h, P < 0.05). No consistent changes were noted for CSA trough level, elimination half-life and area under the concentration-time curve from 0 h to 12 h. Separate analysis of the kidney transplanted patients yielded similar results. CONCLUSIONS: Short-term administration of dipyrone is associated with a mild decrease in CSA blood concentration, which is most prominent in the first few hours after drug intake. In practice, no dose adjustment of CSA seems to be indicated during a short course of dipyrone treatment.