The Integrated Virtual Environment Rehabilitation Treadmill System

Slow gait speed and interlimb asymmetry are prevalent in a variety of disorders. Current approaches to locomotor retraining emphasize the need for appropriate feedback during intensive, task-specific practice. This paper describes the design and feasibility testing of the integrated virtual environment rehabilitation treadmill (IVERT) system intended to provide real-time, intuitive feedback regarding gait speed and asymmetry during training. The IVERT system integrates an instrumented, split-belt treadmill with a front-projection, immersive virtual environment. The novel adaptive control system uses only ground reaction force data from the treadmill to continuously update the speeds of the two treadmill belts independently, as well as to control the speed and heading in the virtual environment in real time. Feedback regarding gait asymmetry is presented 1) visually as walking a curved trajectory through the virtual environment and 2) proprioceptively in the form of different belt speeds on the split-belt treadmill. A feasibility study involving five individuals with asymmetric gait found that these individuals could effectively control the speed of locomotion and perceive gait asymmetry during the training session. Although minimal changes in overground gait symmetry were observed immediately following a single training session, further studies should be done to determine the IVERT’s potential as a tool for rehabilitation of asymmetric gait by providing patients with congruent visual and proprioceptive feedback

The Integrated Virtual Environment Rehabilitation Treadmill System

Slow gait speed and interlimb asymmetry are prevalent in a variety of disorders. Current approaches to locomotor retraining emphasize the need for appropriate feedback during intensive, task-specific practice. This paper describes the design and feasibility testing of the integrated virtual environment rehabilitation treadmill (IVERT) system intended to provide real-time, intuitive feedback regarding gait speed and asymmetry during training. The IVERT system integrates an instrumented, split-belt treadmill with a front-projection, immersive virtual environment. The novel adaptive control system uses only ground reaction force data from the treadmill to continuously update the speeds of the two treadmill belts independently, as well as to control the speed and heading in the virtual environment in real time. Feedback regarding gait asymmetry is presented 1) visually as walking a curved trajectory through the virtual environment and 2) proprioceptively in the form of different belt speeds on the split-belt treadmill. A feasibility study involving five individuals with asymmetric gait found that these individuals could effectively control the speed of locomotion and perceive gait asymmetry during the training session. Although minimal changes in overground gait symmetry were observed immediately following a single training session, further studies should be done to determine the IVERT’s potential as a tool for rehabilitation of asymmetric gait by providing patients with congruent visual and proprioceptive feedback

General Approach to Estimate Error Bars for Quantitative Structure–Activity Relationship Predictions of Molecular Activity

Key requirements for quantitative structure–activity relationship (QSAR) models to gain acceptance by regulatory authorities include a defined domain of applicability (DA) and appropriate measures of goodness-of-fit, robustness, and predictivity. Hence, many DA metrics have been developed over the past two decades. The most intuitive are perhaps distance-to-model metrics, which are most commonly defined in terms of the mean distance between a molecule and its <i>k</i> nearest training samples. Detailed evaluations have shown that the variance of predictions by an ensemble of QSAR models may serve as a DA metric and can outperform distance-to-model metrics. Intriguingly, the performance of ensemble variance metric has led researchers to conclude that the error of predicting a new molecule does not depend on the input descriptors or machine-learning methods but on its distance to the training molecules. This implies that the distance to training samples may serve as the basis for developing a high-performance DA metric. In this article, we introduce a new Tanimoto distance-based DA metric called the sum of distance-weighted contributions (SDC), which takes into account contributions from all molecules in a training set. Using four acute chemical toxicity data sets of varying sizes and four other molecular property data sets, we demonstrate that SDC correlates well with the prediction error for all data sets regardless of the machine-learning methods and molecular descriptors used to build the QSAR models. Using the acute toxicity data sets, we compared the distribution of prediction errors with respect to SDC, the mean distance to <i>k</i>-nearest training samples, and the variance of random forest predictions. The results showed that the correlation with the prediction error was highest for SDC. We also demonstrate that SDC allows for the development of robust root mean squared error (RMSE) models and makes it possible to not only give a QSAR prediction but also provide an individual RMSE estimate for each molecule. Because SDC does not depend on a specific machine-learning method, it represents a canonical measure that can be widely used to estimate individual molecule prediction errors for any machine-learning method

L-cysteine methyl ester overcomes the deleterious effects of morphine on ventilatory parameters and arterial blood-gas chemistry in unanesthetized rats

We are developing a series of thiolesters that produce an immediate and sustained reversal of the deleterious effects of opioids, such as morphine and fentanyl, on ventilation without diminishing the antinociceptive effects of these opioids. We report here the effects of systemic injections of L-cysteine methyl ester (L-CYSme) on morphine-induced changes in ventilatory parameters, arterial-blood gas (ABG) chemistry (pH, pCO2, pO2, sO2), Alveolar-arterial (A-a) gradient (i.e., the index of alveolar gas-exchange within the lungs), and antinociception in unanesthetized Sprague Dawley rats. The administration of morphine (10 mg/kg, IV) produced a series of deleterious effects on ventilatory parameters, including sustained decreases in tidal volume, minute ventilation, inspiratory drive and peak inspiratory flow that were accompanied by a sustained increase in end inspiratory pause. A single injection of L-CYSme (500 μmol/kg, IV) produced a rapid and long-lasting reversal of the deleterious effects of morphine on ventilatory parameters, and a second injection of L-CYSme (500 μmol/kg, IV) elicited pronounced increases in ventilatory parameters, such as minute ventilation, to values well above pre-morphine levels. L-CYSme (250 or 500 μmol/kg, IV) also produced an immediate and sustained reversal of the deleterious effects of morphine (10 mg/kg, IV) on arterial blood pH, pCO2, pO2, sO2 and A-a gradient, whereas L-cysteine (500 μmol/kg, IV) itself was inactive. L-CYSme (500 μmol/kg, IV) did not appear to modulate the sedative effects of morphine as measured by righting reflex times, but did diminish the duration, however, not the magnitude of the antinociceptive actions of morphine (5 or 10 mg/kg, IV) as determined in tail-flick latency and hindpaw-withdrawal latency assays. These findings provide evidence that L-CYSme can powerfully overcome the deleterious effects of morphine on breathing and gas-exchange in Sprague Dawley rats while not affecting the sedative or early stage antinociceptive effects of the opioid. The mechanisms by which L-CYSme interferes with the OR-induced signaling pathways that mediate the deleterious effects of morphine on ventilatory performance, and by which L-CYSme diminishes the late stage antinociceptive action of morphine remain to be determined

DataSheet1_L-cysteine methyl ester overcomes the deleterious effects of morphine on ventilatory parameters and arterial blood-gas chemistry in unanesthetized rats.docx

We are developing a series of thiolesters that produce an immediate and sustained reversal of the deleterious effects of opioids, such as morphine and fentanyl, on ventilation without diminishing the antinociceptive effects of these opioids. We report here the effects of systemic injections of L-cysteine methyl ester (L-CYSme) on morphine-induced changes in ventilatory parameters, arterial-blood gas (ABG) chemistry (pH, pCO2, pO2, sO2), Alveolar-arterial (A-a) gradient (i.e., the index of alveolar gas-exchange within the lungs), and antinociception in unanesthetized Sprague Dawley rats. The administration of morphine (10 mg/kg, IV) produced a series of deleterious effects on ventilatory parameters, including sustained decreases in tidal volume, minute ventilation, inspiratory drive and peak inspiratory flow that were accompanied by a sustained increase in end inspiratory pause. A single injection of L-CYSme (500 μmol/kg, IV) produced a rapid and long-lasting reversal of the deleterious effects of morphine on ventilatory parameters, and a second injection of L-CYSme (500 μmol/kg, IV) elicited pronounced increases in ventilatory parameters, such as minute ventilation, to values well above pre-morphine levels. L-CYSme (250 or 500 μmol/kg, IV) also produced an immediate and sustained reversal of the deleterious effects of morphine (10 mg/kg, IV) on arterial blood pH, pCO2, pO2, sO2 and A-a gradient, whereas L-cysteine (500 μmol/kg, IV) itself was inactive. L-CYSme (500 μmol/kg, IV) did not appear to modulate the sedative effects of morphine as measured by righting reflex times, but did diminish the duration, however, not the magnitude of the antinociceptive actions of morphine (5 or 10 mg/kg, IV) as determined in tail-flick latency and hindpaw-withdrawal latency assays. These findings provide evidence that L-CYSme can powerfully overcome the deleterious effects of morphine on breathing and gas-exchange in Sprague Dawley rats while not affecting the sedative or early stage antinociceptive effects of the opioid. The mechanisms by which L-CYSme interferes with the OR-induced signaling pathways that mediate the deleterious effects of morphine on ventilatory performance, and by which L-CYSme diminishes the late stage antinociceptive action of morphine remain to be determined.</p