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1.  Prediction, by Retinal Location, of the Onset of Diabetic Edema in Patients with Nonproliferative Diabetic Retinopathy 
This manuscript creates a model to predict the local onset of diabetic retinal edema in an at-risk patient group with nonproliferative diabetic retinopathy. It finds that mfERG implicit time and amplitude Z-score, sex, and systolic blood pressure can predict local edema onset with good sensitivity and specificity.
To formulate a model to predict the location of the onset of diabetic retinal edema (DE) in adults with diabetic retinopathy (DR), at risk for DE.
In all, 46 eyes from 23 patients with DR were included. Subjects were followed semiannually until DE developed or the study concluded. The presence or absence of DE within the central 45° at the final visit was the outcome measure, and data from the prior visit were used as baseline. A logistic regression model was formulated to assess the relationship between DE development and: multifocal electroretinogram (mfERG) implicit time (IT) Z-score, mfERG amplitude (Amp) Z-score, sex, diabetes duration, diabetes type, blood glucose, HbA1c, age, systolic (SBP) and diastolic blood pressure, and grade of retinopathy. A total of 35 retinal zones were constructed from the mfERG elements and each was graded for DE. Data from 52 control subjects were used to calculate the maximum IT and minimum Amp Z-scores for each zone. Receiver operating characteristic curves from a fivefold cross-validation were used to determine the model's predictive properties.
Edema developed in 5.2% of all retinal zones and in 35% of the eyes. The mfERG Amp, mfERG IT, SBP, and sex were together predictive of edema onset. Combined, these factors produce a model that has 84% sensitivity and 76% specificity.
Together mfERG, SBP, and sex are good predictors of local edema in patients with DR. The model is a useful tool for assessing risk for edema development and a candidate measure to evaluate novel therapeutics directed at DE.
PMCID: PMC3176012  PMID: 21743017
2.  Task effects, performance levels, features, configurations, and holistic face processing: A reply to Rossion 
Acta psychologica  2009;132(3):286-292.
A recent article in Acta Psychologica (“Picture-plane inversion leads to qualitative changes of face perception” by B. Rossion, 2008) criticized several aspects of an earlier paper of ours (Riesenhuber et al., “Face processing in humans is compatible with a simple shape-based model of vision”, Proc Biol Sci, 2004). We here address Rossion’s criticisms and correct some misunderstandings. To frame the discussion, we first review our previously presented computational model of face recognition in cortex (Jiang et al., “Evaluation of a shape-based model of human face discrimination using fMRI and behavioral techniques”, Neuron, 2006) that provides a concrete biologically plausible computational substrate for holistic coding, namely a neural representation learned for upright faces, in the spirit of the original simple-to-complex hierarchical model of vision by Hubel and Wiesel. We show that Rossion’s and others’ data support the model, and that there is actually a convergence of views on the mechanisms underlying face recognition, in particular regarding holistic processing.
PMCID: PMC2788156  PMID: 19665104
3.  Multifocal VEP (mfVEP) reveals abnormal neuronal delays in diabetes 
This pilot study examined the diagnostic role of multifocal visually evoked potentials (mfVEP) in a small number of patients with diabetes. mfVEP, mfERG, and fundus photographs of both eyes of five patients with diabetes, three with nonproliferative diabetic retinopathy (NPDR) and two without NPDR were examined. Thirteen control subjects were also examined. Eighteen zones were constructed from the 60-element mfVEP stimulus array. mfVEP implicit time (IT) and amplitude (SNR) differences were tested between subject groups. We also examined whether there was a difference in function for patches with and without retinopathy in the NPDR group. Lastly, we compared mfVEP and mfERG results in the same patients. We found significant mfVEP IT differences between controls and all patients with diabetes, controls and diabetics without retinopathy, and between controls and diabetics with retinopathy. The subject groups did not differ significantly in terms of SNR. In the retinopathy group, ITs from zones with retinopathy were significantly longer than ITs from zones without retinopathy (P = 0.016). mfERG IT was more frequently abnormal than mfVEP IT. In addition, mfERG hexagons were twice as likely to be abnormal if the corresponding mfVEP zone was abnormal (P < 0.05). mfVEP implicit times are significantly delayed in patients with diabetes even when there is no retinopathy. These cortical response results are similar, albeit considerably less abnormal, than those previously reported for retinal (mfERG) responses in patients with diabetes. A correlation exists between the location of abnormal mfERG hexagons and abnormal mfVEP zones.
PMCID: PMC2970819  PMID: 20737191
Multifocal; Visually evoked potential; mfVEP; Diabetes; Diabetic retinopathy; mfERG
4.  Drug Discovery for Schistosomiasis: Hit and Lead Compounds Identified in a Library of Known Drugs by Medium-Throughput Phenotypic Screening 
Praziquantel (PZQ) is the only widely available drug to treat schistosomiasis. Given the potential for drug resistance, it is prudent to search for novel therapeutics. Identification of anti-schistosomal chemicals has traditionally relied on phenotypic (whole organism) screening with adult worms in vitro and/or animal models of disease—tools that limit automation and throughput with modern microtiter plate-formatted compound libraries.
A partially automated, three-component phenotypic screen workflow is presented that utilizes at its apex the schistosomular stage of the parasite adapted to a 96-well plate format with a throughput of 640 compounds per month. Hits that arise are subsequently screened in vitro against adult parasites and finally for efficacy in a murine model of disease. Two GO/NO GO criteria filters in the workflow prioritize hit compounds for tests in the animal disease model in accordance with a target drug profile that demands short-course oral therapy. The screen workflow was inaugurated with 2,160 chemically diverse natural and synthetic compounds, of which 821 are drugs already approved for human use. This affords a unique starting point to ‘reposition’ (re-profile) drugs as anti-schistosomals with potential savings in development timelines and costs.
Multiple and dynamic phenotypes could be categorized for schistosomula and adults in vitro, and a diverse set of ‘hit’ drugs and chemistries were identified, including anti-schistosomals, anthelmintics, antibiotics, and neuromodulators. Of those hits prioritized for tests in the animal disease model, a number of leads were identified, one of which compares reasonably well with PZQ in significantly decreasing worm and egg burdens, and disease-associated pathology. Data arising from the three components of the screen are posted online as a community resource.
To accelerate the identification of novel anti-schistosomals, we have developed a partially automated screen workflow that interfaces schistosomula with microtiter plate-formatted compound libraries. The workflow has identified various compounds and drugs as hits in vitro and leads, with the prescribed oral efficacy, in vivo. Efforts to improve throughput, automation, and rigor of the screening workflow are ongoing.
Author Summary
The flatworm disease schistosomiasis infects over 200 million people with just one drug (praziquantel) available—a concern should drug resistance develop. Present drug discovery approaches for schistosomiasis are slow and not conducive to automation in a high-throughput format. Therefore, we designed a three-component screen workflow that positions the larval (schistosomulum) stage of S. mansoni at its apex followed by screens of adults in culture and, finally, efficacy tests in infected mice. Schistosomula are small enough and available in sufficient numbers to interface with automated liquid handling systems and prosecute thousands of compounds in short time frames. We inaugurated the workflow with a 2,160 compound library that includes known drugs in order to cost effectively ‘re-position’ drugs as new therapies for schistosomiasis and/or identify compounds that could be modified to that end. We identify a variety of ‘hit’ compounds (antibiotics, psychoactives, antiparasitics, etc.) that produce behavioral responses (phenotypes) in schistosomula and adults. Tests in infected mice of the most promising hits identified a number of ‘leads,’ one of which compares reasonably well with praziquantel in killing worms, decreasing egg production by the parasite, and ameliorating disease pathology. Efforts continue to more fully automate the workflow. All screen data are posted online as a drug discovery resource.
PMCID: PMC2702839  PMID: 19597541

Results 1-4 (4)