A high-density SNP linkage scan with 142 combined subtype ADHD sib pairs identifies linkage regions on chromosomes 9 and 16.

As part of the International Multi-centre ADHD Genetics project we completed an affected sibling pair study of 142 narrowly defined Diagnostic and Statistical Manual of Mental Disorders, fourth edition combined type attention deficit hyperactivity disorder (ADHD) proband-sibling pairs. No linkage was observed on the most established ADHD-linked genomic regions of 5p and 17p. We found suggestive linkage signals on chromosomes 9 and 16, respectively, with the highest multipoint nonparametric linkage signal on chromosome 16q23 at 99 cM (log of the odds, LOD=3.1) overlapping data published from the previous UCLA (University of California, Los Angeles) (LOD>1, approximately 95 cM) and Dutch (LOD>1, approximately 100 cM) studies. The second highest peak in this study was on chromosome 9q22 at 90 cM (LOD=2.13); both the previous UCLA and German studies also found some evidence of linkage at almost the same location (UCLA LOD=1.45 at 93 cM; German LOD=0.68 at 100 cM). The overlap of these two main peaks with previous findings suggests that loci linked to ADHD may lie within these regions. Meta-analysis or reanalysis of the raw data of all the available ADHD linkage scan data may help to clarify whether these represent true linked loci.

The analysis of 51 genes in DSM-IV combined type attention deficit hyperactivity disorder: association signals in DRD4, DAT1 and 16 other genes.

Attention deficit hyperactivity disorder (ADHD) is a common neurodevelopmental disorder, starting in early childhood and persisting into adulthood in the majority of cases. Family and twin studies have demonstrated the importance of genetic factors and candidate gene association studies have identified several loci that exert small but significant effects on ADHD. To provide further clarification of reported associations and identify novel associated genes, we examined 1,038 single-nucleotide polymorphisms (SNPs) spanning 51 candidate genes involved in the regulation of neurotransmitter pathways, particularly dopamine, norepinephrine and serotonin pathways, in addition to circadian rhythm genes. Analysis used within family tests of association in a sample of 776 DSM-IV ADHD combined type cases ascertained for the International Multi-centre ADHD Gene project. We found nominal significance with one or more SNPs in 18 genes, including the two most replicated findings in the literature: DRD4 and DAT1. Gene-wide tests, adjusted for the number of SNPs analysed in each gene, identified associations with TPH2, ARRB2, SYP, DAT1, ADRB2, HES1, MAOA and PNMT. Further studies will be needed to confirm or refute the observed associations and their generalisability to other samples.

epsilon-Aminocaproic acid plasma levels during cardiopulmonary bypass.

epsilon-Aminocaproic acid (EACA) concentrations achieved during cardiopulmonary bypass (CPB) have not been previously reported. It is unknown whether plasma concentrations reported to inhibit fibrinolysis in vitro (130 microg/mL) are achieved or whether differences in these levels relate to variability in postoperative bleeding. EACA (total intraoperative dose 270 mg/kg) was administered to 27 patients undergoing cardiac reoperation. The plasma EACA concentration was measured by using high-pressure liquid chromatography: 1) 30 min after initiation of drug administration (baseline); 2) 30 min (CPB + 30) after initiation of CPB; 3) 90 min after initiation of CPB. (CPB + 90); and 4) at cardiopulmonary bypass termination (end CPB). Plasma EACA concentrations (microg/mL, min - max, mean +/- SD) were 276-998, 593 +/- 154 at baseline; 147-527, 302 +/- 95 at CPB + 30; 112-500, 314 +/- 100 at CPB + 90; and 84-537, 317 +/- 100 at end CPB. Twenty-four-hour postoperative thoracic drainage and allogeneic red blood cell transfusions were not associated with plasma levels at any time. Although plasma EACA concentrations greater than 130 microg/mL were consistently achieved, we observed a marked variability (more than sixfold) in plasma concentrations and bleeding outcomes despite the use of a weight-based dosing regimen. This variability in drug levels appears to have little relevance to bleeding outcomes, possibly since mean plasma levels exceeded 130 microg/mL during CPB, and nearly all patients (26 of 27) achieved that target level.

Cost-benefit and efficacy of aprotinin compared with epsilon-aminocaproic acid in patients having repeated cardiac operations: a randomized, blinded clinical trial.

BACKGROUND: Aprotinin and epsilon-aminocaproic acid are routinely used to reduce bleeding during cardiac surgery. The marked difference in average wholesale cost between these two drug therapies (aprotinin, $1,080 vs. epsilon-aminocaproic acid, $11) has generated significant controversy regarding their relative efficacies and costs. METHODS: In a multicenter, randomized, prospective, blinded trial, patients having repeated cardiac surgery received either a high-dose regimen of aprotinin (total dose, 6 x 10(6) kallikrein inactivator units) or epsilon-aminocaproic acid (total dose, 270 mg/kg). RESULTS: Two hundred four patients were studied. Overall (data are median [25th-75th percentiles]), aprotinin-treated patients had less postoperative thoracic drainage (511 ml [383-805 ml] vs. 655 ml [464-1,045 ml]; P = 0.016) and received fewer platelet transfusions (0 [range, 0-1] vs. 1 [range, 0-2]; P = 0.036). The surgical field was more likely to be considered free of bleeding in aprotinin-treated patients (44% vs. 26%; P = 0.012). No differences, however, were seen in allogeneic erythrocyte transfusions or in the time required for chest closure. Overall, direct and indirect bleeding-related costs were greater in aprotinin- than in epsilon-aminocaproic acid-treated patients ($1,813 [$1,476-2,605] vs. $1,088 [range, $511-2,057]; P = 0.0001). This difference in cost per case varied in magnitude among sites but not in direction. CONCLUSIONS: Aprotinin was more effective than epsilon-aminocaproic acid at decreasing bleeding and platelet transfusions. Epsilon-aminocaproic acid, however, was the more cost-effective therapy over a broad range of estimates for bleeding-related costs in patients undergoing repeated cardiac surgery. A cost-benefit analysis using the lower cost of half-dose aprotinin ($540) still resulted in a significant cost advantage using epsilon-aminocaproic therapy (P = 0.022).

Maintenance of therapeutic plasma aprotinin levels during prolonged cardiopulmonary bypass using a large-dose regimen.

Aprotinin concentrations in the range of 127-191 kallikrein inactivator units (KIU)/mL at the end of cardiopulmonary bypass (CPB) (< 2 h duration) reduce transfusion requirements. It has been suggested that prolonged CPB may require higher infusion rates which significantly increase cost. We tested the hypothesis that large-dose aprotinin maintains therapeutic plasma levels during prolonged periods of CPB (< 2 h). Aprotinin was administered as follows: 2 x 10(6) KIU upon skin incision; 0.5 x 10(6) KIU/h x 4-h infusion on initiation of CPB; and 2 x 10(6) KIU added to the CPB prime solution. Aprotinin activity was measured 1) 30 min after initiation of drug administration (Pre-CPB); 2) 30 min after initiation of CPB (CPB + 30); 3) 90 min after initiation of CPB (CPB + 90); and 4) at CPB termination (End CPB). CPB duration (mean +/- SD) was 158 +/- 51 min. Plasma aprotinin concentrations (KIU/mL, mean +/- SD) were: 234 +/- 30 at Pre-CPB; 229 +/- 35 at CPB + 30; 184 +/- 27 at CPB + 90; and 179 +/- 22 at End CPB. In all patients, aprotinin levels at the completion of CPB were in the range previously reported to be effective. The authors conclude that large-dose regimen limited to 6 x 10(6) KIU maintained therapeutic plasma aprotinin concentrations during prolonged CPB.