A COMPARISON OF CAUSALITY ASSESSMENT TOOLS FOR SUSPECTED ADVERSE DRUG REACTIONS IN HOSPITALIZED PATIENTS AT A TERTIARY CARE HOSPITAL

Objective: The objective of the study was to compare six causality assessment (CA) tools for suspected adverse drug reactions (ADRs) reported in hospitalized patients at a tertiary care hospital in India. Methods: Intensive ADR monitoring was performed in indoor patients of two randomly selected medicine units. A detailed case report of each suspected ADR (n=120) was provided to six independent experts for CA using either visual analog scale (VAS) or WHO-UMC scale. Investigator assessed causality using Naranjo’s scale, Koh et al. scale, the French method, and Karch and Lasagna scale. Similar causality categories from these scales were coded for correlation. Agreement among experts and that between various CA tools were analyzed using Cohen’s kappa and Fleiss kappa. Reasons for disagreements among different scales were evaluated. Results: A variation was observed in the total number of drugs suspected to cause ADR by experts and investigator. “Likely” and “Plausible” causality were suggested frequently by experts using VAS whereas “Possible” causal association was frequent according to experts using the WHO-UMC scale and also by the investigator using algorithms except Koh et al. scale. None to the slight agreement was observed among experts who used VAS (k=0.117), whereas a substantial agreement was observed among experts using the WHO-UMC scale (k=0.707). A substantial agreement was observed between Karch and Lasagna scale and the French method (k=0.740). Both scales demonstrated moderate agreement with Naranjo’s scale. Disagreement among the WHO-UMC scale, the French method, and Karch and Lasagna scale were associated with polypharmacy, serious ADRs, non-availability of laboratory data, and skin and subcutaneous tissue ADRs. Conclusion: A higher inter-rater agreement with the WHO-UMC scale suggests its utility for CA of suspected ADRs in indoor patients. The French method and Karch and Lasagna scale can be used for CA in hospitalized patients as an adjunct to Naranjo’s scale. Factors associated with disagreement should be considered at the time of reporting ADRs and evaluating causality

Adaptive Gain Modulation in V1 Explains Contextual Modifications during Bisection Learning

The neuronal processing of visual stimuli in primary visual cortex (V1) can be modified by perceptual training. Training in bisection discrimination, for instance, changes the contextual interactions in V1 elicited by parallel lines. Before training, two parallel lines inhibit their individual V1-responses. After bisection training, inhibition turns into non-symmetric excitation while performing the bisection task. Yet, the receptive field of the V1 neurons evaluated by a single line does not change during task performance. We present a model of recurrent processing in V1 where the neuronal gain can be modulated by a global attentional signal. Perceptual learning mainly consists in strengthening this attentional signal, leading to a more effective gain modulation. The model reproduces both the psychophysical results on bisection learning and the modified contextual interactions observed in V1 during task performance. It makes several predictions, for instance that imagery training should improve the performance, or that a slight stimulus wiggling can strongly affect the representation in V1 while performing the task. We conclude that strengthening a top-down induced gain increase can explain perceptual learning, and that this top-down signal can modify lateral interactions within V1, without significantly changing the classical receptive field of V1 neurons

Reducing Crowding by Weakening Inhibitory Lateral Interactions in the Periphery with Perceptual Learning

We investigated whether lateral masking in the near-periphery, due to inhibitory lateral interactions at an early level of central visual processing, could be weakened by perceptual learning and whether learning transferred to an untrained, higher-level lateral masking known as crowding. The trained task was contrast detection of a Gabor target presented in the near periphery (4°) in the presence of co-oriented and co-aligned high contrast Gabor flankers, which featured different target-to-flankers separations along the vertical axis that varied from 2λ to 8λ. We found both suppressive and facilitatory lateral interactions at target-to-flankers distances (2λ - 4λ and 8λ, respectively) that were larger than those found in the fovea. Training reduces suppression but does not increase facilitation. Most importantly, we found that learning reduces crowding and improves contrast sensitivity, but has no effect on visual acuity (VA). These results suggest a different pattern of connectivity in the periphery with respect to the fovea as well as a different modulation of this connectivity via perceptual learning that not only reduces low-level lateral masking but also reduces crowding. These results have important implications for the rehabilitation of low-vision patients who must use peripheral vision to perform tasks, such as reading and refined figure-ground segmentation, which normal sighted subjects perform in the fovea

Optimality of Human Contour Integration

For processing and segmenting visual scenes, the brain is required to combine a multitude of features and sensory channels. It is neither known if these complex tasks involve optimal integration of information, nor according to which objectives computations might be performed. Here, we investigate if optimal inference can explain contour integration in human subjects. We performed experiments where observers detected contours of curvilinearly aligned edge configurations embedded into randomly oriented distractors. The key feature of our framework is to use a generative process for creating the contours, for which it is possible to derive a class of ideal detection models. This allowed us to compare human detection for contours with different statistical properties to the corresponding ideal detection models for the same stimuli. We then subjected the detection models to realistic constraints and required them to reproduce human decisions for every stimulus as well as possible. By independently varying the four model parameters, we identify a single detection model which quantitatively captures all correlations of human decision behaviour for more than 2000 stimuli from 42 contour ensembles with greatly varying statistical properties. This model reveals specific interactions between edges closely matching independent findings from physiology and psychophysics. These interactions imply a statistics of contours for which edge stimuli are indeed optimally integrated by the visual system, with the objective of inferring the presence of contours in cluttered scenes. The recurrent algorithm of our model makes testable predictions about the temporal dynamics of neuronal populations engaged in contour integration, and it suggests a strong directionality of the underlying functional anatomy

Inhibition of HCV 3a genotype entry through Host CD81 and HCV E2 antibodies

<p>Abstract</p> <p>Background</p> <p>HCV causes acute and chronic hepatitis which can eventually lead to permanent liver damage hepatocellular carcinoma and death. HCV glycoproteins play an important role in HCV entry by binding with CD81 receptors. Hence inhibition of virus at entry step is an important target to identify antiviral drugs against HCV.</p> <p>Methods and result</p> <p>The present study elaborated the role of CD81 and HCV glycoprotein E2 in HCV entry using retroviral pseudo-particles of 3a local genotype. Our results demonstrated that HCV specific antibody E2 and host antibody CD81 showed dose- dependent inhibition of HCV entry. HCV E2 antibody showed 50% reduction at a concentration of 1.5 ± 1 μg while CD81 exhibited 50% reduction at a concentration of 0.8 ± 1 μg. In addition, data obtained with HCVpp were also confirmed with the infection of whole virus of HCV genotype 3a in liver cells.</p> <p>Conclusion</p> <p>Our data suggest that HCV specific E2 and host CD81 antibodies reduce HCVpp entry and full length viral particle and combination of host and HCV specific antibodies showed synergistic effect in reducing the viral titer.</p

NF-κB2 signalling in enteroids modulates enterocyte responses to secreted factors from bone marrow-derived dendritic cells

Alternative pathway NF-κB signalling regulates susceptibility towards developing inflammatory bowel disease (IBD), colitis-associated cancer and sepsis-associated intestinal epithelial cell apoptosis and shedding. However, the cell populations responsible for the perturbed alternative pathway NF-κB signalling in intestinal mucosal pathology remain unclear. In order to investigate the contribution of the epithelial compartment, we have tested whether NF-κB2 regulated transcription in intestinal epithelial cells controls the intestinal epithelial response to cytokines that are known to disrupt intestinal barrier permeability. Enteroids were generated from the proximal, middle and distal regions of small intestine (SI) from C57BL/6J wild-type mice and displayed region-specific morphology that was maintained during sub-culture. Enteroids treated with 100 ng/mL TNF were compared with corresponding regions of SI from C57BL/6J mice treated systemically with 0.33 mg/kg TNF for 1.5 h. TNF-induced apoptosis in all regions of the intestine in vitro and in vivo but resulted in Paneth cell degranulation only in proximal tissue-derived SI and enteroids. TNF also resulted in increased enteroid sphericity (quantified as circularity from two-dimensional bright field images). This response was dose and time-dependent and correlated with active caspase-3 immunopositivity. Proximal tissue-derived enteroids generated from Nfκb2−/− mice showed a significantly blunted circularity response following the addition of TNF, IFNγ, lipopolysaccharide (LPS) activated C57BL/6J-derived bone marrow-derived dendritic cells (BMDC) and secreted factors from LPS-activated BMDCs. However, Nfκb1−/− mouse-derived enteroids showed no significant changes in response to these stimuli. In conclusion, the selection of SI region is important when designing enteroid studies as region-specific identity and response to stimuli such as TNF are maintained in culture. Intestinal epithelial cells are at least partially responsible for regulating their own fate by modulating NF-κB2 signalling in response to stimuli known to be involved in multiple intestinal and systemic diseases. Future studies are warranted to investigate the therapeutic potential of intestinal epithelial NF-κB2 inhibition

Cannabidiol Reduces Aβ-Induced Neuroinflammation and Promotes Hippocampal Neurogenesis through PPARγ Involvement

Peroxisome proliferator-activated receptor-γ (PPARγ) has been reported to be involved in the etiology of pathological features of Alzheimer's disease (AD). Cannabidiol (CBD), a Cannabis derivative devoid of psychomimetic effects, has attracted much attention because of its promising neuroprotective properties in rat AD models, even though the mechanism responsible for such actions remains unknown. This study was aimed at exploring whether CBD effects could be subordinate to its activity at PPARγ, which has been recently indicated as its putative binding site. CBD actions on β-amyloid-induced neurotoxicity in rat AD models, either in presence or absence of PPAR antagonists were investigated. Results showed that the blockade of PPARγ was able to significantly blunt CBD effects on reactive gliosis and subsequently on neuronal damage. Moreover, due to its interaction at PPARγ, CBD was observed to stimulate hippocampal neurogenesis. All these findings report the inescapable role of this receptor in mediating CBD actions, here reported

A Neurophysiologically Plausible Population Code Model for Feature Integration Explains Visual Crowding

An object in the peripheral visual field is more difficult to recognize when surrounded by other objects. This phenomenon is called “crowding”. Crowding places a fundamental constraint on human vision that limits performance on numerous tasks. It has been suggested that crowding results from spatial feature integration necessary for object recognition. However, in the absence of convincing models, this theory has remained controversial. Here, we present a quantitative and physiologically plausible model for spatial integration of orientation signals, based on the principles of population coding. Using simulations, we demonstrate that this model coherently accounts for fundamental properties of crowding, including critical spacing, “compulsory averaging”, and a foveal-peripheral anisotropy. Moreover, we show that the model predicts increased responses to correlated visual stimuli. Altogether, these results suggest that crowding has little immediate bearing on object recognition but is a by-product of a general, elementary integration mechanism in early vision aimed at improving signal quality

The spatial range of peripheral collinear facilitation

Contrast detection thresholds for a central Gabor patch (target) can be modulated by the presence of co-oriented and collinear high contrast Gabors flankers. In foveal vision collinear facilitation can be observed for target-to-flankers relative distances beyond two times the wavelength (λ) of the Gabor's carrier, while for shorter relative distances (<2λ) there is suppression. These modulatory influences seem to disappear after 12λ. In this study, we measured contrast detection thresholds for different spatial frequencies (1, 4 and 6 cpd) and target-to-flankers relative distances ranging from 6 to 16λ, but with collinear configurations presented in near periphery at 4° of eccentricity. Results showed that in near periphery collinear facilitation extends beyond 12λ for the higher spatial frequencies tested (4 and 6 cpd), while it decays already at 10λ for the lowest spatial frequency used (i.e., 1 cpd). In addition, we found that increasing the spatial frequency the peak of collinear facilitation shifts towards larger target-to-flankers relative distances (expressed as multiples of the stimulus wavelength), an effect never reported neither for near peripheral nor for central vision. The results suggest that the peak and the spatial extent of collinear facilitation in near periphery depend on the spatial frequency of the stimuli used