Clinical factors and ABCB1 polymorphisms in prediction of antiepileptic drug response: a prospective cohort study

BACKGROUND: The ABCB1 3435C-->T single-nucleotide polymorphism (SNP) or a three-SNP haplotype containing 3435C-->T has been implicated in multidrug resistance in epilepsy in three retrospective case-control studies, but a further three have failed to replicate the association. We aimed to determine the effect of the ABCB1 gene on epilepsy drug response, using a unique large cohort of epilepsy patients with prospectively measured seizure and drug response outcomes. METHODS: The ABCB1 3435C-->T polymorphism and three-SNP haplotype, plus a comprehensive set of tag SNPs across ABCB1 and adjacent ABCB4, were genotyped in a cohort of 503 epilepsy patients with prospectively measured seizure and drug response outcomes. Clinical, demographic, and genetic data were analysed. Treatment outcome was measured in terms of time to 12-month remission, time to first seizure, and time to drug withdrawal due to inadequate seizure control or side-effects. Randomly selected genome-wide HapMap SNPs (n=129) were genotyped in all patients for genomic control. FINDINGS: Number of seizures before treatment was the dominant feature predicting seizure outcome after starting antiepileptic drug therapy, measured by both time to first seizure (hazard ratio 1.34, 95% CI 1.21-1.49, p<0.0001) and time to 12-month remission (0.83, 0.73-0.94, p=0.003). There was no association of the ABCB1 3435C-->T polymorphism, the three-SNP haplotype, or any gene-wide tag SNP with time to first seizure after starting drug therapy, time to 12-month remission, or time to drug withdrawal due to unacceptable side-effects or to lack of seizure control. INTERPRETATION: We found no evidence that ABCB1 common variation influences either seizure or drug withdrawal outcomes after initiation of antiepileptic drug therapy.     

Cannabinoids Stimulate Fibroblastic Colony Formation by Bone Marrow Cells Indirectly via CB<Subscript>2</Subscript> Receptors

Recently, the cannabinoid receptors CB₁ and CB₂ were shown to modulate bone formation and resorption in vivo, although little is known of the mechanisms underlying this. The effects of cannabinoids on mesenchymal stem cell (MSC) recruitment in whole bone marrow were investigated using either the fibroblastic colony-forming unit (CFU-f) assay or high-density cultures of whole bone marrow. Levels of the CB₁ and CB₂ receptors were assessed by flow cytometry. Treatment of CFU-f cultures with the endocannabinoid 2-arachidonylglycerol (2-AG) dose-dependently increased fibroblastic and differentiated colony formation along with colony size. The nonspecific agonists CP 55,940 and WIN 55,212 both increased colony numbers, as did the CB₂ agonists BML190 and JWH015. The CB₁-specific agonist ACEA had no effect, whereas the CB₂ antagonist AM630 blocked the effect of the natural cannabinoid tetrahydrocannabivarin, confirming mediation via the CB₂ receptor. Treatment of primary bone marrow cultures with 2-AG stimulated proliferation and collagen accumulation, whereas treatment of subcultures of MSC had no effect, suggesting that the target cell is not the MSC but an accessory cell present in bone marrow. Subcultures of MSCs were negative for CB₁ and CB₂ receptors as shown by flow cytometry, whereas whole bone marrow contained a small population of cells positive for both receptors. These data suggest that cannabinoids may stimulate the recruitment of MSCs from the bone marrow indirectly via an accessory cell and mediated via the CB₂ receptor. This recruitment may be one mechanism responsible for the increased bone formation seen after cannabinoid treatment in vivo.     

Reproducibility of the cervical range of motion (CROM) device for individuals with sub-acute whiplash associated disorders

Purpose  

The objective of this study was to evaluate the reproducibility of the cervical range of motion device when measuring both active and passive range of motion in a group of individuals with sub-acute Whiplash Associated Disorders (WAD).     

Successful intra-arterial thrombolytic therapy for a right middle cerebral artery stroke in a 2-year-old supported by a ventricular assist device

Embolic stroke is a common complication in patients on ventricular assist devices in both adults and children. The reported incidence of strokes in children supported by VAD's varies from 7 to 38%. The rapid increase in recent years in the availability of both adult and pediatric VADs will likely add to the overall prevalence of strokes in patients being bridged to heart transplant. Strokes in this population can be lethal as they frequently necessitate withdrawal of the extracorporeal device support and withdrawal from the organ transplant waiting list. We present a case of a fully anti-coagulated 29-month-old supported on a Berlin EXCOR LVAD (Berlin, Germany) with embolic stroke which was treated successfully with direct thrombolysis with recombinant tissue plasminogen activator. This is the first report which uses intra-arterial thrombolytics while on a ventricular assist device in a pediatric patient.     

Biomechanical evaluation of the less invasive stabilization system and the 95-degree angled blade plate for the internal fixation of distal femur Fractures in human cadaveric bones with high bone mineral density

BACKGROUND: The less invasive stabilization system (LISS) is an internal fixator that utilizes unicortical locked screws for fixation of distal femur fractures. A question is whether locked unicortical screw fixation is sufficient, when compared with a standard implant such as a blade plate. METHODS: Eight matched pairs of fresh-frozen cadaveric femora were instrumented with either the LISS or a 95-degree blade plate. A 4-cm supracondylar gap fracture model was created and all bone-implant constructs were tested to failure in axial loading. RESULTS: All constructs failed by plastic deformation of the implant. There was no significant difference between the LISS and the blade plate constructs with respect to load to failure. CONCLUSIONS: Despite unicortical fixation axial loading to failure of the LISS did not result in implant/screw pull-out neither proximally nor distally. However, there does not appear to be a biomechanical advantage of using the LISS as opposed to a blade plate in bones with high bone mineral density.     

The influence of native aortic valve calcium and transcatheter valve oversize on the need for pacemaker implantation after transcatheter aortic valve insertion

Objective

Native aortic valve calcium and transcatheter aortic valve oversize have been reported to predict pacemaker implantation after transcatheter aortic valve insertion. We reviewed our experience to better understand the association.