Tacrolimus is a substrate for P-glycoprotein (P-gp) and cytochrome (CYP) P4503A. P-gp is encoded by the multiple drug resistance gene MDR1 and CYP3A is the major enzyme responsible for tacrolimus metabolism. Both MDR1 and CYP3A5 genes have multiple single nucleotide polymorphisms. The objective of this study was to evaluate whether the MDR1 exon21 and exon26 polymorphisms and the CYP3A5 polymorphism are associated with tacrolimus disposition in pediatric heart transplant patients. At 3, 6 and 12 months post transplantation, a significant difference in tacrolimus blood level per dose/kg/day was found between the CYP3A5 *1/*3 (CYP3A5 expressor) vs. *3/*3 (nonexpressor) genotypes with the *1/*3 patients requiring a larger tacrolimus dose to maintain the same blood concentration. There were no significant differences in tacrolimus blood level per dose/kg/day between MDR1 exon21 G2677T and exon 26 C3435T at 3 months, but both were found to have a significant association with tacrolimus blood level per dose/kg/day at 6 and 12 months. We conclude that specific genotypes of MDR1 and CYP3A5 in pediatric heart transplant patients require larger tacrolimus doses to maintain their tacrolimus blood concentration, and that this information could be used prospectively to manage patient's immunosuppressive therapy.

ObjectiveTo examine the independent association between heart rate variability (HRV) and cognitive performance, in a nationally representative population study of older adults. MethodsCross--sectional analysis of wave 1 data from the Irish longitudinal study on ageing (TILDA) was performed. A subset of 4,763 participants who underwent ECG recording during resting and paced breathing periods were used for the analysis. HRV indices were divided into quintiles for comparison of values and cognitive performance was defined using the Montreal cognitive assessment (MOCA) score. Multivariate linear regression was used to model the association between cognition and different quintiles of each HRV index, after adjustment for covariates. ResultsThe mean age was 61.7 ± 8.3 years and 2,618 (55 %) were female. Lower quintiles of SDNN (P = 0.01--paced), LF (P = 0.001--paced), and LF:HF ratio (P = 0.049--paced) were significantly associated with lower MOCA scores (during both recording periods), independent of confounders. Sub--domains of MOCA responsible for the relationship were predominantly memory recall and language. InterpretationReduced HRV is significantly associated with lower cognitive performance at a population level in people aged 50 and older. This further strengthens the relationship between autonomic dysfunction and cognitive disorders.

this is the first study of its kind to show a high correlation between accelerometry, the BBS and TUG. Accelerometry could also distinguish between sway responses to differing balancing conditions and between fallers and non-fallers. Accelerometry was shown to be an efficient, quantitative alternative in the measurement of balance in older people.

No abstract

BackgroundIndividuals with major depressive disorder (MDD) process information with a bias towards negative stimuli. However, little is known on the link between vulnerability to MDD and brain functional anomalies associated with stimulus bias.MethodsA cohort of 38 subjects, of which 14 were patients with acute MDD and 24 were healthy controls (HC), were recruited and compared. The HC group included 10 healthy participants with a first degree family history of depression (FHP) and 14 volunteers with no family history of any psychiatric disease (FHN). Blood oxygen level dependence signals were acquired from functional magnetic resonance imaging (fMRI) during performance in a dot-probe task using fearful and neutral stimuli. Reaction times and the number of errors were also obtained.ResultsAlthough MDD patients and HC showed no behavioral difference, the MDD group exhibited smaller activation in the left middle cingulum. The MDD group also showed smaller activation in the left insula when compared to the HC group or the FHN group. Finally, FHP participants exhibited higher activation in the right Heschl's gyrus compared to FHN participants.ConclusionsThe present study shows that family risk for MDD is associated with increased activation in the Heschl's gyrus. Our results also suggest that acute MDD is linked to reduced activation in the insula and anterior cingulate cortex during processing of subliminal, not recognizable, masked fearful stimuli. Further research should confirm these results in a larger cohort of participants.

Background The course of dilated cardiomyopathy (DCM) leading to heart failure in children varies; survival with conventional treatment is 64% at 5 years. Heart transplantation (HTx) enables improved survival; however, outcomes from listing for transplant are not well described. This study reports survival of patients with DCM from listing with the availability of mechanical bridge to transplant. Methods Patients with a primary diagnosis of DCM (n = 1,098) were identified from a multi-institutional, prospective, registry of patients aged < 18 years listed for HTx from January 1, 1993, to December 31, 2006. Results Characteristics of DCM patients at listing included a mean age of 7.3 years; 51% male, 64% white ethnicity, 77% United Network for Organ Sharing status I, 66% on inotropic support, 28% mechanically ventilated, and 15% on mechanical support. Waitlist mortality was 11%, and 75% underwent HTx at 2 years after listing. Overall 10-year survival after listing was 72%, with higher risk of death associated with arrhythmias, mechanical ventilation, and extracorporeal membrane oxygenation (ECMO) support, but not ventricular assist device (VAD) support. Survival at 10 years post-HTx was 72%, with a higher risk of death associated with black race, older age, mechanical ventilation, longer ischemic time, and earlier era of transplant. Conclusions Transplantation for DCM in the pediatric population offers enhanced survival compared with the natural history. Overall waitlist mortality for DCM is low, with the exception of patients on ECMO, mechanically ventilated, or with arrhythmias. DCM patients fared well after transplant, making HTx a key therapeutic intervention.

In conclusion, individuals with SH (defined as BP > 140/90 mmHg) coupled with OH measured using phasic BP had lower global and executive cognitive performance than those with SH but without OH.

SUMMARYObjective: The identification of "endophenotypes"-measurable variations along the pathways between genes and distal disease state-may help deconstruct focal epilepsies into more sensitive phenomena and improve future efforts to map the genetic underpinnings of the disorder. In this study, we set out to determine if diffusion tensor imaging (DTI)-inferred white matter (WM) alterations represent a suitable structural endophenotype for focal epilepsy. Methods: We recruited 25 patients with sporadic mesial temporal lobe epilepsy (MTLE) with normal magnetic resonance imaging (MRI) findings, 25 of their gendermatched, asymptomatic siblings, and 60 control subjects. Whole-brain, voxelwise statistics were conducted to identify regions of microstructural degeneration in patients with MTLE and/or their asymptomatic siblings. WM tracts exhibiting evidence of microstructural disruption were then reconstructed using deterministic tractography. Diffusion metrics including fractional anisotropy (FA) and mean diffusivity (MD) were compared across groups using a series of one-way multivariate analyses of covariance (MANCOVAs). Results: Voxelwise statistics revealed significant FA reductions in the corpus callosum (CC), bilateral superior longitudinal fasciculi (SLF), bilateral inferior longitudinal fasciculi (ILF), and left corticospinal tract (CST) in MTLE patients only. MD increases were observed in MTLE patients and their asymptomatic siblings in the left SLF and left CST. Deterministic tractography supported the voxelwise results, revealing significant FA alterations in the left SLF and CST in patients only and significant MD alterations in MTLE patients and their unaffected siblings. The diffusion scalars of MTLE patients and their asymptomatic siblings were highly correlated in the SLF and CST ipsilateral to patients' sides of seizure onset. Significance: These findings confirm the presence of microstructural WM alterations in patients with MRI-negative MTLE and provide preliminary support for a diffusionbased endophenotype in the disorder. Further studies of narrow-sense heritability in larger cohorts of first-degree relatives of MTLE patients are required to confirm these results.