Genetic and Immune Predictors for Hypersensitivity Syndrome to Antiepileptic Drugs

Hypersensitivity syndrome reactions (HSR) to antiepileptic drugs (AED) are associated with severe clinical cutaneous adverse reactions (SCAR).Our aims are: to assess HSRs to AEDs using the in vitro lymphocyte toxicity assay (LTA) in patients who manifested HSRs clinically, to correlate LTA results with the clinical syndrome, to correlate LTA results with the human leukocyte antigen (HLA) allele B*1502 (HLA-B*1502) positivity in a Han Chinese-Canadian population, and to determine the cytokine network in this population. HSR patients developed fever and cutaneous eruptions in the presence or absence of organ involvement within 8 weeks of exposure to carbamazepine (CBZ), phenytoin (PHY) or lamotrigine (LTG). Control patients received AEDs without presenting HSR. We investigated 10 CBZ-HSR (4 presented with Stevens-Johnson syndrome (SJS)), 24 CBZ-controls, 10 PHY-HSR (4 presented with drug-induced liver injury (DILI)), 24 PHY-controls, 6 LTG-HSR (1 SJS and 1 DILI) and 24 LTG-controls. There were 30 Han Chinese individuals (14 HSR patients and 16 controls) in our cohort. LTA toxicity greater than 12.5%±2.5% was considered positive. Differences among groups were determined by analysis of variance. In addition, we measured cytokine secretion in the patient sera between 1 month and 3 years after the event. All Han Chinese individuals and 30% of Caucasians were genotyped for HLA-B*1502.A perfect correlation (r=0.92) was observed between positive LTA and clinical diagnosis of DILI and SJS/toxic epidermal necrolysis (TEN). HLA-B*1502 positivity in Han Chinese is a predictor of CBZ-HSR and PHY-HSR. HLA-B*1502-negative Han Chinese receiving only CBZ or a combination of CBZ-PHY tolerated the drug(s) clinically, presenting negative CBZ-LTA and PHY-LTA. However, 3 patients presenting negative CBZ-LTA and PHY-LTA, as well as negative HLA-B*1502, showed positive LTG-LTA (38%, 28% and 25%, respectively), implying that they should not be prescribed LTG. Three patients had LTA positive to both PHY and CBZ, and 3 others had LTA positive to both PHY and LTG. Clinically, all six patients presented HSR to both drugs that they tested positive to (cross-reactivity). Patients were grouped based on the clinical presentation of their symptoms as only rash and fever or a triad that characterizes "true" HSR (rash, fever and DILI or SJS/TEN). Levels of pro-inflammatory cytokines were significantly higher in patient sera compared to control sera. More specifically, the highest levels of tumor necrosis factor (TNF)-α was measured in patients presenting "true" HSR, as were the apoptotic markers Fas, caspase 8 activity and M30. We concluded that LTA is sensitive for DILI and SJS/TEN regardless of drug or ethnicity. HSR prediction will prevent AED-induced morbidity. In Han Chinese, HLA-B*1502 positivity is a predictor for CBZ-HSR and PHY-HSR. Its negativity does not predict a negative LTG-HSR. There is cross-reactivity between AEDs. Additionally, T-cell cytokines and chemokines control the pathogenesis of SJS/TEN and DILI, contributing to apoptotic processes in the liver and in the skin

Volitional Control of Neural Activity Relies on the Natural Motor Repertoire

Background: The results from recent brain-machine interface (BMI) studies suggest that it may be more efficient to use simple arbitrary relationships between individual neuron activity and BMI movements than the complex relationship observed between neuron activity and natural movements. This idea is based on the assumption that individual neurons can be conditioned independently regardless of their natural movement association. Results: We tested this assumption in the parietal reach region (PRR), an important candidate area for BMIs in which neurons encode the target location for reaching movements. Monkeys could learn to elicit arbitrarily assigned activity patterns, but the seemingly arbitrary patterns always belonged to the response set for natural reaching movements. Moreover, neurons that are free from conditioning showed correlated responses with the conditioned neurons as if they encoded common reach targets. Thus, learning was accomplished by finding reach targets (intrinsic variable of PRR neurons) for which the natural response of reach planning could approximate the arbitrary patterns. Conclusions: Our results suggest that animals learn to volitionally control single-neuron activity in PRR by preferentially exploring and exploiting their natural movement repertoire. Thus, for optimal performance, BMIs utilizing neural signals in PRR should harness, not disregard, the activity patterns in the natural sensorimotor repertoire

Histogram-based models on non-thin section chest CT predict invasiveness of primary lung adenocarcinoma subsolid nodules.

109 pathologically proven subsolid nodules (SSN) were segmented by 2 readers on non-thin section chest CT with a lung nodule analysis software followed by extraction of CT attenuation histogram and geometric features. Functional data analysis of histograms provided data driven features (FPC1,2,3) used in further model building. Nodules were classified as pre-invasive (P1, atypical adenomatous hyperplasia and adenocarcinoma in situ), minimally invasive (P2) and invasive adenocarcinomas (P3). P1 and P2 were grouped together (T1) versus P3 (T2). Various combinations of features were compared in predictive models for binary nodule classification (T1/T2), using multiple logistic regression and non-linear classifiers. Area under ROC curve (AUC) was used as diagnostic performance criteria. Inter-reader variability was assessed using Cohen's Kappa and intra-class coefficient (ICC). Three models predicting invasiveness of SSN were selected based on AUC. First model included 87.5 percentile of CT lesion attenuation (Q.875), interquartile range (IQR), volume and maximum/minimum diameter ratio (AUC:0.89, 95%CI:[0.75 1]). Second model included FPC1, volume and diameter ratio (AUC:0.91, 95%CI:[0.77 1]). Third model included FPC1, FPC2 and volume (AUC:0.89, 95%CI:[0.73 1]). Inter-reader variability was excellent (Kappa:0.95, ICC:0.98). Parsimonious models using histogram and geometric features differentiated invasive from minimally invasive/pre-invasive SSN with good predictive performance in non-thin section CT

A Critical Temporal Window for Selectin-dependent CD4+ Lymphocyte Homing and Initiation of Late-Phase Inflammation in Contact Sensitivity

Contact sensitivity (CS) is an inflammatory disorder characterized by early and late phases of leukocyte recruitment. We used a noninvasive intravital microscopy technique allowing for the direct visualization of leukocyte rolling and adhesion on blood vessel endothelium. By blocking specific adhesion molecules, we elucidated the molecular mechanisms mediating early leukocyte recruitment to be E- and P-selectin and demonstrated that leukocyte recruitment in the late phase had a different adhesive profile (mainly α4-integrin). Complete blockade of E- and P-selectin within the first 2 h of leukocyte–endothelial cell interactions (but not later) eliminated selectin-independent leukocyte recruitment at 24 h. Despite the predominance of neutrophils in the early phase, specific elimination of CD4+ lymphocytes in the early phase eliminated the late response. CD4+ lymphocytes homed to skin via E- and P-selectin within the early phase and induced the late phase response. Addition of these same CD4+ lymphocytes 2 h after antigen challenge was too late for these cells to home to the skin and induce late phase responses. Our data clearly demonstrate that the antigen-challenged microenvironment is only accessible to CD4+ lymphocytes for the first 2 h, and that this process is essential for the subsequent recruitment of other leukocyte populations in late phase responses

The Physical Basis for Long-lived Electronic Coherence in Photosynthetic Light Harvesting Systems

The physical basis for observed long-lived electronic coherence in photosynthetic light-harvesting systems is identified using an analytically soluble model. Three physical features are found to be responsible for their long coherence lifetimes: i) the small energy gap between excitonic states, ii) the small ratio of the energy gap to the coupling between excitonic states, and iii) the fact that the molecular characteristics place the system in an effective low temperature regime, even at ambient conditions. Using this approach, we obtain decoherence times for a dimer model with FMO parameters of $\approx$ 160 fs at 77 K and $\approx$ 80 fs at 277 K. As such, significant oscillations are found to persist for 600 fs and 300 fs, respectively, in accord with the experiment and with previous computations. Similar good agreement is found for PC645 at room temperature, with oscillations persisting for 400 fs. The analytic expressions obtained provide direct insight into the parameter dependence of the decoherence time scales.Comment: 5 figures; J. Phys. Chem. Lett. (2011